mantle cell lymphoma (mcl): approach to upfront treatment

Mantle Cell Lymphoma (MCL): Approach to Upfront Treatment

Lauren C Pinter-Brown, MDDirector, UCLA Lymphoma Program

Clinical Professor of MedicineGeffen School of Medicine at UCLA

Copyright © 2011 Research To Practice. All rights reserved.

Interest in Topics Related to the Treatment of Patients with CTCL or PTCL (Percent Responding 9 or 10)

12%

15%

17%

18%

20%

25%

26%

27%

0% 5% 10% 15% 20% 25% 30%

Denileukin diftitox in CTCL

Classification of TCL

Romidepsin/HDAC inhibitors

Stem cell transplant

Skin treatment in CTCL

Pralatrexate in PTCL

Brentuximab vedotin in ALCL

New agents/regimens


Interest in Topics Related to the Treatment of Patients with MCL (Percent Responding 9 or 10)

30%

33%

40%

41%

50%

0% 10% 20% 30% 40% 50% 60%

Maintenancetherapy

Treatment ofrelapsed MCL

Initial therapy forpatients >70 yo

Initial therapy forpatients <70 yo

New agents/regimens

Prognostic Factors: Pathologic

• Blastoid and pleomorphic variants connote poor prognosis

• Small cell variant may have more indolent course; impact of mantle zone or nodular pattern less clear

• Overt peripheral blood involvement with adenopathy appears worse (vs. peripheral blood, marrow and possible splenic involvement without adenopathy)

WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue, 4th edition.

Prognostic Factors: Ki-67 Index

Determann O et al. Blood 2008;111:2385-2387.

• Median overall survival, CHOP-treated subgroup:– <10% Ki-67 index = 112 months – 10% - 30% Ki-67 index = 59 months – ≥30% Ki-67 index = 30 months – p-value = 0.0002

• Median overall survival, R-CHOP treated subgroup: – <10% Ki-67 index = not reached – 10%-30% Ki-67 index = not reached – ≥30% Ki-67 index = 52 months – p-value = 0.0126

Prognostic Factors:Simplified MIPI

Hoster E et al. Blood 2008;111:558-65.

0-3 points applied for each prognostic factor

Sum reflects MIPI score

Low risk: 0-3 points

Intermediate risk: 4-5 points

High risk: 6-11 points

Points Age, yrs ECOG PS

LDH/ULN WBC, cells/mm3

0 <50 0-1 <0.67 <6,700

1 50-59 — 0.67-0.99 6,700-9,999

2 60-69 2-4 1.000-1.49 10,000-14,999

3 ≥70 — ≥1.5000 ≥15,000

Frontline Treatment Considerations

• Optimal frontline standard of care not yet defined• MCL not yet shown to be curable with currently available

frontline treatments • Prolongation of survival by frontline treatment has been

definitely shown• May consider treatment options separately for:

– Patients for whom a dose intensive approach is an option (65 and under without comorbidities)

– Patients for whom a dose intensive approach is not an option (older than 65 or with significant comorbidities)

– Median age is around 60

Patients for Whom a Dose-Intensive Approach is Not an Option

• In truth…– Will likely need additional treatment earlier than if the patient had an

aggressive initial therapy (NCCN database)– ? Similar OS than if the patient had aggressive therapy (Cornell

retrospective data, N=97…in selected asymptomatic patients “watch and wait” is acceptable management1)

– Many choices that include:

• R-bendamustine vs R-CHOP (Rummel data: BR has stat sig increased PFS, 33 vs 23 mo, and better tox profile than R-CHOP in MCL, N=932)

• Modified hyperCVAD (VcR-CVAD) with R maintenance (ECOG-E1405 shows high CR rate3)

• Rituximab alone, R-CVP, R-fludarabine/CDA1. Martin P, JCO 2009; 27:1209-1213.2. Rummel MJ, ASH 2009, abs 405.3. Kahl B, ASH 2009, abs 1661.

Patients for Whom a Dose-Intensive Approach is an Option

• NCCN database, prospective cohort study of pts with MCL <65 yo that R-hyperCVAD or R-CHOP → auto have similar PFS that are better than R-CHOP alone1

• Nordic regimen: R-Maxi-CHOP/R-HDAraC → auto with consolidation with R in presumptive relapse2

• GELA: R-CHOP/R-DHAP → auto3

1. LaCasce A, ASH 2009, abstract 403.2. Geisler CH, Blood 2008; 112:2687-2693.3. Delarue R, ASH 2010, abstract 581.

Consolidation or Maintenance Strategies

• ECOG-E14991: Single dose of yttrium-90-ibritumomab tiuxetan given 4-8 weeks after R-CHOP x 4 in responding patients

• 16/56 patients experienced improvement in response after RIT

• Median failure-free survival: 27 months• Maintenance rituximab: Await presentation of

European MCL Consortium randomized trial

1. Smith M et al. ASH 2007, abstract 389.

PTCL/CTCL: Approaches to Relapsed/Refractory Disease

Lauren C Pinter-Brown, MDDirector, UCLA Lymphoma Program

Clinical Professor of MedicineGeffen School of Medicine at UCLA

What’s the difference between PTCL and CTCL?

• Both groups are mature T-cell neoplasms

• Most nodal and extranodal (excluding skin) PTCLs are aggressive; most CTCLs are indolent

• Be aware that the staging system for mycosis fungoides/Sézary syndrome is a totally different staging system from the Ann Arbor system used for other lymphomas

Classification of PTCL

Mature T-NK neoplasm

Extranodal Nodal Leukemic

PTCL, NOS

ALCL (ALK +)

Angioimmunoblastic (AILT)

Adult T-cell leukemia/lymphoma (ATLL)

Aggressive NK cell leukemia

T-prolymphocytic leukemia (T-PLL)

T-large granular lymphocytic leukemia

(T-LGL)

Extranodal NK/T cell, nasal type

Enteropathy associated (EATL)

Hepatosplenic (ϒΔ)

Classification of CTCL

Cutaneous

Mycosis fungoides/Sézary syndrome (MF/SS)CD30+ lymphoproliferative disorders

Subcutaneous panniculitic T-cell lymphomaCD4+ small/medium pleomorphic T-cell lymphoma

Cutaneous PTCL, NOSCutaneous aggressive CD8+ T-cell lymphoma

Cutaneous NK/T cell lymphoma, nasal type

Outlook for patients with PTCL/CTCL

• Nodal and extranodal PTCL (excluding CTCL) have a median survival of 1-3 years with present therapy

• 5-year overall survival is approximately 25%• The exception is anaplastic large cell lymphoma

(ALCL) ALK+ where 5-year overall survival is 65-95%

• No CTCL is curable with conventional medical therapy

Denileukin diftitox Denileukin diftitox is a recombinant DNA derived cytotoxic protein

composed of IL-2 protein sequence fused to active portion of diphtheria toxin

• Targets tumor cells expressing the high and medium affinity IL-2 receptor (IL-2R); the IL-2 portion binds to the IL-2 receptor, allowing the diphtheria toxin to enter the cell and induce cell death by inhibition of protein synthesis

• Approved for use in patients with relapsed/refractory CTCL with an overall RR=30-44% (20-34% PR) with median duration of response (DOR)=6.9 mo1,2

• In relapsed/refractory T-cell malignancies (excluding CTCL), N=27, RR=48% (46% PR) with median PFS=6 mo3

• Common toxicity includes:

– Immediate: allergic, constitutional– Delayed: vascular capillary leak, primarily in first cycle– Lab: reversible liver function test abnormalities

1. Prince HM, JCO 2010; 28(11): 1870-7.2. Olsen E, JCO 2001; 19(2): 376-88.3. Dang NH, Br J Haematol 2007; 136(3): 439-47.

HDAC inhibitors• Vorinostat (po) and romidepsin (IV) are approved for treatment of

relapsed/refractory CTCL• Vorinostat in relapsed/refractory CTCL ORR = 30%; estimated median

DOR ≥ 185 days1; there is no data to support use of vorinostat in PTCL• Romidepsin in relapsed/refractory CTCL ORR = 34% (31% PR) with

median DOR = 15 mo2

• Romidepsin in relapsed/refractory PTCL ORR 38% (20% PR) with median DOR = 8.9 mo3

• The common toxicities can be classified into 4 symptom complexes: – Gastrointestinal symptoms (diarrhea, nausea, anorexia, weight decrease,

vomiting, constipation)– Constitutional symptoms (fatigue, chills)– Hematologic abnormalities (thrombocytopenia, anemia, neutropenia)– Taste disorders (dysgeusia, dry mouth)

• Abnormal laboratory values include high glucose, elevated creatinine, abnormal EKGs

1. Olsen EA, JCO 2007; 25(23): 3109-15.2. Whittaker SJ, JCO 2010; 28(29): 4485-91.3. Piekarz R, Blood 2011 epub.

Pralatrexate• Novel folate antagonist approved for treatment

of relapsed or refractory PTCL• In patients with relapsed/refractory PTCL

at dose of 30 mg/m2 six out of seven weeks, ORR = 29% (18% PR) with median DOR = 10.1 mo1

• In patients with relapsed/refractory CTCL, the optimal dose was 15 mg/m2 three out of four weeks with an ORR = 43%2

• Common toxicities include: mucositis, thrombocytopenia, neutropenia, anemia

1. O’Connor OA JCO 2011; 29(9):1182-9.2. Horwitz SM, ASH 2010, abstract 2800.

How would I sequence these drugs?

• In relapsed/refractory PTCL (if not using typical salvage chemotherapy):

• (1) Pralatrexate • (2) Romidepsin • (3) Denileukin diftitox

• In relapsed/refractory CTCL (if inappropriate for topical or other FDA-approved therapies such as bexarotene):

• (1) Romidepsin (or vorinostat)• (2) Denileukin diftitox• (3) Pralatrexate


What is your usual preferred initial systemic treatment for MCL in patients older than age 75?

9%

43%

25%

9%

3%

11%

0% 10% 20% 30% 40% 50%

Other

BR

R-CHOP

Modified R-hyper-CVAD

R-hyper-CVAD

R monotherapy


Do you generally use rituximab maintenance in MCL?

57%

25%

18%

0% 10% 20% 30% 40% 50% 60%

No

Yes, in somepatients

Yes, in mostpatients


What is your usual preferred initial systemic treatment for MCL in patients older than age 75?

9%

43%

25%

9%

3%

11%

0% 10% 20% 30% 40% 50%

Other

BR

R-CHOP

Modified R-hyper-CVAD

R-hyper-CVAD

R monotherapy


Do you generally use rituximab maintenance in MCL?

57%

25%

18%

0% 10% 20% 30% 40% 50% 60%

No

Yes, in somepatients

Yes, in mostpatients


What Clinicians Want to Know

A Live CME Event Addressing the Most Common Questions and Controversies in the Current Clinical

Management of Select Hematologic Cancers

Sunday, June 5, 20117:00 PM – 9:30 PMChicago, Illinois

Faculty

Sergio Giralt, MDJohn P Leonard, MD Lauren C Pinter-Brown, MD

ModeratorNeil Love, MD

Antonio Palumbo, MDSusan M O’Brien, MDProfessor Michael Hallek


28%

13%

3%

49%

6%

0% 10% 20% 30% 40% 50% 60%

I have no informationor experience

Relatively welltolerated

Somewhat welltolerated

Not well tolerated

Very poorly tolerated

What is your perception and experience concerning the side effects and tolerability of pralatrexate in patients with TCL?


18%

10%

1%

69%

2%

0% 10% 20% 30% 40% 50% 60% 70% 80%




Not well tolerated


What is your perception and experience concerning the side effects and tolerability of romidepsin in patients with TCL?


28%

13%

3%

49%

6%

0% 10% 20% 30% 40% 50% 60%




Not well tolerated


What is your perception and experience concerning the side effects and tolerability of pralatrexate in patients with TCL?


What Clinicians Want to Know

A Live CME Event Addressing the Most Common Questions and Controversies in the Current Clinical

Management of Select Hematologic Cancers

Sunday, June 5, 20117:00 PM – 9:30 PMChicago, Illinois

Faculty

Sergio Giralt, MDJohn P Leonard, MD Lauren C Pinter-Brown, MD

ModeratorNeil Love, MD

Antonio Palumbo, MDSusan M O’Brien, MDProfessor Michael Hallek

mantle cell lymphoma (mcl): approach to upfront treatment

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