investigator brochure rituxan , mabthera , idec-c2b8 ... · investigator brochure rituxan ,...

INVESTIGATOR BROCHURE

Rituxan, MabThera, IDEC-C2B8 (Rituximab) Eleventh Edition

SPONSORS: Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990 U.S.A.

Biogen Idec Inc. 5200 Research Place San Diego, CA 92122-4616 U.S.A.

F. Hoffmann-La Roche, Ltd. Grenzacherstrasse 124 CH-4070 Basel Switzerland

DATE: 01 November 2006

SAFETY DATA CUTOFF DATE: 15 June 2006

Roche Investigator's Brochure 11th Version December 2006 RO45-2294 -

Table of Contents

1. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

1.1 Nonclinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

1.2 Clinical Experience. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

1.2.1 Clinical Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

1.2.2 Clinical Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

1.2.2.1 Indolent (Low-Grade or Follicular) NHL. . . . . . . . . . . . . . . . . . . . . . . . . 23

1.2.2.2 Diffuse, Large B-Cell NHL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

1.2.2.3 Chronic Lymphocytic Leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

1.2.2.4 Other Malignancies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

1.2.2.5 Non-Malignant Hematologic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 25

1.2.3 Clinical Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

1.3 Guidance for the Investigator . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

3. Physicochemical Properties and Clinical Formulation . . . . . . . . . . . . . . . . . . 27

3.1 Physicochemical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

3.2 Clinical Formulation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

3.3 Stability, Storage, and Handling Instructions . . . . . . . . . . . . . . . . . . . . . . . . . 27

4. Nonclinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

4.1 Nonclinical Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

4.1.1 In Vitro Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

4.1.2 In Vivo Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

4.2 Nonclinical Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

4.3 Nonclinical Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

4.3.1 Single-Dose Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

4.3.2 Repeat-Dose Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

4.3.3 Reproductive Toxicity Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

5. Clinical Experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

5.1 Pharmacokinetics and Pharmacodynamics. . . . . . . . . . . . . . . . . . . . . . . . . . . 32


5.1.1 Pharmacokinetics in Patients with NHL . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

5.1.2 Pharmacodynamics in Patients with NHL. . . . . . . . . . . . . . . . . . . . . . . . . . 34

5.1.3 Relationship between Pharmacokinetics and Pharmacodynamics . . . . . . . 34

5.2 Treatment of Indolent (Low-Grade or Follicular) NHL . . . . . . . . . . . . . . . . . 34

5.2.1 Rituximab Monotherapy in Patients with Previously Untreated IndolentNHL. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

5.2.1.1 Efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

5.2.1.2 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

5.2.2 Rituximab Combined with Chemotherapy or Other Immunotherapy inPatients with Previously Untreated Indolent NHL . . . . . . . . . . . . . . 35

5.2.2.1 Efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

5.2.2.2 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

5.2.3 Maintenance Rituximab in Patients with Indolent NHL . . . . . . . . . . . . . . . 39

5.2.3.1 Efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

5.2.3.2 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

5.2.4 Rituximab Consolidation in Patients with Indolent NHL . . . . . . . . . . . . . . 44

5.2.4.1 Efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

5.2.4.2 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

5.2.5 Rituximab Monotherapy in Patients with Previously Treated IndolentNHL. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

5.2.5.1 Efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

5.2.5.2 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

5.2.6 Retreatment with Rituximab in Patients with Indolent NHL . . . . . . . . . . . 48

5.2.6.1 Efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

5.2.6.2 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

5.2.7 Rituximab Combined with Chemotherapy or Other Immunotherapy inPatients with Previously Untreated or Previously Treated IndolentNHL. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

5.2.7.1 Efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

5.2.7.2 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

5.3 Treatment of Diffuse, Large B-Cell NHL . . . . . . . . . . . . . . . . . . . . . . . . . . . 49


5.3.1 Rituximab in Patients with Previously Untreated Diffuse, Large B—CellNHL. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

5.3.1.1 Efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

5.3.1.2 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

5.3.2 Rituximab in Patients with Previously Treated Diffuse, Large B—Cell . . 54

5.3.2.1 Efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

5.3.2.2 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

5.4 Treatment of HIV-Associated Aggressive NHL . . . . . . . . . . . . . . . . . . . . . . 56

5.4.1.1 Efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

5.4.1.2 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

5.5 Treatment of Chronic Lymphocytic Leukemia . . . . . . . . . . . . . . . . . . . . . . . 58

5.5.1 Rituximab Monotherapy in Patients with Previously Untreated CLL . . . . 58

5.5.1.1 Efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

5.5.1.2 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

5.5.2 Rituximab Combined with Chemotherapy or Other Immunotherapy inPatients with Previously Untreated CLL. . . . . . . . . . . . . . . . . . . . . . 59

5.5.2.1 Efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60

5.5.2.2 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

5.5.3 Rituximab Monotherapy in Patients with Previously Treated CLL . . . . . . 62

5.5.3.1 Efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

5.5.3.2 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

5.5.4 Rituximab Combined with Chemotherapy or Other Immunotherapy inPatients with Previously Treated CLL . . . . . . . . . . . . . . . . . . . . . . . 63

5.5.4.1 Efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

5.5.4.2 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

5.5.5 Rituximab Monotherapy in Patients with Previously Untreated orPreviously Treated CLL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

5.5.5.1 Efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

5.5.5.2 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

5.5.6 Rituximab Combined with Chemotherapy or Other Immunotherapy inPatients with Previously Untreated or Previously Treated CLL . . . . 64


5.5.6.1 Efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

5.5.6.2 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

5.6 Treatment of Mantle Cell Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

5.6.1 Rituximab in Patients with Previously Untreated Mantle Cell Lymphoma 65

5.6.1.1 Efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

5.6.1.2 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

5.6.2 Rituximab in Patients with Previously Treated Mantle Cell Lymphoma . . 67

5.6.2.1 Efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

5.6.2.2 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

5.6.3 Rituximab in Patients with Previously Untreated or Previously TreatedMantle Cell Lymphoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

5.6.3.1 Efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

5.6.3.2 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

5.7 Treatment of Waldenström’s Macroglobulinemia (LymphoplasmacyticLymphoma) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

5.7.1 Rituximab Monotherapy in Patients with Waldenström’sMacroglobulinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

5.7.1.1 Efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

5.7.1.2 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

5.7.2 Rituximab Combined with Chemotherapy or Other Immunotherapy inPatients with Waldenström’s Macroglobulinemia . . . . . . . . . . . . . . 71

5.7.2.1 Efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

5.7.2.2 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

5.8 Treatment of Multiple Myeloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

5.9 Treatment of Hodgkin’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

5.10 Treatment of Posttransplant Lymphoproliferative Disorders . . . . . . . . . . . . 74

5.11 Treatment of Patients with Other Diseases . . . . . . . . . . . . . . . . . . . . . . . . . 75

5.11.1 Treatment of Idiopathic Thrombocytopenic Purpura . . . . . . . . . . . . . . . . 75

5.11.2 Treatment of Thrombotic Thrombocytopenic Purpura . . . . . . . . . . . . . . . 76

5.11.3 Treatment of Autoimmune Hemolytic Anemia and Cold HemagglutininDisease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77


5.11.4 Treatment of Factor VIII Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

6. Guidance for the Investigator . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

6.1 Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

6.2 Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80

6.3 Warnings and Precautions for Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80

6.3.1 Infusion-Related Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80

6.3.1.1 Pulmonary Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80

6.3.1.2 Cardiovascular Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

6.3.1.3 Hypersensitivity Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

6.3.1.4 Rapid Tumor Lysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

6.3.2 Hepatitis B Virus Reactivation with Related Fulminant Hepatitis andOther Viral Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

6.3.3 Hematologic Events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

6.3.4 Severe Bullous Skin Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

6.3.5 Bowel Obstruction and Perforation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

6.3.6 Effects on Ability to Drive and Operate Machinery . . . . . . . . . . . . . . . . . . 82

6.3.7 Effects on Immunization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

6.3.8 Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

6.3.9 Overdoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

6.3.10 Use during Pregnancy and Lactation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

6.3.11 Pediatric Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

6.3.12 Use in Elderly Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

6.3.13 Use in Patients with Bulky Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

6.3.14 Retreatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

6.4 Summary of Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

6.4.1 Rituximab Monotherapy in Patients with Previously Treated IndolentNHL. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

6.4.1.1 Infusion-Related Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86

6.4.1.2 Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86

6.4.1.3 Hematologic Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87


6.4.1.4 Cardiovascular Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87

6.4.2 Rituximab Combined with CHOP Chemotherapy in Patients withPreviously Untreated Diffuse, Large B-Cell NHL . . . . . . . . . . . . . . 87


6.4.2.2 Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

6.4.2.3 Hematologic Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

6.4.2.4 Cardiac Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

6.4.2.5 Neurologic Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

6.4.3 Rituximab as Maintenance Treatment in Patients with Relapsed orRefractory Follicular NHL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90


6.4.3.2 Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94

6.4.3.3 Haematologic Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

6.4.3.4 Cardiac Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

6.4.3.5 IgG levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

6.4.4 Rituximab Combined with CVP Chemotherapy in Patients withPreviously Untreated Indolent NHL . . . . . . . . . . . . . . . . . . . . . . . . . 95

6.4.5 Adverse Events from Postmarketing Experience . . . . . . . . . . . . . . . . . . . . 96

6.4.5.1 Cardiovascular System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

6.4.5.2 Blood and Lymphatic System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

6.4.5.3 Infections and Infestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

6.4.5.4 Respiratory System. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

6.4.5.5 Skin and Appendages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

6.4.5.6 Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

6.4.5.7 Body as a Whole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

6.4.5.8 Urogenital System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

6.4.5.9 Bowel Obstruction and Perforation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

6.4.6 Safety from Ongoing, Company-Sponsored Clinical Trials in Patientswith Non-Hematologic, Non-Malignant Diseases . . . . . . . . . . . . . . 98

6.5 Expected Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

7. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105


List of Tables

Table 1 Pharmacokinetic Parameters after a Single IV Infusion of Rituximab . 33

Table 2 Pharmacokinetic Parameters after Multiple IV Infusions ofRituximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

Table 3 Response Rates for Studies of Rituximab Combination Therapy inPatients with Previously Untreated Indolent NHL . . . . . . . . . . . 36

Table 4 Efficacy Results for Study U0824n: Maintenance Rituximab inPatients with Indolent NHL . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

Table 5 Median Event-Free Survival for the SAKK 35/98 Study:Maintenance Rituximab in Patients with Indolent NHL . . . . . . 41

Table 6 Response Rates for the Induction Phase of the GLSG and EORTCRituximab Maintenance Studies . . . . . . . . . . . . . . . . . . . . . . . . . 43

Table 7 Efficacy Results for Studies of Rituximab Monotherapy in Patientswith Previously Treated Indolent NHL . . . . . . . . . . . . . . . . . . . 46

Table 8 Response Rates for Studies of Rituximab Therapy in Patients withPreviously Untreated Diffuse, Large B-Cell NHL . . . . . . . . . . . 50

Table 9 Response Rates for Studies of Rituximab Therapy in Patients withPreviously Treated Diffuse, Large B-Cell NHL. . . . . . . . . . . . . 55

Table 10 Response Rates for Studies of Rituximab Monotherapy in Patientswith Previously Untreated CLL . . . . . . . . . . . . . . . . . . . . . . . . . 59

Table 11 Response Rates for Studies of Rituximab Combination Therapy inPatients with Previously Untreated CLL . . . . . . . . . . . . . . . . . . 60

Table 12 Response Rates for Studies of Rituximab Monotherapy in Patientswith Previously Treated CLL . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

Table 13 Efficacy Results for Studies of Rituximab Monotherapy in Patientswith Waldenström’s Macroglobulinemia . . . . . . . . . . . . . . . . . . 70

Table 14 Efficacy Results for Studies of Rituximab Combined withChemotherapy in Patients with Waldenström’sMacroglobulinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

Table 15 Rituximab-Related Adverse Events Experienced by ≥5 % of Patients in the Integrated Safety Assessment forStudies of Rituximab Monotherapy in Patients with PreviouslyTreated Indolent NHL. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85


Table 16 Grade 3 or 4 Adverse Events plus Grade 2 Infections Experiencedby ≥ 2 % Patients in Either the CHOP orR-CHOP Group of Study LNH98-5 . . . . . . . . . . . . . . . . . . . . . . 87

Table 17 Induction Phase of Study M39022: Summary of NCI-CTC Grade 3and 4 Adverse Events Reported in ≥ 2 % of 462Patients in Either Group (CHOP or R—CHOP). . . . . . . . . . . . . 92

Table 18 Maintenance Phase of Study M39022: Summary of NCI-CTCGrade 3 and 4 Adverse Events Reported in = 2 % of 332Patients in Either Treatment Group (Observation or RituximabMaintenance) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94

Table 19 IND Safety Reports Since March 2004: Patients withNon-Hematologic, Non-Malignant Diseases . . . . . . . . . . . . . . . 99

Table 20 Expected Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100


List of Figures

Figure 1 Structure of Rituximab: A Murine/Human AntiHuman CD20Monoclonal Antibody . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27


List of Appendices

Appendices Oncology IB Version 11 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119


RITUXAN (Rituximab) Investigator Brochure

SUMMARY OF CHANGES

(Eleventh Edition, 01 November 2006) In this edition of the Investigator Brochure, the clinical sections were modified to include updated safety and/or efficacy data from sponsor-initiated, randomized Phase III studies, as well as data from investigator-initiated studies that contribute to and/or strengthen the basis of scientific knowledge regarding the clinical applications of rituximab. Summaries of the changes by section headings are presented below. In addition to the changes listed below, the terminology “aggressive NHL” was replaced with “diffuse, large B-cell NHL” where appropriate and minor revisions (e.g., grammar, format, and sentence structure) were made to improve clarity and succinctness. Furthermore, any sentences in last year’s investigator brochure that had listed or mentioned additional studies or references of interest, but had not described these studies were deleted; these studies and references that had been mentioned are now listed in Appendix C.

1 SUMMARY

• The approved indications were updated.

1.2 Clinical Experience

• The number of patients treated with rituximab was updated.

1.2.2 Clinical Efficacy

• Information was added regarding approval (in the European Union and many other countries, with the exclusion of the United States) of the use of rituximab as maintenance therapy for patients with relapsed/refractory follicular lymphoma responding to induction therapy with chemotherapy with or without rituximab.

• Information was added regarding approval in the United States of the use of rituximab in the following indications: in combination with CHOP or CHOP-like chemotherapy for the treatment of DLBCL NHL and in combination with CVP or following CVP for the treatment of NHL.

• Updated information was added regarding key studies for the different indications.

• Information from Study M39022 and the GLSG Study was added.

• The statement that additional Phase II and III studies have demonstrated the benefit of rituximab in combination with several other chemotherapy regimens was added.


• Information from the RICOVER-60 Study was added.

1.2.3 Clinical Safety

• Key safety data from Section 6.3 were incorporated into this section.

• Information regarding viral infections was updated and expanded.

• Information regarding bowel obstruction and perforation was added.

5 CLINICAL EXPERIENCE

• A reference to Appendix C was added.

5.2.2 Rituximab Combined with Chemotherapy or Other Immunotherapy in Patients with Previously Untreated Indolent NHL

• Efficacy and safety data were updated for the GLSG study (Hiddemann et al. 2005) and Study M39021 (Marcus et al. 2005).

• Efficacy data were updated for Study FL-2000 (Foussard et al. 2006). The previous reference to personal communication with Salles was removed.

• A reference to an article by Liu et al. 2006 was added.

5.2.3 Maintenance Rituximab in Patients with Indolent NHL

• Efficacy and safety data were updated for Studies E1496 (Hochster et al. 2005; Clinical Study Report E1496, 2006; Clinical Study Report Addendum E1496, 2006) and M39022 (Mabthera Summary of Product Characteristics, 2006). The previous reference to Van Oers et al. 2004 for Study M39022 was removed.

• Efficacy data from the study by Forstpointner et al. 2004 were updated (Dreyling et al. 2006).

• For the SAKK 35/98 Study, Table 5-5 was modified to display event-free survival rather than response rates.

5.2.5 Rituximab Monotherapy in Patients with Previously Treated Indolent NHL

• Efficacy and safety data from a study by Martinelli et al. 2005 were summarized.

5.3 Treatment in Diffuse, Large B-Cell NHL

• The heading title was changed from last year’s title, “Treatment in Aggressive NHL.”

• It was clarified that all studies included in this section included patients with diffuse, large B-cell NHL. It was noted that some studies did include patients


with other histologies as well and that this histology information is provided if it was available.

5.3.1 Rituximab in Patients with Previously Untreated Diffuse, Large B-Cell NHL

• Efficacy and safety data were updated for Studies E4494 (Habermann et al. 2006) and M39045 (MInT) (Pfreundschuh et al. 2006).

• Information from the GELA Study LNH98-5 (Feugier et al. 2005) was included which updates the data from this study (Coiffier et al. 2004) that was included in last year’s investigator brochure.

• Efficacy data from the retrospective study by Sehn et al. 2005 were added.

• Efficacy data from the RICOVER-60 study (Pfreundschuh et al. 2005) were added.

• Histology information for the study by Wilson et al. 2002 was added.


• Efficacy and safety data of the study by Jermann et al. 2004 were included, which updates the interim data from this study (Jost et al. 2001) that was included in last year’s investigator brochure.

• Safety and efficacy data from a study by Kewalramani et al. 2004 were summarized.

5.4 Treatment of HIV-Associated Aggressive NHL

• Efficacy and safety data were added for the studies by Ribera et al. 2005 and Dunleavy et al 2005.

• Updated the safety and efficacy data from Kaplan et al. 2005.

5.5.2 Rituximab Combined with Chemotherapy or Other Immunotherapy in Patients with Previously Untreated CLL

• Interim blinded safety data from Study CLL-8 was added.

• Updated the efficacy data for Study U1989n (Keating et al. 2005b).

• Added information from the retrospective analysis that compares Study U1112s/CALGB 9712 with Study CALGB 9011(Byrd et al. 2005).

5.5.4 Rituximab Combined with Chemotherapy or Other Immunotherapy in Patients with Previously Treated CLL

• Interim blinded safety data from the Study BO17072 was added.

5.6.2 Rituximab in Patients with Previously Treated Mantle Cell Lymphoma

• Efficacy data for the study performed by the GLSG was updated (Dreyling et al. 2006).


5.7.2 Rituximab Combined with Chemotherapy or Other Immunotherapy in Patients with Waldenström’s Macroglobulinemia

• Efficacy and safety data were added for the study by Treon et al. 2005.

5.8 Treatment of Multiple Myeloma

• Data from Study M39028 was included (Zojer et al. 2006), updating the reference in last year’s investigator brochure to Kirchbacher et al. 2002.

5.9 Treatment of Hodgkin’s Disease

• Safety and efficacy data from the GHSG study by Schulz et al. 2005b was added.

5.10 Treatment of Posttransplant Lymphoproliferative Disorders

• Safety data were added for the study by van Esser et al. 2002.

• Safety and efficacy data from Study M39037 (Choquet et al. 2006) were updated.

5.11.2 Treatment of Thrombocytic Thrombocytopenic Purpura

• This section was added.

5.11.3 Treatment of Autoimmune Hemolytic Anemia and Cold Hemagglutinin Disease

• Safety data were added for the study by Cabrera et al. 2004.

5.11.4 Treatment of Factor VIII Deficiency

• Added additional safety information to the study by Wiestner et al. 2002.

5.12 Postmarketing Experience

• This section was deleted. Relevant information is provided in Section 6.4.4.

6.1 Indications

• The approved indications as of October 2006 were updated.

• In reference to the use of rituximab in the United States, the use of rituximab in the following indications was added: in combination with CHOP or CHOP-like chemotherapy for the treatment of DLBCL NHL; in combination with CVP or following CVP for the treatment of NHL; and in rheumatoid arthritis.

• In reference to the use of Mabthera® in the European Union, the indications of rheumatoid arthritis and maintenance therapy for NHL were added.


6.3.2 Hepatitis B Virus Reactivation

• The heading of this section was changed from “Hepatitis B Reactivation” to “Hepatitis B Reactivation with Related Fulminant Hepatitis and Other Viral Infections.”

• Information regarding other serious viral infections was added.

6.3.4 Severe Bullous Skin Reactions


6.3.5 Bowel Obstruction and Perforation


6.3.7 Effects on Immunization

• Updated information from Study 102-12 was added.

6.4.2 Rituximab Combined with CHOP Chemotherapy in Patients with Previously Untreated Diffuse, Large B-Cell NHL or Other Types of Aggressive NHL

• The entry of “Total patients with at least one adverse event” under the “Nervous system disorders” field was removed because it should not have been included in the table.

6.4.3 Rituximab as Maintenance Treatment in Patients with Relapsed or Refractory Follicular NHL


6.4.5 Adverse Events from Postmarketing Experience

• The reference to Table B-4 in Appendix B was added.

• Information regarding additional viral infections was added to Section 6.4.5.3.

• Information regarding severe bullous reactions was added to Section 6.4.5.5.

• Section 6.4.5.9 entitled “Bowel Obstruction and Perforation” was added.

6.4.6 Safety from Ongoing Company-Sponsored Clinical Trials in Patients with Non-Hematologic, Non-Malignant Diseases

• The title of this section was changed from the title in last year’s investigator brochure, “Safety from Ongoing Company-Sponsored Clinical Trials.” The subsection “Rituximab in Patients with Hematologic or Malignant Diseases,” which was in last year’s investigator brochure was deleted.

6.5 Expected Adverse Events

• Updated Table 20.


APPENDIX A

• The tables have been revised and updated to summarize studies presented in the current edition.

APPENDIX B

• Tables B-1, B-2, and B-3 have been updated.

• Table B-4 was added.

APPENDIX C

• This appendix was added.


GLOSSARY OF ABBREVIATIONS

Abbreviation Definition

ABMT autologous bone marrow transplantation

ABVD adriamycin, bleomycin, vincristine, and dacarbazine

ADCC antibody-dependent cellular cytotoxicity

AIHA autoimmune hemolytic anemia

ANC absolute neutrophil count

ASCT autologous stem cell transplantation

AUC area under the curve

CALGB Cancer and Leukemia Group B

CDC complement-dependent cytotoxicity

CDE cyclophosphamide, doxorubicin, and etoposide

CHD cold hemagglutinin disease

CHEMO CHOP-like chemotherapy regimen

CHOP cyclophosphamide, doxorubicin, vincristine, and prednisone

CHVP cyclophosphamide, doxorubicin, etoposide, and prednisone

CI confidence interval

CL clearance

CLL chronic lymphocytic leukemia

Cmax maximum concentration

CR complete response

CRu complete response unconfirmed

CTC common toxicity criteria

CVP cyclophosphamide, vincristine, and prednisolone

DLBCL diffuse, large B-cell lymphoma

EBPG European Best Practice Guidelines

ECOG Eastern Cooperative Oncology Group

EFS event-free survival

EORTC European Organisation for Research and Treatment of Cancer

EPOCH etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin

FC fludarabine and cyclophosphamide

FCM fludarabine, cyclophosphamide, and mitoxantrone

FFS failure-free survival

FM fludarabine and mitoxantrone

FND fludarabine, mitoxantrone, and dexamethasone

G-CSF granulocyte colony-stimulating factor



GELA Groupe d’Etude des Lymphomes de l’Adulte

GHSG German Hodgkin's Lymphoma Study Group

GLP Good Laboratory Practice

GLSG German Low-Grade Lymphoma Study Group

GOELAMS Groupe Ouest Est d’Etude des Leucernies et autres Maladies du Sang

HAART highly active antiretroviral therapy

HACA human anti–chimeric antibody

HAMA human anti–mouse antibody

HBV Hepatitis B virus

HSCT hematopoietic stem cell transplantation

ICE ifosamide, carboplatin, etoposide

IFN interferon

IND Investigational New Drug Application

IPI International Prognostic Index

ITP idiopathic thrombocytopenic purpura

IV intravenous

IWF International Working Formulation

LDH lactate dehydrogenase

LLN lower limit of normal

MCL mantle cell lymphoma

MCP mitoxantrone, chlorambucil, and prednisolone

MInT MabThera ® International Trial

MR minor response

NA not applicable

NCI National Cancer Institute

NHL non-Hodgkin’s lymphoma

nPR nodular partial response

NR not reported

ORR overall response rate

OS overall survival

PFS progression-free survival

PML progressive multifocal leukoencephalopathy

PR partial response

PTLD posttransplant lymphoproliferative disorder

R rituximab



SAKK Swiss Group for Clinical Cancer Research

SLL small lymphocytic lymphoma

SWOG Southwest Oncology Group

TLS tumor lysis syndrome

TNF tumor necrosis factor

TTF time to treatment failure

TTP time to progression

Vss volume of distribution at steady state

WBC white blood cell


1. SUMMARY Rituximab (chimeric anti-CD20 monoclonal antibody; Rituxan or MabThera) is a chimeric murine/human monoclonal antibody that binds to CD20, a hydrophobic transmembrane protein that is present on B lymphocytes, and eliminates these cells potentially via a number of different mechanisms. In the United States, the European Union, and many other countries, rituximab monotherapy has received health authority approval for the treatment of patients with relapsed or chemoresistant, low-grade or follicular, CD20+, B-cell non-Hodgkin’s lymphoma (NHL).

In the United States, the European Union, and many other countries, rituximab has also been approved for use in combination with other therapies. Rituximab in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy is indicated for the treatment of patients with CD20+, diffuse, large B-cell NHL (DLBCL NHL). Rituximab in combination with CVP (cyclophosphamide, vincristine, and prednisolone) chemotherapy is indicated for the treatment of patients with previously untreated, CD20+, follicular, B-cell NHL. In addition, in the United States, rituximab is also indicated for the treatment of low-grade, CD20+, B-cell non-Hodgkin’s lymphoma in patients with stable disease or who achieve a partial or complete response following first-line treatment with CVP chemotherapy.

In the European Union and other countries (excluding the United States), rituximab is also indicated as maintenance therapy in patients with relapsed/refractory follicular lymphoma responding to induction therapy with chemotherapy with or without rituximab.

Further clinical studies of rituximab have been or are being conducted for treatment of several other oncology indications, as well as rheumatoid arthritis and other autoimmune diseases.

This Investigator Brochure summarizes the nonclinical and key clinical experience to date with rituximab, with particular focus on data relevant to hematology and oncology. A separate Investigator Brochure presents studies of rituximab treatment in patients with rheumatoid arthritis and other non-hematologic, non-malignant indications.

1.1 Nonclinical Studies Nonclinical studies show that rituximab binds specifically to the CD20 antigen expressed on B cells (with the exception of plasma cells). In vitro, binding of rituximab promotes complement-mediated lysis as well as antibody-dependent cell-mediated killing of CD20+ cells. Rituximab has also been demonstrated to induce the death of CD20+ cells in the absence of complement or effector cells via a number of pathways, including apoptosis. The relative contribution of these individual mechanisms to overall killing of target cells in vivo is not known. In human tissue cross-reactivity studies, rituximab did not recognize or promote destruction of any normal human tissues other than B cells. Rituximab was well tolerated in cynomolgus monkeys, and no significant toxicologic effects were observed at any of the doses administered. Consistent with the proposed mechanism of action, depletion of > 95 % of peripheral B cells was observed following the first or second dose of rituximab. Recovery of B-cell numbers to baseline levels was observed approximately 6 months after treatment with rituximab. Rituximab has a long


terminal half-life in primates, in the order of days, consistent with the properties of its IgG1 antibody subclass. Overall, nonclinical data are consistent with the proposed mechanism of action of rituximab that supports its use in both oncological and immune-related diseases.

1.2 Clinical Experience The clinical data presented in this Investigator Brochure are derived from the original label-enabling studies conducted in patients with relapsed indolent NHL, significant studies in other NHL subtypes that led to label expansion in and outside the United States, and other studies, conducted in a variety of malignant and non-malignant indications, which are of relevance to the investigator. In addition, safety data and investigator information are derived from the experience of more than 960,000 patients through May 2006, who have been treated with rituximab in the postmarketing setting since 1997.

1.2.1 Clinical Pharmacology Data from NHL patients show that the pharmacokinetics of rituximab are dose dependent after a single infusion; exposure (i.e., maximum concentration [Cmax] and area under the curve [AUC]) increased with increasing dose (dose range, 50–500 mg/kg). Clearance was greater and half-life was shorter for the first infusion (half-life, 4 days) than for subsequent infusions (e.g., fourth infusion half-life, 10 days). This is thought to be a consequence of a predominantly target (CD20)–mediated clearance of rituximab after the first infusion. The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes and the Fc domain can recruit immune effector functions to mediate B-cell lysis. Possible mechanisms of effector-mediated cell lysis include complement-dependent cytotoxicity (CDC) resulting from C1q binding, and antibody-dependent cellular cytotoxicity (ADCC) mediated by one or more of the Fcγ receptors on the surface of granulocytes, macrophages, and natural killer cells. Rituximab binding to CD20 antigen on B lymphocytes has also been demonstrated to induce cell death via apoptosis. After depletion of B cells, this clearance pathway no longer exists, and clearance is low and probably occurs through similar mechanisms to those of IgG1. Non–antigen-specific clearance is mediated through Fcγ receptors located on immune effector cells. Clearance of rituximab may also be under the control of immune system mechanisms regulating humoral immune defense. The long half-life of rituximab may be a result of recycling through the FcRn receptor, which is known to be a major mechanism for the persistence of endogenous IgG1 antibodies. In addition, depletion of circulating B cells may trigger greater recirculation of IgG through FcRn receptors and less elimination through Fcγ receptors as a means to maintain IgG homeostasis. This regulatory mechanism may contribute to the long half-life of IgG1 antibodies, including rituximab. The volume of distribution was small, and there was no significant effect of age, sex, or ethnicity (Asian versus Caucasian) on the pharmacokinetics of rituximab. Non-responders had a more rapid depletion of rituximab than responders, but peak serum rituximab levels did not correlate strongly with response. Mean serum rituximab concentration was inversely correlated with tumor bulk and number of circulating cells at baseline.


1.2.2 Clinical Efficacy 1.2.2.1 Indolent (Low-Grade or Follicular) NHL In the United States, the European Union, and many other countries, health authority approval has been granted for the use of rituximab as monotherapy for the treatment of patients with relapsed or chemoresistant, low-grade or follicular, CD20+, B-cell NHL, based on a pivotal study (102-05) and several Phase II studies. In addition, in the United States, rituximab is indicated for the treatment of low-grade, CD20+, B-cell non-Hodgkin’s lymphoma in patients with stable disease or who achieve a partial or complete response following first-line treatment with CVP chemotherapy. Rituximab monotherapy has also been shown to be safe and effective when used for the treatment of patients with bulky disease and as retreatment of patients who relapsed after initial rituximab therapy, administered in courses consisting of four or eight weekly doses.

In the European Union and other countries (excluding the United States), rituximab is also indicated as maintenance therapy for patients with relapsed/refractory follicular lymphoma responding to induction therapy with chemotherapy with or without rituximab. In a prospective, open-label, international, multi-center, Phase III study (Study M39022) performed by the European Organization for Research and Treatment of Cancer (EORTC), patients who had responded to induction therapy with either CHOP or rituximab plus CHOP were randomized to receive rituximab maintenance therapy or observation. Maintenance treatment with rituximab led to a clinically relevant and statistically significant improvement in progression-free survival (PFS) and overall survival compared with observation alone. Maintenance rituximab treatment after induction therapy with rituximab monotherapy was also investigated in a randomized trial (SAKK 35/98) by the Swiss Group for Clinical Cancer Research (SAKK), and prolonged event-free survival (EFS) has been reported in patients receiving maintenance rituximab compared with those undergoing observation. In addition, compared with observation alone, rituximab maintenance therapy improved the PFS in patients who had achieved a response after receiving FCM (fludarabine, cyclophosphamide, and mitoxantrone) or rituximab plus FCM in a study by the German Low-Grade Lymphoma Study Group (GLSG). Rituximab maintenance also demonstrated an improvement in PFS compared with observation in previously untreated patients who had achieved stable disease or a partial or complete response to CVP induction treatment in Study E1496.

Health authority approval has also been granted for the use of rituximab in combination with CVP chemotherapy in patients with previously untreated, CD20+, follicular NHL in the United States, the European Union and many other countries. Approval was based on results of a randomized, Phase III study (M39021) in which benefit of the concurrent administration of rituximab and CVP chemotherapy compared with chemotherapy alone was demonstrated by improvement in median time to treatment failure (TTF) and median time to progression (TTP). Additional Phase II and III studies have demonstrated the benefit of rituximab in combination with several other chemotherapy regimens (such as fludarabine, mitoxantrone, and dexamethasone [FND]; mitoxantrone, chlorambucil, and prednisolone [MCP]; and cyclophosphamide, doxorubicin, etoposide, and prednisone [CHVP]).


1.2.2.2 Diffuse, Large B-Cell NHL In Study LNH98-5, a randomized, Phase III trial conducted by the Groupe d’Etude des Lymphomes de l’Adulte (GELA), the addition of rituximab to eight cycles of CHOP chemotherapy (R-CHOP) significantly increased the overall response rate (ORR), EFS, and overall survival in elderly patients (≥ 60 years) with previously untreated diffuse, large B-cell lymphoma. Treatment benefited both low-risk and high-risk prognostic groups as determined by International Prognostic Index (IPI). In the United States, the European Union, and many other countries, the results of Study LNH98-5 led to the approval of rituximab in combination with CHOP chemotherapy for the treatment of patients with previously untreated, CD20+, diffuse, large B-cell NHL.

In addition, Study E4494, conducted by ECOG, Southwest Oncology Group (SWOG), and Cancer and Leukemia Group B (CALGB) and sponsored by the National Cancer Institute (NCI), demonstrated an improvement in PFS and overall survival with the addition of rituximab to CHOP induction chemotherapy compared with CHOP induction chemotherapy alone, in the absence of maintenance rituximab, in previously untreated elderly patients (≥ 60 years). Also, in the RICOVER-60 Study, the addition of rituximab to dose-dense therapy with bi-weekly CHOP chemotherapy in elderly patients (61-80 years, stages I-IV) significantly improved the freedom from treatment failure compared with CHOP alone, to an extent that the formal criteria for stopping the trial were met after an interim analysis (Pfreundschuh, 2005).

The results achieved with R-CHOP in elderly patients with diffuse, large B-cell NHL were also confirmed in younger patients (≤ 60 years). Study M39045 (MabThera ® International Trial [MInT]) demonstrated an improvement in complete response (CR) rate, TTF, and overall survival when rituximab combined with CHOP or a CHOP-like chemotherapy regimen was administered to previously untreated patients ≤ 60 years of age with low-risk IPI scores.

Rituximab has been studied in combination with other chemotherapy regimens for the treatment of previously untreated and previously treated patients with diffuse, large B-cell NHL. In addition, rituximab monotherapy has shown activity in the treatment of relapsed diffuse, large B-cell NHL in Phase II studies.

1.2.2.3 Chronic Lymphocytic Leukemia A number of Phase II studies have been completed using rituximab as monotherapy or in combination with chemotherapy in patients with chronic lymphocytic leukemia (CLL). Promising CR rates, with a high number of molecular responses, have been reported for patients treated with rituximab in combination with chemotherapy. Study CALGB 9712, a randomized, Phase II study conducted by CALGB, showed a higher ORR when rituximab was administered concurrently with fludarabine and then followed by rituximab consolidation (90 %) compared with rituximab administered sequentially after fludarabine (77 %). Several Phase III, randomized studies are currently investigating the concurrent administration of rituximab with FC (fludarabine and cyclophosphamide) chemotherapy versus FC chemotherapy alone in patients with CLL who are either previously untreated or in first relapse.


1.2.2.4 Other Malignancies Limited data are available from studies of rituximab for treatment of other malignant, CD20+, B-cell diseases, including HIV-associated NHL, mantle cell lymphoma (MCL), Waldenström’s macroglobulinemia, multiple myeloma, Hodgkin’s disease, posttransplant lymphoproliferative disorder (PTLD), and others.

1.2.2.5 Non-Malignant Hematologic Disorders Limited data are available from studies of rituximab for treatment of non-malignant hematologic disorders such as idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia (AIHA), cold hemagglutinin disease (CHD), and congenital and acquired factor VIII deficiency.

1.2.3 Clinical Safety Safety data with rituximab in the hematologic and oncological settings are largely derived from clinical studies and postmarketing experience in patients with NHL. Experience in settings outside NHL is limited.

The main toxicities reported with rituximab as monotherapy and in combination with chemotherapy are infusion-related reactions. These are primarily associated with the first infusion, may be related to release of cytokines or other chemical mediators, and rarely necessitate discontinuation of treatment. Hypotension, fever, chills, rigors, urticaria, bronchospasm, and angioedema have occurred in association with rituximab infusion as part of an infusion-related complex.

Anaphylactic and other hypersensitivity reactions have been reported following the intravenous (IV) administration of proteins to patients. Adrenaline, antihistamines, and corticosteroids should be available for immediate use in the event of a hypersensitivity reaction to rituximab.

Respiratory failure or insufficiency and pulmonary infiltrates in the context of infusion-related reactions have been reported [8] (see section 6.3.1.1). Patients who experience severe pulmonary events or other severe infusion-related symptoms should have their infusion interrupted immediately, receive aggressive symptomatic treatment, and be closely monitored until the event has resolved completely. Patients with a history of pulmonary insufficiency may be at greater risk of poor outcome and should be treated with increased caution. Further treatment of patients after complete resolution of signs and symptoms has rarely resulted in repeated severe infusion-related reactions.

Angina pectoris and cardiac arrhythmia (such as atrial flutter and fibrillation) have occurred in patients treated with rituximab. Severe cardiac events, including heart failure and myocardial infarction, have been observed, mainly in patients with prior cardiac condition or exposure to cardiotoxic chemotherapy and mostly in association with infusion-related reactions.

Tumor lysis syndrome has been reported to occur after the first rituximab infusion in patients with high numbers of circulating malignant lymphocytes. Patients with a high tumor burden or a high number of circulating malignant cells (> 25 × 109/L), such as patients with CLL or MCL [8, 58], may be at higher risk of especially severe infusion-related reactions. These reactions may be fatal.


Hepatitis B virus (HBV) reactivation, with fulminant hepatitis, hepatic failure, and death, has been reported in some patients with hematologic malignancies treated with rituximab. The majority of patients received rituximab in combination with chemotherapy.

Other serious viral infections, either new, reactivation, or exacerbation, some of which were fatal, have been reported with rituximab treatment. The majority of patients had received rituximab in combination with chemotherapy or as part of a hematopoetic stem cell transplant. Examples of these serious viral infections are infections caused by the herpes viruses (cytomegalovirus, Varicella zoster virus, and Herpes simplex virus), JC virus (progressive multifocal leukoencephalopathy [PML]), and hepatitis C virus.

Gastrointestinal obstruction and perforation, in some cases leading to death, have been observed in patients receiving rituximab for treatment of NHL. In the majority of these cases, rituximab was administered in combination with chemotherapy.

Rare cases of severe bullous skin reactions including toxic epidermal necrolysis and paraneoplastic pemphigus have been reported. Some of these reactions have been associated with a fatal outcome.

In an integrated assessment of safety from six studies of rituximab monotherapy in 356 patients with previously treated indolent NHL [22, 23, 76, 77, 78, 84, 92], severe (Grade 3 or 4) thrombocytopenia was reported in 1.7 % of patients, severe neutropenia was reported in 4.2 % of patients, and severe anemia was reported in 1.1 % of patients. Severe infectious events, including sepsis, occurred in 3.9 % of patients.

In the above-mentioned integrated safety assessment, 4 patients developed a human anti-chimeric antibody (HACA) response following treatment. Two of these patients were retreated without problems. No correlation was seen between HACA response and loss of or interference with response to treatment.

More information on the safety profile of rituximab can be found in section 6.

1.3 Guidance for the Investigator Specific guidelines within the product label approved in the investigator’s country (e.g., Summary of Product Characteristics or Package Insert) should be followed where rituximab is marketed. A summary of guidelines for the investigator is provided in section 6.

2. INTRODUCTION Rituximab is a chimeric murine/human monoclonal antibody that binds to CD20, a hydrophobic transmembrane protein that is present on the cell surface of pre-B lymphocytes and mature B lymphocytes, but not on hematopoietic stem cells, pro-B cells, normal plasma cells, or other normal tissue. In particular, CD20 is present on B lymphocytes in most patients with mature B-cell lymphoma and leukemia. Rituximab binds to CD20 on B lymphocytes and eliminates these cells potentially via a number of different mechanisms.

The novel and specific action of rituximab may fill the unmet medical needs in several CD20+, B-cell disorders.


3. PHYSICOCHEMICAL PROPERTIES AND CLINICAL FORMULATION 3.1 Physicochemical Properties Rituximab is a highly purified 1328–amino acid antibody with an approximate molecular mass of 145 kDa. The chimeric anti-CD20 monoclonal antibody is a glycosylated IgG1-κ immunoglobulin containing murine light- and heavy-chain variable region sequences and human constant region sequences (Figure 1). Rituximab is produced in suspension culture by a Chinese hamster ovary transfectoma containing the TCAE 8 expression vector in a nutrient medium containing 100 µg/mL of the antibiotic gentamicin. The purification process removes gentamicin and process and product impurities, such as high molecular weight aggregates, using protein A–affinity chromatography and anion exchange chromatography.

Figure 1 Structure of Rituximab: A Murine/Human Anti–Human CD20 Monoclonal Antibody

Murine variable regions bind specifically to CD20 on B cells

Human kappa constant regions

Human IgG1 Fc domain

3.2 Clinical Formulation Rituximab is formulated for IV administration as a sterile product in 9.0 mg/mL sodium chloride, 0.7 mg/mL polysorbate 80, 7.35 mg/mL sodium citrate dihydrate, and Water for Injection, USP (pH 6.5). The antibody is supplied for market use in 10-mL and 50-mL vials containing 100 mg of antibody/10 mL of solution or 500 mg of antibody/50 mL of solution at a concentration of 10 mg/mL. No preservative is used since the vial is designed for single use. The product packaging consists of USP Type I borosilicate glass vials (10 mL and 50 mL) with 20-mm plug stoppers and 20-mm plastic flip-off caps.

3.3 Stability, Storage, and Handling Instructions Prepared infusion solutions of rituximab are biologically and chemically stable at 2°–8°C (36°–46°F) for 24 hours and at room temperature for an additional 12 hours. The product should not be used beyond the expiration date stamped on carton. Rituximab vials should be protected from direct sunlight. No incompatibilities between rituximab and polyvinylchloride or polyethylene bags have been observed.


4. NONCLINICAL STUDIES 4.1 Nonclinical Pharmacodynamics In vitro and in vivo studies in cynomolgus monkeys were performed to examine the pharmacologic properties of rituximab. The results of these studies are summarized as follows:

• Rituximab binds with high specificity and high affinity (apparent Kd, 5.2–11 nM) to CD20 expressed on primate B lymphoma cell lines and primary malignant and non-malignant B cells.

• Rituximab is capable of eliminating CD20+ cells via ADCC, CDC, and direct effects induced by rituximab binding to CD20, including the induction of apoptosis. The relative contribution of each mechanism to the overall B-cell killing in vivo is not known [80].

• Rituximab does not recognize or promote destruction of any normal human tissues other than CD20+ B cells; thus, plasma cells and stem cells are spared.

• There is immediate onset of CD20+ B-cell depletion in peripheral blood following single and multiple doses in cynomolgus monkeys.

• After stopping treatment, a normal B-cell pool can be reconstituted from hematopoietic stem cells and CD20- precursor B cells, which are not affected by treatment with rituximab.

4.1.1 In Vitro Studies A series of in vitro studies demonstrated that rituximab is highly specific for the CD20 antigen expressed on primate B lymphoma cell lines and primary malignant or non-malignant B cells, and binds to the cell surface antigen with an apparent affinity of 5.2-11 nM (IDEC Study AS0031). Evidence exists for rituximab having several mechanisms of mediating CD20+ B-cell elimination [80]. Rituximab was shown to bind to the C1q component of complement and initiate CDC, and to have significant activity in assays of ADCC [96]. Direct effects induced by rituximab binding to CD20 have also been described, including the induction of apoptosis.

Human tissue cross-reactivity studies demonstrated that rituximab recognizes the CD20 antigen, which has a very restricted pattern of distribution. Immunoreactivity was observed largely in a subset of cells found in the bone marrow, peripheral blood, lymph node, white pulp of the spleen, and lymphoid follicles of the tonsil. Importantly, reactivity with hematopoietic stem cells was not observed (IDEC Studies IH0027, IH0028, IH0029, and CS0024). Thus, rituximab does not recognize or promote destruction of any normal human tissues other than B cells.

4.1.2 In Vivo Studies Results from experiments in cynomolgus monkeys demonstrated the immediate onset of CD20+ B-cell depletion in the peripheral blood following single and multiple doses of rituximab. B-cell depletion was observed in all monkeys studied, with > 95 % peripheral B-cell depletion following the first or second dose of rituximab. The B-cell compartments within lymphatic tissue, including spleen, mandibular lymph node, and submucosal lymphoid nodules, were also depleted within a short period following treatment. The extent of observed B-cell depletion in peripheral blood and lymphoid tissues appeared to


be both time and dose dependent. Consistent with rituximab binding only to CD20+ B cells, T-cell numbers were unaffected after treatment with rituximab. Time to B-cell recovery was variable; although noted in some animals 7–14 days following administration of the last dose, partial recovery occurred more commonly at 4-8 weeks, and recovery to baseline levels required 3 months or longer. The observed variability did not appear to be dose related, as some animals receiving high doses recovered more rapidly than others receiving lower doses (IDEC Studies AS0032, AS0033, AS0050, and AS0055/55A). The variability in B-cell recovery may be a result of the development of anti-rituximab antibodies in these animals, which may affect rituximab clearance.

In summary, binding of rituximab to CD20 on B cells leads to the specific depletion of B cells by several potential mechanisms. Following cessation of treatment, a normal B-cell pool can be reconstituted from hematopoietic stem cells and CD20– precursor B cells, which are not affected by treatment with rituximab.

4.2 Nonclinical Pharmacokinetics The results of nonclinical pharmacokinetic studies of rituximab are summarized as follows:

• Since the structure of rituximab is based on an IgG1 antibody, its distribution and metabolism are believed to be similar to that of endogenous IgG1 molecules, with the exception of specific distribution to CD20 antigen–bearing cells.

• In cynomolgus monkeys, rituximab has a long terminal half-life (61-311 hours) following a rapid initial distribution phase (half-life, 29-60 hours). Clearance and half-life appear to be dose dependent, with lower clearance and longer half-life observed at higher doses.

• Clearance is partly dependent on CD20 antigen–bearing B cells since binding to circulating B cells reduces levels of free rituximab. Thus, rituximab clearance may be influenced by target antigen–mediated clearance.

The rituximab structure is based on an IgG1 antibody; therefore, its distribution and metabolism are believed to be similar to that of endogenous IgG1 molecules, with the exception of the specific distribution of rituximab to CD20 antigen–bearing cells. Although no specific tissue distribution studies were performed, the in vivo pharmacology studies described previously demonstrated that rituximab distributes outside the vascular space as depletion of CD20+ cells occurs in the lymphatic tissues as well as in the blood. Penetration of rituximab into various tissues may depend on the degree of vascularization. It is not known whether tissue penetration is also dose dependent. Analogous to endogenous IgG1 molecules, it is expected that rituximab is transported through the placental barrier and excreted into milk, in which physiologically low levels of IgG can be found. Free-circulating rituximab enters the metabolic pathway of endogenous soluble IgG, while rituximab bound to CD20+ lymphocytes will be phagocytosed, together with destroyed B cells, by infiltrating macrophages and granulocytes.

In cynomolgus monkeys, rituximab has a long terminal half-life (61-311 hours) following a rapid initial distribution phase (half-life, 29-60 hours; IDEC Study AS0069). Rituximab clearance is partly dependent on CD20 antigen–bearing B cells since binding to


circulating B cells reduces levels of free rituximab. Following depletion of circulating B cells, this clearance pathway is minimal or nonexistent. Non–antigen-specific clearance is mediated through Fcγ receptors located on immune effector cells. Clearance of rituximab may also be under the control of immune system mechanisms regulating humoral immune defense. The long half-life of rituximab may be the result of recycling through the FcRn receptor, which is known to be a major mechanism for the persistence of endogenous IgG1 antibodies. In addition, depletion of circulating B cells may trigger greater recirculation of IgG through FcRn receptors and less elimination through Fcγ receptors as a means of maintaining IgG homeostasis. This regulatory mechanism may contribute to the long half-life of IgG1 antibodies, including rituximab.

Following single IV doses of 10, 30, and 100 mg/kg to cynomolgus monkeys, rituximab showed a rapid initial distribution phase (half-life, 29-60 hours) followed by a longer terminal half-life (61–311 hours; IDEC Study AS0069). In monkeys receiving rituximab 20 mg/kg once weekly for 4 weeks, mean plasma rituximab concentrations of 239-281 µg/mL were reached following the first and second doses (IDEC Study AS0055/ 55A/60A). Similar results were obtained with administration of 20 mg/kg rituximab to monkeys, with animals achieving plasma concentrations of 246 µg/mL after the first weekly dose and 366 µg/mL after the second weekly dose. The maximum plasma concentrations observed in 2 monkeys administered a single IV rituximab dose of 100 mg/kg were 1220 and 2260 µg/mL (IDEC Study AS0069).

Pharmacokinetics were also determined following two IV rituximab doses given 1 week apart at 0.05, 0.2, 0.5, 2, and 10 mg/kg to cynomolgus monkeys (Genentech Study 02-183-0352). Clearance, volume of distribution, and half-life were dose dependent over this range. As the dose increased, clearance and volume of distribution decreased, and half-life increased. Average clearance ranged from 515 ± 52.5 mL/day at 0.05 mg/kg twice weekly to 21.9 ± 5.86 mL/day at 10 mg/kg twice weekly; terminal half-life at these doses averaged 72.5 ± 47.5 hours and 154 ± 43.9 hours, respectively. At doses of 0.2-10 mg/kg twice weekly, volume of distribution at steady state ranged from approximately equal to the physiologic plasma volume (116 mL) to double that (325 mL) for cynomolgus monkeys. At the low dose of 0.05 mg/kg twice weekly, volume of distribution averaged 3970 ± 1220 mL.

In all studies in cynomolgus monkeys, some animals developed antibodies to rituximab that appeared to contribute to faster clearance of drug. This is not unexpected, given that rituximab is a foreign protein in this species.

In summary, the disposition of rituximab in monkeys is dependent on antibody-specific and non-specific processes. Clearance is partly dependent on circulating B cells. Following depletion, a lower clearance and longer half-life is observed.


4.3 Nonclinical Toxicology The results of nonclinical toxicology studies of rituximab are summarized as follows:

• Rituximab was non-toxic to monkeys at the maximum dose of 100 mg/kg in the single-dose toxicology study and at the maximum dosage of 20 mg/kg weekly in the repeat-dose toxicology study.

• In the repeat-dose toxicology study, some monkeys that received four or eight weekly doses of 20 mg/kg rituximab developed an anti-rituximab response.

• Rituximab was well tolerated in pregnant monkeys and did not result in embryotoxicity or teratogenicity when administered weekly during the period of organogenesis at a dose of up to 100 mg/kg.

4.3.1 Single-Dose Study A Good Laboratory Practice (GLP) single-dose toxicology study (IDEC Study AS0069) was conducted in monkeys. Rituximab was administered intravenously at a dose of 10, 30, or 100 mg/kg to one male and one female monkey per dose group. There were no treatment-related effects on mortality, body weight, food consumption, or body temperature. There was one incidence of vomiting by the male animal in the high-dose group 2 days after dosing. No other clinical signs were observed. There was a transient and mild decrease in platelet count for both sexes in the 30 and 100 mg/kg dose groups. Additionally, a decrease in lymphocyte ratio and an increase in neutrophil ratio were observed in all animals 1 day after administration. All hematologic changes were mild, were dose independent, and returned to baseline by Day 7 or 14; therefore, they were not considered to be biologically significant.

4.3.2 Repeat-Dose Study A repeat-dose GLP toxicology study (IDEC Study AS0055/AS0055A) was performed in monkeys. Animals received rituximab at doses of 0 or 20 mg/kg once weekly for 4 or 8 weeks. The vehicle control groups included 1 male and 1 female per group (4 or 8 weeks of dosing), and the treatment groups included 3 males and 3 females per group (4 or 8 weeks of dosing). Animals were euthanized 2 weeks after their last dose. There were no treatment-related effects on mortality, body weight, food consumption, hematology parameters, clinical chemistry, or urinalysis parameters. A possible treatment-related clinical observation included vomiting approximately 15–20 minutes after drug administration in 3 of the treated females (once in 1 female treated for 4 weeks; occasionally in 2 females treated for 8 weeks). It is difficult to interpret the significance of these events given the low incidence and the absence of similar events in the treated males. All other effects were consistent with the expected pharmacologic effects of rituximab: decreased B cells by flow cytometry in peripheral blood, mandibular lymph nodes, and femoral bone marrow; small spleens in 4 of the treated animals (1 male and 1 female treated for 4 weeks; 1 male and 1 female treated for 8 weeks); histopathologic lymphoid atrophy in the spleen, mandibular lymph nodes, and submucosal lymphoid nodules of the colon; and decreased B cells by immunohistochemistry in the mandibular lymph nodes and spleen.

4.3.3 Reproductive Toxicity Studies In a reproductive toxicity study (Genentech Study 01-483-0346), rituximab at doses of 20, 50, or 100 mg/kg were given weekly to pregnant female cynomolgus monkeys during


the period of organogenesis. There were no findings of toxicity to the dams or developing fetuses, and the only effect noted was the dose-dependent pharmacologic depletion of B cells in the lymphoid organs of the fetuses.

5. CLINICAL EXPERIENCE Studies of rituximab, given as monotherapy or in combination with chemotherapy or other immunotherapy, have been conducted in patients with previously untreated or previously treated indolent (low-grade or follicular) NHL, diffuse large B-cell NHL, CLL, other malignant diseases, and non-malignant hematologic disorders. This section summarizes critical studies that support the current approved indications of rituximab in malignant hematologic disorders and/or contribute to the basis of scientific knowledge regarding the clinical applications of rituximab in malignant and non-malignant hematologic disorders. Overviews of these selected studies are presented in Tables A-1 through A-9 of appendix A ( ~xr1i ). Additional publications and/or studies of interest, not described in this section, are listed in appendix C ( ~xr2i ).

5.1 Pharmacokinetics and Pharmacodynamics The summary of clinical pharmacology in NHL patients presented within this section is based on data from Studies 102-01, 102-02, 102-03, 102-05, 102-06, 102-07, and U2035g, as well as two Japanese studies [112, 113]. Overviews of these studies are presented in Tables A-1 and A-2 of appendix A ( ~xr3i ).

5.1.1 Pharmacokinetics in Patients with NHL The key pharmacokinetic findings for rituximab in patients with NHL are summarized as follows:

• The mean Cmax and mean AUC of rituximab increased with increasing dose. • The mean serum half-life of rituximab after the first infusion was usually shorter than

that after subsequent infusions. • The mean serum clearance of rituximab after the first infusion was always greater

than that after subsequent infusions. • The volume of distribution was small, approximately equal to blood volume. • There was no significant effect of age on the pharmacokinetics of rituximab. • There was no significant effect of sex on the pharmacokinetics of rituximab. • There was no significant difference in the pharmacokinetics of rituximab in Japanese

patients compared with non-Japanese patients. • The variability was moderate to high for AUC (20 %–60 %) and Cmax (20 %–50 %). Terminal half-life increased from the first infusion to later infusions, as the overall mean terminal half-life following the first, fourth, sixth, and eighth infusion was 94.1, 238, 340, and 420 hours, respectively. The clearance reflects this pattern, with decreasing values of 0.048, 0.024, and 0.006 µg • hr/mL for the first, fourth, and eighth infusions, respectively (see Table 1and Table 2 for data from individual studies). Following administration of a single dose, clearance of rituximab is thought to be dependent on the elimination of rituximab through CD20 receptor binding followed by cell death. Following administration of multiple doses, clearance of rituximab is probably independent of CD20 receptor binding and will, therefore, be similar to the clearance of IgG. This effect has

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been seen with other monoclonal antibodies [26]. The variability was moderate to high for all pharmacokinetic parameters.

There were no statistically significant differences in half-life and clearance between patients > 60 and < 60 years of age, or between male and female patients.

There was a statistically significant correlation between the number of circulating B cells at baseline and the clearance of rituximab after the first infusion. This confirms the contributory role of B-cell binding in the clearance of rituximab following the initial dose.

Table 1 Pharmacokinetic Parameters after a Single IV Infusion of Rituximab

Mean (SD)

Dose (mg/m2) Study n

AUC (µg • hr/mL)

Half-Life (hours)

Cmax (µg/mL)

CL (L/hr)

Vss (L)

50 102-01 1 1,135 48.4 16.4 0.082 5.75 100 102-01 3 5,439 (1,087) 76.6 (49.2) 44.6 (11.9) 0.048 (0.015) 4.38 (1.28) 125 102-02 3 NR 75.6 (25.5) 68.1 (13.4) 0.038 (0.016) NR 250 102-01 3 36,363 (23,803) 127 (111) 177 (36.7) 0.041 (0.041) 2.83 (0.85) 250 102-02 4 NR 34.8 (17.9) 198 (64.7) 0.096 (0.11) NR 375 102-02 9 NR 59.8 (28.8) 272 (95.2) 0.054 (0.081) NR 375 102-03 7 NR 42.5 (32.5) 237 (43.6) NR NR 375 102-05 13 NR 76.3 (31.1) 206 (59.9) 0.038 (0.018) NR 375 102-06 1 NR 77.1 307 0.019 NR 375 U2035g 5 25,300 (13,257) 243 (69.8) 141 (43.2) 0.046 (0.040) 9.80 (6.19) 500 102-01 3 85,521 (45,246) 174 (145) 352 (75.1) 0.019 (0.01) 2.72 (0.30)

CL = clearance; NR = not reported; Vss = volume of distribution at steady state.


Table 2 Pharmacokinetic Parameters after Multiple IV Infusions of Rituximab

Mean (SD)

Infusion Dose (mg/m2) Study n Half-Life (hours)

Cmax (µg/mL)

CL (L/hr)

Fourth 125 102-02 3 279 (198) 134 (28.5) 0.012 (0.003) 250 102-02 4 112 (63.5) 230 (107) 0.069 (0.102) 375 102-02 9 174 (136) 497 (157) 0.020 (0.035) 375 102-05 13 206 (95.0) 465 (119) 0.009 (0.003) 375 102-06 1 148 770 0.0086 375 102-07 10 305 (103) NR NR 250 or 375 Tobinai et al. 1998* 11 445 (361) NR NR Sixth 375 102-03 10 340 (127.4) 401 (58.6) NR Eighth 375 102-06 1 422.5 994.6 0.0061 375 Tobinai et al. 2004 † 12 433 † 460† NR CL = clearance; NR = not reported. *Japanese patients. †Mean values for all patients combined were not provided in the publication, but were calculated using mean values for responders (n = 7) and non-responders (n = 5).

5.1.2 Pharmacodynamics in Patients with NHL In patients with indolent NHL treated with rituximab monotherapy (375 mg/m2 once weekly for 4 weeks), a marked decline in median peripheral blood B-cell counts was seen within the first three doses, with sustained depletion for up to 6–9 months after treatment in 83 % of patients. B-cell recovery began at approximately 6 months following completion of treatment, with median levels returning to normal between 9 and 12 months.

5.1.3 Relationship between Pharmacokinetics and Pharmacodynamics Non-responders had a more rapid depletion of rituximab than responders, but peak serum rituximab levels did not correlate strongly with response. Mean serum rituximab concentration was inversely correlated with tumor bulk and number of circulating cells at baseline. Thus, a definitive relationship between serum concentration and efficacy cannot be established because of confounding factors such as target-mediated clearance and baseline disease severity.

5.2 Treatment of Indolent (Low-Grade or Follicular) NHL Table A-1 of appendix A ( ~xr4i ) provides an overview of selected studies of rituximab treatment in patients with indolent (low-grade or follicular) NHL, and the study results are described in the following subsections. Unless otherwise specified, patients received the standard approved rituximab dose of 375 mg/m2.

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5.2.1 Rituximab Monotherapy in Patients with Previously Untreated Indolent NHL

Two key studies of rituximab monotherapy for patients with previously untreated indolent NHL are described below. Studies of rituximab monotherapy followed by extended dosing (maintenance) are described in section 5.2.3.

5.2.1.1 Efficacy In Study M39006 [18, 107], 50 patients with newly diagnosed Stage II–IV follicular lymphoma and low tumor burden were treated with rituximab once weekly for 4 weeks. Based on best response within the first year, there was an ORR of 80 %, complete response or complete response unconfirmed (CR/CRu) rate of 49 %, and partial response (PR) rate of 31 %. At a median follow-up of 5 years, median duration of PFS was 18 months. The estimated 5-year relapse-free survival rate was 28 % for all patients.

In a study by Witzig et al. [128], 36 patients with previously untreated, Stage III or IV, Grade I, follicular NHL were treated with rituximab once weekly for 4 weeks. The ORR was 72 %, with a CR rate of 36 %. The median TTP was 2.2 years. Among 6 patients who had elevated lactate dehydrogenase (LDH) levels at baseline, the ORR was 33 %, with a median TTP of 6 months.

5.2.1.2 Safety In Study M39006 [18], the most frequent adverse events were Grade 1 or 2 fever, headache, asthenia, pain, rash, laryngitis, rhinitis, paresthesia, hypotension, and nausea. There was 1 case each of Grade 3 or 4 hypotension and hypertension; these events resolved with standard medical intervention. No hematologic toxicity was observed, and only one minor infection developed.

Witzig et al. [128] reported on 35 patients who were assessable for toxicity. The most common Grade 1 or 2 toxicity was fatigue, reported in 10 patients. Grade 3 or 4 adverse events were observed in 5 patients (14 %). Grade 3 adverse events included neutropenia, leukopenia, rash, hemorrhage, infection without neutropenia, and colitis. There were two Grade 4 events: urticaria and rash. Both Grade 4 events and the Grade 3 neutropenia were considered to be attributable to rituximab by the treating physician.

5.2.2 Rituximab Combined with Chemotherapy or Other Immunotherapy in Patients with Previously Untreated Indolent NHL

Summarized below are data from five representative key studies of rituximab plus chemotherapy or other immunotherapy in patients with previously untreated indolent NHL. The rituximab dosing interval and total number of doses (typically six to eight) varied with the chemotherapy regimen administered. Studies of rituximab plus chemotherapy followed by maintenance rituximab are described in section 5.2.3.

5.2.2.1 Efficacy Table 3summarizes the response rates for the five key studies of rituximab plus chemotherapy or other immunotherapy in patients with previously untreated indolent NHL.


Table 3 Response Rates for Studies of Rituximab Combination Therapy in Patients with Previously Untreated Indolent NHL

Response: % of Patients Reference (Study)

Treatment Group * n Complete Partial Overall

Hiddemann et al. 2004; Hiddemann et al. 2005 (GLSG study) †

R-CHOP CHOP

428 † (total) 20 % 17 %

77 % 73 %

96 % 90 %

Herold et al. 2004 (Study M39023) †

R-MCP MCP

201 † (total) 49.5 % 25 %

42.9 % ‡

50 % ‡ 92.4 % 75 %

Marcus et al. 2005 (Study M39021)

R-CVP CVP

162 §

159 § 41 % ¥

10 % ¥ 40 % 47 %

81 % 57 %

Salles et al. 2004; Foussard et al. 2006 (Study FL-2000)

6 months: R-CHVP/IFN CHVP/IFN 18 months: R-CHVP/IFN CHVP/IFN

184 175

184 175

76 % ¥ 49 % ¥

79 %¥ 63 % ¥

18 % 36 %

5 %

10 %

94 % Þ

85 % Þ

85 % Þ 73 % Þ

McLaughlin et al. 2003 (Study U0794n)

R-FND FND + delayed R

76 73

92 % ¥ 85 % ¥

8 % 10 %

100 % Þ 95 % Þ

CHVP = cyclophosphamide, doxorubicin, etoposide, and prednisone; FND = fludarabine, mitoxantrone, and dexamethasone; GLSG = German Low-Grade Lymphoma Study Group; R = rituximab; MCP = mitoxantrone, chlorambucil, and prednisolone. *See Table A-1 of appendix A ( ~xr5i ) for detailed description of dosing regimens. †Study included patients with MCL, but only results from patients with follicular lymphoma are presented. ‡PR rate was not provided in the publication, but was calculated by subtracting the CR rate from the ORR. §Number of evaluable patients. ¥Includes CR and CRu. ÞORR was not provided in the publication, but was calculated by adding the CR and PR rates.

5.2.2.1.1 Rituximab Combined with CHOP In a study by the German Low-Grade Lymphoma Study Group [51, 52], patients with previously untreated follicular lymphoma, lymphoplasmacytic lymphoma, or MCL were randomized to receive six 21-day cycles of CHOP, alone or in combination with rituximab. Patients who achieved a response and were < 60 years of age (younger patients) underwent a second randomization to receive either myeloablative radiochemotherapy with subsequent autologous stem cell transplantation (ASCT), or IFN-α maintenance. Patients who achieved a response and were ≥ 60 years of age (older patients) received IFN-α maintenance. Among 428 patients with follicular lymphoma, R-CHOP was associated with a significantly higher ORR compared with CHOP (96 % versus 90 %; p = 0.011) and a longer TTF (median not reached versus 2.6 years; p < 0.0001). Among the 347 responders evaluable for treatment strategies post-remission, 79 younger patients underwent ASCT (44 after R-CHOP and 35 after CHOP), 121 younger patients received IFN-α maintenance (69 after R-CHOP and 52 after CHOP), and 122 older patients received IFN-α maintenance (63 after R-CHOP and 59 after CHOP) (Hiddemann, 2004). After a median observation time of 18 months, 28 (13 %) patients in the R-CHOP group experienced treatment failure versus 61 (30 %) in the

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CHOP group. Analysis of risk of treatment failure demonstrated that R-CHOP significantly reduced the risk of treatment failure by 60 % (p<0.001) when compared with CHOP alone. The duration of response was significantly longer in the R-CHOP group compared with the CHOP group (p = 0.001). The estimated 2-year overall survival rate was significantly improved (p = 0.016) in the R-CHOP group (95 %) compared with the CHOP group (90 %) [52]. Study results for patients with MCL are presented in section 5.6.1.

5.2.2.1.2 Rituximab Combined with MCP In Study M39023 [50], 358 previously untreated patients with Stage III or IV follicular lymphoma, immunoplasmacytic lymphoma, or MCL were randomized to receive eight 28-day cycles of MCP, alone or in combination with rituximab. The ORR and CR rate for all patients were 85.5 % and 42 %, respectively, for the R-MCP group versus 65.5 % and 20 %, respectively, for the MCP group (p < 0.0001). Among the 201 patients with follicular NHL, the ORR and CR rate were 92.4 % and 49.5 %, respectively, for the R-MCP group versus 75 % and 25 %, respectively, for the MCP group (p < 0.0001). Among all patients, EFS was significantly prolonged for the R-MCP group compared with the MCP group (p < 0.001) and the Kaplan–Meier estimated 2-year EFS rate was 69 % for the R-MCP group and 44 % for the MCP group (p < 0.0001). Among patients with follicular NHL, the estimated 2-year EFS rate was 83 % for the R-MCP group and 43 % for the MCP group (p < 0.0001).

5.2.2.1.3 Rituximab Combined with CVP In Study M39021, 322 patients with previously untreated, indolent, B-cell NHL were randomized to receive eight 21-day cycles of CVP chemotherapy, alone or in combination with rituximab. A total of 321 patients received therapy and were analyzed for efficacy. At a median follow-up of 42 months, median TTF (time from randomization to progression, relapse, initiation of new lymphoma treatment, stable disease after the fourth cycle, or death) was 27 months for the R-CVP group and 6.6 months for the CVP group (p < 0.0001). Median TTP (time from randomization to progression, relapse, or death) was 33.6 months for the R-CVP group and 14.5 months for the CVP group (p < 0.0001) [106]. The ORR and the CR/CRu rate were 81 % and 41 %, respectively, for the R-CVP group and 57 % and 10 %, respectively, for the CVP group (p < 0.0001) [82]. Based on Kaplan-Meier estimates, overall survival rate at 3 years was 89 % in the R-CVP group and 81 % in the CVP group (p = 0.07) [106].

5.2.2.1.4 Rituximab Combined with CHVP/IFN GELA and Groupe Ouest Est d’Etude des Leucernies et autres Maladies du Sang (GOELAMS) conducted Study FL-2000, an open-label, multicenter, randomized, Phase III trial of rituximab combined with CHVP/IFN (cyclophosphamide, doxorubicin, etoposide, and prednisone combined with interferon-α2a) in 359 patients with previously untreated, follicular NHL who met criteria for high tumor burden [99]. Patients were randomized to CHVP (six 28-day cycles of CHVP followed by six 56-day cycles of CHVP) or R-CHVP (six 28-day cycles of CHVP in combination with six doses of rituximab). In addition, both groups received IFN-α2a three times a week for 18 months. Patients in the R-CHVP/IFN group had a significantly improved response to therapy compared with patients in the CHVP/IFN group, both at 6 months and 18 months. At


6 months, the R-CHVP/IFN and CHVP/IFN groups had a CR/CRu rate of 76 % and 49 %, respectively, and a PR rate of 18 % and 36 %, respectively. At 18 months, the R-CHVP/IFN and CHVP/IFN groups had a CR/CRu rate of 79 % and 63 %, respectively, and a PR rate of 5 % and 10 %, respectively [99]. With a median follow-up of 3.5 years, the median duration of EFS was 3 years in the CHVP/IFN group. In the R-CHVP/IFN group, the median EFS has not been reached. The estimated 3.5-year EFS rate was 67 % in the R-CHVP/IFN group and 46 % in the CHVP/IFN group (p < 0.0001). The overall survival rate at 42 months was significantly improved (p = 0.029) in the R-CHVP/IFN group (91 %) compared with the CHVP/IFN group (84 %) [35].

5.2.2.1.5 Rituximab Combined with FND In Study U0794n [85], 149 patients with Stage IV small lymphocytic (n = 42) or follicular (n = 107) lymphoma were randomized to receive eight 28-day cycles of FND, either concurrently with six infusions of rituximab (R-FND) or followed by six infusions of rituximab (FND + delayed rituximab). In addition, both groups received monthly IFN-α2b maintenance therapy for 1 year. Median duration of follow-up was 30 months. For all patients combined, the CR/CRu rate was 89 % and the PR rate was 9 %. There was a 92 % CR/CRu rate and 8 % PR rate in the R-FND group and an 85 % CR/CRu rate and 10 % PR rate in the FND + delayed rituximab group. The estimated 3-year failure-free survival (FFS) rate was slightly higher for the R-FND group compared with the FND + delayed rituximab group (77 % versus 64 %; p = 0.11). The overall survival rate at 3 years was 95 % for both the R-FND and FND + delayed rituximab groups. Based on additional data from a total of 160 evaluable patients, the estimated 5-year FFS rate was 70.4 % for the R-FND group and 44.2 % for the FND + delayed rituximab group (p = 0.009) [60]. A comparison of these results to other treatment options is presented in Liu et al. [74].

5.2.2.2 Safety 5.2.2.2.1 Rituximab Combined with CHOP In the GLSG Study, adverse events in the R-CHOP group and the CHOP group were comparable with the exception of an increased incidence of severe granulocytopenia observed in the R-CHOP group. Grade 3 or 4 granulocytopenia occurred after 63 % and 53 % of the treatment cycles in the R-CHOP and CHOP groups, respectively. The incidence of severe infections after treatment cycles was similar between groups (5 % R-CHOP versus 7 % CHOP). The majority of nonhematologic adverse events were of mild to moderate severity and the most frequent included alopecia, nausea, and vomiting. The incidence of rituximab-infusion related adverse events was 7 % for the first infusion [52].

5.2.2.2.2 Rituximab Combined with MCP Safety data for Study M39023 were not updated in the 2004 publication by Herold et al. However, in an earlier report [49], an interim analysis of 106 evaluable patients after 414 treatment cycles in the R-MCP group and 347 treatment cycles in the MCP group (7.5 versus 6.8 per patient) demonstrated a tendency for more adverse events in the R-MCP group than the MCP group (375 versus 266). Myelotoxicity accounted for the main Grade 4 toxicity in each treatment group, with Grade 3 leukopenia being more common in the R-MCP group than in the MCP group (13 % versus 6 % of cycles). There was no increase


in the frequency of infections or reductions in chemotherapy dose in the R-MCP group versus the MCP group.

5.2.2.2.3 Rituximab Combined with CVP In Study M39021 [82], the proportion of patients who reported at least one adverse event was comparable between groups (R-CVP, 97 %; CVP, 95 %). The majority of AEs in both groups were mild to moderate in intensity. More adverse events occurred within 24 hours of study treatment in the R-CVP group (71 %) compared with the CVP group (51 %). Fourteen patients (9 %) had a Grade 3 or 4 rituximab infusion-related reaction, and 2 of these patients were withdrawn from study treatment. Grade 3 or 4 neutropenia was reported at a higher incidence in patients in the R-CVP group (24 %) compared with the CVP group (14 %). There was no difference between groups in the overall infection rate or incidence of neutropenic sepsis. No treatment-related deaths occurred, but 5 patients in the R-CVP group experienced life-threatening events.

5.2.2.2.4 Rituximab Combined with CHVP/IFN Only hematologic toxicity data are available for Study FL-2000. Grade 3 or 4 neutropenia was reported in 51 % of patients in the R-CHVP/IFN group and 59 % of patients in the CHVP/IFN group. Grade 3 or 4 thrombocytopenia was reported in 2 % of patients in each group, and Grade 3 or 4 anemia was reported in approximately 5 % of patients in each group. Grade 3 or 4 infection occurred in 2 % of patients receiving R-CHVP/IFN and none of the patients receiving CHVP/IFN (data on file at Genentech).

5.2.2.2.5 Rituximab Combined with FND Based on the preliminary report for Study U0794n [85], the incidence of neutropenia was slightly higher in the R-FND (concurrent administration) group compared with the FND + delayed rituximab group, but the incidence of infections was comparable between the two groups. A total of 19 % of patients did not complete all eight courses of FND.

5.2.3 Maintenance Rituximab in Patients with Indolent NHL Studies of rituximab as maintenance therapy have been conducted in patients with indolent NHL after induction therapy with rituximab, chemotherapy, or rituximab plus chemotherapy. Presented below are data from two studies of maintenance rituximab after rituximab monotherapy, one study of maintenance rituximab after chemotherapy, and two studies of maintenance rituximab after either chemotherapy alone or rituximab plus chemotherapy. Rituximab was administered at a dose of 375 mg/m2 in all five studies.

5.2.3.1 Efficacy 5.2.3.1.1 Maintenance Rituximab after Induction with Rituximab

Monotherapy Study U0824n [47] investigated rituximab as induction and maintenance therapy in 62 patients with Stage II–IV indolent NHL (38 with follicular NHL and 24 with small lymphocytic lymphoma [SLL]). Sixty patients were previously untreated and 2 patients had relapsed after initial radiation therapy. Sixty patients completed the induction course (rituximab once weekly for 4 weeks) and were evaluable for response. Patients with an objective response or stable disease 2 weeks after completing induction rituximab were eligible to receive additional maintenance courses (rituximab once weekly for 4 weeks),


administered every 6 months for up to four courses. Forty-six patients received at least one course of maintenance rituximab. Response to treatment is summarized in Table 4. With a median follow-up of 30 months, the estimated median duration of PFS was 34 months. PFS rates at 1 and 2 years were 69 % and 64 %, respectively. The estimated PFS rate at 3 years was 49 %. With a median follow-up of 55 months, the median duration of PFS was 37 months for all patients and 52 months for those with follicular lymphoma.

Table 4 Efficacy Results for Study U0824n: Maintenance Rituximab in Patients with Indolent NHL

Response: No. ( %) of Patients

Endpoint n * Complete Partial Overall Stable Disease Progression

Induction response † (at 6 weeks)

60 4 (7 %) 24 (40 %) 28 (47 %) 27 (45 %) 5 (8 %)

Best response ‡ 60 22 (37 %) 22 (37 %) 44 (73 %) 11 (18 %) 5 (8 %) *Number of evaluable patients. †After completion of the full course of induction rituximab therapy. ‡After completion of induction rituximab and at least one course of maintenance rituximab therapy.

In a multicenter, randomized study (SAKK 35/98), Ghielmini et al. [39] enrolled a total of 202 patients with previously untreated or previously treated follicular NHL. During the induction phase, patients received standard rituximab therapy (once weekly for 4 weeks). A total of 185 patients were evaluable for response during induction, and 151 patients with a response or stable disease were then randomized to receive either maintenance rituximab (single infusions at Months 3, 5, 7, and 9) or no treatment. For the induction phase, the ORR was 67 % (9 % CR rate) among previously untreated patients and 46 % (8 % CR rate) among previously treated patients. Event-free survival by maintenance treatment is presented in Table 5. At a median follow-up of 36 months, the median duration of EFS was 23.2 months among patients who received maintenance rituximab and 11.8 months among patients who received no further treatment (p = 0.024); this effect was particularly notable in previously untreated patients and in patients who responded to induction rituximab.


Table 5 Median Event-Free Survival for the SAKK 35/98 Study: Maintenance Rituximab in Patients with Indolent NHL

Population Maintenance

Group Median EFS*

(Months) P-Value

Rituximab maintenance 23.2 All randomized patients (n = 151)

Observation 11.8 0.024

Rituximab maintenance 36 Previously untreated patients (n= 51)

Observation 19 0.009

Rituximab maintenance 36 Patients who responded to induction

rituximab therapy at Week 12 (n = 96)

Observation 16 0.004

*At a median follow-up of 36 months.

5.2.3.1.2 Maintenance Rituximab after Induction with Chemotherapy In the Phase III ECOG Study E1496 [53, 54], 516 previously untreated patients with Stage III or IV, indolent NHL, classified as Subtype A (small lymphocytic), B (follicular small cleaved), or C (follicular mixed) according to the International Working Formulation (IWF) lymphoma classification were enrolled. Patients were randomized to receive six to eight cycles of CVP or FC chemotherapy. FC induction chemotherapy was discontinued because of toxicity. Among CVP-treated patients with a response or stable disease, 322 underwent a second randomization to either rituximab maintenance therapy (once weekly for 4 weeks, administered every 6 months for four courses) or observation. The study was terminated early, as the O’Brien–Fleming boundary for PFS was crossed with 303 evaluable patients (one-sided p = 0.00008). Among the 303 evaluable patients, disease progression or death was reported for 31 of the 154 patients randomized to maintenance rituximab and 56 of the 149 patients randomized to observation. Among patients treated with induction CVP, median duration of PFS was 4.2 years for those in the maintenance rituximab arm and 1.5 years for those in the observation arm. Estimated PFS rates for the rituximab and observation groups were 74 % and 42 %, respectively, at 2 years (∼2.5 years after study entry) and 58 % and 34 %, respectively, at 4 years (∼4.5 years after study entry) [54]. Among the 237 patients with follicular lymphoma, the estimated PFS at 4 years (∼4.5 years after study entry) was significantly prolonged (p = 0.0000003) in patients who received rituximab maintenance (56 %) versus observation (33 %) [53]. PFS was significantly prolonged with rituximab versus observation regardless of histology (p < 0.02), residual disease (p < 0.008), or high tumor burden (p = 0.00005). With 17 deaths (6 %) and a median follow-up of 1.2 years among survivors, the estimated 2-year survival rate after maintenance randomization was 95 % and 91 % for the rituximab and observation groups, respectively [54]. Among the patients with follicular lymphoma, the estimated 4-year survival rate was 88 % and 72 % for the rituximab maintenance and observation groups, respectively (p = 0.03) [53].


5.2.3.1.3 Maintenance Rituximab after Induction with Chemotherapy Alone or Rituximab plus Chemotherapy

In a study by the GLSG [34], 195 patients with previously treated follicular, mantle cell, or lymphoplasmacytic/ lymphoplasmacytoid lymphoma were randomized to receive four 28-day cycles of FCM (fludarabine, cyclophosphamide, and mitoxantrone) chemotherapy, alone or in combination with rituximab. Patients who achieved a response to induction (R-FCM or FCM) were subsequently randomized to receive no further treatment or two additional courses of rituximab therapy (once weekly for 4 weeks), at 3 and 9 months after completion of induction therapy. Table 6 presents the response rates after induction for the first 65 evaluable patients with follicular NHL that was reported by Forstpointner in 2004 [34], updated response rates have not been published. Improved outcomes had been observed in the initial 147 patients, thus the remaining 48 patients received R-FCM. Among those with follicular lymphoma, the median duration of PFS was not reached at 3 years for the R-FCM group but was estimated to be 21 months for the FCM group [34]. Among the 138 evaluable patients who had received R-FCM in the induction phase of the study, an improvement in the median PFS was observed in those randomized to rituximab maintenance treatment compared with those randomized to the observation (p = 0.035) [27]. The overall 3-year survival rate was improved in the rituximab maintenance group (82 %) compared with that observed in the observation group (55 %, p = 0.056). Study results for patients with MCL are presented in section 5.6.2

In Study M39022 by the European Organization for Research and Treatment of Cancer, 465 patients with relapsed or refractory follicular NHL were randomized to receive six 21-day cycles of CHOP chemotherapy, alone or in combination with rituximab [75]. Those with a CR or PR underwent a second randomization to receive either no further treatment or maintenance rituximab (once every 3 months until relapse or for a maximum of 2 years). A total of 334 patients who achieved a CR or PR following induction therapy were randomized to rituximab maintenance treatment (n = 167) or observation (n = 167). For the induction phase, there was a significantly higher ORR and CR rate in the R-CHOP group compared with that observed in the CHOP group (p = 0.0003 and p = 0.0005, respectively), with similar PR rates in both groups (Table 6). For the maintenance phase, after a median observation time of 28 months, the estimated median PFS (42.2 months) in the maintenance rituximab group was significantly prolonged compared with that observed in the observation group (14.3 months, p < 0.0001). The risk of experiencing progressive disease or death was reduced by 61 % in the rituximab maintenance group compared with that observed in the observation group (95 % confidence interval [CI]; 45 %-72 %). Kaplan-Meier estimated PFS rates at 12 months were 78 % in the rituximab maintenance group versus 57 % in the observation group. An analysis of overall survival confirmed the significant benefit of rituximab maintenance treatment over observation (p = 0.0039 log-rank test). Rituximab maintenance treatment reduced the risk of death by 56 % (95 % CI; 22 %-75 %). The benefit of rituximab maintenance treatment was confirmed in all subgroups analyzed, regardless of the induction treatment regimen or the quality of response to the induction treatment (PR or CR) [75].


Table 6 Response Rates for the Induction Phase of the GLSG and EORTC Rituximab Maintenance Studies


Treatment Group n * Complete Partial Overall

Forstpointner et al. 2004 (GLSG Study) †

R-FCM FCM

35 30

40 % 23 %

54 % 47 %

94 % 70 %

Mabthera Summary of Product Characteristics, 2006 (EORTC Study M39022)

R-CHOP CHOP

167 167

29 % 16 %

58 % 58 %

87 % 74 %

*Number of evaluable patients. †Study included patients with MCL, but only results from patients with follicular lymphoma are presented.

5.2.3.2 Safety 5.2.3.2.1 Maintenance Rituximab after Induction with Rituximab

Monotherapy In Study U0824n [47], 2 patients experienced Grade 3 or 4 events during the first course of rituximab treatment (induction): 1 patient had chills/rigors, and 1 patient had flushing, dyspnea, and chest pain, which led to study discontinuation. Toxicity observed with maintenance rituximab was less common than with induction rituximab, with no additional Grade 3 or 4 events observed.

In the SAKK 35/98 study [39], all 202 patients were evaluable for toxicity. During the induction phase, 19 patients (9.5 %) experienced non-hematologic Grade 3 or 4 adverse events. Grade 3 or 4 hematologic toxicity occurred in 37 patients (18.3 %), with the most frequently reported event being neutropenia, which occurred in 9.4 % of patients. Two patients experienced life-threatening adverse events (fatal cardiac event and acute myeloblastic leukemia), and 2 patients experienced severe infusion-related symptoms resulting in permanent discontinuation from treatment. During the maintenance phase, four serious adverse events (two malignancies, one infection, and one neuropathy) were reported in the observation group and eight serious adverse events (two malignancies, two infections, two surgical complications, one pneumopathy, and one agranulocytosis) were reported in the maintenance rituximab group. Grade 3 or 4 hematologic toxicities were comparable between both arms, as was late toxicity beyond 1 year. Lymphocyte subset analysis demonstrated that T-helper, T-suppressor, and NK cells remained relatively stable, while B cells declined rapidly during the induction phase of the study. At 1 year, levels returned to above baseline in the observation arm, but remained depressed in the maintenance rituximab arm, although both arms appeared to recover upon further follow-up. The decrease in B-cell levels at 1 year in the maintenance rituximab arm was accompanied by a reduction in IgM levels to 72 % of baseline.

5.2.3.2.2 Maintenance Rituximab after Induction with Chemotherapy For Study E1496, events that occurred in the rituximab maintenance arm were consistent with the known toxicity profile for rituximab, and most were mild or moderate in severity. Adverse events that occurred at a ≥5 % higher frequency among patients who received maintenance rituximab (e.g., leukopenia, anemia, granulocytopenia, diarrhea, nausea, fatigue, asthenia, infections, lung disorders, and nervous system events) are


consistent with the known toxicity profile for rituximab, and most were mild or moderate in severity. Granulocytopenia and cardiac disorders are the only Grade 3 or 4 events that occurred at an increased frequency of at least 2 % among patients in the maintenance rituximab group compared with those in the observation group. Adverse events leading to death occurred in one patient who had been randomized to the observation group [13, 14].

5.2.3.2.3 Maintenance Rituximab after Induction with Chemotherapy Alone or Rituximab plus Chemotherapy

The GLSG study [34] did not differentiate safety results between mantle cell and follicular lymphoma. Grade 3 or 4 granulocytopenia occurred after 40 % of all cycles with a comparable frequency in both the R-FCM and FCM groups. Lymphocytopenia was more frequent in the R-FCM group compared with the FCM group (51.2 % versus 39.4 % of patients; p = .006). The difference was not correlated with an increase in infectious complications. World Health Organization Grade 3 or 4 infections occurred in only 1.5 % of all cycles, and there was no difference in frequency between the two treatment groups. Non-hematologic adverse events consisted mainly of mild to moderate nausea and vomiting, which occurred at similar frequencies in the two groups. Adverse events related to rituximab were seen mainly after the first infusion. In 4 patients, rituximab therapy had to be discontinued because of severe allergic reactions.

In Study M39022, adverse events observed during the induction phase were similar for the R-CHOP and CHOP groups. A total of 332 patients (166 rituximab maintenance, 166 observation) were included in the safety evaluation of the maintenance phase of the study. During the maintenance phase of the study, leukopenia occurred in 21 % of patients in the observation group versus 29 % of patients in the rituximab maintenance group. Neutropenia was reported in 12 % and 23 % of patients in the observation group and rituximab maintenance group, respectively. There was a higher incidence of Grade 3 or 4 neutropenia (observation 4 %, rituximab 10 %) and leukopenia (observation 2 %, rituximab 5 %) in the rituximab maintenance group compared with the observation group. The incidence of Grade 3 or 4 thrombocytopenia (observation 1 %, rituximab <1 %) was low in both groups. Grade 3 or 4 infections occurred in 3 % and 11 % of patients in the observation group and rituximab maintenance group, respectively. Grade 3 or 4 infections reported in ≥1 % of patients in the rituximab maintenance group included pneumonia (2 %), respiratory tract infection (2 %), febrile infection (1 %), and herpes zoster (1 %) [75].

5.2.4 Rituximab Consolidation in Patients with Indolent NHL Rituximab has been studied as consolidation following induction treatment with chemotherapy alone. Results from two representative trials are described below.

5.2.4.1 Efficacy In Study ML17162 by Zinzani et al. [132], previously untreated patients were randomized to receive six 21-day cycles of either FM (fludarabine and mitoxantrone) chemotherapy or CHOP chemotherapy. Six weeks after completing chemotherapy, patients from both arms who experienced a CR but remained bcl-2/IgH positive by polymerase chain reaction and patients who experienced a PR were assigned to receive rituximab once weekly for 4 weeks. Patients who achieved a CR and bcl-2/IgH negativity


underwent observation. Patients without a response to induction treatment discontinued the study. Of the 151 patients enrolled, 140 were included in the analysis. Of those 140 patients, 95 (41 from the FM arm and 54 from the CHOP arm) received sequential immunotherapy with rituximab for 4 weeks. The ORR was similar in the FM arm (96 %) and CHOP arm (98 %); however, the CR rate was higher in the FM arm (68 %) than the CHOP arm (42 %). In the overall study population (n = 140), immunotherapy led to significant improvement in both CR rate (57 % after chemotherapy versus 86 % after rituximab) and combined CR and bcl-2/IgH negativity response rate (29 % after chemotherapy versus 61 % after rituximab).

In the SWOG 9800 study by Maloney et al. [79], 84 patients were treated with six 21-day cycles of CHOP chemotherapy followed by rituximab consolidation (once weekly for 4 weeks). The ORR after CHOP was 72 %. Improvement in response following rituximab consolidation occurred in 16 patients (19 %), with 14 patients improving from PR to CR, 1 patient improving from stable disease to CR, and 1 patient improving from CRu to CR. The 2-year PFS rate was 76 %, and the 2-year overall survival rate was 95 %.

5.2.4.2 Safety In Study ML17162 by Zinzani et al. [132], most adverse events related to rituximab were moderate. Grade 1 or 2 infusion reactions were observed during the first rituximab infusion in 28 of 95 patients (29 %); subsequent infusions were well tolerated.

In the SWOG 9800 study [79], toxicity was evaluated in 73 patients following rituximab consolidation therapy. Grade 4 neutropenia was observed in 1 patient. Twelve patients were noted to have Grade 3 toxicities.

5.2.5 Rituximab Monotherapy in Patients with Previously Treated Indolent NHL

The initial rituximab approval was based on the efficacy of rituximab monotherapy in the treatment of patients with relapsed or refractory indolent NHL. Rituximab monotherapy has been investigated in this setting in multiple studies, most of them at a dose of 375 mg/m2, given once weekly for 4 weeks. This section summarizes efficacy and safety data from the pivotal study (102-05), an extended dosing study in which patients received rituximab for 8 rather than 4 weeks (Study 102-06), a study in patients with bulky disease (Study 102-08B), pooled efficacy data from patients with bulky disease enrolled in multiple studies, and data from a study of rituximab administration in patients with gastric marginal zone NHL.

5.2.5.1 Efficacy Table 7 summarizes efficacy data for the three above-mentioned studies of rituximab monotherapy in patients with previously treated indolent NHL.


Table 7 Efficacy Results for Studies of Rituximab Monotherapy in Patients with Previously Treated Indolent NHL

Response: No. ( %) of

Patients Median Duration † (Months)

Reference (Study)

Rituximab Dosing

Regimen n CR PR ORR Follow-Up

Period Response TTP McLaughlin et al. 1998 (Study 102-05)

Once weekly for 4 weeks

166 * 10 (6 %)

70 (42 %)

80 (48 %) 11.8 Not reported 13

Piro et al. 1999 (Study 102-06)


37 * 5 (14 %)

16 (43 %)

21 (57 %) 19.4 Not reported

Not reached

Davis et al. 1999 (Study 102-08B)


31 * 1 (3 %) 11 (35 %)

12 (39 %) Not reported 5.9 8.1

Martinelli et al. 2005


26‡ 12 (46 %)

8 (31 %)

20 (77 %) 28 Not reported Not reached

Note: CR = complete response,, ORR = overall response rate, PR = partial response *Number included in the intent-to-treat analysis. †For responders. ‡Evaluable patients.

5.2.5.1.1 Rituximab Monotherapy, Weekly for 4 Weeks In Study 102-05, the pivotal trial by McLaughlin et al. [84], 166 patients with relapsed or chemoresistant, indolent, B-cell NHL received rituximab once weekly for 4 weeks. The ORR in the intent-to-treat population was 48 %, with a 6 % CR rate and a 42 % PR rate. The projected median TTP for responding patients was 13.0 months. At a median follow-up of 11.8 months, the median TTP for responders was 13 months. In a subgroup analysis, the ORR was higher in patients with IWF B, C, and D (follicular) histologic subtypes as compared with the IWF A (SLL) subtype (60 % versus 13 %). The ORR was 78 % in patients previously treated with autologous bone marrow transplantation (ABMT) versus 43 % in patients with no ABMT. Neither age, sex, β2 microglobulin level, LDH level, nor presence of bulky disease had a statistically significant effect on response to rituximab.

5.2.5.1.2 Rituximab Monotherapy, Weekly for 8 Weeks In Study 102-06, a multicenter, single-arm study by Piro et al. [92], 37 patients with relapsed or chemoresistant, indolent, B–cell NHL received rituximab once weekly for 8 weeks. The ORR in the intent-to-treat population was 57 %, with a CR rate of 14 % and a PR rate of 43 %. At a median of 19.4 months of observation, the median TTP for the 21 responding patients had not been reached.

5.2.5.1.3 Rituximab Monotherapy, Weekly for 4 Weeks, in Bulky Disease Davis et al. [23] reported results from a Phase II study (102-08B) in which 31 patients with relapsed or refractory, bulky (> 10 cm in diameter), low-grade or follicular NHL


received rituximab once weekly for 4 weeks. For the intent-to-treat analysis, the ORR was 39 %, with a CR rate of 3 % and a PR rate of 35 %. The median time to response was 50 days. Among the 12 responding patients, the median duration of response was 5.9 months and the median TTP was 8.1 months.

In pooled data from multiple studies of rituximab given once weekly for 4 weeks to 39 patients with bulky, low-grade or follicular NHL, the ORR was 36 %, with a CR rate of 3 %, PR rate of 33 %, and a median TTP for responding patients of 9.6 months [1, 75].

5.2.5.1.4 Rituximab Monotherapy, Weekly for 4 Weeks, in Gastric Marginal Zone NHL

In a Phase II study, rituximab (375 mg/m2 once weekly for 4 weeks) was administered to 27 patients with gastric marginal zone NHL that was resistant to or not eligible for anti-Helicobacter pylori therapy [83]. Among the 26 evaluable patients, the ORR was 77 %, with a CR rate of 46 % and a PR rate of 31 %. After a median follow-up of 28 months, 14 patients (54 %) were free of disease and all were alive. After a median follow-up of 33 months, two patients had relapsed. No correlation between the presence of the 18q21 translocation and response to treatment was observed.

5.2.5.2 Safety 5.2.5.2.1 Rituximab Monotherapy, Weekly for 4 Weeks In Study 102-05 [84], adverse events generally occurred during therapy or within the first 30 days following therapy. The majority were Grade 1 or 2 infusion-related events that were observed with the first infusion. There were 18 Grade 3 adverse events and 2 Grade 4 events (arrhythmia and neutropenia).

5.2.5.2.2 Rituximab Monotherapy, Weekly for 8 Weeks In Study 102-06 [92], the most common events were during the treatment period and were infusion related. Twenty-four treatment-related Grade 3 events occurred in 10 patients, 2 of whom withdrew from the study as a result. One Grade 3 hypotensive event was reported during the first infusion, and the patient recovered. One patient was hospitalized because of Grade 3 infection.

5.2.5.2.3 Rituximab Monotherapy, Weekly for 4 Weeks, in Bulky Disease In Study 102-08B [23], 93 % of adverse events were Grade 1 or 2. Four patients had treatment-related Grade 3 or 4 non-hematologic events, consisting of pulmonary disorders in 2 patients, chills in 1 patient, and infusion-related hypotension and pain in 1 patient. Events resolved in 75 % of patients. Seven patients had transient Grade 3 or 4 levels of one or more hematologic parameters. No patients developed a HACA response. Mean serum immunoglobulin levels did not decrease to less than the normal range.

5.2.5.2.4 Rituximab Monotherapy, Weekly for 4 Weeks, in Gastric Marginal Zone NHL

Among the 27 intent-to-treat patients with gastric marginal zone NHL who received rituximab, the most frequent Grade 3 or 4 hematologic toxicity was lymphopenia, observed in 4 patients (15 %). The most frequent nonhematologic toxicities were Grade 1 or 2 infusion-related symptoms associated with the first infusion. One patient experienced


severe infusion-related events that resolved following a reduction in the infusion rate [83].

5.2.6 Retreatment with Rituximab in Patients with Indolent NHL Retreatment with rituximab monotherapy has been evaluated in patients with indolent NHL who had relapsed after achieving a response with rituximab. One representative Phase II trial is described below.

5.2.6.1 Efficacy In Study 102-08R [22], 58 patients with relapsed or chemoresistant, indolent, B–cell NHL who had relapsed after achieving an objective clinical response to a prior course of rituximab were retreated with rituximab once weekly for 4 weeks. Two patients received two retreatment courses during the study (under a separate patient number for each course), for a total of 60 patient numbers (57 evaluable). The ORR was 40 %, with a CR rate of 11 % and a PR rate of 30 %. For responding patients, the estimated median TTP was 16.3 months, and the Kaplan-Meier estimated median duration of response was 17.8 months. This compared favorably with the median TTP and median duration of response achieved after the prior course of rituximab (9.8 and 12.4 months, respectively).

5.2.6.2 Safety The majority of the adverse events (92 %) in Study 102-08R [22] were Grade 1 or 2 and occurred during the first infusion. The incidence of adverse events with rituximab retreatment in Study 102-08R (n = 60) was similar to that with initial rituximab treatment in the pivotal study, 102-05 (n = 166) (any adverse event, 95.0 % versus 89.7 %; Grade 3 or 4 adverse events, 13.3 % versus 14.8 %). A total of 69 % of the Grade 3 and 4 adverse events were considered to be unrelated to treatment. None of the patients developed a HACA response, which was prospectively assessed in this study. Neutropenia occurred during the 1-year follow-up period in 2 patients.

5.2.7 Rituximab Combined with Chemotherapy or Other Immunotherapy in Patients with Previously Untreated or Previously Treated Indolent NHL

Presented below are the results from a representative study of rituximab combined with chemotherapy in a mixed population of patients with previously untreated or previously treated indolent NHL.

5.2.7.1 Efficacy In Study 102-03 [21], R-CHOP was administered to 38 patients with indolent NHL, 29 (76 %) of whom had not received prior antilymphoma therapy. Therapy consisted of six 21-day cycles of CHOP chemotherapy, beginning on Day 8, with rituximab administered on Days 1, 6, 48, 90, 134, and 141 [20]. The ORR was 100 %, with a CR rate of 58 %, PR rate of 42 %, median TTP for all patients of 82.3 months, and median duration of response of 83.5 months. Using the International Workshop Response Criteria, the ORR was 100 %, with a CR/CRu rate of 87 % and a PR rate of 13 %.

5.2.7.2 Safety Safety data from Study 102-03 were reported in an earlier publication [20]. Of the 40 patients enrolled, 38 patients received at least one dose of R-CHOP, and 35 patients


completed treatment. Grade 3 or 4 adverse events occurred in 30 patients. The most frequent Grade 3 or 4 events were neutropenia (n = 24), leukopenia (n = 10), and alopecia (n = 7). All infusion-related events attributed to rituximab (occurring in 19 % of patients) were Grade 1 or 2 in severity. A total of 75 % of adverse events were attributed to CHOP chemotherapy. No HACA response was detected.

5.3 Treatment of Diffuse, Large B-Cell NHL All studies summarized in this section included patients with diffuse, large B-cell NHL. Some studies included patients with other histologies as well; histologies are summarized if the data was available. Table A-2 of appendix A ( ~xr6i ) includes an overview of the study results described within this section. Unless otherwise specified, patients received the standard approved rituximab dose of 375 mg/m2.


Studies of rituximab combined with chemotherapy have been conducted in patients with previously untreated diffuse, large B-cell NHL. Efficacy and safety results are presented below for three Phase III, randomized trials (GELA Study LNH98-5, ECOG Study E4494, and Study M39045 [MInT]) of CHOP or a CHOP-like chemotherapy regimen (ranging from six to eight cycles) administered alone or in combination with rituximab (ranging from four to eight doses). Results are also presented for two Phase II trials of chemotherapy administered with rituximab for six cycles: Study 102-10/U0715s and a study reported by Wilson et al. [126] (in which 14 of 34 patients were previously treated). In addition, safety results are presented for Study U2035g, a Phase III, randomized study of CHOP versus R-CHOP that was terminated prematurely because of the positive results obtained in the interim analysis of Study LNH98-5 and slow accrual. Also, efficacy results are presented from the RICOVER-60 Study that was terminated prematurely due to the positive efficacy results observed in an interim analysis. Efficacy results from a retrospective analysis of R-CHOP versus CHOP are included as well.

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5.3.1.1 Efficacy Table 8 summarizes response rates for studies of rituximab combined with chemotherapy in patients with previously untreated diffuse, large B-cell NHL.

Table 8 Response Rates for Studies of Rituximab Therapy in Patients with Previously Untreated Diffuse, Large B-Cell NHL


Treatment Group n * OS rate Complete Partial Overall

Coiffier et al. 2002 ; Feugier et al. 2005 (GELA Study LNH98-5)

R-CHOP CHOP DLBCL: all pts

202 197

58 % †

45 % † 75 % ‡

63 % ‡ 7 % 6 %

82 % §

69 % §

Habermann et al. 2006 (Study E4494)

R-CHOP CHOP DLBCL: all pts

267 270

67 % ¥

58 % ¥ NR NR 77 %

76 %

Pfreundschuh et al. 2006 (Study M39045 [MInT])

R-CHEMO CHEMO DLBCL: all pts

355 350

93 % Þ

84 % Þ 86 % 68 %

NR NR

Vose et al. 2002 (Study 102-10/U0715s)

R-CHOP DLBCL: 67 % of pts

33 87 %£ 61 % 36 % 97 %

Wilson et al. 2002 R-EPOCH Previously untreated Previously treated

34 20∆

14**

79 %††

NR

76 % 85 %

64 %

9 % 0 %

21 %

85 % 85 %

85 %

CHEMO = CHOP-like chemotherapy regimen; EPOCH = etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin; NR = not reported; OS = overall survival. *Number of evaluable patients. †Overall survival at 5 years. ‡Includes CR and CRu. §Best response after Cycle 4 or 8. ¥Overall survival at 3 years, based on an inverse probability weighted analysis to remove effect of maintenance rituximab treatment. ÞOverall survival at 3 years. £Overall survival at ≥ 60 months. ∆All patients had large B-cell lymphoma. **Histologies included large B-cell as well as other poor-prognosis lymphomas. ††Overall survival at 1 year.

5.3.1.1.1 Rituximab Combined with CHOP or a CHOP-Like Regimen In Study LNH98-5, conducted by GELA, 399 elderly patients (≥ 60 years) with previously untreated diffuse, large B-cell lymphoma received eight 21-day cycles of CHOP chemotherapy, alone or in combination with rituximab. The addition of rituximab did not require reductions in the dose intensity of CHOP components. CR rate was statistically significantly higher with R-CHOP versus CHOP treatment (75 % versus 63 %; p = 0.005) [17]. After a median observation time of 5 years, R-CHOP led to a highly statistically significant increase in median duration of EFS compared with CHOP


(3.8 versus 1.1 years; p = 0.00002), with ”event” defined as death, relapse or progression of lymphoma, or institution of new anti-lymphoma treatment. At a median follow-up of 5 years, the median duration of PFS was not reached in the R-CHOP group and was estimated to be 1 year in the CHOP group (p < 0.00001), and the median duration of overall survival was not reached in the R-CHOP group and was estimated to be 3.1 years in the CHOP group (p = 0.0073) [32].

In Study E4494 [45], 632 elderly patients (≥ 60 years) with previously untreated diffuse, large B-cell lymphoma received six or eight 21-day cycles of CHOP, alone or in combination with four or five doses of rituximab. Patients who achieved either a CR or PR after induction treatment with either R-CHOP or CHOP underwent a second randomization to receive maintenance rituximab (once weekly for 4 weeks, repeated every 6 months for four cycles [2 years total]) or no further treatment. A total of 632 patients were randomly assigned to induction and 415 were randomly assigned to maintenance. A total of 546 patients (267 R-CHOP and 270 CHOP) were evaluable for the analysis of induction treatment, and 352 (174 rituximab maintenance and 178 observation) were evaluable for the analysis of maintenance treatment. The ORR before the second randomization to maintenance or observation was 77 % with R-CHOP and 76 % with CHOP. With a median follow-up of 3.5 years, the TTF favored R-CHOP over CHOP as induction treatment, but there was no difference in overall survival; the 3-year PFS rate was 53 % and 46 % in the R-CHOP and CHOP groups, respectively (p = 0.04). Analysis of rituximab maintenance treatment demonstrated that the 2-year PFS rate was 76 % in the rituximab maintenance group versus 61 % in the observation group (p =0.009). Because of the potential confounding effects of maintenance rituximab on the induction comparison, an inverse probability weighted statistical analysis was performed to compare induction regimens in the absence of maintenance rituximab. The results of this analysis of induction regimens (R-CHOP versus CHOP) showed that, in the absence of maintenance rituximab, the risk of progression, relapse, or death was reduced by approximately 36 % among patients in the R-CHOP arm compared with those in the CHOP arm (hazard ratio, 0.64; p = 0.003). In addition, the estimated 3-year overall survival rate was 67 % for patients who received R-CHOP and 58 % for patients who received CHOP alone (hazard ratio, 0.72; p = 0.05). Analysis of results after the second randomization demonstrated that for patients randomized to R-CHOP, additional rituximab exposure beyond induction was not associated with further improvements in PFS or overall survival [45].

In the RICOVER-60 Study, elderly patients (61-80 years, stages I-IV) with previously untreated CD20+ diffuse, large B-cell NHL were randomized to receive 6 or 8 cycles of CHOP-14 with or without rituximab. Radiotherapy was administered to sites of initial bulk and/or extranodal involvement. A planned interim analysis was performed on 828 evaluable patients (median age 68 years). The freedom from treatment failure after R-CHOP-14 (n =414) was significantly improved compared with that observed after CHOP-14 (n=413) alone (p=0.000025). The statistical significance of this finding met the formal efficacy criterion for stopping the trial; thus, the study was stopped on 17 June 2005 [90].


In the MInT study (M39045), 824 younger patients (18–60 years) with previously untreated low-risk, diffuse, large B-cell NHL were randomized to receive six cycles of CHOP or a CHOP-like chemotherapy regimen (CHEMO), alone or in combination with rituximab [91]. For patients with extranodal involvement or bulky disease, it was determined at baseline whether treatment should include radiotherapy. The formal criteria for stopping the study were met at the first interim analysis, which was performed on 326 evaluable patients. At a median follow-up of 34 months, for the intent-to-treat population analysis, the estimated 3-year EFS rate was significantly increased in the R-CHEMO group (79 %) compared with the CHEMO group (59 %, log-rank p < 0.0001). Among evaluable patients (n = 715), the CR rate was significantly higher for the R-CHEMO group compared with the CHEMO group (86 % versus 68 %; p < 0.0001), as was the overall survival rate at 3 years (93 % versus 84 %; log-rank p = 0.001).

In Study 102-10/U0715s, a Phase II study, 33 patients with previously untreated aggressive NHL received up to six 21-day cycles of CHOP chemotherapy in combination with rituximab [121]. The ORR was 97 %, with 20 patients (61 %) achieving a CR. After a median follow-up of 62 months, 29 patients (88 %) were alive and 27 (81 %) were progression free. During the follow-up period, disease progression occurred for 2 of the 15 patients with an IPI score of < 2 (including one death) and 4 of the 18 patients with an IPI score of ≥ 2 (including three deaths) [122].

A retrospective analysis of 292 DLBCL patients in British Columbia was performed to investigate the efficacy outcomes of R-CHOP compared with CHOP over a 3-year period. The 3-year period spanned a period of 18 months before the British Columbia Cancer Agency recommended that rituximab be included in combination with CHOP as treatment for all newly diagnosed DLBCL patients to 18 months following that date. Patients were classified into “pre-rituximab” (median follow-up of 42 months) and “post-rituximab” (median follow-up of 24 months) groups, depending upon their date of treatment. The PFS (risk ratio of 0.56, p = 0.002) and the overall survival (risk ratio of 0.40, p < 0.0001) were significantly improved in patients from the post-rituximab era compared with patients from the pre-rituximab era. Improvements were observed regardless of age [104].

5.3.1.1.2 Rituximab Combined with EPOCH In a study by Wilson et al. [126], 23 previously untreated patients and 15 extensively pretreated patients with poor-prognosis lymphoma received 21-day cycles (mean, four cycles) of EPOCH (etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin) in combination with rituximab. A total of 30 % of patients had an ECOG performance status of ≥2, and 61 % had high-intermediate or high IPI scores. All 23 untreated patients had large B-cell lymphoma (de novo). Among the 15 pretreated patients, the histology findings were as follows: 7 large B-cell lymphoma (3 de novo, 4 transformed), 3 follicular center cell, 2 HIV-associated lymphoma, 1 mantle cell, 1 small lymphocytic, and 1 LP-Hodgkin’s disease. Thirty-four patients were evaluable for response: 20 previously untreated patients and 14 previously treated patients. The CR rate was 85 % among previously untreated patients and 64 % among previously treated patients. Among 7 patients who were resistant to their last chemotherapy regimen, 3 (42 %) achieved a CR. At a median follow-up of 12 months, the PFS and overall


survival rates among previously untreated patients were 85 % and 79 %, respectively, and no patient with a CR had relapsed.

5.3.1.2 Safety 5.3.1.2.1 Rituximab Combined with CHOP or a CHOP-Like Regimen The final results of Study LNH98-5 indicated that the toxicities of rituximab and CHOP are additive when administered together as R-CHOP, and few differences were identified between R-CHOP and CHOP except for the well-described infusion-related reactions characteristic of rituximab [17]. Grade 3 or 4 infection occurred in 12 % of R-CHOP-treated patients and 20 % of CHOP-treated patients. The incidence of cardiac events during treatment was higher in the R-CHOP group (47 %) than the CHOP group (35 %). This difference was the result of a higher incidence of Grade 1 events in the R-CHOP group (24 %) compared with the CHOP group (13 %). Grade 3 or 4 cardiac events occurred at the same frequency (8 %) in both groups. There were more reports of supraventricular arrhythmias and tachycardias in the R-CHOP group than the CHOP group. The incidence of herpes zoster was higher in the R-CHOP group (n = 9) than the CHOP group (n = 2). Grade 3 or 4 adverse events related to the infusion of rituximab were observed in 9 % of patients.

In Study E4494, the most common Grade 3 or 4 toxicities for the R-CHOP and CHOP induction arms were neutropenia (78 % in both), anemia (17 % versus 16 %, respectively), thrombocytopenia (14 % versus 10 %, respectively), and infection (17 % versus 16 %, respectively). Lethal toxicities reported in the R-CHOP and CHOP groups included infection (8 [3.0 %] versus 7 patients [2.5 %], respectively), cardiac events (1.9 % versus 1.8 %, respectively [5 patients in both]), and pulmonary events (0.4 % [1 patient] in both). An increased incidence of Grade 3 or 4 granulocytopenia was observed in patients in the rituximab maintenance group (12 %) compared with patients in the observation group (4 %) [45].

In the MInT study [91], no differences in toxicity were reported between the R-CHEMO and CHEMO groups. The most frequent adverse events included infection (7 % R-CHEMO, 8 % CHEMO) and leukocytopenia (7 % R-CHEMO, 6 % CHEMO).

In Study 102-10/U0715s (Clinical Study Report [CSR] U0715s) all R-CHOP–treated patients had adverse events, and 31 (94 %) had at least one Grade 3 or 4 event. The most frequently reported Grade 3 or 4 adverse events were neutropenia (73 % of patients), leukopenia (21 %), anemia (12 %), and nausea, pain, and asthenia (< 10 %). Grade 4 neutropenia or leukopenia was reported in 22 patients, and 18 patients required treatment with G-CSF. Rituximab infusion–related events were usually Grade 1 or 2, mostly consisting of fever (n = 10) and chills (n = 11). Serious adverse events were reported to be similar to those expected with CHOP chemotherapy alone. No treatment-related fatalities were reported, but two deaths occurred: one as a result of progressive disease 52 weeks after starting therapy, and one as a result of stroke 28 weeks after starting therapy. Hospitalization was required for 12 patients (36 %), most commonly for neutropenic fever.

Study U2035g, a Phase III, randomized study of R-CHOP versus CHOP, was closed after enrollment of 91 patients because of the positive results obtained in the interim analysis


of Study LNH98-5 and slow accrual. In that study, patients received six to eight 21-day cycles of CHOP, alone or in combination with rituximab. Four patients (R-CHOP, 1 patient; CHOP, 3 patients) were discontinued from the study prior to receiving any study treatment. Therefore, 87 patients received study treatment (R-CHOP, 44 patients; CHOP, 43 patients) and were considered to be evaluable for safety. At the time of closure, 77 % of the 87 evaluable patients had experienced at least one Grade 3 or 4 adverse event. As reported in the U2035g CSR, adverse events for which the incidence in the R-CHOP group was ≥ 4 % higher than that in the CHOP group were chest pain (R-CHOP, 3 patients; CHOP, 0 patients) and leukopenia (R-CHOP, 27 patients; CHOP, 24 patients). The incidence of Grade 3 or higher leukopenia, anemia, and thrombocytopenia was similar between the two treatment groups. Leukopenia was the most frequent hematologic adverse event (R-CHOP, 61 % of patients; CHOP, 56 %). One R-CHOP-treated patient experienced sepsis that resulted in death. Rituximab infusion-associated adverse events were reported as occurring in the first three cycles only. Two R-CHOP–treated patients (5 %) and 1 CHOP-treated patient (2 %) died; all three deaths occurred during the treatment phase or shortly after discontinuing treatment early in the study. Serious adverse events were reported in 12 R-CHOP–treated patients (27 %) and 18 CHOP-treated patients (42 %); the most common serious adverse event in each treatment group was leukopenia (R-CHOP, 14 %; CHOP, 21 %). None of the 5 R-CHOP–treated patients evaluated for HACA demonstrated a HACA response [15].

5.3.1.2.2 Rituximab Combined with EPOCH For the study reported by Wilson et al. [126], safety results are provided for the 23 previously untreated patients, who received a total of 93 cycles of R-EPOCH. Hospitalization because of fever and neutropenia was required for 20 % of cycles. Neutropenia was reported for 57 % of cycles, and thrombocytopenia (platelet count of <50,000/µL) was reported for 18 % of cycles. One infection-related death occurred secondary to disseminated aspergillosis. Grade 2–4 gastrointestinal toxicity was observed in 6 % of cycles.

5.3.2 Rituximab in Patients with Previously Treated Diffuse, Large B-Cell

Studies of rituximab given as monotherapy or in combination with chemotherapy have been conducted in patients with previously treated diffuse, large B-cell NHL. Results are presented below for two Phase II studies of rituximab monotherapy, a study reported by Tobinai et al. [112] (all patients previously treated) and Study SO15165 by Coiffier et al. [16] (83 % of patients previously treated). Results are also presented for a Phase II study of rituximab combined with EPOCH chemotherapy [59], in which all patients were previously treated. In addition, results of a study of rituximab combined with ifosfamide, carboplatin, and etoposide (ICE) are presented [66]. Results of another study of rituximab combined with EPOCH [126], which included previously untreated patients as well as previously treated patients, are presented in section 5.3.1.

5.3.2.1 Efficacy Table 9 presents the response rates for the studies by Tobinai et al. [112], Coiffier et al. [16], Jermann et al. [59], and Kewalramani et al. 2004 [66].


Table 9 Response Rates for Studies of Rituximab Therapy in Patients with Previously Treated Diffuse, Large B-Cell NHL

Response: No. ( %) of Patients Reference

(Study) Dosing Regimen/ Treatment Group n * CR PR ORR

Tobinai et al. 2004

Rituximab once weekly for 8 weeks

All patients: 57 †

DLBCL patients: 52 15

(26 %) 6 (11 %) 21

(37 %)

Coiffier et al. 1998 (Study SO15165)

Pooled analysis ‡ of two groups: low-dose rituximab (375 mg/m2 once weekly for 8 weeks) and high-dose rituximab (375 mg/m2 once weekly for 1 week followed by 500 mg/m2 once weekly for 7 weeks)

All patients: 52 §, ¥

DLBCL patients: 30

5 (10 %)

Not

reported

12

(23 %)

Not reported

17

(33 %)

11 (37 %)

Jermann et al. 2004

Four to six 21-day cycles of R-EPOCH

All patients: 50 Þ

DLBCL patients: 25 14

(28 %) 20

(40 %) 34

(68 %)

Kewalramani et al. 2004

Three cycles of R-ICE, at 2-week intervals (4 doses of 375 mg/m2 rituximab: 48 hrs before Day 1 of cycle 1 and Day 1 of each cycle)

Eligible patients: 36 DLBCL: All patients

19 (53 %)

9 (25 %) 28 (78 %)

Note: CR = complete response; DLBCL = diffuse, large B-cell lymphoma; ORR = overall response rate; PR = partial response. *Number of evaluable patients. †Five of the evaluable patients had MCL. ‡Analysis was pooled because the overall response rate was not statistically significantly different between the low-dose and high-dose rituximab groups (32 % versus 31 %). §A total of 83 % were previously treated. ¥Of the 52 evaluable patients, 30 had DLBCL, 12 had MCL, 1 had follicular lymphoma, and 9 had no histology specified. ÞOf the 50 enrolled patients, 25 had DLBCL, 18 had transformed B-cell lymphoma (14 follicular and 4 composite), and 7 had MCL; 3 of these patients (histology not specified) were not evaluable for response.

5.3.2.2 Safety 5.3.2.2.1 Rituximab Monotherapy, Weekly for 8 Weeks In a study by Tobinai et al. [112], 59 of 67 evaluable patients (88 %) developed non-hematologic toxicities, which were classified as Grade 1 or 2 for 58 of the 59 patients. Hematologic toxicities were reported for 29 patients (43 %), with 11 of 29 patients experiencing Grade 3 or 4 events. Three months after completion of rituximab treatment, 1 patient developed a Grade 3 upper respiratory infection with Grade 4 neutropenia. No HACA response was detected in the 40 patients tested at 3 months or the 25 patients tested at 6 months. Two patients died within 30 days after the last rituximab infusion. Both patients were withdrawn early from study treatment because of aggressive lymphoma progression and were given salvage chemotherapy. Fourteen and 15 days after initiating chemotherapy, both patients developed Grade 4 neutropenia and septic shock, leading to death.

In Study SO15165 [16], the majority of adverse events were Grade 1 or 2. Infections were observed in 39 % patients treated with low-dose rituximab (eight doses at


375 mg/m2) and 31 % of patients treated with high-dose rituximab (one dose at 375 mg/m2 dose followed by seven doses at 500 mg/m2). There were no Grade 3 or 4 infectious episodes. Two patients discontinued treatment because of a drug-related adverse event: 1 patient in the low-dose group who experienced anaphylactic shock after the first infusion and 1 patient in the high-dose group who developed rash, arthralgia, fever, and thrombocytopenia after the second infusion. Grade 3 neutropenia occurred in 1 patient in the high-dose group. Severe lymphocytopenia occurred in 61 % of patients in the low-dose group and 81 % of patients in the high-dose group. However, these results may have been confounded by the fact that lymphocytopenia was present in the majority of these patients at baseline. Serum immunoglobulin levels remained within normal limits throughout the study.

5.3.2.2.2 Rituximab Combined with EPOCH Fourteen of 50 patients (28 %) experienced infusion-related reactions that most commonly occurred during the first infusion. There were six deaths reported in the study by Jermann et al. (2004). Two of the deaths, one occurring after the first cycle of treatment and one after the fourth cycle, were sudden and considered possibly related to treatment. Of 181 cycles, febrile neutropenia requiring hospitalization occurred in 13 (7 %), Grade 3 or 4 anemia occurred in 15 (8 %), and Grade 3 or 4 thrombocytopenia occurred in 2 (4 %). One patient developed signs of secondary myelodysplastic syndrome after study entry, after three cycles of treatment.

5.3.2.2.3 Rituximab Combined with ICE Transient Grade 3 or 4 infusion-related reactions were observed in four of 36 patients (11 %) and occurred during the first infusion only. Thirty-four of 36 patients (94 %) completed all treatment cycles. Delays in treatment primarily resulted from Grade 3 or 4 neutropenia and/or thrombocytopenia. Delays in treatment were minimal with a range of time to complete treatment of 35 to 59 days. The most frequent Grade 3 or 4 nonhematologic adverse event was febrile neutropenia reported in 8 of 106 treatment cycles (7.5 %). No RICE-related adverse events prevented subsequent ASCT.

5.4 Treatment of HIV-Associated Aggressive NHL Table A-2 of appendix A ( ~xr7i ) provides an overview of selected studies of rituximab treatment in patients with HIV-associated aggressive NHL. Presented below are the results from three studies of rituximab combined with CHOP chemotherapy (followed by maintenance rituximab in one study), one study of rituximab combined with dose-adjusted EPOCH, and one study of rituximab combined with CDE (cyclophosphamide, doxorubicin, and etoposide) chemotherapy. Unless otherwise specified, patients received the standard approved rituximab dose of 375 mg/m2.

5.4.1.1 Efficacy In a Study AMC-010, a Phase III trial reported by Kaplan et al. [62], patients with HIV-associated aggressive NHL were randomized 2:1 to receive either CHOP chemotherapy in combination with rituximab followed by three monthly maintenance doses of rituximab (n = 99) or CHOP chemotherapy alone (n = 50). In the R-CHOP group, the median age was 43.5 years; 80 % of the patients had Stage III/IV disease; 81 % had diffuse, large B-cell NHL; and the median CD4+ lymphocyte count was 130/µL. In the CHOP group, the median age was 40 years; 78 % of the patients had Stage III/IV disease;

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78 % had diffuse, large B-cell NHL; and the median CD4+ lymphocyte count was 147/µL. Twenty-five percent and 22 % of patients had CD4+ counts of < 50/µL in the R-CHOP group and CHOP group, respectively. CR/CRu rates of 58 % and 47 % were reported with R-CHOP and CHOP, respectively (p = 0.147). No statistically significant differences in TTP (125 weeks for R-CHOP, 85 weeks for CHOP), PFS (45 weeks for R-CHOP, 38 weeks for CHOP), or overall survival (139 weeks for R-CHOP, 110 weeks for CHOP) were observed between the two groups. Absolute CD4+ lymphocyte count was significantly associated with CR rate and PFS.

In a Phase II study by Ribera et al. [97], 60 HIV-infected patients with newly diagnosed diffuse, large B-cell NHL were enrolled to receive six cycles of R-CHOP with highly active antiretroviral therapy (HAART). CNS prophylactic treatment with methorexate, cytarabine, and hydrocortisone was administered in each cycle. The administration of G-CSF was recommended as well. The median CD4+ count was 152/µL. After a median follow-up of 2 years, the 2-year survival probability was 63 %. Among the complete responders, the probability of maintaining that response and remaining alive at 2 years was 89 %. The combination of HAART with R-CHOP was feasible and effective. Six months following completion of treatment, virologic and immunologic responses were maintained in 81 % of patients and achieved in 64 %.

In a Phase II study by Boue et al. [4], 61 patients received six cycles of R-CHOP. Of the 61 patients, 72 % had DLBCL. The median CD4+ count was 171/µL, and all patients received G-CSF at the first cycle. For the 50 evaluable patients, the ORR was 88 %, with a CR/CRu rate of 80 % and a PR rate of 8 %. The median duration of overall survival was not reached at a median follow-up of 18 months.

In a Phase II study by Dunleavy et al. [28], 27 patients were enrolled to receive a minimum of three cycles of dose-adjusted R-EPOCH in combination with HAART. Patients were to receive G-CSF in each cycle as well as CNS prophylactive methotrexate. The median CD4+ count was 212/µL and 93 % of the patients had diffuse, large B-cell NHL. Among 24 evaluable patients, the CR/CRu rate was 88 %, the PR rate 4 %, and the ORR 92 %. At a median follow-up of 25 months, the PFS and overall survival were 77 % and 72 %, respectively. The results demonstrated a low probability of non-tumor related deaths among patients in remission. The OS was 92 % among patients with a CD4+ count >100 /µL versus 48 % in patients with a CD4+ count <100 /µL.

In a Phase II study by Spina et al. [108], 72 patients were treated with 28-day cycles of CDE in combination with rituximab. Patients were also treated concomitantly with HAART. The majority of patients (69 %) had advanced-stage disease, and the median CD4+ count was 161/µL. The ORR was 75 %, with a CR rate of 69 % and a PR rate of 6 %.

5.4.1.2 Safety In Study AMC-010 [62], the incidence of Grade 4 neutropenia was 61 % for the R-CHOP group versus 48 % for the CHOP group, the incidence of deaths due to infection was 14 % versus 2 % (p = 0.035), and the incidence of deaths due to progressive lymphoma was 14 % versus 29 %. Of note, 60 % of the patients with infection-related deaths had an absolute CD4+ count of < 50/µL at study initiation [62]; 83 % had an absolute neutrophil


count (ANC) of < 1000/µL at the time of the infection-associated death (Kaplan, 2003). No other study of R-CHOP in patients with HIV-associated aggressive NHL has reported similar toxicity in terms of infection-related deaths when rituximab was added to CHOP chemotherapy.

In the Phase II study by Ribera et al. [97], the most frequent Grade 3 or 4 events included infections (12 %), gastrointestinal disorders (9 %), and neurologic disorders (2 %).

Of the 60 patients evaluated for safety in the study by Boue et al. [4], 15 % had febrile neutropenia, 34 % had bacterial infections, and 3 % had opportunistic infections.

In the Phase II study by Dunleavy et al. [28], neutropenia, thrombocytopenia, and neutropenic fever were observed in associaton with 41 %, 26 %, and 33 % of the 81 cycles of R-EPOCH administered, respectively. No treatment-related deaths occurred.

In the study by Spina et al. [108], Grade 3 or 4 neutropenia was observed in 80 % of patients, and 25 % developed bacterial infections during neutropenia.

5.5 Treatment of Chronic Lymphocytic Leukemia A number of Phase II clinical studies have been completed in which rituximab was administered as monotherapy or in combination with chemotherapy to patients with CLL. However, no data are available from comparative or Phase III studies. Table A-3 of Appendix A ( ~xr8i ) provides an overview of selected studies of rituximab treatment in patients with CLL (or SLL), and the study results are described within this section. Unless otherwise specified, patients received the standard approved rituximab dose of 375 mg/m2.

5.5.1 Rituximab Monotherapy in Patients with Previously Untreated CLL

Study results are presented below for two key studies of rituximab monotherapy in patients with previously untreated CLL: a study of induction rituximab followed by maintenance rituximab for those who respond and an extended dosing study in which patients received rituximab for 8 rather than 4 weeks.

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5.5.1.1 Efficacy Table 10 summarizes response rates for two studies of rituximab monotherapy in patients with previously untreated CLL.

Table 10 Response Rates for Studies of Rituximab Monotherapy in Patients with Previously Untreated CLL

Response: % of Patients Reference Dosing Regimen n Complete Partial Overall

Hainsworth et al. 2003 (Study U2098n)

Rituximab once weekly for 4 weeks, plus three additional courses at 6-month intervals

43 * 28 †

4 % 9 %

47 % 49 %

51 % 58 %

Thomas et al. 2001 Rituximab once weekly for 8 weeks

21 19 % 67 % ‡ 90 % ‡

Note: Hainsworth study includes patients with small lymphocytic lymphoma. *All evaluable patients. †Evaluable patients receiving at least one additional course of maintenance rituximab. ‡Includes nodular partial response. In Study U2098n [46], 44 patients with previously untreated CLL or small lymphocytic lymphoma (SLL) were treated with rituximab once weekly for 4 weeks. For the 43 evaluable patients, the ORR after the standard four-dose regimen was 51 %, with a 4 % CR rate. Patients with a response or stable disease received three additional rituximab courses (once weekly for 4 weeks) at 6-month intervals. Twenty-eight patients received one or more additional courses with rituximab. The ORR after additional rituximab was 58 %, with a CR rate of 9 %. The median duration of PFS was 18.6 months after a median follow-up of 20 months. The PFS rate was 62 % after 1 year and 49 % after 2 years.

In a study by Thomas et al. [111], 21 patients with previously untreated CLL were treated with rituximab once weekly for 8 weeks. An ORR of 90 % was reported, with a CR rate of 19 %.

5.5.1.2 Safety In Study U2098n [46], rituximab was well tolerated, with no incidences of cumulative toxicity or opportunistic infections, and only 2 cases of Grade 3 or 4 infusion-related toxicity.

No unexpected toxicities were observed in the study reported by Thomas et al. [111], and most adverse events were Grade 1 or 2 fever, chills, or hypotension related to the first infusion.

5.5.2 Rituximab Combined with Chemotherapy or Other Immunotherapy in Patients with Previously Untreated CLL

Rituximab has been studied in combination with chemotherapy regimens in patients with previously untreated CLL. Two key studies, one of rituximab combined with fludarabine and one of rituximab combined with FC chemotherapy, have been completed and are described below. In addition, a randomized, Phase III study of rituximab combined with


FC chemotherapy (Study CLL-8) is being conducted in previously untreated patients with Binet Stage B or C CLL. Interim pooled safety data is presented from this ongoing study.

5.5.2.1 Efficacy Table 11 summarizes response rates for studies of rituximab combination therapy in patients with previously untreated CLL.

Table 11 Response Rates for Studies of Rituximab Combination Therapy in Patients with Previously Untreated CLL

Response: No. ( %) of Patients

Reference (Study) Treatment Group n Complete Partial Overall

Byrd et al. 2003 (Study U1112s/CALGB 9712)

Sequential: Fludarabine, followed by rituximab consolidation *

Concurrent: Rituximab plus fludarabine, followed by rituximab consolidation *

53

51

15 (28 %)

24 (47 %)

26 (49 %)

22 (43 %)

41 (77 %)

46 (90 %)

Keating et al. 2005a; Keating et al. 2005b (Study U1989n)

R-FC † 224 72 % nPR: 10 % PR:

12 %

94 % ‡

nPR = nodular partial response, defined as a CR, except that one or more lymphoid nodules or aggregates were present upon bone marrow biopsy. *Rituximab consolidation therapy given to patients with stable disease or better. †See Table A-3 of appendix A ( ~xr9i ) for detailed description of dosing regimens. ‡Includes nPR.

5.5.2.1.1 Rituximab Combined with Fludarabine In Study U1112s/CALGB 9712 [6], 104 patients with previously untreated but symptomatic CLL received either sequential dosing in which fludarabine (six 28-day cycles) was followed by rituximab consolidation (once weekly for 4 weeks) for those with stable disease or better, or concurrent dosing in which rituximab plus fludarabine (six 28-day cycles) was followed by rituximab consolidation (once weekly for 4 weeks) for those with stable disease or better. Of the 104 patients enrolled, 59 % had Rai Stage I or II disease, and 41 % had Rai Stage III or IV disease. The ORR and CR rate reported in the concurrent dosing group (90 % and 47 %, respectively) were superior to those in the sequential dosing group (77 % and 28 %, respectively). In a retrospective analysis of the findings from this study (CALGB 9212, n = 104) compared with the outcomes observed in a similar study of fludarabine alone (CALGB 9011, n = 178), patients who received rituximab plus fludarabine experienced a significantly improved (p < 0.001, multivariate analysis) PFS (2-year probability of 0.67) compared with patients who received fludarabine alone (2 year-probability of 0.45). Overall survival was significantly improved as well (p = 0.0006, multivariate analysis) in patients who received rituximab plus fludarabine (2-year probability of 0.93) compared with patients who received fludarabine alone (2-year probability of 0.81) [7].

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5.5.2.1.2 Rituximab Combined with FC In Study U1989n [64, 65], 224 patients with previously untreated Rai Stage III or IV CLL received six 28-day cycles of R-FC. The ORR was 94 %, with a CR rate of 72 %, nodular partial response (nPR) rate of 10 %, and PR rate of 12 % [65]. A total of 74 % of patients completed six cycles of therapy [64].

5.5.2.2 Safety 5.5.2.2.1 Rituximab Combined with Fludarabine During the induction phase of Study U1112s/CALGB 9712 [6], the incidence of the following Grade 3 or 4 events was higher among patients receiving rituximab combined with fludarabine in the concurrent dosing group compared with patients receiving fludarabine alone in the sequential dosing group: neutropenia (76 % versus 39 %), thrombocytopenia (20 % versus 10 %), and infusion-related reactions, including fever, chills/rigors, dyspnea, and hypotension (20 % versus 6 %). All of the patients in the concurrent dosing group exhibited infusion-related adverse events, including fever, chills/rigors, dyspnea, and hypotension, which were mostly Grade 1 or 2 in severity. Nine percent of patients in the sequential dosing group experienced infusion-related adverse events. During the rituximab consolidation phase, the incidence of Grade 3 or 4 neutropenia was 19 % in the concurrent dosing group versus 8 % in the sequential dosing group. Opportunistic infections (e.g., varicella-zoster virus and herpes simplex virus) were less frequent in the concurrent dosing group (8 of 51 patients) than the sequential dosing group (14 of 53 patients). Of the first 44 patients in the concurrent dosing group, 9 developed Grade 3 or 4 dyspnea, hypoxemia, or hypotension when the full dose of rituximab was given on the first day. However, after a “stepped” dosing regimen was introduced (50 mg/m2 on Day 1, 325 mg/m2 on Day 2, and 375 mg/m2 on Day 5 of Cycle 1), none of the last 7 patients enrolled experienced these symptoms.

5.5.2.2.2 Rituximab Combined with FC In Study U1989n [64], in which 224 patients were treated with R-FC, 58 patients (26 %) did not complete the prescribed six courses of therapy. The major cause of premature discontinuation was persistent cytopenia, noted in 28 patients. Neutropenia led to discontinuation of therapy in 21 patients. Dose reductions were required in 35 patients, and 9 of these had to discontinue therapy despite dose reductions. The first dose of rituximab was associated with infusional symptoms, which were responsive to meperidine or hydrocortisone. Grade 3 or 4 toxicities occurred in 2 % of patients. Grade 3 and 4 neutropenia occurred in 24 % and 28 %, respectively, of 927 assessable courses. Grades 3 and 4 thrombocytopenia occurred in 4 % and < 1 %, respectively, of 927 courses. Only 2.6 % of the courses were associated with major infections. Two patients experienced death from infection, at 4 and 7 weeks. Hypogammaglobulinemia was noted for IgG in 75 patients, IgA in 46 patients, and IgM in 50 patients. Sequential follow-up of immunoglobulin levels was not mandated in this study.

Results from an interim analysis of pooled data (as of 30 April 2006) from 496 patients in the ongoing Study CLL-8, in which patients were treated with R-FC or FC, are presented. Grade 3 toxicities occurred in 26 % of patients and Grade 4 toxicities occurred in 19 % of patients. Leukopenia (6 % Grade 3, 3 % Grade 4), and neutropenia (3 % Grade 3, 7 % Grade 4) were among the most frequent Grade 3 and 4 toxicities. Infections were


reported in 8 % of patients. Grade 3 infections were reported in 4 % of patients and Grade 4 infections in 2 % of patients. The most common infections were pneumonia (2 % of patients) and herpes zoster (1 %).

5.5.3 Rituximab Monotherapy in Patients with Previously Treated CLL Presented within this section are three key studies of rituximab monotherapy in patients with previously treated CLL: two studies at the standard weekly dose of 375 mg/m2, and one at weekly doses ranging from 500 to 2250 mg/m2.

5.5.3.1 Efficacy Table 12 summarizes response rates for three studies of rituximab monotherapy in patients with previously treated CLL.

Table 12 Response Rates for Studies of Rituximab Monotherapy in Patients with Previously Treated CLL

Response: No. ( %) of Patients Reference (Study) Dosing Regimen n CR PR ORR

Itälä et al. 2002 (Study M39017)

375 mg/m2 once weekly for 4 weeks 24 0 8 (35 %) * 8 (35 %) *

Huhn et al. 2001 (Study M39025)

375 mg/m2 once weekly for 4 weeks † 28 ‡ 0 7 (25 %) * 7 (25 %) *

O’Brien et al. 2001 § (Study U0825n)

500, 650, or 825 mg/m2 once weekly ¥

1000 or 1500 mg/m2 once weekly ¥ 2250 mg/m2 once weekly ¥

24 ‡ 7 ‡ 8 ‡

0 0 0

5 (21 %) 3 (43 %) 6 (75 %)

5 (21 %) 3 (43 %) 6 (75 %)

Note: CR = complete response, ORR = overall response rate, PR = partial response *National Cancer Institute criteria. †Because of lethal complications with the 16th patient, the first rituximab dose for all subsequent patients was administered as follows: 50 mg on Day 1, 150 mg on Day 2, and the remainder on Day 3. ‡Number of evaluable patients. §Study included patients with other B-cell lymphoid leukemias, but only results from patients with CLL are presented. ¥Doses 2–4. All patients received rituximab 375 mg/m2 for Dose 1.

5.5.3.2 Safety 5.5.3.2.1 Rituximab Monotherapy, Weekly for 4 Weeks In Study M39017 [57], 75 % of the 24 patients enrolled experienced adverse events related to rituximab infusions. None of these events necessitated interruption of rituximab administration. There were 2 cases of Grade 3 adverse events: 1 case of hypotension and 1 case of arthralgia.

In Study M39025 [56], one treatment-related death occurred in a patient with a WBC (white blood cell) count of 274,000/µL. Ten hours after the first infusion of rituximab, the patient developed a syndrome of multiorgan failure with renal failure and finally cardiac arrest [69]. An autopsy revealed leukostasis and Richter’s transformation. Twenty-nine patients who received full protocol-specified treatment experienced 86 adverse events. Grade 3 or 4 toxicity occurred in 20 patients, the most frequent being infection (n = 5), including sinusitis, laryngitis, pneumonia, herpes zoster, and phlegmon


of the arm. One patient experienced septicemia 1 month after initiation of rituximab and later died of pulmonary aspergillosis.

5.5.3.2.2 Rituximab Monotherapy, Weekly at Higher Doses For Study U0825n [88], safety reporting included both patients with CLL (n = 40) and patients with other mature B-cell leukemias (n = 10). A total of 94 % of the 50 patients experienced adverse events with the first dose of rituximab, the majority of which were Grade 1 or 2 fever or chills. Grade 3 or 4 adverse events occurred in 6 of 50 patients (12 %) during the first infusion; of those 6 patients, only 1 had a diagnosis of CLL. The toxicity of subsequent escalated doses was minimal, with the exception of the highest dose level (2250 mg/m2). At that dose level, 67 % of patients had a Grade 1 or 2 toxicity, but no Grade 3 or 4 toxicities were reported.

5.5.4 Rituximab Combined with Chemotherapy or Other Immunotherapy in Patients with Previously Treated CLL

A study of rituximab combined with FC chemotherapy in patients with previously treated CLL has been completed and is described below. In addition, a randomized, Phase III study of rituximab combined with FC chemotherapy (Study BO17072) is being conducted in rituximab-naïve patients with CLL who are in their first relapse and are sensitive to fludarabine (remission of ≥ 6 months) if previously treated with a fludarabine-containing regimen. Interim pooled safety data is presented from this ongoing study.

5.5.4.1 Efficacy In Study U2335s [124], 177 patients with previously treated CLL (42 % Rai Stage IV) were treated with six 28-day cycles of R-FC. The ORR was 73 %, with a CR rate of 25 %, nPR rate of 16 %, and PR rate of 32 %. Median follow-up was 28 months for all patients and 35 months for surviving patients. Median TTP was 28 months. Median duration of overall survival was 42 months.

5.5.4.2 Safety All six intended courses of treatment were administered to 46 % of patients, with myelosuppression being the most common reason for discontinuing treatment. Rituximab-related toxicities occurred in 63 % of patients in association with the first infusion; all were Grade 1 or 2, with the exception of 1 case of Grade 3 shortness of breath. Grade 3 and Grade 4 neutropenia were noted in 15 % and 66 % of patients, respectively. Grade 3 and Grade 4 thrombocytopenia were noted in 16 % and 18 % of patients, respectively. Grade 3 or 4 anemia was observed in 24 % of patients. Major infections, defined as sepsis, pneumonia, or infection requiring hospitalization, occurred in 16 % of patients, and minor infections were observed in 18 % of patients. Late neutropenia (Grade 3 or 4 events occurring > 30 days after the last course of therapy in patients whose ANC had recovered to > 1000/µL) was seen in 5 of 45 patients who had experienced a CR. Five other cases were reported in patients with relapsed or residual disease.

Results from an interim analysis of pooled data (as of 30 April 2006) from 378 patients in the ongoing Study BO17072, in which patients were treated with R-FC or FC, are presented. Grade 3 toxicities occurred in 49 % of patients and Grade 4 toxicities occurred in 40 % of patients. Neutropenia (16 % Grade 3, 21 % Grade 4), anemia (8 % Grade 3,


3 % Grade 4), and thrombocytopenia (6 % Grade 3, 2 % Grade 4) were among the most frequent Grade 3 and 4 toxicities. Infections were reported in 43 % of patients. Grade 3 infections were reported in 10 % of patients and Grade 4 infections in 6 % of patients. The most common infections were upper respiratory tract infection (7 % of patients) and pneumonia (5 %).

5.5.5 Rituximab Monotherapy in Patients with Previously Untreated or Previously Treated CLL

Presented below are the results from a representative study of rituximab monotherapy in a mixed population of patients with previously untreated or previously treated CLL.

5.5.5.1 Efficacy In a dose intensification study (U0971n) by Byrd et al. [5], 33 previously untreated (n = 6) and previously treated (n = 27) patients with CLL (7 with SLL) received rituximab monotherapy. An initial dose of 100 mg was given over 4 hours (25 mg/hr) to three cohorts of patients. Patients then received either 250 mg/m2 or 375 mg/m2 on Day 3, and the same dose thereafter 3 times per week for 4 weeks. For two cohorts, treated at 250 mg/m2 (n = 3) and 375 mg/m2 (n = 7), all subsequent infusions were given using a standard administration schedule. For the third cohort, treated at 375 mg/m2 (n = 23), the second infusion was given using a standard administration schedule, and all subsequent infusions were given over 1 hour. The maximum total dose received was 1125 mg/m2 per week. Among the 29 evaluable patients, the ORR was 52 %, with a CR rate of 3 % and a PR rate of 48 % (data are not available by rituximab dose). The ORR was 83 % for the 6 previously untreated patients and 37 % for the 27 previously treated patients. The median response duration for the 15 responding patients was 10 months.

5.5.5.2 Safety Thirteen patients (39 %) experienced transient hypoxemia, hypertension, or dyspnea that required interruption of the first infusion. Only 1 patient, who experienced a Grade 4 infusion-related event, withdrew from the study prematurely. Transient thrombocytopenia was noted in 3 of 6 patients with an initial platelet count of < 50,000/µL. Other hematologic events were transient and without clinical significance.

5.5.6 Rituximab Combined with Chemotherapy or Other Immunotherapy in Patients with Previously Untreated or Previously Treated CLL

Presented below are the results from a representative study of rituximab combined with chemotherapy in a mixed population of patients with previously untreated or previously treated CLL.

5.5.6.1 Efficacy In Study M39024 [100], 31 patients with CLL (68 % Binet Stage B, 32 % Binet Stage C) who were previously untreated (n = 20) or treated but fludarabine- and anthracycline-naïve (n = 11) received four 28-day cycles of fludarabine and four rituximab infusions (at Weeks 9, 13, 17, and 21; first two rituximab infusions given in conjunction with the third and fourth fludarabine cycles). The ORR was 87 %, with a CR rate of 33 % and a PR rate of 55 %. Of the 10 patients who achieved a CR, 5 were previously untreated and 9 were


Binet Stage B. With a median follow-up of 54 weeks, the median duration of response was 75 weeks.

5.5.6.2 Safety One patient died following a cerebral bleed. Ten percent had Grade 3 or 4 anemia, 25 % had Grade 3 or 4 leukopenia, 42 % had Grade 3 or 4 neutropenia, and 9 % had Grade 3 or 4 thrombocytopenia. The most frequent non-hematologic adverse events were infections (52 % of patients) and infusion-related reactions such as chills (39 %), fever (32 %; one Grade 3 event), and erythema (26 %). A total of 32 infections were observed in 16 patients. Most were respiratory (10 of 32) and herpes virus (7 of 32) infections, and four infections (all Grade 3 or 4) were fever of unknown origin.

5.6 Treatment of Mantle Cell Lymphoma Table A-4 of appendix A ( ~xr10i ) provides an overview of selected studies of rituximab treatment in patients with MCL, and the study results are described within this section. Unless otherwise specified, patients received the standard approved rituximab dose of 375 mg/m2.

5.6.1 Rituximab in Patients with Previously Untreated Mantle Cell Lymphoma

Presented below are results from key studies of rituximab in patients with previously untreated MCL: two studies of rituximab combined with CHOP, one study of rituximab given after ASCT, and one study of rituximab combined with high-dose sequential chemotherapy.

5.6.1.1 Efficacy 5.6.1.1.1 Rituximab Combined with CHOP In a Phase II trial by Howard et al. [55], 40 patients with previously untreated MCL received six 21-day cycles of CHOP in combination with rituximab. The ORR was 96 %, with a CR rate of 48 %. The median duration of PFS was 16.6 months. No patient remained in remission longer than 36 months after study entry.

In a study performed by the GLSG [72], patients with previously untreated follicular lymphoma, lymphoplasmacytic lymphoma, or MCL were randomized to receive six 21-day cycles of CHOP, alone or in combination with rituximab. Patients who achieved a response and were < 60 years of age (younger patients) underwent a second randomization to receive either myeloablative radiochemotherapy with subsequent ASCT, or IFN-α maintenance. Patients who achieved a response and were ≥ 60 years of age (older patients) received IFN-α maintenance. Among the 121 evaluable MCL patients, efficacy was improved in the R-CHOP group compared with the CHOP group, as demonstrated by the ORR (94 % versus 75 %; p = 0.0054), CR rate (34 % versus 7 %; p = 0.00024), and median TTF (21 versus 14 months; p = 0.0131). Among patients who underwent ASCT, there was no significant difference in PFS after R-CHOP versus CHOP induction, as relapses occurred in 4 of 14 patients in the R-CHOP group and 1 of 9 patients in the CHOP group (p = 0.47; median duration of PFS not reached). Similarly, among patients who received IFN maintenance, there was no significant difference in median duration of PFS after R-CHOP versus CHOP induction (19 versus 13 months;

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p = 0.18). However, the number of patients was too low and the median follow-up too short to draw definitive conclusions. Study results for patients with follicular lymphoma are presented in section 5.2.2.

5.6.1.1.2 Rituximab Following ASCT In a study by Mangel et al. [81], 20 previously untreated, newly diagnosed patients with advanced (Stage III or IV) MCL received intensive chemotherapy followed by ASCT and then two courses of rituximab once weekly for 4 weeks, at 8 and 24 weeks after ASCT. Outcomes were compared with 40 historically matched control patients treated with conventional anthracycline- or FC-based chemotherapy. At a median follow-up of 30 months post-diagnosis, 17 of the 20 patients treated with ASCT + rituximab were alive and in remission (1 patient had relapsed and 2 had died). At a median follow-up of 80 months post-diagnosis, 33 of the 40 patients treated with conventional chemotherapy had relapsed or progressed, and 29 had died. Compared with patients receiving conventional chemotherapy, those treated with ASCT + rituximab had a higher overall survival rate (65 % versus 88 % at 3 years; p = 0.052) and a higher PFS rate (29 % versus 89 % at 3 years; p < 0.00001).

5.6.1.1.3 Rituximab Combined with High-Dose Sequential Chemotherapy In a study by Gianni et al. [43], 28 younger patients (< 61 years of age) with previously untreated MCL were treated with de-bulking chemotherapy (either doxorubicin- or cisplatin-based therapy) followed by a rituximab-supplemented, four-step, high-dose sequence of chemotherapy and subsequent ASCT. Chemotherapy consisted of high doses of the following agents, given in cycles that were usually 21 days in length (depending on recovery from toxicity): cyclophosphamide (Cycle 1), cytarabine (Cycle 2), melphalan (Cycle 3), and mitoxantrone plus melphalan (Cycle 4). Patients received a total of six rituximab infusions, two after cyclophosphamide, two after cytarabine, and two after mitoxantrone plus melphalan. The CR rate for the 27 evaluable patients was 100 %. With a median follow-up of 35 months, the estimated EFS rate at 54 months was 79 %.

5.6.1.2 Safety 5.6.1.2.1 Rituximab Combined with CHOP In the study reported by Howard et al. [55], most of the observed toxicity was attributed to CHOP chemotherapy. Seven patients developed febrile neutropenia, and 1 patient died of neutropenic sepsis 12 days after receiving his first cycle of therapy. Infusional reactions were reported in 50 % of patients, but none of the reactions required hospitalization, and all infusions were subsequently resumed without sequelae.

In the GLSG study [72], Grade 3 or 4 granulocytopenia was more frequent in the R-CHOP group than the CHOP group (63 % versus 53 % of patients; p = 0.01). However, the incidence of Grade 3 or 4 infections was similar in the R-CHOP (5 %) and CHOP (6 %) groups.

5.6.1.2.2 Rituximab Following ASCT In the study by Mangel et al. [81], 1 patient had reactivation of HBV during induction chemotherapy. No significant infusion-related toxicities were seen with rituximab, but 2


patients developed transient neutropenia. Interstitial pneumonitis developed after transplantation in 6 patients.

5.6.1.2.3 Rituximab Combined with High-Dose Sequential Chemotherapy In the study by Gianni et al. [43], 100 % of patients experienced Grade 4 hematologic adverse events, and 64 % experienced a fever of unknown origin or a documented infection. Cytomegalovirus reactivation was noted in 6 patients (21 %). There was one treatment-related death secondary to cardiac arrhythmia in a patient with a history of tachyarrhythmias.

5.6.2 Rituximab in Patients with Previously Treated Mantle Cell Lymphoma

Presented below are results from two key studies of rituximab in patients with previously treated MCL: one study of rituximab combined with thalidomide and one study of rituximab combined with FCM chemotherapy.

5.6.2.1 Efficacy 5.6.2.1.1 Rituximab Combined with Thalidomide In Study ML17171 [63], 16 patients with MCL who had relapsed or were resistant to standard CHOP (or CHOP-like) chemotherapy were treated with rituximab (once weekly for 4 weeks) in combination with thalidomide. The ORR was 81 %, with a CR rate of 31 % and a PR rate of 50 %. The median duration of PFS was 20.4 months, and the estimated 3-year overall survival rate was 75 %.

5.6.2.1.2 Rituximab Combined with FCM In a study performed by the GLSG [27, 34], 195 patients with previously treated follicular, mantle cell, or lympho-plasmocytic/lymphoplasmacytoid lymphoma were randomized to receive four 28-day cycles of FCM chemotherapy, alone or in combination with rituximab. Patients who achieved a response to induction (R-FCM or FCM) were subsequently randomized to receive no further treatment or two additional courses of rituximab therapy (once weekly for 4 weeks), at 3 and 6 months after completion of induction therapy. Among the 48 evaluable MCL patients, the ORR was 58 % in the R-FCM group and 46 % in the FCM group. With a median observation time of 18 months, there was a statistically significant improvement in duration of overall survival in the R-FCM group (median not reached) compared with the FCM group (estimated median, 11 months; p < 0.005) (Forstpointner et al. 2004). An improvement in the median PFS after the end of induction treatment was observed in the rituximab maintenance group compared with the observation group (p = 0.049) [27]. Study results for patients with follicular NHL are presented in section 5.2.3.

5.6.2.2 Safety 5.6.2.2.1 Rituximab Combined with Thalidomide In Study ML17171 [63], adverse events associated with thalidomide included fatigue, constipation, and peripheral neuropathy. Venous thromboembolic events were observed in 2 patients. One patient experienced severe neutropenia associated with thalidomide that improved after discontinuation of treatment. Rituximab toxicity was confined to infusional events during the first administration.


5.6.2.2.2 Rituximab Combined with FCM The GLSG study [34] did not differentiate safety results between mantle cell and follicular lymphoma. Grade 3 or 4 granulocytopenia occurred after 40 % of all cycles with a comparable frequency in both the R-FCM and FCM groups. Lymphocytopenia was more frequent in the R-FCM group compared with the FCM group (51.2 % versus 39.4 % of patients; p = .006). The difference was not correlated with an increase in infectious complications. World Health Organization Grade 3 or 4 infections occurred in only 1.5 % of all cycles, and there was no difference in frequency between the two treatment groups. Non-hematologic adverse events consisted mainly of mild to moderate nausea and vomiting, which occurred at similar frequencies in the two groups. Adverse events related to rituximab were seen mainly after the first infusion. In 4 patients, rituximab therapy had to be discontinued because of severe allergic reactions.

5.6.3 Rituximab in Patients with Previously Untreated or Previously Treated Mantle Cell Lymphoma

Presented below are results from two key studies of rituximab in mixed populations of patients with previously untreated or previously treated MCL: one study of induction rituximab followed by either maintenance rituximab or observation and one study of rituximab monotherapy.

5.6.3.1 Efficacy 5.6.3.1.1 Maintenance Rituximab after Rituximab Monotherapy In a study reported by Ghielmini et al. [40], 104 patients with previously untreated or previously treated MCL received rituximab once weekly for 4 weeks. Patients with stable disease or better at Week 12 received either four more doses of rituximab (at Months 3, 5, 7, and 9) or no further treatment. The two groups were similar with regard to ORR, CR rate, and duration of response (15 months). The median duration of EFS was not statistically significantly different at a median follow-up of 29 months (6 versus 12 months) in the observation and prolonged treatment groups.

5.6.3.1.2 Rituximab Monotherapy, Weekly for 4 Weeks In Study M39003 [33], 74 patients with previously untreated or previously treated MCL received rituximab once weekly for 4 weeks. Another 57 patients with immunocytoma or SLL were also treated. Among those with MCL, the ORR was 38 % for previously untreated patients and 37 % for previously treated patients. The median duration of response among patients with MCL was 1.2 years (median follow-up, 1.3 years).

5.6.3.2 Safety 5.6.3.2.1 Maintenance Rituximab after Rituximab Monotherapy During the induction phase of the study by Ghielmini et al. [40], the majority of toxicities were mild infusion-related symptoms during the first infusion. There were two deaths unrelated to disease progression: 1 patient died of a probable myocardial infarction, and 1 patient died of Pneumocystis carinii pneumonia. Thirteen percent of patients in Arm A (no maintenance treatment) and 9 % in Arm B (maintenance rituximab) had Grade 3 or 4 hematologic toxicity. During the maintenance phase, there were six serious adverse events in Arm A (including two second tumors) and eight in Arm B (including one second tumor, one case of septic shock, and one cardiac death).


5.6.3.2.2 Rituximab Monotherapy, Weekly for 4 Weeks In the study by Foran et al. [33], toxicities were summarized for all histologies combined. Eight patients did not finish therapy because of adverse events, including anaphylaxis (n = 3), atrial fibrillation/heart failure (n = 1), elevated liver function tests (n = 1), syncope (n = 2), and urticaria and hypotension (n = 1). One patient died of splenic rupture. Thirty-one episodes of infection (most mild to moderate) were seen.

5.7 Treatment of Waldenström’s Macroglobulinemia (Lymphoplasmacytic Lymphoma)

Table A-5 of appendix A ( ~xr11i ) provides an overview of selected studies of rituximab treatment in patients with Waldenström’s macroglobulinemia, and the study results are described within this section. Unless otherwise specified, patients received the standard approved rituximab dose of 375 mg/m2.

5.7.1 Rituximab Monotherapy in Patients with Waldenström’s Macroglobulinemia

Four key studies of rituximab monotherapy in patients with both previously untreated and previously treated Waldenström’s macroglobulinemia are described below.

5.7.1.1 Efficacy Table 13 summarizes efficacy data for the four studies of rituximab monotherapy.

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Table 13 Efficacy Results for Studies of Rituximab Monotherapy in Patients with Waldenström’s Macroglobulinemia


Patients Median Duration (months)

Reference

Rituximab Dosing

Regimen * n Partial Minor Overall Follow-Up

Period Response TTP/TTF

Gertz et al. 2004


69 † (35 previously

treated)

19 (28 %)

17 (25 %)

36 (52 %)

‡ Not

reported 27 Not

reported

Treon et al. 2001

Once weekly for 4 or 8 weeks, or three times weekly

30 (23 previously

treated)

8 (27 %)

10 (33 %)

18 (60 %) Not reported

Not reported

8 (TTF) §

Treon et al. 2005

Once weekly for 4 or 8 weeks

29 (17 previously

treated)

14 (48 %)

5 (17 %)

19 (66 %) 29 18+ (PR) 20+ (MR)

14 (TTP)

Dimopoulos et al. 2002

Once weekly for 4 or 8 weeks

27 (12 previously

treated)

12 (44 %)

NA 12 (44 %) 15.7 Not reported

16 (TTP)

MR = minor response; NA = not applicable. TTF = time to treatment failure, TTP = time to progression *See Table A-5 of appendix A ( ~xr12i ) for detailed description of dosing regimens. †Number of evaluable patients. ‡ORR of 35 % for previously untreated patients and 20 % for previously treated patients. §For responders.

5.7.1.2 Safety In the study by Gertz et al. [38], 72 patients were evaluated for toxicity. Grade 4 adverse events were reported in 8 patients; non-hematologic events included hypercalcemia (n = 1), hyperglycemia (n = 1), hyperkalemia (n = 2), hypermagnesemia (n = 1), and dyspnea (n = 1). Twenty-nine patients (40.3 %) experienced Grade 3 adverse events, with hyperglycemia being the most commonly observed (n = 6), followed by hyperkalemia (n = 4) and hyponatremia (n = 4). Grade 1 or 2 adverse events observed included fever (32 %) and rigors/chills (51.4 %). In a separate publication, Ghobrial et al. [41] noted that 29 of 54 patients (54 %) with IgM measurements available had an increase in serum IgM following rituximab administration. This elevation was transient, as elevated IgM levels were observed in 13 of 22 patients evaluated at 2 months and 4 of 15 patients evaluated at 4 months.

In the Treon et al. [114] study in 30 patients, 5 patients (16.6 %) had either transient fever, chills, mild blood pressure decrease, mild hypoxia, urticaria, or other rash with the first infusion. One patient developed a localized herpes simplex type 2 infection.

In a separate publication, Treon et al. [116] reported on paradoxical increases in serum IgM in patients treated with rituximab 375 mg/m2 once weekly for 4 weeks. Included in

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this analysis were 11 patients who were treated at the author’s institution and had serum IgM levels measured within 12 weeks of beginning rituximab treatment. Ten of 11 patients had a marked increase in serum IgM levels, with 8 patients demonstrating a ≥ 25 % increase. Serum viscosity also increased in all 8 patients who had measurements performed before and after rituximab therapy. One patient developed a central nervous system bleed when serum viscosity increased from 2.9 to 10.1 CP following 4 weeks of therapy. Four patients were treated with at least one plasmapheresis for increased serum viscosity, and 3 of those 4 also had adverse events that were thought to be related to increased serum IgM and hyperviscosity: subdural hemorrhage in 1 patient and worsening headache and/or epistaxis in 2 patients.

In the Treon et al. 2005 [117] study in 29 patients, the majority of adverse events were Grade 1 or 2 infusion-related events, with most occurring in association with the first infusion. Two patients had Grade 3 adverse events attributed to rituximab: monoarticular arthralgia and neutropenia. One patient previously treated with fludarabine and steroids died of P. carinii pneumonia during the study, but the event was considered to be unrelated to treatment.

In the study by Dimopoulos et al. [25], all adverse events were Grade 1 or 2 and primarily consisted of infusion-related reactions. Four infections were observed: herpes zoster, erysipelas, bronchitis, and urinary tract infection. The authors also noted in some patients a transient increase in serum IgM levels 15 to 30 days after the initiation of therapy.

In addition to Ghobrial et al. [41] and Treon et al. [116], Donnelly et al. 2001 noted transient paradoxical increases in serum IgM following initiation of rituximab treatment in a retrospective case series of 6 patients with previously treated Waldenström’s macroglobulinemia who received up to 12 rituximab infusions in a variety of schedules. There was a median 1.48-fold increase in serum IgM levels compared with pretreatment levels. In all 6 patients, these increases were transient. Two patients underwent plasmapheresis therapy and were known to have progressing disease.

5.7.2 Rituximab Combined with Chemotherapy or Other Immunotherapy in Patients with Waldenström’s Macroglobulinemia

Three studies of rituximab combined with chemotherapy in patients with Waldenström’s macroglobulinemia are described below.

5.7.2.1 Efficacy Table 14 summarizes efficacy data for three studies of rituximab combined with chemotherapy.


Table 14 Efficacy Results for Studies of Rituximab Combined with Chemotherapy in Patients with Waldenström’s Macroglobulinemia


Patients Median Duration

(months)

Reference Dosing Regimen * n CR PR MR ORR Follow-Up

Period TTP/ TTF

Dimopoulos et al. 2004

Rituximab combined with dexamethasone and cyclophosphamide

34 previously untreated

NR 26 (78 %)

NR NR 18 Not reached

Treon et al. 2004b

Rituximab combined with fludarabine

43 previously

untreated or treated

3 (7 %)

32 (74 %)

4 (9 %)

39 (90 %)

17 Not reached

Treon et al. 2005

R-CHOP 13 previously

treated

3† (23 %

)

8 (62 %)

1 (7 %)

12 (92 %)

NR NR

Note: CR = complete response, MR = minor response, NR = not reported, ORR = overall response rate, PR = partial response, TTF = time to treatment failure, TTP = time to progression *See Table A-5 of appendix A ( ~xr13i ) for detailed description of dosing regimens. †Unconfirmed.

5.7.2.2 Safety In the study by Dimopoulos et al. [24] of rituximab combined with dexamethasone and cyclophosphamide, 20 % of patients developed mild or moderate toxicities related to the rituximab infusion, including fever, rigors, and headache. Grade 3 or 4 neutropenia was observed in 15 % of patients, and 1 patient died of interstitial pneumonia.

In the study by Treon et al. [115] of rituximab combined with fludarabine, 56 % of patients developed Grade 3 or 4 neutropenia, and therapy was discontinued for several patients after the fourth or fifth course of fludarabine (at Week 19 or 23) because of persistent neutropenia and/or thrombocytopenia. Adverse events included herpes zoster (n = 3), parasthesias (n = 3), pneumonitis (n = 2), bladder cancer (n = 1), high-grade lymphoma (n = 1), and subdural hemorrhage (n = 1). Two patients died, 1 because of influenza pneumonia and 1 because of a possible secondary malignancy.

In the study by Treon et al. [117] of R-CHOP, the therapy was well tolerated by the majority of patients. Two patients experienced febrile neutropenia with bacteremia and recovered without complications. One patient experienced prolonged thrombocytopenia that was ongoing. No significant changes in effector cells (CD3+, CD4+, CD8+, CD16+/56+) were observed.

5.8 Treatment of Multiple Myeloma Clinical experience with rituximab in the setting of multiple myeloma is very limited, with studies confined to small numbers of patients. Table A-6 of appendix A ( ~xr14i )

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page 131Roche Investigator's Brochure 11th Version December 2006 RO45-2294 -

provides an overview of selected studies of rituximab treatment in patients with multiple myeloma, and the results are described within this section. Unless otherwise specified, patients received the standard approved rituximab dose of 375 mg/m2.

In Study M39028 [133], 10 patients with previously treated multiple myeloma received rituximab once weekly for 4 weeks. None of the patients achieved an objective response. Two patients had stable disease at 6 months. Four patients had stable paraprotein levels for 3 months, but 2 of those patients had clinical deterioration. No significant toxicities were observed. Peripheral B cells significantly decreased at 3 months and IgM levels decreased in all patients.

In a study by Lim et al. [73], 6 patients with previously treated multiple myeloma received rituximab as maintenance therapy following single high-dose melphalan and autologous hematopoietic stem cell transplantation (HSCT). Rituximab was administered starting 30 days after HSCT and every 3 months thereafter for 2 years. With a median follow-up of 6 months (range, 2–14 months), 3 patients experienced a CR, and the other 3 patients were responding to rituximab treatment. The rituximab infusions were generally well tolerated, with no significant toxicities other than rigors and fever associated with the first infusion. One patient developed idiopathic pneumonitis, which responded to corticosteroids.

5.9 Treatment of Hodgkin’s Disease There are limited data to date on the use of rituximab for treatment of Hodgkin’s disease. Table A-7 of ( ~xr15i ) provides an overview of selected studies of rituximab treatment in patients with Hodgkin’s disease, and the results are described within this section. Unless otherwise specified, patients received the standard approved rituximab dose of 375 mg/m2.

In a study by Younes et al. [130], 41 patients with previously untreated Hodgkin’s disease were enrolled in a study in which rituximab was administered weekly during the first 6 weeks of ABVD (adriamycin, bleomycin, vincristine, and dacarbazine) chemotherapy at a standard dose and schedule. Thirty-five patients (88 %) had nodular sclerosing type disease. Thirty-six patients were evaluable for efficacy, and all responded to therapy. The EFS rate was 83 %, with a median follow-up of 21 months. For the 40 patients evaluable for safety, the majority of adverse events were Grade 1 or 2. One patient developed P. carinii pneumonia, and 2 patients developed neutropenic fever. In total, 232 cycles of ABVD had been given, and all patients had received rituximab weekly for 6 weeks.

In a study by the German Hodgkin's Lymphoma Study Group (GHSG) [101], 17 patients with previously treated lymphocyte-predominant Hodgkin’s disease received rituximab once weekly for 4 weeks. A response was observed in 15 of 17 evaluable patients (88 %). Ten patients achieved a CR and 5 patients achieved a PR, with a median duration of response of 32 months [101]. The median TTP was 31 months [102]. Adverse events (including fever, chills, rhinitis, and nausea) were transient, were usually mild to moderate, and responded to outpatient treatment [101].

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5.10 Treatment of Posttransplant Lymphoproliferative Disorders B-cell PTLD is a serious complication observed after transplantation. There is no consensus on treatment modalities in this setting. Rituximab monotherapy has been given for the treatment of CD20+ PTLD after bone marrow and solid organ transplantation. Table A-8 of appendix A ( ~xr16i ) provides an overview of key studies in this setting, and the results are described within this section. Unless otherwise specified, patients received the standard approved rituximab dose of 375 mg/m2.

In Study M39037 by Choquet et al. [12], rituximab was administered once weekly for 4 weeks to 46 patients with either B-cell PTLD after HSCT or B-cell PTLD that had not improved after tapering of immunosuppressive drugs in solid organ transplantation. A total of 43 patients were evaluable for efficacy. At Day 80, 19 patients (44 %) had achieved a response (9 CR, 3 CRu, and 7 PR). At Day 360, responses were maintained in 68 % of the patients. Only 1 patient who had attained a CR had relapsed. Normal levels of LDH was the only factor predictive of response (p = 0.007; odds ratio = 6.9). At 1 year, the estimated overall survival was 67 %. The median survival time was 454 days. The number of lymphoproliferative sites was the only factor predictive of survival (p = 0.0354; hazard ratio = 3.8). Rituximab was well tolerated, with only two serious adverse events considered related to rituximab. The most frequent events included transplant rejection (22 %), abdominal pain (20 %), and dyspnea (17 %).

In a Phase II study by Oertel et al. [89], 25 patients with previously untreated or previously treated PTLD following a variety of solid organ transplants (kidney, n = 7; lung, n = 6; heart, n = 6; liver, n = 5; kidney/pancreas, n = 1) were treated with rituximab once weekly for 4 weeks. The ORR was 64 %, with a CR rate of 52 %. The median duration of response was 29.6 months, and the median duration of overall survival was 38.8 months. Adverse events were limited to two Grade 1 infusion-related reactions (pain/fever).

In a study by Milpied et al. [87], 32 patients with PTLD following solid organ transplantation (n = 26) or bone marrow transplantation (n = 6) were treated with two to eight infusions of rituximab as either first-line therapy following reduction of immunosuppressants or salvage therapy following chemotherapy. Twenty-two patients (69 %) responded, 17 (65 %) of those treated following solid organ transplantation and 5 (83 %) of those treated following bone marrow transplantation. Of the 22 responders, 15 remained in response at a median follow-up of 8 months, with an estimated 1-year overall survival rate of 73 %. Rituximab was found to be well tolerated.

The European Best Practice Guidelines (EBPG) Expert Group on Renal Transplantation (EBPG, 2002) has recommended that both rituximab monotherapy and rituximab in combination with CHOP can be used for the treatment of PTLD in renal transplant patients in Europe.

In a study by Berney et al. [3], 5 intestinal transplant recipients diagnosed with PTLD received prolonged first-line treatment with rituximab at 125 mg/m2 on Day 1, 250 mg/m2 on Day 4, and 375 mg/m2 on Day 8 and weekly thereafter until full remission. All 5 patients achieved full remission and remained disease free for a median of 8 months. One patient developed respiratory symptoms during a rituximab infusion; these symptoms responded to discontinuation of the infusion.

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In a study by Serinet et al. [105], 6 pediatric liver transplant recipients diagnosed with PTLD received rituximab once weekly for 3 to 4 weeks. Five patients experienced a complete and durable remission, while 1 patient died from cerebral lymphoma. Two patients had a reaction to the first infusion, including headache and an anaphylactic reaction that resolved with discontinuation of the infusion. Transient neutropenia was reported for 2 patients. All patients experienced severe hypogammaglobulinemia that required immunoglobulin support.

In a study by Van Esser et al. [119], 15 patients at high risk of PTLD who had viral reactivation after T-cell–depleted allogeneic stem cell transplantation received preemptive therapy with a single rituximab infusion [119]. In addition, 2 patients with a diagnosis of PTLD prior to preemptive therapy were given two rituximab infusions. Comparison of this cohort with a historical cohort having the same risk profile (n = 26) showed a reduction in PTLD incidence (18 % versus 49 %). In addition, the PTLD mortality was 0 % in this study, compared with 26 % for the historical cohort. One patient in the preemptive therapy cohort developed PTLD and achieved a CR after receiving a second infusion of rituximab and a donor lymphocyte infusion. B-cell lymphopenia was observed for several months in 12 patients. Grade 3 or 4 opportunistic infections were observed in all 8 patients who had chronic graft versus host disease and in 3 of the 7 patients who did not have chronic graft versus host disease.

In a study by Ganne et al. [36] conducted in 8 patients with PTLD after solid organ transplantation, 7 patients achieved a CR with stable graft function after treatment with rituximab once weekly for 4 weeks. One patient had a relapse and received a second course of rituximab (once weekly for 4 weeks). The patient who did not respond to rituximab received chemotherapy. No adverse events were seen with this therapy. At the last follow-up (mean, 22.5 months after diagnosis), all patients were alive, 7 had functioning grafts, and 1 was on maintenance dialysis. Rituximab proved effective at inducing long-term remission in PTLD patients, without the morbidity associated with chemotherapy.

5.11 Treatment of Patients with Other Diseases Rituximab is currently being investigated in non-malignant disorders such as rheumatoid arthritis; relapsed or refractory ITP; thrombotic thrombocytopenic purpura; AIHA; CHD; and congenital and acquired factor VIII deficiency. Studies of rituximab for the treatment of rheumatoid arthritis and other non-hematologic, non-malignant indications are presented in a separate Investigator Brochure available from the Sponsor. Table A-9 of appendix A ( ~xr17i ) provides an overview of selected rituximab studies in hematologic non-malignant disorders, and the study results are described within this section. Unless otherwise specified, patients received the standard approved rituximab dose of 375 mg/m2.

5.11.1 Treatment of Idiopathic Thrombocytopenic Purpura Rituximab has been administered as a single agent once weekly for up to 4 weeks to patients with relapsed or refractory ITP, although no large studies have been conducted in this patient population. Studies have not been consistent in the definition of CR, which ranged from an increase in platelet count to >100,000/µL to a normalization of platelet

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count for a minimum of 30 days. Presented below are results from key studies of rituximab in patients with previously treated ITP.

In a study by Stasi et al. [110], 25 patients with chronic ITP who had been previously treated with two to five therapies were given rituximab once weekly for 4 weeks. Ten patients (40 %) achieved a response; 5 patients achieved a CR (platelet count >100,000/µL), and 5 patients achieved a PR (platelet count of 50,000 - 100,000/µL). Twenty-seven adverse events of Grade 1 or 2 severity were observed in 18 patients. These events, including fever, chills, and nausea, occurred most commonly during the first infusion.

In a study by Giagounidis et al. [42], 12 patients with previously treated ITP were given rituximab once weekly for 4 weeks. Five patients (41 %) achieved a CR (normalization of platelet count for at least 30 days), and 2 patients (17 %) achieved a PR (platelet count >30,000/µL for at least 30 days). Adverse events included meningococcal meningitis 10 months following completion of therapy in a previously splenectomized patient, and protracted thrombocytosis (platelet count >1 × 106/µL) after two rituximab doses and AIHA in another patient.

In the largest study reported to date, Cooper et al. [19] investigated treatment with rituximab once weekly for 4 weeks in 57 refractory ITP patients (31 with prior splenectomy) who had received at least two previous treatments. The median follow-up was 11 months. Thirty-one of 57 (54 %) achieved a response (platelet count >50,000/µL); 18 patients achieved a CR (platelet count >150,000/µL), and 13 patients achieved a PR (platelet count 50,000–150,000/µL). The majority of patients with a response (29 of 31) responded within 8 weeks of the first infusion. Sixteen of 18 patients who achieved a CR still maintained a normal platelet count after a median of 72.5 weeks. Approximately 50 % of the responding patients had a prior splenectomy, which did not appear to influence the likelihood of a response to rituximab. Seven of the 31 responders had concurrent therapy with steroids or IV immunoglobulin because of extremely low platelet counts when rituximab therapy was instituted. Thirty-three of 57 patients (58 %) experienced first infusion reactions, all of which were rated Grade 1 or 2 with the exception of 1 case of Grade 3 bronchospasm. Of note, 27 patients were premedicated with steroids, which appeared to lower the rate of mild infusion reactions. There was no occurrence of serious infections or increased incidence of minor infections.

5.11.2 Treatment of Thrombotic Thrombocytopenic Purpura Rituximab has demonstrated efficacy in case reports and small cohorts of patients with acute refractory thrombotic thrombocytopenic purpura that is associated with an ADAMTS13 deficiency [11] [n = 2]; [44] [n = 3]; [129] [n = 1]; [2] [n = 4]; [68] [n = 2]; [95] [n = 5]). ADAMTS13 is a metalloprotease that prevents the formation of platelet thrombi in the microcirculation. Two trials are presented: a trial of rituximab administered as treatment or prophylactive intervention in 11 patients [31] and a trial of rituximab administered as a treatment intervention in 15 patients [103].

In a multicenter, open-label, prospective trial in 11 patients with thrombotic thrombocytopenic purpura as a result of anti-ADAMTS13 antibodies, 4 weekly infusions of rituximab (375 mg/m2) were administered. Six patients were treated while experiencing an acute refractory episode and all achieved a clinical remission (restoration


of ADAMTS13 plasma activity to >10 %). Prophylactive treatment was administered to 5 patients who had severe relapsing thrombotic thrombocytopenic purpura and persistent anti-ADAMTS13 antibodies and were in remission. In all 11 patients, anti-ADAMTS13 antibodies became undetectable and significant plasma ADAMTS13 activity was measured (18 % - 75 %). Rituximab was well tolerated in this patient population [31].

In an open-label, prospective trial in 15 patients with acute refractory thrombotic thrombocytopenic purpura who had progressive clinical disease or deterioration of laboratory parameters, weekly infusions of rituximab (375 mg/m2) were administered (range 2 to 8 infusions). Within 22 days of the first infusion, all patients experienced clinical remission and attained normal laboratory parameters. None of the patients (n = 13) who had anti-ADAMTS13 antibodies at study entry had detectable levels of antibodies post-treatment. The treatment was well tolerated with no significant decreases in CD19+ cell levels and immunoglobulin levels noted. No infectious complications were observed [103].

5.11.3 Treatment of Autoimmune Hemolytic Anemia and Cold Hemagglutinin Disease

Data regarding rituximab treatment of AIHA or CHD are limited to a very small number of patients, primarily from case reports. Key study results are presented below.

In a multicenter, retrospective study conducted by questionnaire [9], 34 previously treated patients with either idiopathic or disease-related AIHA were analyzed for response to rituximab therapy (dosage not specified), given alone or in combination with other therapy (mainly steroids). Nineteen patients (63 %) achieved a CR (hemoglobin of >10 g/dL or an increase of >1.5 g/dL) and 4 patients (13 %) achieved a PR (hemoglobin of >9 g/dL or an increase of 1.0–1.5 g/dL). There was no difference in response based on prior splenectomy. The median increase in hemoglobin was 5.9 g/dL. There were no significant toxicities.

In a pediatric study reported by Zecca et al. [131], 15 patients (median age, 2 years) were treated with rituximab for a median of 3 weekly doses. Nine children had isolated AIHA, 1 had AIHA and concomitant pure red cell aplasia, and 5 had Evans syndrome (AIHA and immune-mediated thrombocytopenia). All patients had previously received two or more immunosuppressive treatments, and 2 patients had been splenectomized during the course of the disease. All patients received IV immunoglobulins following rituximab treatment. Thirteen patients (87 %) demonstrated a response to treatment, defined as an increase in hemoglobin of ≥1 g/dL and a 50 % reduction in absolute reticulocyte count. Three patients who relapsed 7–10 months after the first exposure to rituximab achieved disease remission after retreatment with rituximab. Adverse events included infusion related-reactions (fever or cough) in 3 patients and varicella, which occurred in 1 patient 2 months following rituximab and resolved with therapy.

A study by Quartier et al. [94] reported responses, as defined by normalization of hemoglobin levels and reduction in reticulocyte counts, in 6 children with steroid-resistant AIHA. Patients remained in complete remission at last follow-up, 15–22 months after treatment with rituximab once weekly for 4 weeks. Two serious adverse events were noted: One patient developed Escherichia coli pyelonephritis. Another patient developed febrile bronchitis after completion of therapy; the bronchitis responded to treatment with


antibiotics. Five patients received prophylactic IV immunoglobulin replacement for 9–10 months because of below normal IgG serum concentrations.

Several adult or pediatric patients with refractory AIHA or CHD have been successfully treated with rituximab, defined as an increase in hemoglobin level and a normalization of reticulocyte count [71, 70, 37].

5.11.4 Treatment of Factor VIII Deficiency Limited data have been reported on rituximab treatment in patients with congenital and acquired factor VIII deficiency. Results of key studies are presented below.

Wiestner et al. [125] reported on the reduction of acquired factor VIII inhibitors in 4 patients with an immunosuppressive regimen that included weekly rituximab administered concurrently with a short course of rapidly tapered steroids. Patients entered the study with factor VIII activity ranging from < 1 % to 4 % (normal range, 70 %–200 %) and inhibitor titers ranging from 5 to 60 Bethesda units. In 3 of the 4 patients, factor VIII levels normalized and the inhibitor became undetectable between 3 and 12 weeks after the start of therapy. The effects lasted 17–22 months without maintenance treatment. All 3 responding patients had spontaneously occurring inhibitors. The fourth patient had mild hemophilia A and developed both an auto- and an allo-antibody response following treatment with recombinant factor VIII. Rituximab was well tolerated. One patient experienced decreased gamma-globulin levels at 3 months that recoverd by 7 months. In a patient who entered the study with hepatitis C, rituximab treatment did not worsen this pre-existing infection.

In a study by Stasi et al. [109], 10 patients with previously untreated or previously treated acquired factor VIII deficiency were given rituximab once weekly for 4 weeks. A CR, defined as normal factor VIII activity and undetectable factor VIII inhibitor titers, was observed in 8 of 10 patients. The 2 patients who did not respond had factor VIII inhibitors of >100 Bethesda units/mL. Those 2 patients subsequently responded to treatment with rituximab plus cyclophosphamide. One patient with a CR was administered recombinant factor VIIa prior to rituximab for management of a recent bleed. Three patients with a CR experienced a relapse and then responded to retreatment with rituximab. Three patients experienced Grade 1 infusion reactions that did not result in study drug discontinuation. No other adverse events occurred.

There have been reports of an improved immune response to immune tolerance therapy for factor VIII inhibitor after rituximab therapy [86], activity in patients with factor VIII allo-antibodies [93], and a case report of rituximab activity in congenital hemophilia with inhibitor, showing a decrease in the frequency of spontaneous bleeding [30]. These limited case reports did not include information regarding safety.

6. GUIDANCE FOR THE INVESTIGATOR This section includes safety data from the Core Data Sheet, U.S. Prescribing Information, Summary of Product Characteristics, and postmarketing studies, and is based on experience from the use of rituximab primarily in the oncology setting [75].


6.1 Indications The indications as of October 2006 are provided.

In the United States, rituximab is indicated for the following:

Non-Hodgkin’s Lymphoma

• Rituximab is indicated for the treatment of patients with relapsed or refractory, low-grade or follicular, CD20+, B-cell non-Hodgkin's lymphoma.

• Rituximab is indicated for the first-line treatment of follicular, CD20+, B-cell non-Hodgkin’s lymphoma in combination with CVP chemotherapy.

• Rituximab is indicated for the treatment of low-grade, CD20+, B-cell non-Hodgkin’s lymphoma in patients with stable disease or who achieve a partial or complete response following first-line treatment with CVP chemotherapy.

• Rituximab is indicated for the first-line treatment of diffuse large B-cell, CD20+, non-Hodgkin's lymphoma in combination with CHOP or other anthracycline-based chemotherapy regimens.

Rheumatoid Arthritis

• Rituximab in combination with methotrexate is indicated to reduce signs and symptoms in adult patients with moderately- to severely- active rheumatoid arthritis who have had an inadequate response to one or more tumour necrosis factor (TNF) antagonist therapies.

Outside the United States, MabThera (rituximab) is indicated for the following:

Non-Hodgkin’s Lymphoma

• MabThera is indicated for treatment of patients with stage III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapy.

• MabThera is indicated for the treatment of previously untreated patients with stage III-IV follicular lymphoma in combination with CVP chemotherapy.

• MabThera is indicated for the treatment of patients with CD20+, diffuse, large B-cell non-Hodgkin’s lymphoma in combination with CHOP chemotherapy.

• MabThera maintenance therapy is indicated for patients with relapsed/refractory follicular lymphoma responding to induction therapy with chemotherapy with or without MabThera.

Rheumatoid Arthritis

• MabThera in combination with methotrexate is indicated for the treatment of adult patients with severe active rheumatoid arthritis who have had an inadequate response or intolerance to other disease-modifying anti-rheumatic drugs including one or more TNF inhibitor therapies.


6.2 Contraindications Rituximab is contraindicated in patients with known hypersensitivity to rituximab, any component of the product, or murine proteins (Kornbrot, 1994).

6.3 Warnings and Precautions for Use 6.3.1 Infusion-Related Reactions Rituximab is associated with infusion-related reactions, which may be related to release of cytokines or other chemical mediators [127]. Severe infusion-related reactions might be clinically indistinguishable from hypersensitivity reactions or cytokine release syndrome. Severe infusion-related reactions with fatal outcomes have been reported during postmarketing use. Severe reactions usually manifested within 1 to 2 hours after initiation of the first rituximab infusion, were characterized by pulmonary events (see section 6.3.1.1), and included, in some cases, rapid tumor lysis and features of tumor lysis syndrome (see section 6.3.1.4) in addition to fever, chills, rigors, hypotension, urticaria, and angioedema and other symptoms.

Patients with a high tumor burden or a high number of circulating malignant cells (> 25 × 109/L), such as patients with CLL or MCL [58, 8], may be at higher risk of especially severe infusion-related reactions and should only be treated with extreme caution and when other therapeutic alternatives have been exhausted. These patients should be very closely monitored throughout the first infusion. Consideration should be given to the use of a reduced infusion rate for the first infusion in these patients.

Rituximab infusions should be administered in an environment in which full resuscitation facilities are immediately available, and under the close supervision of an experienced oncologist or hematologist. Patients who experience severe infusion-related symptoms should be closely monitored until complete resolution of their symptoms occurs.

Hypotension, fever, chills, rigors, urticaria, bronchospasm, and angioedema have occurred in association with rituximab infusion as part of an infusion-related symptom complex. These infusion-related symptoms are usually reversible with interruption of the infusion. Treatment of infusion-related symptoms with diphenhydramine and acetaminophen is recommended. Additional treatment with bronchodilators or IV saline may be indicated. In most cases, the infusion can be resumed at a 50 % reduction in rate (e.g., from 100 mg/hr to 50 mg/hr) when symptoms have completely resolved. Most patients who have experienced non–life-threatening infusion-related reactions have been able to complete the full course of rituximab therapy.

6.3.1.1 Pulmonary Events Pulmonary events have included hypoxia, pulmonary infiltrates, and acute respiratory failure. Some of these events have been preceded by severe bronchospasm and dyspnea. Acute respiratory failure may be accompanied by events such as pulmonary interstitial infiltration or edema, visible on a chest X-ray. In some cases, symptoms worsened over time, while in others, initial improvement was followed by clinical deterioration. Patients who experience severe pulmonary events should have their infusion interrupted immediately and should receive aggressive symptomatic treatment. These patients should be closely monitored until the pulmonary event has resolved completely. Patients with a history of pulmonary insufficiency may be at greater risk of poor outcome and should be


treated with increased caution. Further treatment of patients after complete resolution of signs and symptoms has rarely resulted in repeated severe infusion-related reactions.

6.3.1.2 Cardiovascular Events Since hypotension may occur during rituximab infusion, consideration should be given to withholding antihypertensive medications 12 hours prior to and throughout rituximab infusions. Angina pectoris and cardiac arrhythmia (such as atrial flutter and fibrillation) have occurred in patients treated with rituximab. Therefore, patients with a history of cardiac disease should be monitored closely.

6.3.1.3 Hypersensitivity Reactions Anaphylactic and other hypersensitivity reactions have been reported following the IV administration of proteins to patients. Adrenaline, antihistamines, and corticosteroids should be available for immediate use in the event of a hypersensitivity reaction to rituximab.

6.3.1.4 Rapid Tumor Lysis Rituximab mediates the rapid lysis of benign and malignant CD20+ cells. Signs and symptoms (e.g., hyperuricemia, hyperkalemia, hypocalcemia, acute renal failure, and elevated LDH) consistent with tumor lysis syndrome (TLS) have been reported to occur after the first rituximab infusion in patients with high numbers of circulating malignant lymphocytes. Prophylaxis for TLS should be considered for patients at risk of developing rapid tumor lysis. These patients should be followed closely, and appropriate laboratory monitoring should be performed. Appropriate medical therapy should be provided for patients who develop signs and symptoms consistent with rapid tumor lysis. Following treatment for and complete resolution of signs and symptoms, subsequent rituximab therapy has been administered in conjunction with prophylactic therapy for TLS in a limited number of cases [8].

6.3.2 Hepatitis B Virus Reactivation with Related Fulminant Hepatitis and Other Viral Infections

HBV reactivation, with fulminant hepatitis, hepatic failure, and death, has been reported in some patients with hematologic malignancies treated with rituximab. The majority of patients received rituximab in combination with chemotherapy.

Rituximab should be used cautiously in patients with a history of HBV infection.

For patients who develop viral hepatitis, rituximab and any concomitant chemotherapy should be discontinued and appropriate treatment initiated. There are insufficient data to determine if it is safe to resume rituximab therapy in patients who develop hepatitis subsequent to HBV reactivation.

Other serious viral infections, either new, reactivation, or exacerbation, some of which were fatal, have been reported with rituximab treatment. The majority of patients had received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant. Examples of these serious viral infections are infections caused by the herpes viruses (cytomegalovirus, Varicella zoster virus, and Herpes simplex virus), JC virus (progressive multifocal leukoencephalopathy [PML]), and hepatitis C virus.


6.3.3 Hematologic Events Caution should be exercised when considering treatment of patients with a neutrophil count of <1.5 × 109/L or platelet count of <75 × 109/L, as clinical experience with such patients is limited. Rituximab has been used without inducing myelotoxicity in patients who underwent ABMT and in other risk groups with a presumable reduced bone marrow function. Consideration should be given to the need for regular full blood counts, including platelet counts, during rituximab monotherapy. When rituximab is given in combination with chemotherapy, regular full blood counts should be performed according to usual medical practice.

6.3.4 Severe Bullous Skin Reactions Severe bullous skin reactions including toxic epidermal necrolysis and paraneoplastic pemphigus have been reported rarely. Some of these reactions have been associated with a fatal outcome.

6.3.5 Bowel Obstruction and Perforation Gastrointestinal obstruction and perforation, in some cases leading to death, have been observed in patients receiving rituximab for treatment of NHL. In the majority of these cases, rituximab was administered in combination with chemotherapy. Complaints of abdominal pain, especially early in the course of treatment, should prompt a thorough diagnostic evaluation and appropriate treatment.

6.3.6 Effects on Ability to Drive and Operate Machinery It is not known whether rituximab has an effect on the ability to drive and operate machinery. However, the pharmacologic activity and adverse events reported to date do not indicate that such an effect is to be expected.

6.3.7 Effects on Immunization Rituximab treatment may impair the ability to generate secondary humoral responses as suggested by a small study in 11 lymphoma patients challenged with recall antigens (tetanus toxoid and poliovirus) before and after rituximab treatment [118].

The safety of immunization with any vaccine, particularly live viral vaccines, following rituximab therapy, is currently under investigation. A multicenter randomized study (Study 102-12) is being conducted to evaluate the effect of rituximab monotherapy on primary humoral response, recall response, and maintenance of acquired immunity to specific antigens in patients with relapsed B-cell NHL compared with untreated, age-matched, healthy control subjects. Immune response data from this ongoing study were not available yet as of the data cutoff date for this investigator brochure (15 June 2006). Interim safety data from this study was available for 205 subjects in the safety population and is briefly summarized. Among the 107 NHL subjects who received rituximab and a study vaccination, events reported in more than 2 subjects included chills (4 % of subjects), anemia (3 %), hypersensitivity (3 %), pyrexia (3 %), chills (4 %), and fatigue (3 %). Among the 98 control subjects who received a study vaccination, events reported in more than 2 subjects included pruritus (8 %), headache (4 %), peripheral edema (4 %), pharyngolarnygeal pain (3 %), and erythema (3 %). The incidence of infections and infestations was 8 % and 5 % among the NHL and control groups,


respectively. One subject in the control group and 2 subjects in the NHL group experienced a Grade 3 or 4 infection.

6.3.8 Interactions At present, no data are available on possible drug interactions with rituximab.

Patients with human anti–mouse antibody (HAMA) or HACA titers may develop allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies [67]. In an integrated review of data from 356 rituximab-treated patients with indolent NHL, 4 patients developed a HACA response following treatment. Two of these patients were retreated without problems. No correlation was seen between HACA response and loss of or interference with response to treatment.

The tolerability of simultaneous or sequential combination of rituximab with agents other than CHOP or CVP chemotherapy or agents that are liable to cause depletion of normal B cells is not well defined.

6.3.9 Overdoses No data regarding overdoses is available from clinical trials in humans. Single doses higher than 500 mg/m2 have not been tested in company-sponsored oncology trials. Doses of up to 1000 mg have been tested in immunology trials.

6.3.10 Use during Pregnancy and Lactation In a reproductive toxicity study, rituximab at doses of 20, 50, or 100 mg/kg were given weekly to pregnant female cynomolgus monkeys during the period of organogenesis. There were no findings of toxicity to the dams or developing fetuses, and the only effect noted was the dose-dependent pharmacologic depletion of B cells in the lymphoid organs of the fetuses.

It is not known whether rituximab can cause fetal harm when administered to pregnant women or whether it affects reproductive capacity. However, as IgG immunoglobulins are known to cross the placental barrier, rituximab may cause B-cell depletion in the fetus. For these reasons, rituximab should not be administered to pregnant women unless the possible benefit outweighs the potential risk.

Women of childbearing age should employ effective contraceptive methods during and for up to 12 months after treatment with rituximab.

The use of rituximab during lactation has not been studied. It is not known whether rituximab is excreted in human breast milk. Given, however, that maternal IgG enters breast milk, rituximab should not be administered to nursing mothers.

6.3.11 Pediatric Use The safety and efficacy of rituximab in pediatric patients have not been established.

6.3.12 Use in Elderly Patients In patients receiving rituximab monotherapy, the incidence of adverse events was similar in elderly (≥ 65 years; n = 94) and younger (n = 237) patients (88.3 % versus 92.0 % for any adverse event; 16.0 % versus 18.1 % for Grade 3 or 4 adverse events) [22, 23, 76, 77, 78, 84, 92].


6.3.13 Use in Patients with Bulky Disease During treatment and follow-up, patients with bulky disease (lesions > 10 cm in diameter) receiving rituximab monotherapy (n = 39) had a higher incidence of Grade 3 or 4 adverse events than patients without bulky disease (n = 195; 25.6 % versus 15.4 %), the most frequent of which were infusion-related or hematologic events. During the treatment period, the most common Grade 3 or 4 events included neutropenia (10 % of patients), hypotension (5 %), dyspnea (5 %), and anemia (5 %) in patients with bulky disease, and chills (2 %), anemia (2 %), and leukopenia (2 %) in patients without bulky disease. The incidence of any adverse event was similar in these two groups (92.3 % in those with bulky disease versus 89.2 % in those without bulky disease) [22, 23, 76, 77, 78, 84, 92].

6.3.14 Retreatment The percentage of patients reporting any adverse event (95 %) and Grade 3 or 4 adverse events (13.3 %) upon retreatment with further courses of rituximab monotherapy (n = 60) was similar to the percentage of patients reporting any adverse event (89.7 %) and Grade 3 or 4 adverse events (14.8 %) upon initial exposure to rituximab (n = 166) [22].

6.4 Summary of Adverse Events 6.4.1 Rituximab Monotherapy in Patients with Previously Treated

Indolent NHL This section presents adverse events identified from an integrated assessment of safety from six studies of rituximab monotherapy in 356 patients with previously treated indolent NHL: Studies 102-01 [78], 102-02 [76, 77], 102-05 [84], 102-06 [92], 102-08B [23], and 102-08R [22]. Most patients received one course consisting of rituximab 375 mg/m2 once weekly for 4 weeks. However, 58 patients in Study 102-08R received more than one course, 37 patients in Study 102-06 received 375 mg/m2 once weekly for 8 weeks, and 25 patients in Studies 102-01 and 102-02 received doses other than 375 mg/m2 once weekly for 4 weeks, with single doses ranging up to 500 mg/m2. A total of 39 patients had bulky disease. The adverse events in this section were considered by the investigator to be related to or of unknown relationship to rituximab and occurred after the first dose of rituximab and up to 12 months after treatment was completed. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) scale (1998).

Table 15 provides a summary of the most common rituximab-related adverse events (≥ 5 % of patients) identified from the integrated assessment of safety.


Table 15 Rituximab-Related Adverse Events Experienced by ≥ 5 % of Patients in the Integrated Safety Assessment for Studies of Rituximab Monotherapy in Patients with Previously Treated Indolent NHL

No. ( %) of Patients Body System/ Adverse Event

All Grades (n = 356)

Grade 3 or 4 (n = 356)

Any event 324 (91.0 %) 63 (17.7 %)

Body as a whole

Fever 172 (48.3 %) 2 (0.6 %)

Chills 113 (31.7 %) 8 (2.2 %)

Asthenia 64 (18.0 %) 1 (0.3 %)

Headache 45 (12.6 %) 2 (0.6 %)

Throat irritation 27 (7.6 %) 0

Abdominal pain 25 (7.0 %) 2 (0.6 %)

Cardiovascular system Hypotension 35 (9.8 %) 3 (0.8 %)

Digestive system

Nausea 61 (17.1 %) 1 (0.3 %)

Vomiting 24 (6.7 %) 1 (0.3 %)

Blood and lymphatic system

Leukopenia 44 (12.4 %) 10 (2.8 %)

Neutropenia 40 (11.2 %) 15 (4.2 %)

Thrombocytopenia 34 (9.6 %) 6 (1.7 %)

Metabolic and nutritional disorders Angioedema 38 (10.7 %) 1 (0.3 %)

Hyperglycemia 19 (5.3 %) 1 (0.3 %)

Musculoskeletal system Myalgia 29 (8.1 %) 1 (0.3 %)

Arthralgia 21 (5.9 %) 2 (0.6 %)

Nervous system Dizziness 26 (7.3 %) 0

Respiratory system Bronchospasm 28 (7.9 %) 5 (1.4 %)

Rhinitis 26 (7.3 %) 1 (0.3 %)

Respiratory system (continued)

Increased cough 18 (5.1 %) 1 (0.3 %)

Skin and appendages

Pruritus 44 (12.4 %) 1 (0.3 %)

Rash 40 (11.2 %) 1 (0.3 %) Roche Investigator's Brochure 11th Version December 2006 RO45-2294 -


All Grades (n = 356)

Grade 3 or 4 (n = 356)

Urticaria 26 (7.3 %) 3 (0.8 %) Note: Infections are not included in this table. Adverse events that were related to or of unknown relationship to treatment and occurred in < 5 % and ≥ 1 % of patients are listed below, with the percentage of patients with Grade 3 or 4 events indicated in parentheses as applicable. Infections are excluded from the list but are summarized in a separate section below.

• Body as a whole: back pain (0.3 %), chest pain, neck pain, tumor pain, pain, flushing, malaise, and cold syndrome

• Cardiovascular system: hypertension (0.3 %), tachycardia, arrhythmia (0.6 %), and orthostatic hypotension

• Digestive system: diarrhea, dyspepsia, anorexia, dysphagia (0.3 %), stomatitis, and constipation

• Blood and lymphatic system: anemia (1.1 %) • Metabolic and nutritional disorders: peripheral edema, face edema, LDH increase,

hypocalcemia, and weight decrease • Musculoskeletal system: pain (0.3 %) and hypertonia • Nervous system: anxiety, paresthesia, hypoesthesia, agitation, insomnia, and

vasodilatation • Respiratory system: dyspnea (0.8 %), chest pain, and respiratory disease • Skin and appendages: night sweats and sweating • Special senses: lacrimation disorder, conjunctivitis, ear pain, and tinnitus The following adverse events were reported in <1 % of patients: coagulation disorders, asthma, lung disorder, bronchiolitis obliterans, hypoxia, abdominal enlargement, pain at the infusion site, bradycardia, lymphadenopathy, nervousness, depression, and dysgeusia.

6.4.1.1 Infusion-Related Reactions An infusion-related symptom complex consisting of fever and chills/rigors occurred in the majority of patients during the first rituximab infusion. Other frequently occurring infusion-related symptoms included nausea, urticaria, fatigue, headache, pruritus, bronchospasm, dyspnea, sensation of tongue or throat swelling (angioedema), rhinitis, vomiting, hypotension, flushing, and pain at disease sites. These reactions generally occurred within 30 minutes to 2 hours after initiation of the first infusion, and resolved with slowing or interruption of the rituximab infusion and with supportive care (e.g., IV saline, diphenhydramine, and acetaminophen). The incidence of infusion-related symptoms decreased from 77 % (7 % Grade 3 or 4) with the first infusion to approximately 30 % (2 % Grade 3 or 4) with the fourth infusion and 14 % (no Grade 3 or 4 events) with the eighth infusion.

6.4.1.2 Infections Rituximab-induced B-cell depletion occurred in 70 %–80 % of patients but was associated with decreased serum immunoglobulins only in a minority of patients. Infectious events, irrespective of causal assessment, occurred in 30.3 % of 356 patients:


18.8 % had bacterial infections, 10.4 % had viral infections, 1.4 % had fungal infections, and 5.9 % had infections of unknown etiology. Severe infectious events (Grade 3 or 4), including sepsis, occurred in 3.9 % of patients: 1.4 % during the treatment period and 2.5 % during the follow-up period. As these were single-arm trials, the contributory role of rituximab versus underlying NHL and its previous treatment to the development of these infectious events cannot be determined.

6.4.1.3 Hematologic Events Severe (Grade 3 or 4) thrombocytopenia was reported in 1.7 % of patients, severe neutropenia was reported in 4.2 % of patients, and severe anemia was reported in 1.1 % of patients. A single case of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following rituximab therapy were reported.

6.4.1.4 Cardiovascular Events Cardiovascular events were reported in 18.8 % of patients during the treatment period. The most frequently reported events were hypotension and hypertension. Two patients (0.6 %) experienced Grade 3 or 4 arrhythmia (including ventricular and supraventricular tachycardia) during a rituximab infusion, and 1 patient with a history of myocardial infarction experienced angina pectoris, which evolved into a myocardial infarction 4 days later.

6.4.2 Rituximab Combined with CHOP Chemotherapy in Patients with Previously Untreated Diffuse, Large B-Cell NHL

Table 16 shows all treatment-related Grade 3 or 4 adverse events plus Grade 2 infections reported in ≥ 2 % of patients in either treatment group (CHOP or R-CHOP) in Study LNH98-5, a randomized Phase III clinical trial in patients with previously untreated diffuse, large B-cell NHL (n = 398). Adverse events were graded according to the NCI CTC scale.

Table 16 Grade 3 or 4 Adverse Events plus Grade 2 Infections Experienced by ≥ 2 % Patients in Either the CHOP or R-CHOP Group of Study LNH98-5


CHOP (n = 196)

R-CHOP (n = 202)

Any event (i.e., Grade 3 or 4 adverse events plus Grade 2 infections) 148 (75.5 %) 164 (81.2 %)

Infections and infestations Bronchitis * 16 (8.2 %) 24 (11.9 %) Urinary tract infection 18 (9.2 %) 20 (9.9 %) Pneumonia 15 (7.7 %) 11 (5.4 %) Herpes zoster * 3 (1.5 %) 8 (4.0 %) Sepsis 7 (3.6 %) 4 (2.0 %) Septic shock 7 (3.6 %) 4 (2.0 %) Implant infection 5 (2.6 %) 4 (2.0 %) Superinfection lung 4 (2.0 %) 5 (2.5 %)



CHOP (n = 196)

R-CHOP (n = 202)

Septicemia staphylococcal 3 (1.5 %) 5 (2.5 %) Acute bronchitis * 1 (0.5 %) 5 (2.5 %) Lung infection 4 (2.0 %) 2 (1.0 %) Sinusitis * 0 5 (2.5 %)

Blood and lymphatic system disorders Febrile neutropenia † 47 (24.0 %) 46 (22.8 %) Neutropenia 10 (5.1 %) 11 (5.4 %) Anemia 10 (5.1 %) 9 (4.5 %)

Respiratory, thoracic, and mediastinal disorders Dyspnea * 7 (3.6 %) 18 (8.9 %) Cough 7 (3.6 %) 8 (4.0 %) Rhinitis 5 (2.6 %) 2 (1.0 %) Rhinorrhea 4 (2.0 %) 1 (0.5 %)

General disorders & administration site conditions

Pyrexia 34 (17.3 %) 26 (12.9 %)

Fatigue 14 (7.1 %) 9 (4.5 %)

General physical health deterioration 10 (5.1 %) 10 (5.0 %)

Mucosal inflammation NOS 5 (2.6 %) 8 (4.0 %)

Shivering * 2 (1.0 %) 7 (3.5 %)

Chest pain 4 (2.0 %) 4 (2.0 %)

Fall 4 (2.0 %) 3 (1.5 %)

Influenza-like illness 3 (1.5 %) 4 (2.0 %)

General disorders & administration site conditions (continued)

Malaise 4 (2.0 %) 2 (1.0 %)

Multi-organ failure 4 (2.0 %) 2 (1.0 %)

Asthenia 1 (0.5 %) 4 (2.0 %)

Edema lower limb 1 (0.5 %) 4 (2.0 %)

Gastrointestinal disorders

Vomiting 13 (6.6 %) 8 (4.0 %)

Abdominal pain * 9 (4.6 %) 13 (6.4 %)

Constipation 8 (4.1 %) 6 (3.0 %)

Nausea 9 (4.6 %) 4 (2.0 %)

Diarrhea 5 (2.6 %) 5 (2.5 %)



CHOP (n = 196)

R-CHOP (n = 202)

Vascular disorders

Venous thrombosis deep limb 6 (3.1 %) 6 (3.0 %)

Hypotension 3 (1.5 %) 5 (2.5 %)

Hypertension * 1 (0.5 %) 5 (2.5 %)

Venous thrombosis 1 (0.5 %) 4 (2.0 %)

Cardiac disorders

Cardiac failure 11 (5.6 %) 9 (4.5 %)

Atrial fibrillation * 1 (0.5 %) 5 (2.5 %)

Pulmonary edema 2 (1.0 %) 4 (2.0 %)

Nervous system disorders

Paresthesia 2 (1.0 %) 5 (2.5 %)

Investigations

Abnormal ejection fraction 4 (2.0 %) 4 (2.0 %)

Positive blood culture 4 (2.0 %) 1 (0.5 %)

Metabolism and nutrition disorders

Anorexia 5 (2.6 %) 4 (2.0 %)

Musculoskeletal, connective tissue, and bone disorders

Back pain 2 (1.0 %) 5 (2.5 %)

Psychiatric disorders

Confusion 5 (2.6 %) 0

Endocrine disorders

Diabetes mellitus inadequate control 4 (2.0 %) 2 (1.0 %) Note: For preferred terms, British spelling was changed to American spelling. NOS = not otherwise specified *Adverse events that were reported at a higher incidence (≥ 2 % difference) in the R-CHOP group compared with the CHOP group and, thus, may be attributable to R-CHOP. †Febrile neutropenia as reported by investigators: fever and neutropenia with or without documented infection (see also Infections section below).

6.4.2.1 Infusion-Related Reactions Grade 3 or 4 infusion-related reactions (defined as starting during or within 1 day of an infusion with rituximab) occurred in approximately 9 % of patients at the time of the first cycle of R-CHOP. The incidence of Grade 3 or 4 infusion-related reactions had decreased to <1 % by the eighth cycle of R-CHOP. The symptoms were consistent with those observed during monotherapy (see section 6.4.1) and included fever, chills, hypotension, hypertension, tachycardia, dyspnea, bronchospasm, nausea, vomiting, pain, and features


of TLS. Additional reactions reported in isolated cases at the time of R-CHOP therapy were myocardial infarction, atrial fibrillation, and pulmonary edema.

6.4.2.2 Infections The incidence of Grade 2–4 infections and/or febrile neutropenia was 55.4 % in the R-CHOP group and 51.5 % in the CHOP group. Febrile neutropenia (i.e., no report of concomitant documented infection) was reported only during the treatment period, in 20.8 % in the R-CHOP group and 15.3 % in the CHOP group. The overall incidence of Grade 2–4 infections was 45.5 % in the R-CHOP group and 42.3 % in the CHOP group, with no difference in the incidence of systemic bacterial and fungal infections. Grade 2-4 fungal infections (including both systemic and localized) were more frequent in the R-CHOP group (4.5 %) than the CHOP group (2.6 %); this difference was attributable to a higher incidence of localized Candida infections during the treatment period. The incidence of Grade 2–4 herpes zoster, including ophthalmic herpes zoster, was higher in the R-CHOP group (4.5 %) than the CHOP group (1.5 %), with 7 of the 9 cases in the R-CHOP group occurring during the treatment period.

6.4.2.3 Hematologic Events After each treatment cycle, Grade 3 or 4 leukopenia occurred more frequently in the R-CHOP group than the CHOP group (88 % versus 79 %), as did Grade 3 or 4 neutropenia (97 % versus 88 %). There was no evidence that neutropenia was more prolonged in the R-CHOP group. No difference between the two treatment groups was observed with respect to Grade 3 or 4 anemia (R-CHOP, 14 %; CHOP, 19 %) and Grade 3 or 4 thrombocytopenia (R-CHOP, 15 %; CHOP, 16 %). The time to recovery from all hematologic abnormalities was comparable in the two treatment groups.

6.4.2.4 Cardiac Events The incidence of Grade 3 or 4 cardiac arrhythmias, predominantly supraventricular arrhythmias such as tachycardia and atrial flutter/fibrillation, was higher in the R-CHOP group (14 patients, 6.9 %) than the CHOP group (3 patients, 1.5 %). All of these arrhythmias either occurred in the context of a rituximab infusion or were associated with predisposing conditions such as fever, infection, acute myocardial infarction, or preexisting respiratory and cardiovascular disease. No difference between the R-CHOP and CHOP group was observed in the incidence of other Grade 3 or 4 cardiac events, including heart failure, myocardial disease, and manifestations of coronary artery disease.

6.4.2.5 Neurologic Events During the treatment period, 4 patients (2 %) in the R-CHOP group, all with cardiovascular risk factors, experienced thromboembolic cerebrovascular accidents during the first treatment cycle. In contrast, 3 patients (1.5 %) had cerebrovascular events in the CHOP group, all of which occurred during the follow-up period. There was no difference between treatment groups in the incidence of other thromboembolic events.

6.4.3 Rituximab as Maintenance Treatment in Patients with Relapsed or Refractory Follicular NHL

The following data are from a Phase III clinical trial (Study M39022) where patients with relapsed or refractory follicular NHL were randomized in a first phase to induction treatment with CHOP or rituximab plus CHOP (R-CHOP) (Mabthera Summary of


Product Characteristics, 2006). Patients who responded to induction treatment with CHOP or R-CHOP were randomized in a second phase to receive no further treatment (observation) or rituximab maintenance treatment. Rituximab maintenance treatment consisted of a single infusion of rituximab at 375 mg/m2 body surface area administered every 3 months for a maximum period of 2 years or until disease progression.

In the induction phase of the trial, a total of 462 patients (228 CHOP, 234 R-CHOP) contributed to the safety evaluation of the two induction regimens. The Grade 3 and 4 adverse events that occurred in ≥2 % of the patients during the induction phase are summarized in Table 17.


Table 17 Induction Phase of Study M39022: Summary of NCI-CTC Grade 3 and 4 Adverse Events Reported in ≥2 % of 462 Patients in Either Group (CHOP or R-CHOP)

No. ( %) of Patients

Body System/ Adverse Event

CHOP (n = 288)

R-CHOP (n = 234)

Any event 152 (67 %) 185 (79 %)

Gastrointestinal disorders

Nausea* 9 (4 %) 13 (6 %)

Vomiting 8 (4 %) 7 (3 %)

Abdominal pain 6 (3 %) 4 (2 %)

Diarrhoea 5 (2 %) 6 (3 %)

Constipation* 1 (<1 %) 7 (3 %)

Stomatitis* 1 (<1 %) 4 (2 %)

Blood and lymphatic system disorders

Neutropenia* 108 (47 %) 129 (55 %)

Leucopenia 106 (46 %) 111 (47 %)

Thrombocytopenia 18 (8 %) 17 (7 %)

Febrile neutropenia* 8 (4 %) 14 (6 %)

Haematotoxicity 12 (5 %) 9 (4 %)

Anaemia 5 (2 %) 6 (3 %)

General and administration site conditions

Asthenia 10 (4 %) 5 (2 %)

Pyrexia 6 (3 %) 7 (3 %)


Sensory disturbance 4 (2 %) 7 (3 %)

Skin and subcutaneous tissue disorders

Alopecia* 15 (7 %) 30 (13 %)

Skin disorder* 2 (<1 %) 4 (2 %)

Infections and infestations

Neutropenic Infection 18 (8 %) 15 (6 %)

Sepsis 5 (2 %) 3 (1 %)

Urinary tract infection 4 (2 %) 3 (1 %)


Table 17 Induction Phase of Study M39022: Summary of NCI-CTC Grade 3 and 4 Adverse Events Reported in ≥2 % of 462 Patients in Either Group (CHOP or R-CHOP) (Cont.)

No. ( %) of Patients

Body System/ Adverse Event

CHOP (n = 288)

R-CHOP (n = 234)

Respiratory, thoracic and mediastinal disorders

Dyspnoea 6 (3 %) 3 (1 %)

Musculoskeletal and connective tissue disorders

Back pain* 1 (<1 %) 4 (2 %)

Metabolism and nutrition disorders

Hyperglycaemia 5 (2 %) 4 (2 %)

Immune system disorders

Hypersensitivity* - 10 (4 %)

Cardiac disorders

Cardiac disorder 6 (3 %) 2 (<1 %) *Adverse events that were reported at higher incidence (≥2 % difference) in the R-CHOP group compared to observation and therefore, may be attributable to rituximab.

A total of 332 patients (166 observation, 166 rituximab maintenance) were included in the safety evaluation of the maintenance phase of the study. Rituximab was administered at a dose of 375 mg/m2 body surface area once every 3 months until disease progression or for a maximum period of two years. The Grade 3 and 4 adverse events that occurred in ≥2 % of the patients during the maintenance phase are summarized in Table 18.


Table 18 Maintenance Phase of Study M39022: Summary of NCI-CTC Grade 3 and 4 Adverse Events Reported in ≥ 2 % of 332 Patients in Either Treatment Group (Observation or Rituximab Maintenance)


Observation (n = 166)

Rituximab (n = 166)

Any event 38 (23 %) 61 (37 %)

General and administration site conditions

Asthenia 4 (2 %) 1 (<1 %)

Infections and infestations

Pneumonia* 1 (<1 %) 3 (2 %)

Respiratory tract infection* - 3 (2 %)

Blood and lymphatic system disorders

Neutropenia* 7 (4 %) 17 (10 %)

Leucopenia* 4 (2 %) 8 (5 %)

Haematotoxicity 3 (2 %) 2 (1 %)


Sensory disturbance 2 (1 %) 3 (2 %)

Skin and subcutaneous tissue disorders

Alopecia* - 3 (2 %)

Vascular disorders

Hypertension 2 (1 %) 3 (2 %)

Cardiac disorders

Cardiac disorder* 4 (2 %) 6 (4 %) *Adverse events that were reported at higher incidence (≥2 % difference) in the rituximab maintenance group compared to observation and, therefore, may be attributable to rituximab.

6.4.3.1 Infusion-Related Reactions During maintenance treatment, non-serious signs and symptoms suggestive of an infusion-related reaction were reported in 41 % of patients as general disorders (mainly asthenia, pyrexia, influenza-like illness, pain) and in 7 % of patients as immune system disorders (hypersensitivity). Serious infusion-related reactions (defined as serious adverse events starting during or within one day of a rituximab infusion) occurred in <1 % of patients treated with rituximab maintenance.

6.4.3.2 Infections The proportion of patients with grade 1 to 4 infections was 25 % in the observation group and 45 % in the rituximab maintenance group. Grade 3 or 4 infections occurred in 3 % and 11 % of patients in the observation group and rituximab maintenance group, respectively. Grade 3 or 4 infections reported in ≥1 % of patients in the rituximab


maintenance group included pneumonia (2 %), respiratory tract infection (2 %), febrile infection (1 %), and herpes zoster (1 %). In a large proportion of infections (all grades), the infectious agent was not specified or isolated; however, in cases when an infectious agent was specified, the most frequently reported underlying agents were bacteria (observation 2 %, rituximab maintenance 10 %), viruses (observation 7 %, rituximab maintenance 11 %), and fungi (observation 2 %, rituximab maintenance 4 %). There was no cumulative toxicity in terms of infections reported over the 2-year maintenance period.

6.4.3.3 Haematologic Events Leukopenia (any grade) occurred in 21 % of patients in the observation group versus 29 % of patients in the rituximab maintenance group. Neutropenia was reported in 12 % and 23 % of patients in the observation group and rituximab maintenance group, respectively. There was a higher incidence of Grade 3 or 4 neutropenia (observation 4 %, rituximab maintenance 10 %) and leukopenia (observation 2 %, rituximab maintenance 5 %) in the rituximab maintenance group compared with the observation group. The incidence of Grade 3 or 4 thrombocytopenia (observation 1 %, rituximab <1 %) was low in both groups.

6.4.3.4 Cardiac Disorders The incidence of Grade 3 or 4 cardiac disorders was comparable between the two treatment groups (4 % observation, 5 % rituximab maintenance). Cardiac events were reported as serious adverse events in <1 % of patients in the observation group and in 3 % of patients in the rituximab maintenance group. Events in the rituximab maintenance group included atrial fibrillation (1 %), myocardial infarction (1 %), left ventricular failure (<1 %), and myocardial ischemia (<1 %).

6.4.3.5 IgG levels After induction treatment, median IgG levels were below the lower limit of normal (LLN) (<7 g/L) in both the observation and the rituximab maintenance groups. In the observation group, the median IgG level subsequently increased to above the LLN, but remained constant in the rituximab maintenance group. The proportion of patients with IgG levels below the LLN was approximately 60 % in the rituximab maintenance group throughout the 2-year treatment period, while the proportion decreased in the observation group (36 % after 2 years).

6.4.4 Rituximab Combined with CVP Chemotherapy in Patients with Previously Untreated Indolent NHL

Data regarding adverse events in patients treated with R-CVP were based on Study M39021 (Marcus, 2005), a Phase III clinical trial of 321 patients comparing R-CVP with CVP. Differences between the treatment groups with respect to the type and incidence of adverse events were mainly accounted for by events typically associated with rituximab monotherapy. More patients in the R-CVP group than the CVP group experienced an adverse event within 24 hours of an infusion (71 % versus 51 %). The following NCI CTC Grade 3 or 4 adverse events occurred at a ≥ 2 % higher frequency in the R-CVP group compared with the CVP group and therefore may be attributable to R-CVP: fatigue (3.7 % versus 1.3 %) and neutropenia (3.1 % versus 0.6 %).


A total of 9 % of patients reported signs and symptoms of severe or life-threatening (Grade 3 or 4) infusion-related reactions, which was comparable to that observed with monotherapy.

The overall proportion of patients with infections and infestations during and for 28 days after treatment was comparable between groups (R-CVP, 33 %; CVP, 32 %). The most common of these were upper respiratory tract infections, particularly nasopharyngitis.

A total of 24 % of patients in the R-CVP group and 14 % of patients in the CVP group experienced Grade 3 or 4 neutropenia during treatment, but the incidence of Grade 4 neutropenia was comparable between treatment groups. The higher incidence of neutropenia in the R-CVP group was not associated with a higher incidence of infections and infestations.

The incidence of Grade 3 or 4 anemia (R-CVP, 0.6 %; CVP, 1.9 %) and cardiac events (R-CVP, 4 %; CVP, 5 %) was comparable for both groups.

6.4.5 Adverse Events from Postmarketing Experience The lists of countries in which rituximab induction treatment has been approved as of October 2006 are provided in appendix B ( ~xr18i ) for the following indications: relapsed or chemoresistant, low-grade or follicular, CD20+, B-cell NHL (Table B-1); Stage III or IV, follicular NHL in combination with CVP chemotherapy (Table B-2); and CD20+, diffuse, large B-cell NHL in combination with CHOP chemotherapy (Table B-3). In addition, rituximab maintenance treatment of relapsed/refractory follicular lymphoma responding to induction therapy with chemotherapy has been approved in the list of countries provided in Table B-4. The sections below provide descriptions of serious adverse events that were reported as part of the continuing postmarketing surveillance of rituximab safety.

6.4.5.1 Cardiovascular System Severe cardiac events, including heart failure and myocardial infarction, have been observed, mainly in patients with prior cardiac conditions or exposure to cardiotoxic chemotherapy and mostly in association with infusion-related reactions. Fatal cardiac failure with symptomatic onset weeks after rituximab therapy has been reported rarely. Vasculitis, predominantly cutaneous, such as leukocytoclastic vasculitis, has been reported very rarely.

6.4.5.2 Blood and Lymphatic System Cases of pancytopenia and aplastic anemia have been very rarely reported. Rarely, the onset of neutropenia has occurred more than 4 weeks after the last infusion of rituximab [10, 120]. In very rare isolated cases, the duration of recovery from neutropenia was prolonged [98].

In patients with Waldenström’s macroglobulinemia, transient increases in serum IgM levels have been observed following initiation of rituximab therapy. These increases may result in hyperviscosity syndrome requiring plasmapheresis.

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6.4.5.3 Infections and Infestations There have been some very rare, isolated cases of HBV reactivation, which in some cases have been fatal [123]. The majority of these reports occurred in patients treated with rituximab in combination with myelosuppressive chemotherapy regimens. Rituximab should be used cautiously in patients with a history of HBV infection.

Other serious viral infections, either new, reactivation, or exacerbation, some of which were fatal, have been reported with rituximab treatment. The majority of patients had received rituximab in combination with chemotherapy or as part of a hematopoetic stem cell transplant. Examples of these serious viral infections are infections caused by the herpes viruses (cytomegalovirus, Varicella zoster virus, and Herpes simplex virus), JC virus (PML), and hepatitis C virus.

A report in the literature described an increase in fatal infections among patients with HIV-associated NHL treated with R-CHOP compared with CHOP alone [61].

6.4.5.4 Respiratory System Respiratory failure or insufficiency and pulmonary infiltrates in the context of infusion-related reactions have been reported [8] (see section 6.3.1.1). Pulmonary infiltrates not related to infusion-related reactions and interstitial pneumonitis have been reported rarely. There have been a limited number of reports of bronchiolitis obliterans with onset up to 6 months after rituximab therapy.

6.4.5.5 Skin and Appendages Severe bullous skin reactions including toxic epidermal necrolysis and paraneoplastic pemphigus have been reported rarely. Some of these reactions have been associated with a fatal outcome.

6.4.5.6 Nervous System Cases of cranial neuropathy with or without peripheral neuropathy have been reported rarely. Signs and symptoms of cranial neuropathy, such as severe vision loss, hearing loss, loss of other senses, and facial nerve palsy, occurred at various times up to several months after completion of rituximab therapy.

6.4.5.7 Body as a Whole Serum sickness–like reactions have been reported rarely [48].

6.4.5.8 Urogenital System Renal toxicity has been very rarely reported in patients administered concomitant cisplatin therapy.

6.4.5.9 Bowel Obstruction and Perforation Gastrointestinal obstruction and perforation, in some cases leading to death, have been observed in patients receiving rituximab for treatment of NHL. In the majority of these cases, rituximab was administered with chemotherapy. Complaints of abdominal pain, especially early in the course of treatment, should prompt a thorough diagnostic evaluation and appropriate treatment.


6.4.6 Safety from Ongoing, Company-Sponsored Clinical Trials in Patients with Non-Hematologic, Non-Malignant Diseases

Rituximab is currently being investigated in patients with rheumatoid arthritis and other non-hematologic, non-malignant diseases such as multiple sclerosis, systemic lupus erythematosus, and ulcerative colitis. Studies in these patients are presented in a separate Investigator Brochure available from the Sponsor. Table 19 provides a list of adverse events filed as Investigational New Drug Application (IND) safety reports since March 2004 for patients with non-hematologic, non-malignant diseases. It should be noted that these adverse events are not considered expected for the purpose of regulatory reporting for oncology trials.


Table 19 IND Safety Reports Since March 2004: Patients with Non-Hematologic, Non-Malignant Diseases

Preferred term Indication Source

Arthritis bacterial Rheumatoid arthritis WA 16291

Inflammation (arytenoiditis) Rheumatoid arthritis WA 16291

Myocardial infarction Rheumatoid arthritis WA17042/102-20

Pyelonephritis Rheumatoid arthritis WA17043/U2644G

Bronchopulmonary aspergillosis Lung transplant rejection U2400S

Cardiac tamponade Rheumatoid arthritis WA17042/102-20

Pneumonia primary atypical Rheumatoid arthritis WA16855/U2653G

Hepatitis B Rheumatoid arthritis WA17042/102-20

Septic shock Rheumatoid arthritis WA16855/U2653G

Oligodendroglioma Rheumatoid arthritis WA17531/102-21

Diverticulitis Rheumatoid arthritis WA17042/102-20

Death Rheumatoid arthritis WA17042/102-20

Sudden death Rheumatoid arthritis WA17531/102-21

Convulsion Rheumatoid arthritis WA17043/U2644G

Meningitis Multiple sclerosis U2786G

Death Rheumatoid arthritis WA17531/102-21

Pneumonia Multiple sclerosis U2786G

Intra-uterine death Multiple sclerosis U2786G

Breast cancer Rheumatoid arthritis WA17531/102-21

Lacunar infarction Rheumatoid arthritis WA17531/102-21

Lupus nephritis Systemic lupus erythematosus U2971G

Coronary artery disease Rheumatoid arthritis WA16855/U2653G

Large intestine perforation Rheumatoid arthritis WA17531/102-21

Death Systemic lupus erythematosus U2971G Notes: Expedited safety reports were required for serious unexpected adverse events considered to be related to rituximab. Per company standard operating procedure, deaths of unknown cause, regardless of causality, were also reported on an expedited basis.

6.5 Expected Adverse Events Table 20 lists all adverse events that, for regulatory reporting purposes, are considered to be expected when the Investigator Brochure is used as the reference document, regardless of their seriousness, in patients treated with rituximab for B-cell malignancies. This list was compiled using data from the Sponsor’s current Core Data Sheet, U.S. Prescribing Information, Summary of Product Characteristics, and ongoing company-sponsored trials.


Table 20 Expected Adverse Events

System Organ Class/ Adverse Event Preferred Term Comments

Infections and infestations Severe infections, including sepsis, occurred in 3.9 % of patients in studies of rituximab monotherapy

Sepsis * Bronchitis NOS Fungal infection NOS Herpes viral pneumonia * Herpes zoster Herpes zoster ophthalmic Meningitis staphylococcal Intrathecal administration Pneumonia NOS * Aspergillosis * In association with concomitant chemotherapy Serious viral infection* Infections include JC virus (PML), cytomegalovirus,

Herpes simplex virus, Parvovirus B19, Varicella zoster virus, West Nile virus, and hepatitis C virus.

Candidal infection NOS Bronchitis acute NOS Sinusitis NOS Tuberculosis Atypical pneumonia

Blood and lymphatic system disorders Pancytopenia * Leukopenia NOS Neutropenia * Thrombocytopenia Red cell aplasia Aplastic anemia Febrile bone marrow aplasia Hemolytic anemia NOS Anemia NOS Lymphadenopathy Coagulation disorder NOS Febrile neutropenia Thrombocytopenia * Late onset neutropenia Prolonged pancytopenia Prolonged neutropenia



Respiratory disorders Dyspnea NOS † Cough aggravated Asthma NOS † Obliterative bronchiolitis * Bronchospasm NOS † Respiratory disorder NOS Acute respiratory failure † Pulmonary embolism Lung infiltration NOS Pulmonary interstitial infiltration Pneumonitis NOS * Interstitial pneumonitis Hypoxia † Rhinitis NOS

General disorders and administration site disorders

Pyrexia † Fatigue Asthenia Pain NOS † Rigors † Chest pain Injection site pain Pain at the infusion site Edema peripheral Malaise †

Hepatobiliary disorders Hepatitis B virus reactivation * Acute hepatitis Hepatitis In association with concomitant chemotherapy

Gastrointestinal disorders Vomiting NOS † Abdominal pain NOS Constipation Nausea † Diarrhea NOS Throat irritation † Intestinal perforation* Intestinal obstruction* Dyspepsia



Gastrointestinal disorders (continued) Dysphagia Stomatitis Abdominal distension Abdominal enlargement Tongue edema † Pharyngeal edema †

Vascular disorders Flushing † Hypotension NOS † Hypertension NOS † Vasculitis Cerebrovascular accident NOS Thromboembolic events Vasodilatation Orthostatic hypotension Deep vein thrombosis Thrombosis

Cardiac disorders Cardiac failure NOS † Atrial fibrillation Atrial flutter Ventricular tachycardia † Supraventricular tachycardia † Tachycardia NOS † Pulmonary edema NOS † Bradycardia NOS Arrhythmia NOS † Angina pectoris † Myocardial infarction †

Nervous system disorders Headache NOS Dizziness (excluding vertigo) Encephalopathy Hypoesthesia Dysgeusia Cranial neuropathy NOS Peripheral neuropathy NOS Facial nerve disorder NOS Facial nerve palsy Hypertonia



Nervous system disorders (continued) Paresthesia

Investigations Blood LDH increased † Weight decreased Drug-specific antibody present HACA and HAMA

Metabolism and nutrition disorders Hyperuricemia † Hyperkalemia † Hypocalcemia † Hyperglycemia NOS Anorexia

Musculoskeletal, connective tissue, and bone disorders

Neck pain Myalgia Osteonecrosis‡ Occurred in a patient with lymphoma and SLE Arthralgia Back pain

Psychiatric disorders Agitation Insomnia Nervousness Depression NOS Anxiety NEC

Ear and labyrinth disorders Ear pain Tinnitus Deafness NOS Hearing loss

Eye disorders Lacrimal disorder NOS Blindness NOS Vision loss Conjunctivitis NOS

Injury, poisoning, and procedural complications

Anaphylactoid reaction † Subdural hematoma Secondary to thrombocytopenia



Immune system disorders Immune complex mediated hypersensitivity (serum sickness–like reaction)

Cytokine release syndrome † Hypersensitivity NOS † Anaphylactic reaction †

Neoplasms (benign, malignant, and unspecified), including cysts and polyps

Tumor lysis syndrome † Tumor pain

Renal and urinary disorders Renal failure acute †

Skin and subcutaneous tissue disorders Urticaria NOS † Angioneurotic edema † Face edema † Rash NOS Pruritus NOS Night sweats Sweating increased Leukocytoclastic vasculitis Dermatitis bullous * Severe bullous skin reactions Paraneoplastic pemphigus * Toxic epidermal necrolysis *

NEC = not elsewhere classified; NOS = not otherwise specified. Note: For preferred terms, British spelling was changed to American spelling. *Some events have been associated with fatal outcomes. †Indicates events seen predominantly in infusion-related reactions. Some events have been associated with fatal outcomes. Refer to Section 6.3 for additional details. ‡Data obtained after the safety data cut-off date of 15 June 2006.


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79. Maloney DG, Press OW, Braziel RM, Unger JM, LeBlanc ML, Grogan TM, et al. A Phase II trial of CHOP followed by rituximab chimeric monoclonal anti-CD20 antibody for treatment of newly diagnosed follicular non-Hodgkin's lymphoma: SWOG 9800. Blood (ASH Annual Meeting Abstracts) 2001;98(11):843A, #3502.

80. Maloney DG, Smith B, Rose A. Rituximab: Mechanism of action and resistance. Semin Oncol 2002;29(1 Suppl 2):2-9.

81. Mangel J, Leitch HA, Connors JM, Buckstein R, Imrie K, Spaner D, et al. Intensive chemotherapy and autologous stem-cell transplantation plus rituximab is superior to conventional chemotherapy for newly diagnosed advanced stage mantle-cell lymphoma: A matched pair analysis. Ann Oncol 2004;15(2):283-90.

82. Marcus R, Imrie K, Belch A, Cunningham D, Flores E, Catalano J, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 2005;105(4):1417-23.

83. Martinelli G, Laszlo D, Ferreri AJ, Pruneri G, Ponzoni M, Conconi A, et al. Clinical activity of rituximab in gastric marginal zone non-Hodgkin's lymphoma resistant to or not eligible for anti-Helicobacter pylori therapy. J Clin Oncol 2005;23(9):1979-83.

84. McLaughlin P, Grillo-Lopez AJ, Link BK, Levy R, Czuczman MS, Williams ME, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program. J Clin Oncol 1998;16(8):2825-33.

85. McLaughlin P, Rodriguez MA, Hagemeister FB, Romaguera J, Sarris AH, Younes A, et al. Stage IV indolent lymphoma: A randomized study of concurrent vs. sequential use of FND chemotherapy (fludarabine, mitoxantrone, dexamethasone) and rituximab (R) monoclonal antibody therapy, with interferon maintenance. Proc Am Soc Clin Oncol 2003;22:#2269.

86. Medeiros BC, Geraghty S, Stabler SP. Improved response to immune tolerance therapy for factor VIII inhibitor after Rituximab therapy. Blood (ASH Annual Meeting Abstracts) 2002;100(11):103B, #3890.

87. Milpied N, Vasseur B, Parquet N, Garnier JL, Antoine C, Quartier P, et al. Humanized anti-CD20 monoclonal antibody (rituximab) in post transplant B-lymphoproliferative disorder: a retrospective analysis on 32 patients. Ann Oncol 2000;11(Suppl 1):113-6.

88. O'Brien SM, Kantarjian H, Thomas DA, Giles FJ, Freireich EJ, Cortes J, et al. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol 2001;19(8):2165-70.

89. Oertel SHK, Zeidler K, Papp-Vary M, Reinke P, Jonas S, Verschuuren E, et al. Monotherapy with the anti-CD20 antibody rituximab (ritux) in patients


with post-transplant lympho-proliferative disease (PTLD). Results of a multicentre phase II study. Blood (ASH Annual Meeting Abstracts) 2003;102(11):413a, #1501.

90. Pfreundschuh M, Kloess M, Schmits R, Zeynalova S, Lengfelder E, Franke A, et al. Six, Not Eight Cycles of Bi-Weekly CHOP with Rituximab (R-CHOP-14) Is the Preferred Treatment for Elderly Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Results of the RICOVER-60 Trial of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL). Blood (ASH Annual Meeting Abstracts) 2005;106(11):#13.

91. Pfreundschuh M, Trumper L, Osterborg A, Pettengell R, Trneny M, Imrie K, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: A randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006;7(5):379-91.

92. Piro LD, White CA, Grillo-López AJ, Janakiraman N, Saven A, Beck TM, et al. Extended rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. Ann Oncol 1999;10(6):655-61.

93. Pruthi RK, Schmidt KA, Slaby JA, Hook CC, Nichols WL. Rituximab in treatment of high titer FVIII inhibitor in congenital hemophilia A (HA). Blood (ASH Annual Meeting Abstracts) 2002;100(11):104B, #3893.

94. Quartier P, Brethon B, Philippet P, Landman-Parker J, Le Deist F, Fischer A. Treatment of childhood autoimmune haemolytic anaemia with rituximab. Lancet 2001;358(9292):1511-3.

95. Reddy P, Deauna-Limayo D, Cook J, Ganguly S, Blecke C, Bodensteiner D, et al. Rituximab in the treatment of relapsed thrombotic thrombocytopenic purpura. Ann Hematol 2005;84(4):232-5.

96. Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 1994;83(2):435-45.

97. Ribera J-M, Oriol A, Morgades M, Gonzalez-Barca E, Miralles P, Lopez-Guillermo A, et al. Treatment with Rituximab, CHOP and Highly Active Antiretroviral Therapy (HAART) in AIDS-Related Diffuse Large B-Cell Lymphomas (DLBCL). Study of 60 Patients. Blood (ASH Annual Meeting Abstracts) 2005;106(11):#774.

98. Saikia TK, Menon H, Advani SH. Prolonged neutropenia following anti CD20 therapy in a patient with relapsed follicular non-Hodgkin's lymphoma and corrected with IVIG. Ann Oncol 2001;12(10):1493-4.

99. Salles GA, Foussard C, Nicolas M, Franck M, Chantal D, Thierry L, et al. Rituximab Added {alpha}IFN+CHVP Improves the Outcome of Follicular Lymphoma Patients with a High Tumor Burden: First Analysis of the GELA-


GOELAMS FL-2000 Randomized Trial in 359 Patients. Blood (ASH Annual Meeting Abstracts) 2004;104(11):#160.

100. Schulz H, Klein SK, Rehwald U, Reiser M, Hinke A, Knauf WU, et al. Phase 2 study of a combined immunochemotherapy using rituximab and fludarabine in patients with chronic lymphocytic leukemia. Blood 2002a;100(9):3115-20.

101. Schulz H, Rehwald U, Reiser M, Ruediger T, Morschhauser F, Diehl V, et al. Phase II trial of rituximab in patients with relapsed CD20-positive Hodgkin's lymphoma: An update from the German Hodgkin's Lymphoma Study Group (GHSG). Blood (ASH Annual Meeting Abstracts) 2002b;100(11):775a, #3066.

102. Schulz H, Trelle S, Reiser M, Sieber M, Diehl V, Engert A. Rituximab in Relapsed Lymphocyte Predominant Hodgkin's Disease (LPHD). Long-Term Results of a Phase-II Study from the German Hodgkin Lymphoma Study Group (GHSG). Blood (ASH Annual Meeting Abstracts) 2005;106(11):#1503.

103. Scully M, Cavenagh J, Hagger D, Benjamin S, Mackie I, McHin SJ, et al. Normalisation of ADAMTS 13 Activity and Disappearance of ADAMTS 13 Antibody Following Rituximab in Acute Refractory Thrombotic Thrombocytopenic Purpura. Blood (ASH Annual Meeting Abstracts) 2005;106(11):#1230.

104. Sehn LH, Donaldson J, Chhanabhai M, Fitzgerald C, Gill K, Klasa R, et al. Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol 2005;23(22):5027-33.

105. Serinet MO, Jacquemin E, Habes D, Debray D, Fabre M, Bernard O. Anti-CD20 monoclonal antibody (rituximab) treatment for Epstein-Barr virus-associated, B-cell lymphoproliferative disease in pediatric liver transplant recipients. Journal Of Pediatric Gastroenterology And Nutrition 2002;34(4):389-93.

106. Solal-Celigny P, Imrie K, Belch A, Robinson KS, Cunningham D, Rueda A, et al. Mabthera (Rituximab) Plus CVP Chemotherapy for First-Line Treatment of Stage III/IV Follicular Non-Hodgkin's Lymphoma (NHL): Confirmed Efficacy with Longer Follow-Up. Blood (ASH Annual Meeting Abstracts) 2005;106(11):#350.

107. Solal-Celigny P, Salles GA, Brousse N, Franchi-Rezgui P, Soubeyran P, Delwail V, et al. Single 4-Dose Rituximab Treatment for Low-Tumor Burden Follicular Lymphoma (FL): Survival Analyses with a Follow-Up (F/Up) of at Least 5 Years. Blood (ASH Annual Meeting Abstracts) 2004;104(11):#585.

108. Spina M, Simonelli C, Vaccher E, Rossi G, Jaeger U, Sparano JA, et al. Rituximab and infusional cyclophosphamide, doxorubicin and etoposide (CDE) in combination with HAART: A safe and highly active regimen in


HIV-related non-Hodgkin's lymphomas (NHL). Blood (ASH Annual Meeting Abstracts) 2003;102(11):123a, #421.

109. Stasi R, Brunetti M, Stipa E, Amadori S. Selective B-cell depletion with rituximab for the treatment of patients with acquired hemophilia. Blood 2004;103(12):4424-8.

110. Stasi R, Pagano A, Stipa E, Amadori S. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura. Blood 2001;98(4):952-7.

111. Thomas DA, O'Brien SA, Giles FJ, Cortes J, Faderl S, Kantarjian H, et al. Single agent Rituxan in early stage chronic lymphocytic leukemia (CLL). Blood (ASH Annual Meeting Abstracts) 2001;98(11):#1533.

112. Tobinai K, Igarashi T, Itoh K, Kobayashi Y, Taniwaki M, Ogura M, et al. Japanese multicenter phase II and pharmacokinetic study of rituximab in relapsed or refractory patients with aggressive B-cell lymphoma. Ann. Onc. 2004;15(5):821-30.

113. Tobinai K, Kobayashi Y, Narabayashi M, Ogura M, Kagami Y, Morishima Y, et al. Feasibility and pharmacokinetic study of a chimeric anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab) in relapsed B-cell lymphoma. Ann. Onc. 1998;9(5):527-34.

114. Treon SP, Agus TB, Link B, Rodrigues G, Molina A, Lacy MQ, et al. CD20-directed antibody-mediated immunotherapy induces responses and facilitates hematologic recovery in patients with Waldenström’s macroglobulinemia. J Immunother 2001;24(3):272-9.

115. Treon SP, Branagan A, Wasi P, Emmanouilides CA, Frankel SR, Lister A, et al. Combination Therapy with Rituximab and Fludarabine in Waldenström’s Macroglobulinemia. Blood (ASH Annual Meeting Abstracts) 2004a;104(11):#753.

116. Treon SP, Branagan AR, Hunter Z, Santos D, Tournhilac O, Anderson KC. Paradoxical increases in serum IgM and viscosity levels following rituximab in Waldenström's macroglobulinemia. Ann Oncol 2004b;15(10):1481-3.

117. Treon SP, Emmanouilides C, Kimby E, Kelliher A, Preffer F, Branagan AR, et al. Extended rituximab therapy in Waldenström’s macroglobulinemia. Ann Oncol 2005;16(1):132-8.

118. Van der Kolk LE, Baars JW, Prins MH, Van Oers MH. Rituximab treatment results in impaired secondary humoral immune responsiveness. Blood 2002;100(6):2257-9.

119. van Esser JWJ, Niesters HGM, van der Holt B, Meijer E, Osterhaus ADME, Gratama JW, et al. Prevention of Epstein-Barr virus-lymphoproliferative disease by molecular monitoring and preemptive rituximab in high-risk patients after allogeneic stem cell transplantation. Blood 2002;99(12):4364-9.


120. Voog E, Morschhauser F, Solal-Celigny P. Neutropenia in patients treated with rituximab. N Engl J Med 2003;348(26):2691-4.

121. Vose JM, Link BK, Grossbard ML, Czuczman M, Grillo-López A, Gilman P, et al. Phase II study of rituximab in combination with CHOP chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma. J Clin Oncol 2001;19(2):389-97.

122. Vose JM, Link BK, Grossbard ML, Czuczman M, Grillo-López AJ, Benyunes M, et al. Long term follow-up of a phase II study of rituximab in combination with CHOP chemotherapy in patients with previously untreated aggressive non-Hodgkin's lymphoma (NHL). Blood (ASH Annual Meeting Abstracts) 2002;100(11):361a, #1396.

123. Westhoff TH, Jochimsen F, Schmittel A, Stöffer-Meilicke M, Schäfer JH, Zidek W, et al. Fatal hepatitis B virus reactivation by an escape mutant following rituximab therapy. Blood 2003;102(5):1930.

124. Wierda W, O'Brien S, Wen S, Faderl S, Garcia-Manero G, Thomas D, et al. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol 2005;23(18):4070-8.

125. Wiestner A, Cho HJ, Asch AS, Michelis MA, Zeller JA, Peerschke EIB, et al. Rituximab in the treatment of acquired factor VIII inhibitors. Blood 2002;100(9):3426-8.

126. Wilson WH, Gutierrez M, O'Connor P, Frankel S, Jaffe E, Chabner BA, et al. The role of rituximab and chemotherapy in aggressive B-cell lymphoma: A preliminary report of dose-adjusted EPOCH-R. Semin Oncol 2002;29(1 Suppl 2):41-7.

127. Winkler U, Jensen M, Manzke O, Schulz H, Diehl V, Engert A. Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8). Blood 1999;94(7):2217-24.

128. Witzig TE, Vukov AM, Habermann TM, Geyer S, Kurtin PJ, Friedenberg WR, et al. Rituximab Therapy for Patients With Newly Diagnosed, Advanced-Stage, Follicular Grade I Non-Hodgkin's Lymphoma: A Phase II Trial in the North Central Cancer Treatment Group. J Clin Oncol 2005;23(6):1103-8.

129. Yomtovian R, Niklinski W, Silver B, Sarode R, Tsai HM. Rituximab for chronic recurring thrombotic thrombocytopenic purpura: A case report and review of the literature. Br J Haematol 2004;124(6):787-95.

130. Younes A, McLaughlin P, Goy A, Medeiros LJ, Jones D, Fayad L, et al. Rituximab plus ABVD therapy for newly diagnosed patients with classical Hodgkin's disease: A novel combination program targeting the cancer cells


and the microenvironment. Blood (ASH Annual Meeting Abstracts) 2003;102(11):27a, #83.

131. Zecca M, Nobili B, Ramenghi U, Amendola G, Rosito P, Jankovic M, et al. Rituximab for the treatment of refractory autoimmune hemolytic anemia in children. Blood (ASH Annual Meeting Abstracts) 2002;100(11):444a, #1722.

132. Zinzani PL, Pulsoni A, Perrotti A, Soverini S, Zaja F, De Renzo A, et al. Fludarabine plus mitoxantrone with and without rituximab versus CHOP with and without rituximab as front-line treatment for patients with follicular lymphoma. J Clin Oncol 2004;22(13):2654-61.

133. Zojer N, Kirchbacher K, Vesely M, Hubl W, Ludwig H. Rituximab treatment provides no clinical benefit in patients with pretreated advanced multiple myeloma. Leuk Lymphoma 2006;47(6):1103-9.


APPENDIX A. OVERVIEW OF SELECTED CLINICAL TRIALS OF RITUXIMAB

Table A- 1. Studies of Rituximab in Patients with Indolent (Low-Grade or Follicular) Non-Hodgkin’s Lymphoma ...............................................................................2

Table A- 2. Studies of Rituximab in Patients Aggressive Non-Hodgkin’s Lymphoma..........6 Table A- 3. Studies of Rituximab in Patients with Chronic Lymphocytic Leukemia or

Small Lymphocytic Lymphoma ........................................................................8 Table A- 4. Studies of Rituximab in Patients with Mantle Cell Lymphoma............................9 Table A- 5. Studies of Rituximab in Patients with Waldenström’s Macroglobulinemia .......12 Table A- 6. Studies of Rituximab in Patients with Multiple Myeloma ..................................13 Table A- 7. Studies of Rituximab in Patients with Hodgkin’s Disease ..................................14 Table A- 8. Studies of Rituximab in Patients with Posttransplant Lymphoproliferative

Disorders ..........................................................................................................15 Table A- 9. Additional Studies of Rituximab .........................................................................16


Table A- 1. Studies of Rituximab in Patients with Indolent (Low-Grade or Follicular) Non-Hodgkin’s Lymphoma

Reference (Study Name/Number) Study Design Treatment Status Treatment Regimen

No. of Patients

Maloney et al. 1994 (Study 102-01)

Phase I Previously treated Rituximab 10–500 mg/m2 (single dose) 15

Maloney et al. 1997a, 1997b (Study 102-02)

Phase I/II, multicenter Previously treated Rituximab 125–375 mg/m2 once weekly for 4 weeks 47

Czuczman et al. 1999, 2004 (Study 102-03)

Phase II, multicenter Previously untreated or previously treated

Six 21-day cycles of R-CHOP (first CHOP cycle on Day 8; rituximab on Days 1, 6, 48, 90, 134, and 141)

38

McLaughlin et al. 1998 (Study 102-05) (pivotal study)

Multicenter Previously treated Rituximab once weekly for 4 weeks 166

Piro et al. 1999 (Study 102-06)

Phase II, multicenter Previously treated Rituximab once weekly for 8 weeks 37

Martinelli et al. 2005 Phase II Previously treated Rituximab once weekly for 4 weeks 27

Tobinai et al. 1998 Phase I, multicenter, dose-escalation

Previously treated Rituximab 250 mg/m2 or 375 mg/m2 once weekly for 4 weeks 12

Colombat et al. 2001; Solal-Celigny et al. 2004 (Study M39006)

Phase II, multicenter Previously untreated Rituximab once weekly for 4 weeks 50

Witzig et al. 2005 (North Central Cancer Treatment Group study)

Phase II Previously untreated Rituximab once weekly for 4 weeks 36

Hiddemann et al. 2004; Hiddemann et al. 2005 (GLSG study) *

Phase III, randomized, multicenter

Previously untreated Six 21-day cycles of CHOP vs. R-CHOP (rituximab on Day 1 of each cycle), followed by IFN-α for responders ≥ 60 years or myeloablative radiochemotherapy with subsequent ASCT vs. IFN-α for responders < 60 years

428 *,†

Herold et al. 2002, 2004 (Study M39023)


Previously untreated Eight 28-day cycles of MCP vs. R-MCP (rituximab on Day 1 of each cycle)

358 (total) 201 (follicular)

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No. of Patients

Marcus et al. 2005; Solal-Celigny et al. 2005 (Study M39021)


Previously untreated Eight 21-day cycles of CVP vs. R-CVP (rituximab on Day 1 of each cycle)

322

Salles et al. 2004; Foussard et al. 2006 (Study FL-2000)


Previously untreated CHVP (six 28-day cycles of CHVP followed by six 56-day cycles of CHVP) vs. R-CHVP (six 28-day cycles of CHVP with rituximab on Days 1 and 8 of third and fourth cycles and on Day 1 of fifth and sixth cycles); both groups received IFN-α2a 4.5 MU three times a week for 18 months

359

McLaughlin et al. 2003; Jiang et al. 2003 (Study U0794n)

Randomized Previously untreated R-FND (eight 28-day cycles of FND with six doses of rituximab given during first five cycles) vs. FND + delayed rituximab (eight 28-day cycles of FND followed by six monthly doses of rituximab); both groups received maintenance IFN-α2b monthly for 1 year

149


Phase II, multicenter Previously untreated Induction rituximab once weekly for 4 weeks, followed by maintenance rituximab (once weekly for 4 weeks, given every 6 months for four courses) for patients with a CR, PR, or stable disease

60‡,§ (induction)

46‡,§,¥ (maintenance)

Ghielmini et al. 2004 (SAKK 35/98 study)

Phase II, randomized, multicenter

Previously untreated or previously treated

Induction rituximab once weekly for 4 weeks, followed by observation vs. maintenance rituximab (once every 2 months for four infusions total) for patients with a CR, PR, or stable disease

202 (induction)78

(observation) 73

(maintenance)

Hochster et al. 2004; Hochster et al. 2005 (Study E1496)

Phase III, randomized Previously untreated Six to eight cycles of induction CVP, followed by observation vs. maintenance rituximab (once weekly for 4 weeks, given every 6 months for four courses) for patients with a CR, PR, or stable disease

401 Þ (induction

CVP) 149§

(observation) 154§

(maintenance rituximab)



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No. of Patients

Forstpointner et al. 2004; Dreyling et al. 2006 (GLSG study) a


Previously treated Four 28-day cycles of FCM vs. R-FCM (rituximab on the day before each FCM cycle), followed by observation vs. maintenance rituximab (once weekly for 4 weeks, at 3 and 9 months after completion of induction therapy) for patients with a CR or PR

81 *,†

(As updated in Dreyling et al.

2006)

Mabthera Summary of Product Characteristics, 2006 (EORTC study, M39022)

Phase III, randomized Previously treated Six 21-day cycles of CHOP vs. R-CHOP (rituximab on Day 1 of each cycle), followed by observation vs. maintenance rituximab (once every 3 months until relapse or for a maximum of 2 years) for patients with a CR or PR

465 (induction)

167§ (observation)

167§ (maintenance

rituximab)

Zinzani et al. 2004 (Study ML17162)

Randomized, multicenter Previously untreated Six 21-day cycles of induction FM vs. CHOP, followed by observation for bcl-2/IgH–negative patients with a CR vs. rituximab consolidation (once weekly for 4 weeks) for patients with a PR or bcl-2/IgH–positive patients with a CR

140§ (induction)

28§ (observation) 95§ (rituximab consolidation)

Maloney et al. 2001 (SWOG 9800 study)

Phase II, multicenter Previously untreated Six 21-day cycles of CHOP, followed 4 weeks later by rituximab (once weekly for 4 weeks) for patients with a CR or PR

84 §

Davis et al. 1999 (Study 102-08B)

Phase II, multicenter, patients with bulky disease

Previously treated Rituximab once weekly for 4 weeks 31

Davis et al. 2000b (Study 102-08R)

Phase II, multicenter Previously treated Rituximab once weekly for 4 weeks 60

ASCT = autologous stem cell transplantation; CHOP = cyclophosphamide 750 mg/m2 on first day, doxorubicin 50 mg/m2 on first day, vincristine 1.4 mg/m2 on first day, and prednisone 100 mg on first 5 days; GLSG = German Low-Grade Lymphoma Study Group; IFN = interferon; R = rituximab. Note: Rituximab dose is 375 mg/m2 unless otherwise specified. *Patients with mantle cell lymphoma were also enrolled; results for these patients are presented separately (see Table A-4 of Appendix A). †Patients with follicular lymphoma only.



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‡Includes patients with small lymphocytic lymphoma. §Evaluable patients. ¥Received at least one course of maintenance rituximab. ÞAn additional 115 patients received FC (fludarabine and cyclophosphamide) as induction therapy, but treatment was discontinued because of toxicity.



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Table A- 2. Studies of Rituximab in Patients with Aggressive Non-Hodgkin’s Lymphoma

Reference (Study Name/Number) Study Design/Histology Treatment Status Treatment Regimen No. of Patients

U2035g CSR (Study U2035g)

Phase III, randomized, multicenter/Aggressive NHL

Previously untreated Six to eight 21-day cycles of CHOP vs. R-CHOP (rituximab on Day 1 of each cycle, 2 days before CHOP)

91

Tobinai et al. 2004 Phase II, multicenter/DLBCL and mantle cell lymphoma

Previously treated Rituximab once weekly for 8 weeks 68 (57 evaluable: 52 DLBCL,

5 mantle cell)

Coiffier et al. 2002, 2004 ; Feugier et al. 2005 (GELA Study LNH98-5)

Phase III, randomized, multicenter/DLBCL

Previously untreated Eight 21-day cycles of CHOP vs. R-CHOP (rituximab on Day 1 of each cycle)

399

Jermann et al. 2004 Phase II, multicenter/DLBCL and other histologies

Previously treated Four to six 21-day cycles of R-EPOCH (rituximab on Day 1 of each cycle)

50 (25 DLBCL)

Pfreundschuh et al. 2005 (RICOVER-60 Study)

Phase III, multicenter/DLBCL

Previously untreated Six or eight cycles of CHOP-14 vs. R-CHOP-14 (rituximab on Days 1, 15, 29, 43, 57, 71, 85, and 99). Radiotherapy was administered to sites of initial bulk and/or extranodal involvement.

828 (evaluable)

Habermann et al. 2006 (Study E4494)


Previously untreated Six or eight 21-day cycles of induction CHOP vs. R-CHOP (first CHOP cycle on Day 1; four to five doses of rituximab, on Days –7, –3, 41, 83, and 125), followed by observation vs. maintenance rituximab (once weekly for 4 weeks, given every 6 months for four courses) for patients with a CR or PR

632 (induction) 208 (observation) 207 (maintenance

rituximab)

Pfreundschuh et al. 2006 (Study M39045 [MInT])


Previously untreated Six cycles of CHEMO vs. R-CHEMO (rituximab every 3 weeks)

824

Vose et al. 2002; U0715s CSR (Study102-10/U0715s)

Phase II, multicenter/DLBCL and other histologies

Previously untreated Six 21-day cycles of R-CHOP (rituximab on Day 1 of each cycle, 2 days before CHOP)

33



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Reference (Study Name/Number) Study Design/Histology Treatment Status Treatment Regimen No. of Patients

Wilson et al. 2002 Phase II, multicenter/DLBCL and other histologies


R-EPOCH (rituximab on Day 1 of each 21-day cycle) 38 (30 DLBCL)

Coiffier et al. 1998 (Study SO15165)

Phase II, multicenter/DLBCL and other histologies


Low-dose rituximab (375 mg/m2 once weekly for 8 weeks) vs. high-dose rituximab (375 mg/m2 once weekly for 1 week followed by 500 mg/m2 once weekly for 7 weeks)

54 (52 evaluable: 30 DLBCL)

Kewalramani et al. 2004 Phase II/DLBCL Previously treated Three cycles of R-ICE, at 2-week intervals (4 doses of 375 mg/m2 rituximab: 48 hrs before Day 1 of cycle 1 and Day 1 of each cycle)

36 (eligible)

Kaplan et al. 2003; Kaplan et al. 2005 (Study AMC-010)

Randomized/HIV-associated aggressive NHL

Not specified CHOP vs. R-CHOP (rituximab on Day 1 of each cycle, 2 days before CHOP, plus three monthly maintenance rituximab doses after completion of chemotherapy)

149

Ribera et al. 2005 Phase II/AIDS-related DLBCL

Previously untreated Six cycles of R-CHOP with HAART 60

Boue et al. 2002 Phase II, multicenter/HIV-associated aggressive NHL

Not specified Six cycles of R-CHOP (rituximab on Day 1 of each cycle)

61

Dunleavy et al. 2005 Phase II, AIDS-related lymphoma

Not specified Minimum of three cycles of dose-adjusted EPOCH with HAART and rituximab (rituximab on Days 1 and 4)

27

Spina et al. 2003 Phase II, multicenter/HIV-associated aggressive NHL

Not specified R-CDE (rituximab on Day 1 of each 28-day cycle) in combination with HAART

72

CDE = cyclophosphamide 187.5 mg/m2, doxorubicin 12.5 mg/m2, and etoposide 60 mg/m2 on Days 1–4; CHEMO = CHOP-like chemotherapy ; CHOP = cyclophosphamide 750 mg/m2 on first day, doxorubicin 50 mg/m2 on first day, vincristine 1.2 mg/m2 on first day, and prednisone 100 mg on first 5 days; CR = complete response; DLBCL = diffuse, large B-cell lymphoma; EPOCH = etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin; GELA = Groupe d’Etude des Lymphomes de l’Adulte; HAART = highly active antiretroviral therapy; MInT = MabThera® International Trial; PR = partial response; R = rituximab; R-ICE= rituximab plus ifosamide, carboplatin, and etoposide. Note: Rituximab dose is 375 mg/m2 unless otherwise specified.



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Table A- 3. Studies of Rituximab in Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Reference (Study Name/Number) Study Design Treatment Status Treatment Regimen No. of Patients


Phase II, multicenter, patients with CLL or SLL

Previously untreated Induction rituximab once weekly for 4 weeks, followed by maintenance rituximab (once weekly for 4 weeks, given every 6 months for three courses) for patients with a CR, PR, or stable disease

44 (induction) 28 (maintenance

rituximab)

Thomas et al. 2001 (Study U01988n)

Patients with CLL Previously untreated Rituximab once weekly for 8 weeks 31

Byrd et al. 2003 (Study U1112s/CALGB 9712)

Phase II, randomized, patients with CLL

Previously untreated Six 28-day cycles of fludarabine 25 mg/m2, either followed by rituximab consolidation (once weekly for 4 weeks) for patients with stable disease or better (sequential), or given concurrently with rituximab (Days 1 and 4 of first cycle; Day 1 of subsequent cycles) and then followed by rituximab consolidation (once weekly for 4 weeks) for patients with stable disease or better (concurrent)

104

Keating et al. 2005 (Study U1989n)

Phase II, multicenter, patients with CLL

Previously untreated Six 28-day cycles of R-FC 224

Study CLL-8 Phase III, multicenter, patients with CLL

Previously untreated Six 28-day cycles of R-FC vs. FC 496*

Itälä et al. 2002 (Study M39017)

Multicenter, patients with CLL

Previously treated Rituximab once weekly for 4 weeks 24

Huhn et al. 2001; Kunzmann et al. 2001 (Study M39025)


Previously treated Rituximab once weekly for 4 weeks † 31

O’Brien et al. 2001 (Study U0825n)

Phase I, dose-escalation, patients with CLL or other mature B-cell leukemias

Previously treated Rituximab once weekly for four doses (see below) Dose 1: rituximab 375 mg/m2 Doses 2–4 (once weekly): 500, 650, or 825 mg/m2; OR 1000 or 1500 mg/m2; OR 2250 mg/m2

40 (CLL)



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Wierda et al. 2005 (Study U2335s)


Previously treated Six 28-day cycles of R-FC 177

Study BO17072 Phase III, multicenter, patients with CLL who are in their first relapse and are sensitive to fludarabine

Previously treated Six 28-day cycles of R-FC vs. FC Cycle 1: rituximab 375 mg/m2

Cycles 2-6: rituximab 500 mg/m2

378*

Byrd et al. 2001 (Study U0971n)

Multicenter, dose-intensification, patients with CLL or SLL


Day 1: Rituximab 100 mg ‡ Day 3: Rituximab 250 or 375 mg/m2 Subsequent doses: Rituximab 250 mg/m2 (same dose as on Day 3, standard administration) three times a week for 4 weeks OR 375 mg/m2 (same dose as on Day 3, standard administration OR non-standard administration§) three times a week for 4 weeks

33

Schulz et al. 2002 (Study M39024)

Phase II, multicenter, patients with CLL


Four 28-days cycles of fludarabine (25 mg/m2 on Days 1–5) and four rituximab infusions (at Weeks 9, 13, 17, and 21; first two infusions given in conjunction with third and fourth fludarabine cycles)

31

CLL = chronic lymphocytic leukemia; CR = complete response; FC=fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 on Days 1–3, every 28 days; R-FC = rituximab 375 mg/m2 on Day 1, fludarabine 25 mg/m2 on Days 2–4, and cyclophosphamide 250 mg/m2 on Days 2–4 of Cycle 1, and rituximab 500 mg/m2 on Day 1, fludarabine 25 mg/m2 on Days 1–3, and cyclophosphamide 250 mg/m2 on Days 1–3 of Cycles 2–6; PR = partial response; SLL = small lymphocytic lymphoma Note: Rituximab dose is 375 mg/m2 unless otherwise specified. *As of April 30, 2006, the number of patients that were included in the safety database for these ongoing studies. †Because of lethal complications with the 16th patient, the first rituximab dose for all subsequent patients was administered as follows: 50 mg on Day 1, 150 mg on Day 2, and the remainder on Day 3. ‡Rituximab 100 mg was given over 4 hours (25 mg/hr) initially. §For two cohorts (receiving either 250 mg/m2 or 375 mg/m2), all subsequent infusions were given using a standard administration schedule. For the third cohort (receiving 375 mg/m2 only), the second infusion was given using a standard administration schedule, and all subsequent infusions were given over 1 hour.



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Table A- 4. Studies of Rituximab in Patients with Mantle Cell Lymphoma


Howard et al. 2002 Phase II, multicenter, Previously untreated Six 21-day cycles of R-CHOP (rituximab on Day 1 of each cycle, 2 days before CHOP)

40

Lenz et al. 2005 (GLSG study) a


Previously untreated Six 21-day cycles of CHOP vs. R-CHOP (rituximab on Day 1 of each cycle), followed by IFN-α for responders ≥ 60 years or myeloablative radiochemotherapy with subsequent ASCT vs. IFN-α for responders < 60 years

121 *,†

Mangel et al. 2004 Phase II, randomized multicenter

Previously untreated Intensive chemotherapy followed by ASCT and then rituximab (once weekly for 4 weeks, at Weeks 8 and 24) vs. conventional anthracycline- or FC-based chemotherapy in historically matched controls

20 (treated) 40 (control)

Gianni et al. 2003 Multicenter Previously untreated Standard doxorubicin- or cisplatin-based de-bulking chemotherapy followed by rituximab-supplemented, four-step, high-dose sequence of chemotherapy ‡ and subsequent ASCT

28

Kaufmann et al. 2004 (Study ML17171)

Phase II Previously treated Thalidomide (starting at 200 mg/day and escalating to 400 mg/day on Day 15) until progression or relapse, combined with rituximab (on Days 1, 8, 15, and 22)

16

Forstpointner et al. 2004; Dreyling et al. 2006 (GLSG study) a


Previously treated Four 28-day cycles of FCM vs. R-FCM (rituximab on the day before each FCM cycle), followed by observation vs. maintenance rituximab (once weekly for 4 weeks, at 3 and 6 months after completion of induction therapy) for patients with a CR or PR

47 *,† (As updated by

Dreyling et al. 2006)

Ghielmini et al. 2005 Blood

Multicenter Previously untreated or previously treated

Rituximab once weekly for 4 weeks, followed by observation vs. maintenance rituximab (infusions at Months 3, 5, 7, and 9) for patients with stable disease or better at Week 12

104



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Foran et al. 2000 (Study M39003)


Rituximab once weekly for 4 weeks 74

ASCT = autologous stem cell transplantation; CHOP = cyclophosphamide 750 mg/m2 on first day, doxorubicin 50 mg/m2 on first day, vincristine 1.4 mg/m2 on first day, and prednisone 100 mg on first 5 days; CR = complete response; FC = fludarabine and cyclophosphamide; FCM = fludarabine 25 mg/m2 on first 3 days, cyclophosphamide 200 mg/m2 on first 3 days, and mitoxantrone 8 mg/m2 on first day; GLSG = German Low-Grade Lymphoma Study Group; IFN = interferon; PR = partial response; R = rituximab. Note: Rituximab dose is 375 mg/m2 unless otherwise specified. *Patients with follicular lymphoma were also enrolled; results for these patients are presented separately (see Table 1 of Appendix A). †Evaluable patients. ‡Chemotherapy consisted of the following agents, given in cycles usually 21 days in length (depending on recovery from toxicity): cyclophosphamide 7 g/m2 (Cycle 1), cytarabine 2 g/m2 every 12 hours for 6 days (Cycle 2), melphalan 180 mg/m2 (Cycle 3), and mitoxantrone 60 mg/m2 plus melphalan 180 mg/m2 (Cycle 4). Patients received six rituximab infusions, two after cyclophosphamide, two after cytarabine, and two after mitoxantrone plus melphalan.



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Table A- 5. Studies of Rituximab in Patients with Waldenström’s Macroglobulinemia


Gertz et al. 2004; Ghobrial et al. 2003



Treon et al. 2001 Multicenter Previously untreated or previously treated

Rituximab once weekly for 4 or 8 weeks, or three times weekly *

30

Treon et al. 2005 Phase II, multicenter Previously untreated or previously treated

Induction rituximab once weekly for 4 or 8 weeks † 29

Dimopoulos et al. 2002 Phase II, multicenter Previously untreated or previously treated

Induction rituximab once weekly for 4 or 8 weeks ‡ 27

Dimopoulos et al. 2004 Phase II Previously untreated Six 21-day cycles of dexamethasone 20 mg on Day 1, rituximab on Day 1, and cyclophosphamide 100 mg/m2 BID on Days 1–5

34

Treon et al. 2004b Multicenter Previously untreated or previously treated

Rituximab (at Weeks 1–4, 17, 18, 30, and 31) combined with fludarabine 25 mg/m2 once daily for 5 days (at Weeks 5, 9, 13, 19, 23, and 27)

43

Treon et al. 2005 Single center Previously treated 6 cycles of R-CHOP (rituximab on Day 1) 13

BID = twice a day. CHOP = cyclophosphamide 750 mg/m2 on first day, doxorubicin 50 mg/m2 on first day, vincristine 1.4 mg/m2 on first day, and prednisone 100 mg on first 5 days; R = rituximab Note: Rituximab dose is 375 mg/m2 unless otherwise specified. *Nineteen patients received one course (rituximab once weekly for 4 weeks); 7 patients received two courses (1 patient had 3 months between courses); 1 patient received a single rituximab dose; 3 patients received rituximab three times weekly for approximately 4 weeks. †All 29 patients received one course (rituximab once weekly for 4 weeks), at Weeks 1–4; 26 patients without evidence of progression after the first course received a second course, at Weeks 12–16. ‡All 27 patients received one course (rituximab once weekly for 4 weeks); 22 patients without evidence of progression after the first course received a second course, with 3 months between courses.



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Table A- 6. Studies of Rituximab in Patients with Multiple Myeloma


Zojer et al. 2006 (Study M39028)

Phase II Previously treated Rituximab once weekly for 4 weeks 10

Lim et al. 2002 Phase I/II, multicenter Previously treated High-dose melphalan and autologous HSCT 6

HSCT = hematopoietic stem cell transplantation.

Note: Rituximab dose is 375 mg/m2 unless otherwise specified.



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Table A- 7. Studies of Rituximab in Patients with Hodgkin’s Disease


Younes et al. 2003 Phase II Previously untreated ABVD (standard dose and schedule) combined with rituximab (once weekly for first 6 weeks)

41

Schulz et al. 2002, 2005 (GHSG study)

Phase II Previously treated Rituximab once weekly for 4 weeks 17

ABVD = adriamycin, bleomycin, vincristine, and dacarbazine; GHSG = German Hodgkin's Lymphoma Study Group. Note: Rituximab dose is 375 mg/m2 unless otherwise specified.



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Table A- 8. Studies of Rituximab in Patients with Posttransplant Lymphoproliferative Disorders


Choquet et al. 2006 (Study M39037)

Phase II, multicenter Not specified Rituximab once weekly for 4 weeks 46

Oertel et al. 2003 Phase II, multicenter Previously untreated or previously treated


Milpied et al. 2000 Multicenter Previously untreated or previously treated

Two to eight infusions of rituximab 32

Berney et al. 2002 Not specified Previously untreated Rituximab at 125 mg/m2 on Day 1, 250 mg/m2 on Day 4, and 375 mg/m2 on Day 8 and weekly thereafter until full remission

5

Serinet et al. 2002 Not specified Not specified Rituximab once weekly for 3 or 4 weeks 6

Van Esser et al. 2002 Not specified Not specified One preemptive rituximab infusion (plus one additional rituximab infusion for patients who develop PTLD after the first infusion), or two rituximab infusions for patients with established diagnosis of PTLD prior to preemptive therapy, vs. historical controls

17 (treated) 26 (control)

Ganne et al. 2003 Not specified Not specified Rituximab once weekly for 4 weeks, followed by retreatment (rituximab once weekly for 4 weeks) for patients who experience a relapse

8

PTLD = posttransplant lymphoproliferative disorder. Note: Rituximab dose is 375 mg/m2 unless otherwise specified.



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Table A- 9. Additional Studies of Rituximab


Idiopathic Thrombocytopenic Purpura

Stasi et al. 2001 Not specified Previously treated Rituximab once weekly for 4 weeks 25

Giagounidis et al. 2002 Multicenter Previously treated Rituximab once weekly for 4 weeks 12

Cooper et al. 2004 Multicenter Previously treated Rituximab once weekly for 4 weeks 57

Thrombotic Thrombocytopenic Purpura

Fakhouri et al. 2005 Multicenter Previously treated Rituximab once weekly for 4 weeks 11

Scully et al. 2005 Not specified Previously treated Rituximab once weekly for 2-8 weeks 15

Autoimmune Hemolytic Anemia or Cold Hemagglutinin Disease

Cabrera et al. ASH 2004 Multicenter, retrospective

Previously treated Rituximab (dosage not specified) 34

Zecca et al. 2002 Multicenter, pediatric patients

Previously treated Rituximab once weekly for 2–4 weeks 15

Quartier et al. 2001 Pediatric patients Previously treated Rituximab once weekly for 4 weeks 6

Factor VIII Deficiency

Wiestner et al. 2002 Multicenter Not specified Rituximab once weekly for 2 or 4 weeks 4

Stasi et al. 2004 Multicenter Previously untreated or previously treated


Note: Rituximab dose is 375 mg/m2 unless otherwise specified.



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APPENDIX B. COUNTRIES IN WHICH RITUXIMAB IS APPROVED

Table B- 1. Countries in Which Rituximab is Approved for the Treatment of Patients with Relapsed or Chemoresistant Indolent NHL.............................................18

Table B- 2. Countries in Which Rituximab is Approved in Combination with CVP for the Treatment of Patients with Previously Untreated Indolent NHL...............19

Table B- 3. Countries in Which Rituximab is Approved in Combination with CHOP for the Treatment of Patients with Diffuse, Large B-Cell NHL............................20

Table B- 4. Countries in Which Rituximab is Approved as Maintenance Treatment of Patients with Relapsed/Refractory Follicular Lymphoma Responding to Induction Therapy with Chemotherapy ...........................................................21


Table B- 1. Countries in Which Rituximab is Approved for the Treatment of Patients with Relapsed or Chemoresistant Indolent NHL

Country Date

Approval Country Date

Approval Country Date

Approval Albania 15 Mar 03 Germany 02 Jun 1998 Pakistan 22. Jul 04Argentina 13 Feb 1998 Greece 02 Jun 1998 Palestine 04. Apr 05 Armenia 10 Jan 2005 Guatemala 03 Mar 1999 Poland 02. Jun 98 Aruba 22 Nov 2001 Honduras 17 Jul 2002 Portugal 02. Jun 98 Australia 06 Oct 1998 Hong Kong 11 May 2000 Panama 07 Apr 99Austria 02 Jun 1998 Hungary 02 Jun 1998 Peru 24 Apr 00Azerbaidjan 03 Oct 2005 Iceland 02 Jun 1998 Philippines 28. Jul 98Bahrain 14 Jun 1998 India 19.02.1998 Qatar 28. Jul 99 Bangladesh 20 Apr 1998 Ireland 02 Jun 1998 Romania 09 Mar 00Belarus 15 Nov 2001 Indonesia 01 Jul 2004 Russia 16. Sep 98Bolivia 24 Apr 2001 Israel 01 Sep 2002 Serbia-Montenegro 17 Jul 98Bosnia-Herzegovina

15 Feb 2004 Italy 02 Jun 1998 Singapore 26. Aug 98

Belgium 02 Jun 1998 Kuwait 01 Sep 2002 Slovakia 02. Jun 98Brazil 29 Jun 1998 Japan 20 Jun 2001 Slovenia 02. Jun 98 Bulgaria 21 Jul 1999 Jordan 12 Mar 2003 South Africa 01. Sep 99 Cambodia 03 Aug 2001 Jamaica 30 Jul 2002 South Korea 21. Nov 03 Canada 17 Mar 2000 Kazakhstan 14 Nov 2003 Sri Lanka 05. Jun 04 Chile 31 Dec 1998 Laos 02 Jun 1998 Spain 02. Jun 98 China 15 Mar 2000 Latvia 02. Jun 98 Sweden 02. Jun 98 Colombia 13 Jul 1999 Lebanon 03. Jul 01 Switzerland 27. Nov 97 Costa Rica 20 Apr 1999 Liechtenstein 02. Jun 98 Thailand 22 Dec 1998Croatia 14 Jan 2002 Lithuania 02. Jun 98 Taiwan 31 Dec 2001 Cuba 29 Nov 2002 Luxembourg 02. Jun 98 Turkmenistan 31. Aug 05 Curacao 14 Dec 2001 Malta 02. Jun 98 Trinidad and Tobago 28 Mar 2002 Cyprus 02 Jun 1998 Macedonia 25. Jul 01 Turkey 03. Apr 02Czech Rep. 02 Jun 1998 Malaysia 23 Dec 1999 Ukraine 22 Oct 2003 Denmark 02 Jun 1998 Mexico 22 May1998 United Arab Emirates 24. Apr 00Dominican Rep.

29 Nov 2001 Morocco 26. Sep 01 United Kingdom 02. Jun 98

Ecuador 27 Dec 2001 Nepal 13 Dec 2000 Uzbekistan 27 Oct 2004 Estonia 02 Jun 1998 Netherlands 02. Jun 98 Uruguay 15 Dec 1998 Egypt 30 Jul 2002 New Zealand 11 Mar 1999 USA 26. Nov 97El Salvador 13 Apr 2000 Nicaragua 03. Nov 03 Venezuela 19. Jul 00 Finland 02 Jun 1998 Norway 02. Jun 98 Vietnam 31 Mar 00France 02 Jun 1998 Oman 12 Oct 2004


Table B- 2. Countries in Which Rituximab is Approved in Combination with CVP for the Treatment of Patients with Previously Untreated Indolent NHL

Country Date Approval Country Date Approval Country Date ApprovalAlbania 15 Mar 03 Greece 02 Aug 04 Singapore 09 Mar 05Armenia 10 Jan 05 Guatemala 19 Oct 04 Slovakia 02 Aug 04Aruba 12 Oct 04 Honduras 08 Dec 04 Slovenia 02 Aug 04Australia 18 Jan 05 Hong Kong 19 Feb 05 South Africa 31 Dec 05Austria 02 Aug 04 Hungary 02 Aug 04 South Korea 18 May 05Azerbaidjan 03 Oct 05 Iceland 02 Aug 04 Sri Lanka 05 Jun 04Bahrain 10 Oct 2005 India 01 Feb 06 Spain 02 Aug 04Bangladesh No official

approval required for line extension

Ireland 02 Aug 04 Sweden 02 Aug 04

Belgium 02 Aug 04 Israel 20 Mar 05 Switzerland 23 Aug 04Brazil 16 Jan 06 Italy 02 Aug 04 Taiwan 26 Apr 05Bulgaria 28 Dec 04 Jamaica 26 Apr 06 Trinidad and

Tobago 30 Jun 05

Cambodia 11 Jun 04 Kuwait 25 Apr 05 Turkmenistan 31 Aug 05Canada 20 Dec 05 Laos 22 Jul 04 United

Kingdom 02 Aug 04

Chile 23 Mar 05 Latvia 02 Aug 04 Uruguay 02 Mar 05China 02 Nov 05 Lebanon 22 Dec 04 USA 29 Sep 06Colombia 14 Jan 05 Liechtenstein 23 Aug 04 Venezuela 31 May 05Costa Rica 02 Nov 05 Lithuania 02 Aug 04 Vietnam 01 Dec 05Croatia 01 Aug 05 Luxembourg 02 Aug 04 Albania 15 Mar 03Curacao 01 Mar 04 Malta 02 Aug 04 Cyprus 02 Aug 04 Netherlands 02 Aug 04 Czech Rep. 02 Aug 04 New Zealand 02 Sep 04 Denmark 02 Aug 04 Nicaragua 28 Jan 05 Dominican Rep.

10 Aug 04 Norway 02 Aug 04

Ecuador 13 Jul 04 Palestine 04 Apr 05 Estonia 02 Aug 04 Poland 02 Aug 04 Finland 02 Aug 04 Portugal 02 Aug 04 France 02 Aug 04 Romania 23 Mar 05 Germany 02 Aug 04 Russia 02 Sep 05


Table B- 3. Countries in Which Rituximab is Approved in Combination with CHOP for the Treatment of Patients with Diffuse, Large B-Cell NHL

Country Date of

Approval Country Date of Approval Country Date of ApprovalAlbania 15 Mar 03 Finland 21 Mar 02 Norway 26 Feb 02Argentina 11 Apr 03 France 21 Mar 02 Oman 12 Oct 04Armenia 10 Jan 05 Germany 21 Mar 02 Palestine 04 Apr 05Aruba 22 Nov 01 Greece 21 Mar 02 Panama 13 May 02Australia 31 May 02 Guatemala 02 Oct 01 Philippines 28 Aug 01Austria 21 Mar 02 Honduras 15 Dec 01 Poland 21 Mar 02Azerbaidjan 03 Oct 05 Hong Kong 08 Jul 02 Portugal 21 Mar 02Bahrain 16 Jan 05 Hungary 21 Mar 02 Romania 01 Jun 02Bangladesh No official

approval required for

line extension

Iceland 13 Oct 03 Russia 26 Dec 01

Belgium 21 Mar 02 India 06 Nov 01 Serbia and Montenegro

13 Jun 02

Bosnia-Herzegovina

15 Feb 04 Indonesia 01 Jul 04 Singapore 26 Jul 02

Brazil 18 Sep 02 Ireland 21 Mar 02 Slovakia 21 Mar 02Bulgaria 09 Sep 02 Israel 14 Aug 02 Slovenia 21 Mar 02Cambodia 11 Jun 04 Italy 21 Mar 02 South Africa 11 Dec 03Canada 06 Nov 02 Jamaica 30 Jul 02 South Korea 21 Nov 03Chile 14 Feb 05 Japan 19 Sep 03 Spain 21 Mar 02China 11 Jul 05 Kuwait 01 Sep 02 Sweden 21 Mar 02Colombia 01 Feb 02 Laos 22 Jul 04 Sri Lanka 05 Jun 04Costa Rica 02 May 02 Latvia 21 Mar 02 Switzerland 04 Mar 02Croatia 08 Dec 03 Liechtenstein 04 Mar 02 Taiwan 29 Jan 03Cuba 29 Nov 02 Lithuania 21 Mar 02 Thailand 28 Aug 02Curacao 14 Dec 01 Luxembourg 21 Mar 02 Trinidad and

Tobago 28 Mar 02

Cyprus 21 Mar 02 Malaysia 24 Jan 03 Turkey 28 Oct 04Czech Rep. 21 Mar 02 Malta 21 Mar 02 Turkmenistan 31 Aug 05Denmark 21 Mar 02 Mexico 19 Mar 02 United Kingdom 21 Mar 02Dominican Rep.

29 Nov 01 Morocco 26 Aug 02 Uruguay 25 Nov 02

Ecuador 30 May 02 Netherlands 21 Mar 02 USA 10 Feb 06El Salvador 18 Sep 02 New Zealand 24 Jan 02 Venezuela 18 Sep 02Estonia 21 Mar 02 Nicaragua 03 Nov 03


Table B- 4. Countries in Which Rituximab is Approved as Maintenance Treatment of Patients with Relapsed/Refractory Follicular Lymphoma Responding to Induction Therapy with Chemotherapy

Country Date Approval Country Date Approval Austria 07 Jul 06 Latvia 07 Jul 06 Belgium 07 Jul 06 Liechtenstein 07 Jul 06 Cyprus 07 Jul 06 Lithuania 07 Jul 06 Czech Rep. 07 Jul 06 Luxembourg 07 Jul 06 Denmark 07 Jul 06 Malta 07 Jul 06 Ecuador 03 Jul 06 Netherlands 07 Jul 06 Estonia 07 Jul 06 Norway 07 Jul 06 Finland 07 Jul 06 Philippines 14 Feb 06 France 07 Jul 06 Poland 07 Jul 06 Germany 07 Jul 06 Portugal 07 Jul 06 Greece 07 Jul 06 Norway 07 Jul 06 Guatemala 23 Jun 06 Spain 07 Jul 06 Hungary 07 Jul 06 Sweden 07 Jul 06 Iceland 07 Jul 06 Switzerland 07 Jul 06 Ireland 07 Jul 06 United Kingdom 07 Jul 06 Italy 07 Jul 06


APPENDIX C. ADDITIONAL RELEVANT PUBLICATIONS AND/OR STUDIES OF RITUXIMAB IN PATIENTS WITH HEMATOLOGIC MALIGNANCIES

1 TREATMENT OF INDOLENT (LOW-GRADE OR FOLLICULAR) NHL ...............23 1.1 Treatment with Rituximab and Other Therapies in Patients with Indolent

(Low-Grade or Follicular) NHL .........................................................................23 1.2 Maintenance Rituximab in Patients with Indolent NHL.....................................24 1.3 Rituximab Consolidation in Patients with Indolent NHL...................................24 1.4 Retreatment with Rituximab in Patients with Indolent NHL..............................25 1.5 Rituximab Combined with Chemotherapy or Other Immunotherapy in

Patients with Previously Untreated or Previously Treated Indolent NHL..........25 2 TREATMENT OF DIFFUSE, LARGE B-CELL NHL ................................................26 2.1 Rituximab in Patients with Previously Untreated Diffuse, Large B-Cell NHL

.............................................................................................................................26 2.2 Rituximab in Patients with Previously Treated Diffuse, Large B-Cell NHL .....26 3 TREATMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA ...................................27 3.1 Rituximab Combined with Chemotherapy or Other Immunotherapy in

Patients with Previously Treated CLL................................................................27 3.2 Rituximab Combined with Chemotherapy or Other Immunotherapy in

Patients with Previously Untreated or Previously Treated CLL.........................27 4 TREATMENT OF MANTLE CELL LYMPHOMA .....................................................27 4.1 Rituximab in Patients with Previously Untreated Mantle Cell Lymphoma .......27 4.2 Rituximab in Patients with Previously Treated Mantle Cell Lymphoma ...........27 4.3 Rituximab in Patients with Previously Untreated or Previously Treated

Mantle Cell Lymphoma ......................................................................................28 5 TREATMENT OF PATIENTS WITH OTHER DISEASES.........................................28 5.1 Retreatment of Idiopathic Thrombocytopenic Purpura ......................................28


1 TREATMENT OF INDOLENT (LOW-GRADE OR FOLLICULAR) NHL

1.1 Treatment with Rituximab and Other Therapies in Patients with Indolent (Low-Grade or Follicular) NHL

Bosly A, Van den Neste E, Vandenberghe P, Van Hoof A, Bron D, Van Droogenbroeck J, et al. Mabthera Followed by Roferon Induces Prolonged Responses in Patients with Refractory/Relapsing Low Grade Lymphomas. A Phase II Study from the Belgian Hematological Society. Exp Hematol 2001;29(8):72, #282.

Cabanillas F, McLaughlin P, Hagemeister F, Rodriguez MA, Romaguera JE, Younes A, et al. Molecular Responses with FND plus Rituxan Chemoimmunotherapy for Stage IV Indolent Follicular Non-Hodgkin's Lymphoma. Blood 2000;96(11):331A, #1429.

Czuczman MS, Fallon A, Mohr A, Stewart C, Klippenstein D, Loud P, et al. Phase II Study of Rituximab plus Fludarabine in Patients (pts) with Low-Grade Lymphoma (LGL): Final Report. Blood 2001;98(11):601a, #2518.

Di Bella NJ, Reynolds C, Faragher D, Muscato J, Boehm KA. An Open-Label, Pilot Study of Pentostatin, Mitoxantrone, and Rituximab, in Previously Untreated, Stage III or IV, Low-Grade Non-Hodgkin's Lymphoma. Blood 2003;102(11):299b, #4920.

Ebeling P, Schuett P, Seeber S, Nowrousian MR. Combined Therapy with Rituximab, Fludarabine, Cyclophosphamide, and Dexamethasone (R-FCD) in Patients with Low-Grade Lymphoma. Blood 2002;100(11):296b, #4723.

Emmanouilides C, Territo M, Menco H, Patel R, Rosen P. Mitoxantrone-Cyclophosphamide-Rituximab: An Effective and Safe Combination for Indolent NHL. Hematol Oncol 2003;21(3):99-108.

Hagemeister FB, McLaughlin P, Fayad L, Samaniego F, Dang N, Goy A, et al. Rituximab, Fludarabine, Mitoxantrone, and Dexamethasone (R-FND) for Relapsed Indolent Lymphomas (RIL). Blood 2005;106(11):2771A, #941.

Kimby E, Geisler C, Hagberg H, Holte H, Lehtinen T, Sundström C. Rituximab (Mabthera®) as Single Agent and in Combination with Interferon-α−2a as Treatment of Untreated and First Relapse Follicular or Other Low-Grade Lymphomas. A Randomized Phase II Study M39035. Blood 2000;96(11):577a, #2479.

Sacchi S, Federico M, Vitolo U, Boccomini C, Vallisa D, Baldini L, et al. Clinical Activity and Safety of Combination Immunotherapy with Interferon-Alpha 2a and Rituximab in Patients with Relapsed Low Grade Non-Hodgkin's Lymphoma. Haematologica 2001;86(9):951-8.

Martinelli G, Laszlo D, Mancuso P, Santoro P, Pruneri G, Vanazzi A, et al. Rituximab plus Chlorambucil in Low-Grade Non-Hodgkin's Lymphomas (NHL): Clinical Results of a Phase II Study. Blood 2002;100(11):777a, #3073.


Martinelli G, Laszlo D, Bertolini F, Pastano R, Mancuso P, Calleri A, et al. Chlorambucil in Combination with Induction and Maintenance Rituximab is Feasible and Active in Indolent Non-Hodgkin's Lymphoma. Br J Haematol 2003;123(2):271-7.

van der Kolk LE, Grillo-Lopez AJ, Baars JW, van Oers MH. Treatment of Relapsed B-Cell Non-Hodgkin's Lymphoma with a Combination of Chimeric Anti-CD20 Monoclonal Antibodies (Rituximab) and G-CSF: Final Report on Safety and Efficacy. Leukemia 2003;17(8):1658-64.

1.2 Maintenance Rituximab in Patients with Indolent NHL CORAL Protocol. GELA - Recherche Clinique (GELARC): The CORAL Group (Sponsor). Randomized Study of ICE Plus Rituximab (R-ICE) Versus DHAP Plus Rituximab (R-DHAP) in Previously Treated Patients with CD20-Positive Diffuse Large B-Cell Lymphoma, Eligible for Transplantation Followed by Randomized Maintenance Treatment with Rituximab. Amendment 1. 20 June 2003.

GISELLE (Gemzar In Second Line Lymphoma Evaluation) Protocol. National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) (Sponsor). A Phase III Study of Gemcitabine, Dexamethasone, and Cisplatin (GDP) Compared to Dexamethasone, Cytarabine, and Cisplatin (DHAP) as Salvage Chemotherapy for Patients with Relapsed or Refractory Aggressive Histology Non-Hodgkin’s Lymphoma Prior to Autologous Stem Cell Transplant and Followed by Maintenance Rituximab Versus Observation. Amendment 2. 22 July 2005.

NHL-13 Protocol. AGMT Austria (Sponsor). A Multicentre, Randomized Phase III Study of Rituximab as Maintenance Treatment Versus Observation Alone in Patients with Aggressive B-Cell Lymphoma. Amendment 1. 09 January 2006.

PRIMA (Primary Rituximab and Maintenance) Protocol. Groupe d’Etude des Lymphomes de L’Adulte (GELA) (Sponsor). A Multicentre Phase III Open-Label Randomized Study in Patients with Advanced Follicular Lymphoma Evaluating the Benefit of Maintenance Therapy with Rituximab after Induction of Response with Chemotherapy Plus Rituximab in Comparison with No Maintenance Therapy. Version 4. 16 August 2006.

Witzens-Harig M, Hensel M, Neben K, Benner A, Schmier JW, Dreger P, et al. Rituximab Maintenenance Therapy in CD20+ B-Cell Non-Hodgkin’s Lymphoma: First Interim Results of a Prospective Randomised Phase II Study. Blood (ASH Annual Meeting Abstracts) 2005;106(11):#2454.

1.3 Rituximab Consolidation in Patients with Indolent NHL Brugger W, Hirsch J, Repp R, Frank G, Guenther S, Wichard V, et al. Long-Term Remission in Follicular Lymphoma (FL) and Mantle Cell Lymphoma (MCL) with Rituximab Consolidation after High-Dose Chemotherapy and Autologous Stem Cell Transplantation: Extended Follow-Up of a Multicenter Phase II Study. Blood (ASH Annual Meeting Abstracts) 2005;106(11):#2078.


1.4 Retreatment with Rituximab in Patients with Indolent NHL Bairey O, Dann EJ, Herishanu Y, Ruchlemer R, Tadmor T, Gavish I, et al. Rituximab Retreatment in B-Cell Non-Hodgkin’s Lymphoma Patients. Blood (ASH Annual Meeting Abstracts) 2005;106(11):#2455.

Lemieux B, Bouafia F, Thieblemont C, Hequet O, Arnaud P, Tartas S, et al. Second Treatment with Rituximab in B-Cell Non-Hodgkin's Lymphoma: Efficacy and Toxicity on 41 Patients Treated at CHU-Lyon Sud. Hematol J 2004;5(6):467-71.

1.5 Rituximab Combined with Chemotherapy or Other Immunotherapy in Patients with Previously Untreated or Previously Treated Indolent NHL

Davis TA, Maloney DG, Grillo-López AJ, White CA, Williams ME, Weiner GJ, et al. Combination immunotherapy of relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma with rituximab and interferon-α−2a. Clin Cancer Res 2000;6(7):2644-52.

de Vos S, Dakhil S, McLaughlin P, Saleh M, Belt R, Flowers C, et al. Bortezomib plus Rituximab in Patients with Indolent Non-Hodgkin's Lymphoma (NHL): A Phase 2 Study. Blood (ASH Annual Meeting Abstracts) 2005;106(11):#17.

Khouri IF, Saliba RM, Hosing CM, Acholonu SA, Fayad LE, Korbling MJ, et al. Autologous Stem Cell (AUTO) vs Non-Myeloablative Allogeneic Transplantation (NMT) after High-Dose Rituximab (HD-R) -Containing Conditioning Regimens for Relapsed Chemosensitve Follicular Lymphoma (FL). Blood (ASH Annual Meeting Abstracts) 2005;106(11):#48.

Ladetto M, Ricca I, Benedetti F, Vitolo U, Patti C, Rambaldi A, et al. Rituximab-Supplemented High-Dose Sequential Chemotherapy (HDS) Has Superior Response Rate and Event-Free Survival (EFS) Compared to R-CHOP in Poor Risk Follicular Lymphoma (FL) at Diagnosis: Results from a Multicenter Randomized GITMO Trial. Blood (ASH Annual Meeting Abstracts) 2005;106(11):#675.

Robinson KS, Williams ME, Cohen P, Tulpule A, van der Jagt RH, Herst JA, et al. Bendamustine HCl (TREANDATM) Treatment in Combination with Rituximab Results in Objective Responses in Patients with Refractory/Relapsed Indolent B-Cell and Mantle Cell Non-Hodgkin's Lymphoma: Results from Phase II Multicenter Study (SDX-105-02). Blood (ASH Annual Meeting Abstracts) 2005;106(11):#923.

Rummel MJ, Al-Batran SE, Kim SZ, Welslau M, Hecker R, Kofahl-Krause D, et al. Bendamustine Plus Rituximab Is Effective and Has A Favorable Toxicity Profile in the Treatment of Mantle Cell and Low-Grade Non-Hodgkin's Lymphoma. J Clin Oncol 2005;23(15):3383-9.

Schulz H, Skoetz N, Bohlius J, Trelle S, Kober T, Greb A, et al. Does Combined Immunochemotherapy with the Monoclonal Antibody Rituximab Improve Overall Survival in the Treatment of Patients with Indolent Non-Hodgkin’s Lymphoma?


Preliminary Results of a Comprehensive Meta-Analysis. Blood (ASH Annual Meeting Abstracts) 2005;106(11):#351.

Vitolo U, Rossi G, Cabras MG, Liberati AM, Chiappella A, Levis A, et al. Effect of Adding Rituximab (R) to Induction Treatment and High Dose Chemotherapy (HDC) Prior to Autologous Stem Cell Transplantation (ASCT) as First Line Therapy in Stage III-IV Diffuse Large B-Cell Lymphoma (B-DLCL) at Poor Prognosis. Blood (ASH Annual Meeting Abstracts) 2005;106(11):#676.

2 TREATMENT OF DIFFUSE, LARGE B-CELL NHL

2.1 Rituximab in Patients with Previously Untreated Diffuse, Large B-Cell NHL

Sonneveld P, van Putten W, Holte H, Biesma D, van Marwijk-Kooy M, Kramer M, et al. Intensified CHOP with Rituximab for Intermediate or High-Risk Non-Hodgkin's Lymphoma: Interim Analysis of a Randomized Phase III Trial in Elderly Patients by the Dutch HOVON and Nordic Lymphoma Groups. Blood (ASH Annual Meeting Abstracts) 2005;106(11):#16.

Trneny M, Belada D, Vasova I, Pytlik R, Kozak T, Sykorova A, et al. Rituximab Combination with Anthracyclin Based Chemothrapy Significantly Improved the Outcome of Young Patients with Diffuse Large B-Cell Lymphoma in Low as Well in High Risk Subgroups. Blood (ASH Annual Meeting Abstracts) 2005;106(11):#2444.

2.2 Rituximab in Patients with Previously Treated Diffuse, Large B-Cell NHL

Canales MA, Palacios A, Martinez-Chamorro C, Cruz MA, Moraleda JM, Terol MJ, et al. Re-Treatment with Rituximab Plus Chemotherapy in Patients with Diffuse Large B-Cell Lymphoma (DLBCL): A Spanish Multicenter Study. Blood (ASH Annual Meeting Abstracts) 2005;106(11):#2457.

Sieniawski M, Glossmann J-P, Reineke T, Diehl V, Engert A, Josting A. Rituximab Added to an Intensified Salvage Chemotherapy Program Followed by Autologous Stem Cell Transplantation Improve in Relapsed and Refractory Aggressive Non-Hodgkin’s Lymphoma. Blood (ASH Annual Meeting Abstracts) 2005;106(11):#1150.

Haioun C, Mounier N, Emile JF, Feugier P, Coiffier B, Tilly H, et al. Rituximab vs Observation after High-Dose Consolidative First-Line Chemotherapy (HDC) with Autologous Stem Cell Transplantation in Poor Risk Diffuse Large B-Cell Lymphoma. Final Analysis of the LNH98-B3 GELA Study. Blood (ASH Annual Meeting Abstracts) 2005;106(11):#677.


3 TREATMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA

3.1 Rituximab Combined with Chemotherapy or Other Immunotherapy in Patients with Previously Treated CLL

Lamanna N, Kalaycio M, Maslak P, Heaney ML, Brentjens R, Jurcic J, et al. Pentostatin, Cyclophosphamide, and Rituximab (PCR) Has Comparable Activity but Appears To Be Better Tolerated Than Fludarabine, Cyclophosphamide, and Rituximab (FCR) in Patients with Previously Treated Chronic Lymphocytic Leukemia. Blood (ASH Annual Meeting Abstracts) 2005;106(11):#2127.

3.2 Rituximab Combined with Chemotherapy or Other Immunotherapy in Patients with Previously Untreated or Previously Treated CLL

Eichhorst BF, Busch R, Duehrsen U, Schulz H, Wendtner CM, Goebeler ME, et al. CHOP Plus Rituximab (CHOP-R) in Fludarabine (F) Refractory Chronic Lymphocytic Leukemia (CLL) or CLL with Autoimmune Hemolytic Anemia (AIHA) or Richter's Transformation (RT): First Interim Analysis of a Phase II Trial of the German CLL Study Group (GCLLSG). Blood (ASH Annual Meeting Abstracts) 2005;106(11):#2126.

4 TREATMENT OF MANTLE CELL LYMPHOMA

4.1 Rituximab in Patients with Previously Untreated Mantle Cell Lymphoma Romaguera JE, Fayad L, Rodriguez MA, Broglio KR, Hagemeister FB, Pro B, et al. High Rate of Durable Remissions After Treatment of Newly Diagnosed Aggressive Mantle-Cell Lymphoma With Rituximab Plus Hyper-CVAD Alternating with Rituximab Plus High-Dose Methotrexate and Cytarabine. J Clin Oncol 2005;23(28):7013-23.

4.2 Rituximab in Patients with Previously Treated Mantle Cell Lymphoma Brugger W, Hirsch J, Repp R, Frank G, Guenther S, Wichard V, et al. Long Term Remission in Follicular Lymphoma (FL) and Mantle Cell Lymphoma (MCL) with Rituximab Consolidation after High-Dose Chemotherapy and Autologous Stem Cell Transplantation: Extended Follow-Up of a Multicenter Phase II Study. Blood (ASH Annual Meeting Abstracts) 2005;106(11):#2078.

Robinson KS, Williams ME, Cohen P, Tulpule A, van der Jagt RH, Herst JA, et al. Bendamustine HCl (TREANDATM) Treatment in Combination with Rituximab Results in Objective Responses in Patients with Refractory/Relapsed Indolent B-Cell and Mantle Cell Non-Hodgkin's Lymphoma: Results from Phase II Multicenter Study (SDX-105-02). Blood (ASH Annual Meeting Abstracts) 2005;106(11):#923.

Rummel MJ, Al-Batran SE, Kim SZ, Welslau M, Hecker R, Kofahl-Krause D, et al. Bendamustine Plus Rituximab is Effective and Has a Favorable Toxicity Profile in the Treatment of Mantle Cell and Low-Grade Non-Hodgkin's Lymphoma. J Clin Oncol 2005;23(15):3383-9.


4.3 Rituximab in Patients with Previously Untreated or Previously Treated Mantle Cell Lymphoma

Capote FJ, Gonzalez-Barca E, Bergua JM, Pascual MJ, Garcia-Boyero R, Ribera JM, et al. Autologous Stem Cell Transplantation and Rituximab for Mantle Cell Lymphoma. ASH Annual Meeting Abstracts 2005;106(11):2092.

5 TREATMENT OF PATIENTS WITH OTHER DISEASES

5.1 Retreatment of Idiopathic Thrombocytopenic Purpura Hasan AN, Bussel JB. Re-Treatment with Rituximab in ITP: Comparison of Standard Dose with 2 Forms of Augmented Rituximab. Blood (ASH Annual Meeting Abstracts) 2005;106(11):#1237.


investigator brochure rituxan , mabthera , idec-c2b8 ... · investigator brochure rituxan ,...

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