Download - RTP TV: An 8-Part Live CME Webcast Series
Part VII – Non-Hodgkin Lymphoma/Chronic Lymphocytic LeukemiaTuesday, July 26, 20117:30 PM – 8:30 PM ET
RTP TV: An 8-Part Live CME Webcast Series
Stephanie A Gregory, MDThe Elodia Kehm Chair of HematologyProfessor of MedicineDirector, Section of HematologyRush University Medical CenterChicago, Illinois
John P Leonard, MDRichard T Silver Distinguished Professor of Hematology and Medical OncologyProfessor of Medicine, Weill Cornell Medical CollegeNew York, New York
Neil Love, MDResearch To PracticeMiami, Florida
Disclosures for Moderator Neil Love, MD
Dr Love is president and CEO of Research To Practice, which receives funds in the form of educational grants to develop CME activities from the following commercial interests: Allos Therapeutics, Amgen Inc, Astellas Pharma Global Development Inc, AstraZeneca Pharmaceuticals LP, Aureon Laboratories Inc, Bayer HealthCare Pharmaceuticals/Onyx Pharmaceuticals Inc, Biogen Idec, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb Company, Celgene Corporation, Cephalon Inc, Daiichi Sankyo Inc, Dendreon Corporation, Eisai Inc, EMD Serono Inc, Genentech BioOncology, Genomic Health Inc, ImClone Systems, a wholly owned subsidiary of Eli Lilly and Company, Lilly USA LLC, Millennium: The Takeda Oncology Company, Mundipharma International Limited, Myriad Genetics Inc, Novartis Pharmaceuticals Corporation, OSI Oncology, Sanofi and Seattle Genetics
Disclosures for Stephanie A Gregory, MD
Advisory Committee
Amgen Inc, Cephalon Inc, Genentech BioOncology, Novartis Pharmaceuticals Corporation, Spectrum Pharmaceuticals Inc
Speakers Bureau Cephalon Inc
Disclosures for John P Leonard, MD
Consulting Agreements
Biogen Idec, Bristol-Myers Squibb Company, Celgene Corporation, Cephalon Inc, EMD Serono Inc, Genentech BioOncology, GlaxoSmithKline, Millennium: The Takeda Oncology Company, Novartis Pharmaceuticals Corporation, Pfizer Inc, Sanofi
Agenda — Non-Hodgkin Lymphoma/Chronic Lymphocytic Leukemia
• Module 1: Follicular Lymphoma (FL)
• Module 2: Chronic Lymphocytic Leukemia (CLL)
• Module 3: Mantle-Cell Lymphoma (MCL)
• Module 4: Diffuse Large B-Cell Lymphoma (DLBCL)
• Questions and answers
Dr Gregory (Case A): Follicular Lymphoma
• 6/2004: 54 yo man with diffuse supraclavicular, bilateral axillary and inguinal and intra-abdominal adenopathy, largest 2.8 cm
• Lab results: All normal, including LDH
• Inguinal node bx: Follicular lymphoma Grade II/III
• BM bx: Positive for lymphoma (20%)
• FLIPI score: 2
Inguinal Node Biopsy Results: Follicular Lymphoma Grade 2
6-15/hpf
1. If this patient presented to you now in 2011, which first-line therapy would you generally recommend?
42%
17%
7%
17%
14%
3%
0% 5% 10% 15% 20% 25% 30% 35% 40% 45%
Other
Watch and wait
R monotherapy
R-CVP
BR
R-CHOP
Baseline CT of abdomenJune 11, 2004
Multiple intra-abdominal nodes
CT scan 12 weeks after 4 weeks of rituximab
induction
Markedly decreased adenopathy in all areas
Induction Induction rituximabrituximab
375 mg/m2 weekly x 4
Restage- week 12
End study treatment
<PR or PD
≥PR/CR
Rituximab re-treatment at Rituximab re-treatment at progressionprogression
Single 375 mg/m2 IV q4wk
Continue to rituximab failure
Rituximab maintenanceRituximab maintenance
Single 375 mg/m2 IV q12wk
Continue to rituximab failure
Primary endpoint is time to rituximab failure
RANDOMIZE
N = 600+ patients – closed
REGISTER
ECOG 4402 RESORT Trial
Dr Gregory (Case A): Follicular Lymphoma
• 6/21/2011: Remains asymptomatic in complete remission
• Labs: Normal except for mildly decreased IgG (794), IgA (144) and IgM (21)
• Patient has had no infections
• CT scans every 6 months – no evidence of disease
• Remains on clinical trial w/o Rx interruption
Ardeshna KM et al. Proc ASH 2010;Abstract 6.
An Intergroup Randomised Trial of Rituximab vs a Watch & Wait Approach
in Patients with Advanced Stage,Asymptomatic, Non-Bulky Follicular Lymphoma
Kirit M Ardeshna, Paul Smith, Wendi Qian, June Warden, Lindsey Stevens,Christopher FE Pocock, Fiona Miall, David Cunningham, John Davies, Andrew Jack,
Jan Walewski, A Burhan Ferhanoglu, Ken Bradstock and David C Linch
Rituximab (R) vs a Watch and Wait Strategy in Patients with Stage II-IV Asymptomatic, Nonbulky FL
Ardeshna K et al. Proc ASH 2010;Abstract 6.
• Improved PFS in R arms (P < 0.001)• Time to initiation of new treatment in the R arms:
– 33 mo vs not reached at 4 yr (P < 0.001)• No difference in OS (P > 0.5)• Quality of life no worse
Arm A Arm B Arm C
Intervention Observe R x 4 wk R x 4 wk
Maintenance — — R q2m x 2 yr
Number 187 84 192
CR/PR (%) 2/3 43/30 54/33
3-yr progression-free survival 33% 60% 81%
Time to next treatment 33 mo NR NR
0 1 2 3 4 5
With permission from Ardeshna KM et al. Proc ASH 2010;Abstract 6.
Proportionof patients
withno new
treatmentinitiated % requiring Rx at 3 yr
Watch and wait = 52% Rituximab = 20% Rituximab and maintenance rituximab = 9%
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Years from randomisation
Time to Initiation of New Therapy
Preliminary Results of Quality of Life (QOL) Analyses from the Intergroup Phase III Randomised Trial of Rituximab vs a Watch and Wait Approach in Patients with Advanced Stage, Asymptomatic, Non-Bulky Follicular Lymphoma (FL)Ardeshna KM et al. International Conference on Malignant Lymphoma 2011.
Salles G et al. Lancet 2011;377(9759):42-51.
PRIMA: Rituximab Maintenance After R-Chemo
• Two years of treatment: Every 8 weeks
• Three-year progression-free survival
R maintenance: 75% Control: 58%
• Gr 3-4 infection
R maintenance: 24% Control: 17%
• Treatment discontinued
R maintenance: 4% Control: 2%
PRIMA: Progression-Free Survival
Salles G et al. Lancet 2011;377(9759):42-51.
Rituximab maintenance Observation HR p-value
Progression-free survival
74.9% 57.6% 0.55 <0.0001
Median follow-up of 36 months
PRIMA: Quality of Life
Salles G et al. Lancet 2011;377(9759):42-51.
• EORTC QLQ-C30 global health status mean scores in rituximab maintenance vs observation:
– 75.5 (95% CI 72.8-78.2) vs 75.2 (95% CI 72.0-78.4), p-value = 0.89
• Mean adjusted FACT-G total scores at the end of treatment in rituximab maintenance vs observation:
– 86.6 (95% CI 85.0-88.3) vs 87.2 (95% CI 85.3-89.1), p-value = 0.68
FIT Study Schema
Not eligible
Start of study
6-12 weeks after last dose of induction
Patients with previously untreated FL
Hagenbeek A et al. Proc ASH 2010;Abstract 594.
90Y-ibritumomab (n = 207)
Rituximab 250 mg/m2 IV on day −7 and day 0 +
90Y-ibritumomab 14.8 MBq/kg (0.4 mCi/kg)[max 1184 MBq (32 mCi)]
on day 0
CONSOLIDATION
No further treatment (n = 202)
CONTROL
First-line therapy with chlorambucil, CVP, CHOP, CHOP-like,
fludarabine combination or rituximab combination
INDUCTION
CR/CRu or PR
NRPD
RANDOMIZATION
0
25
50
75
100
0 12 24 36 48 60
Cu
mu
lati
ve P
erce
nta
ge
90Y-ibritumomabControl
207202
108144
N F
PFS from Time of Randomization (Months)
Overall PFS for Treatment Groups
90Y-ibritumomab: n = 207Median PFS: 49 mo
Control: n = 202 Median PFS: 15 mo
The 5-year overall PFS was 29% in the control arm compared to 47% in the 90Y-ibritumomab
armHR = 1.95 (95% CI: 1.52 – 2.50); P < 0.001
With permission from Hagenbeek A et al. Proc ASH 2010;Abstract 594.
• N = 676
• Rituximab (n = 340) vs bortezomib/rituximab (n = 336)
• Progression-free survival: 11.0 vs 12.8 months, HR = 0.82, p-value = 0.039
• ≥Gr 3 AEs: 21% vs 46%
• Serious AEs: 11% vs 18%
Eligibility
High-risk FL with high tumor burden
Stage II-IV disease
Grade 1-3a disease
FLIPI-1 score of 3, 4 or 5
Arm 1BR q28d x 6
Rituximab d1, 4 wks after completion of induction,
q8wk x 2 yrs
ECOG-E2408: A Phase II Trial of BR Followed by Rituximab vs Bortezomib-BR (VBR) Followed by Rituximab vs BR Followed by Lenalidomide/Rituximab
Target Accrual = 250 (open)
www.ClinicalTrials.gov, July 2011.
RArm 2
VBR q28d x 6Rituximab as in Arm 1
Arm 3BR q28d x 6
Lenalidomide q28d x 13 immediately after induction
Rituximab as in Arm 1
B = bendamustine, V = bortezomib, R = rituximab
Dr Leonard (Case B): Follicular Lymphoma
• 8/2006: Currently 61 yo otherwise healthy female artist w/2-cm groin node; asymptomatic
• Bx: Follicular Grade II/III
• Imaging: Diffuse lymphadenopathy (LAN) 2-3 cm range
• Observed 3 years, slowly progressive disease
• Imaging: Mass over 12 cm
• Labs remain normal including LDH
58-year-old 75-year-old
R-CHOP 32% 5%
R-bendamustine 36% 34%
R-CVP 26% 32%
Rituximab monotherapy 1% 24%
What is currently your usual preferred regimen for a patient with FL who requires initial treatment?
Patterns of Care in Medical Oncology: Management of NHL and CLL 2010.
Dr Leonard (Case B): Follicular Lymphoma
• Bendamustine/rituximab therapy is initiated• Excellent response, 75% LAN reduction, no
symptoms• Tolerated well but dose reduction in last 2 cycles
– Mild cytopenias, fatigue, nausea, IV hydration needed
• 9/2010: R maintenance initiated every 2 months• Patient doing well
Before BR After BR
RAPID-FIRE QUESTIONS
• 59 yo man with bulky follicular lymphoma but minimally symptomatic. What is the optimal regimen?
• After bendamustine fails, what is the next step?
• Does rituximab change the natural history of follicular lymphoma?
• Patient with poor performance status whose FL progressed on rituximab monotherapy
Follicular Lymphoma
Dr Leonard (Case C): CLL
• Currently 75 yo married businessman presents with mild lymphoadenopathy and lymphocytosis
• PMH: Diabetes, hyperlipidemia
• Followed off therapy
• Develops progressive lymphocytosis (70k) anemia, splenomegaly, fatigue
• Trisomy 12 (intermediate risk)
2. Which first-line therapy would you generally recommend for this patient?
6%
6%
37%
25%
20%
6%
0% 5% 10% 15% 20% 25% 30% 35% 40%
Other
Chlorambucil
R-CHOP
BR
FR
FCR
National Patterns of Care Among Clinical Investigators (N = 25): Preferred Initial Treatment for Younger and Older Patients with CLL (Normal Cytogenetics)
Patterns of Care in Medical Oncology: Management of NHL and CLL 2010.
60 yo 75 yo
FCR 68% 12%
FR 17% 33%
BR 8% 29%
Dr Leonard (Case C): CLL
• F-R x 6 cycles (delayed cycle 6)
• Tolerated well, mild cytopenias
• Patient is active with minimal symptoms
Informative for Prognosis or Therapy Decision-Making?
• Cytogenetics and/or FISH
– t(11;14)
– t(11q;v)
– +12
– del(13q)
– del(17p)
• Molecular Genetic Analysis
– Immunoglobulin heavy chain variable gene (IgHV) mutation status
• Flow Cytometry or Immunohistochemistry
– CD38
– Zap 70
CLL-8: Progression-Free Survival with FC versus FCR
Hallek M et al. Lancet 2010;376:1164-74.
Chemoimmunotherapy Chemotherapy p-value
Progression-free survival
51.8 mos 32.8 mos <0.0001
Hallek M et al. Lancet 2010;376(9747):1164-74.
FCR(n = 408)
FC(n = 409)
Hazard ratio p-value
3-year PFS 65% 45% 0.56 <0.0001
3-year OS 87% 83% 0.67 0.01
Impact of FC versus FCR on Progression-Free and Overall Survival in CLL
Eligibility
Untreated Binet C CLL or
Binet B or A with ≥ one of
B-symptoms, progressive lymphocytosis, marrow failure; massive, progressive or painful splenomegaly; or massive lymph nodes or nodal clustersNo 17p deletion by FISH
FCR
BR
Phase III Trial of Combined Immunochemotherapy with FCR versus BR in Previously Untreated CLL
Target Accrual = 550 (open)
www.ClinicalTrials.gov, April 2011.
R
German CLL Study Group
RAPID-FIRE QUESTIONS
• FCR versus BR for up-front therapy: Which agents, when and for whom?
• What is the recommended dose of bendamustine for elderly patients?
• Is there still a role for single-agent chlorambucil?
Chronic Lymphocytic Leukemia
• What is the optimal use of alemtuzumab in CLL?
• Role of bone marrow biopsy in CLL
• Guidelines regarding re-treatment with rituximab: Role of ofatumumab
Chronic Lymphocytic Leukemia
Dr Gregory (Case D): Mantle-Cell Lymphoma
• 2/2008: 61 yo male w/progressive asymptomatic lymphadenopathy in left neck and right groin
• 8/2008: Lymph node bx = MCL– Staging workup– CT CAP: Diffuse cervical, axillary, inguinal and
mesenteric adenopathy, largest 4.7 cm in the inguinal area
– Labs: Normal including LDH and beta2 microglobulin
– BM bx: 10% involvement by lymphoma
Low Power Cross Sectional Lymph Node Biopsy Showing Replacement by MCL
High Power Showing MCL
Immunohistochemistry
CD5
CD20
CYCLIN D1
KI-67
Bone Marrow Biopsy Showing Involvement by Lymphoma
Initial Staging CT Scan: 8/2008
Mesenteric LN: 4.5 x 3.1 cmInguinal LN 4.7 x 3.2 cm
3. Which treatment would you generally recommend for this patient as first-line therapy?
15%
27%
24%
31%
3%
0% 10% 20% 30% 40%
R-CHOP
R-CHOP ASCT
R-hyper-CVAD or other Ara-C-containing regimen
BR
Other
• 8/2008 - 1/2009: Patient treated on ECOG-E1405
– 8/2008 - 1/2009: Randomized to VcR-CVAD– Randomized to SCT w/o rituximab maintenance
• 4/2011: Patient remains in CR as of last office visit
Dr Gregory (Case D): Mantle-Cell Lymphoma
E1405: A Phase II Study of VcR-CVAD Induction Followed by Maintenance Rituximab for Untreated MCL
REGISTER
SD, PR, CR
Rituximab Maintenance
Rituximab: 375 mg/m2 IV weekly over 4 consecutive weeks.
To begin 4-6 weeks after chemo q6m for a total of 4 courses.
Autologous Stem Cell Transplantation
This treatment arm is optional.
Transplant-eligible pts may be consolidated with ASCT using the institution’s local guidelines.
Patients will be monitored for PFS and OS.
Patients receiving maintenance rituximab may have stem cells harvested (for possible future use).
Patients who come off protocol therapy to receive ASCT may have stem cells harvested according to local institutional guidelines.
Accrual Goal = 72
VcR-CVAD induction
Inguinal LN Smaller: 2.8 x 1.4 cm
Restaging Scan After 4 Cycles: 12/2008
No abnormal inguinal adenopathyNo abnormal intra-abdominal adenopathy
Restaging Scan After 6 Cycles: 1/2009
No abnormal intra-abdominal adenopathy
Rituximab Maintenance Significantly Prolongs Duration of Remission in Elderly Patients with Mantle Cell Lymphoma. First Results of a Randomized Trial of the European MCL Network
Kluin-Nelemans J et al.European Hematology Association 2011;Presidential Symposium.
European MCL Maintenance Study
• >60 yo with Stage II-IV MCL
• Not eligible for HDT
EligibilityCR/CRu or PR
RANDOMIZATION
RANDOMIZATION
R-CHOP
R-FC
RANDOMIZATION
RANDOMIZATION
R maintenance375 mg/m2 q2m
IFN maintenance
Kluin-Nelemans J et al. European Hematology Association 2011;Presidential Symposium.
Efficacy (N = 223 evaluable) Rituximab IFNHazard
ratio p-value
Remission duration – All pts 51 mos 24 mos 0.56 0.0117
Overall survival – All pts
3-yr OS – CHOP-R inductionNR
85%NR
70%NR—
NS0.0375
Gr 3/4 Adverse Events
Leukocytopenia 17% 36% — —
Thrombocytopenia 7% 16% — —
Infection 7% 7% — —
Outcomes of Maintenance Therapy in Elderly Patients (Median: 70 yo) with MCL (Median F/U: 30 Months)
Kluin-Nelemans J et al. European Hematology Association 2011;Presidential Symposium.
“Rituximab maintenance after R-CHOP induction should be considered the new standard for elderly patients with MCL.”
Treatment
Chemo-Immunotherapy and ASCT
Bortezomib D1,8,15,22 every 56 days x 10
Bortezomib D1,4,8,11 every 21 days x 4
A Randomized Phase II Trial of Maintenance vs Consolidation Bortezomib Therapy Following Aggressive Chemo-Immunotherapy and ASCT for Previously Untreated MCL
Target Accrual = 150 (active, not recruiting)
www.ClinicalTrials.gov, April 2011.
Protocol ID: CALGB-50403
R
Dr Leonard (Case E): Mantle-Cell Lymphoma
• Currently 66 yo married female teacher
– 1998: Presents with lymphocytosis, splenomegaly, originally CLL suspected
• 2007: Dx of MCL on positive FISH for t(11;14)
• Watched for 9 years
• 2/2010: Increased lymphocytosis, splenomegaly, anemia
Dr Leonard (Case E): Mantle-Cell Lymphoma
• 2/2010: CHOP-R x 3 cycles, minimal response progression
• Oral PEP-C x 2 months progression
• BR x 6 cycles, excellent response for 4 months
– Progresses 7/2010
• Part B R-hyper-CVAD (methotrexate/ARA-C) x 1 cycle, not tolerated well
• 3/2011: Btk inhibitor (PCI-32765) on study
– Excellent response for past 3 months
Before Btk Inhibitor After Btk Inhibitor
The Btk Inhibitor, PCI-32765, Induces Durable Responses with Minimal Toxicity in Patients with Relapsed/Refractory B-Cell Malignancies: Results from a Phase I Study
Fowler N et al. Proc ASH 2010;Abstract 964.
Response with PCI-32765 in Relapsed/Refractory B-Cell Malignancies in a Phase IA Study
Fowler N et al. Proc ASH 2010;Abstract 964.
100%
80%
60%
40%
20%
0%
Be
st
Res
po
ns
e, %
MCL CLL/SLL DLBCL FL
7/978% 9/13
69%
2/729%
4/1331%
CR
PR
Dr Gregory (Case F): DLBCL
• 1999: 20 yo male college student with DLBCL – No B symptoms, no PMH– Positive for CD20, CD10 and CD45– IPI Score: 1
• 5/2000: Completes CHOP x 8
• Restaging CT after 4 cycles: 50% in mass size, negative Gallium scan
• 6/2000: Restaging PET scan high SUV in mediastinum
• Biopsy: DLBCL
• 8/2000: ESHAP salvage therapy, BEAM, autoSCT
• Post-transplant consolidative RT to mediastinum
• Repeat CT scans: Negative for 5 years
• Patient lost to follow-up
Dr Gregory (Case F): DLBCL
• 8/2009 (9 years later): Negative CTs
• 1/2010: Bilateral inguinal adenopathy found on PE, largest 3.7 cm left inguinal area
• CT CAP: 2.9 x 3.7 cm, left inguinal lymph node, enlarged left para-aortic nodes and mass around rectal area
• PET/CT: Consistent with abdominal lesion involving retroperitoneal lymph nodes, abdominal lymph nodes; celiac and pelvic lesion consistent with neoplasm, presumably lymphoma
– Enlarged metabolically active lesion rectal region
• MUGA: LVEF — 52%
PET Scan at Relapse: 2010
Dr Gregory (Case F): DLBCL
• Colonoscopy: Rectal erythema, edematous folds, friability and an aphthous ulcer; biopsy negative for DLBCL
• BM bx: Negative• LN bx: DLBCL• Flow cytometry: Bright CD45, CD20, CD19, CD10
and monoclonal kappa • Labs: Normal, LDH 280• Patient received 2 cycles of R-ICE and repeat auto
transplant• Presently in complete remission one year
post-transplant
• IPI = 1– A = Age of 30– P = Performance Status - 1– L = LDH: 280– E = Extra Nodal -1– S = Stage - IIE? (Was mass arising from rectum?
Or was this a nodal mass pushing in on rectum?)
Dr Gregory (Case F): DLBCL
Maintenance with Rituximab After Autologous Stem Cell Transplantation in Relapsed Patients with CD20 Diffuse Large B-cell Lymphoma (DLBCL): CORAL Final Analysis
Gisselbrecht C et al. Proc ASCO 2011;Abstract 8004.
CORAL: EFS by Post-ASCT Maintenance Rituximab versus Observation
Gisselbrecht C et al. Proc ASCO 2011;Abstract 8004.
PFS and OS also did not differ between post-ASCT maintenance rituximab and observation.
Rituximab (n = 122)
Observation(n = 120) p-value
Event-free survival 45% 47% 0.7435
4. Do you order specific screening tests for hepatitis for patients who are about to initiate treatment with rituximab and who have no history of or risk factors for hepatitis?
68%
9%
0%
23%
0% 10% 20% 30% 40% 50% 60% 70% 80%
No
Yes, both hepatitisB and C
Yes, hepatitis Conly
Yes, hepatitis Bonly
NCCN Clinical Practice Guidelines in Oncology, Non-Hodgkin Lymphomas, v3.2011.
Hepatitis B Screening in Patients Receiving Anti-CD20 Antibody (Rituximab)
• No risk factors:– Hepatitis B surface antigen and core antibody
• Risk factors or prior history of hepatitis B:– Add e-antigen
• If positive, check viral load and consult with gastroenterologist
R-CHOP2 cycles
R-ICE 4 cycles
www.clinicaltrials.gov, July 2011.
Eligibility Criteria
Bulky Stage II or Stage III/IV DLBCL
Target Accrual: 99
ECOG-E3404: Response-Adapted Therapy for Aggressive NHL Based on Early PET Scanning
R-CHOP4 Cycles
PETSCAN
+
-
Interim Positron Emission Tomography Scans in Diffuse Large B-cell Lymphoma: An Independent Expert Nuclear Medicine Evaluation of the Eastern Cooperative Oncology Group E3404 Study
Horning SJ et al.Blood 2010;115(4):775-7.
Interim PET Scans
Horning SJ et al. Blood 2010;115(4):775-7.
• PET scans read by three independent reviewers
• Moderate agreement among readers (68% by ECOG criterion)
• Proportion of positive PET scans relatively low (range 16% to 34%)
• PET interpretation should be standardized
RAPID-FIRE QUESTIONS
• What is the role of maintenance therapy in follicular lymphoma after transformation?
• Use of bendamustine/rituximab in DLBCL
• Would you ever consider a transplant at first remission?
• Is there any clinical benefit to using dose-dense R-CHOP?
Diffuse Large B-Cell Lymphoma
Schedule of Events
Tuesday, August 2Chronic Myeloid LeukemiaSusan M O’Brien, MDNeil P Shah, MD, PhD