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Follicular Lymphoma Transformed Lymphoma Diffuse Large B-Cell Lymphoma

Follicular Lymphoma Transformed Lymphoma Diffuse Large B-Cell Lymphoma. John P. Leonard, M.D. Richard T. Silver Distinguished Professor of Hematology and Medical Oncology Professor of Medicine, Weill Cornell Medical College Associate Director, Weill Cornell Cancer Center.

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Follicular Lymphoma Transformed Lymphoma Diffuse Large B-Cell Lymphoma

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  1. Follicular LymphomaTransformed LymphomaDiffuse Large B-Cell Lymphoma John P. Leonard, M.D. Richard T. Silver Distinguished Professor of Hematology and Medical Oncology Professor of Medicine, Weill Cornell Medical College Associate Director, Weill Cornell Cancer Center

  2. Interest in Topics Related to the Treatment of Patients with FL (Percent Responding 9 or 10) 52% New agents/regimens 35% Initial therapy for patients <70 yo “Watch and wait” vs rituximab 34% monotherapy 33% Initial therapy for patients >70 yo 32% Rituximab maintenance 30% Treatment of relapsed FL 0% 10% 20% 30% 40% 50% 60%

  3. Interest in Topics Related to the Treatment of Patients with DLBCL (Percent Responding 9 or 10) Therapy for relapsed 48% DLBCL 38% New agents/regimens Cell origin 36% biomarkers/risk Post-transplant 35% relapse 31% R-CHOP alternatives 31% Radioimmunotherapy 0% 10% 20% 30% 40% 50% 60%

  4. What is your usual induction regimen for an otherwise healthy 60-year-old patient who requires initial systemic treatment for FL? 20% R-CHOP 1% BR (B at 120 mg/m2 d1, d2 q4wk) 9% BR (B at 120 mg/m2 d1, d2 q3wk) 21% BR (B at 90 mg/m2 d1, d2 q4wk) 9% BR (B at 90 mg/m2 d1, d2 q3wk) R-CVP 24% 8% Rituximab monotherapy FCR 5% 3% Other 0% 5% 10% 15% 20% 25% 30%

  5. Do you generally recommend R maintenance after R-chemotherapy?

  6. Follicular LymphomaTransformed LymphomaDiffuse Large B-Cell Lymphoma John P. Leonard, M.D. Richard T. Silver Distinguished Professor of Hematology and Medical Oncology Professor of Medicine, Weill Cornell Medical College Associate Director, Weill Cornell Cancer Center

  7. 2 opposite FL management approaches: • Aggressive strategies • Objective of treatment – cure or extended survival • CHOP-R (B-R) + R maintenance or RIT or other • Hoping that more intensive strategy will pay off • Downside – more toxicity in short term • Gentler strategies • Objective of treatment – disease control, less toxicity • Rituximab + other biologics • Hoping that less intensity will improve QOL • Downside – is it less effective in long term?

  8. Bendamustine-Rituximab (B-R) vs CHOP-R StiL NHL 1-2003 Bendamustine-Rituximab Follicular Waldenström‘s Marginal zone Small lymphocytic Mantle cell R CHOP-Rituximab Bendamustine 90 mg/m2 day 1+2 + R day 1, max 6 cycles, q 4 wks. CHOP-R, max 6 cycles, q 3 wks. Rummel et al.: Blood 114: 168 (abstr #405), 2009

  9. B-R vs CHOP-R - Toxicities (all CTC-grades)

  10. Median Progression-Free Survival BR, 54.9 months vs CHOP-R, 34.8 months Hazard ratio, 0.57 p-value = 0.00012 Rummel et al.: Blood 114: 168 (abstr #405), 2009

  11. Progression-Free Survival: Subentities • BR vs CHOP-R: • Follicular, p = 0.0281 • Mantle cell, p = 0.0146 • Marginal zone, p = 0.6210 • Waldenström, p = 0.0024 Rummel et al.: Blood 114: 168 (abstr #405), 2009

  12. Randomized Trial of Rituximab VersusWatch-and-Wait in Stage II-IV Asymptomatic Nonbulky Follicular Lymphoma: Study Design Arm A Watch-and-Wait R A N D O M I Z E (n = 187) • Eligibility criteria: • Stage II-IV FL • Grade 1-3a • Asymptomatic • ECOG PS 0/1 • Low tumor burden Arm B Rituximab 375 mg/m2/week × 4 (n = 84) Arm C Rituximab 375 mg/m2/week × 4→375 mg/m2 q 2 months × 12 (n = 192) Primary endpoint: time to initiation of new therapy Ardeshna et al. ASH 2010; abstract 6.

  13. Preliminary analysis of rituximab vs. watch and wait in stage II-IV, asymptomatic, non-bulky FL: Efficacy and safety Ardeshna et al. ASH 2010, Abstract 6.

  14. Preliminary analysis of rituximab vs. watch and wait in stage II-IV, asymptomatic, non-bulky FL Proportion of patients with no new treatment initiated HR (Rituximab vs W+W) = 0.37, 95% CI = 0.25, 0.56, p < 0.001HR (Rituximab + M vs W+W) = 0.20, 95% CI = 0.13, 0.29, p < 0.001HR (Rituximab + M vs Rituximab) = 0.57, 95% CI = 0.29, 1.12, p = 0.10 With permission from Ardeshna et al. ASH 2010, Abstract 6.

  15. Preliminary analysis of rituximab vs. watch and wait in stage II-IV, asymptomatic, non-bulky FL HR (Rituximab vs W+W) = 0.46, 95% CI = 0.33, 0.65, p < 0.001HR (Rituximab + M vs W+W) = 0.21, 95% CI = 0.15, 0.29, p < 0.001HR (Rituximab + M vs Rituximab) = 0.43, 95% CI = 0.24, 0.72, p = 0.001 With permission from Ardeshna et al. ASH 2010, Abstract 6.

  16. PRIMA: Study design INDUCTION MAINTENANCE Rituximab maintenance 375 mg/m2every 8 weeks for 2 years‡ Registration High tumor burden untreated follicular lymphoma Immunochemotherapy 8 x Rituximab +8 x CVP or 6 x CHOP or 6 x FCM CR/CRu PR Random 1:1* Observation‡ PD/SD off study * Stratified by response after induction, regimen of chemo and geographic region ‡ Frequency of clinical, biological and CT-scan assessments identical in both arms Five additional years of follow-up Salles et al, ASH 2010.

  17. Primary endpoint (PFS): 36 monthsfollow-up Salles GA et al. Proc ASH 2010;Abstract 1788.

  18. Safety during rituximab maintenance Salles GA et al. Proc ASH 2010;Abstract 1788.

  19. 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 FIT Study Schema Start of study R ANDOMI ZAT I ON Patients with previously untreated FL First-line therapy with chlorambucil, CVP, CHOP, CHOP-like, fludarabine combination, or rituximab combination 6-12 weeks after last dose of induction CR/CRu or PR INDUCTION NR PD Not eligible CVP = cyclophosphamide, vincristine, prednisone;CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; CR = complete response; CR/u = unconfirmed CR; PR = partial response; NR = no response;PD = progressive disease. Morschhauser et al. J Clin Oncol 2008;26:5156-5164. Hagenbeek et al, ASH 2010.

  20. Overall PFS for Treatment Groups The 5-year overall PFS was 29% in the control arm compared with 47% in the 90Y-ibritumomab armHR = 1.95 (95% CI: 1.52 – 2.50); P < 0.001 100 75 90Y-ibritumomab: n = 207Median PFS: 49 mo Cumulative Percentage 50 25 Control: n = 202 Median PFS: 15 mo N F 90Y-ibritumomab 207 108 Control 202 144 0 0 12 24 36 48 60 PFS from Time of Randomization (Months) At risk: 90Y-ibritumomab 207 174 133 113 98 80 Control 202 117 83 67 65 46 With permission from Hagenbeek et al, ASH 2010.

  21. R-ACVBP (vs R-CHOP in DLBCL < 60 aaIPI = 1) Doxo: 37,5 CPM: 600 Rituximab: 187 • Increased dose-intensity (mg/m2.wk) compared to R-CHOP • Sequential consolidation using  second-line agents • Ifosfamide, VP16, Ara-C • CNS prophylaxis • High-dose IV Methotrexate • Intrathecal Methotrexate • R-ACVBP (every two weeks) • PDN: 60 mg/m2; d1-d5 • Ritux: 375 mg/m2 ; d1 • Doxo: 75 mg/m2; d1 • CPM: 1200 mg/m2; d1 • Vindesine: 2 mg/m2; d1 & d5 • Bleomycin 10 mg; d1 & d5 • Methotrexate (IT) 15 mg; d1 • G-CSF 5 µg/kg/d; d6-d13 • Methotrexate • 3 g/m2; d1-d15 • R-Ifosfamide-VP16 • Ritux: 375 mg/m2; d1 • Ifosfamide: 1.5g/m2; d1 • VP16: 300 mg/m2; d1 • Ara-C • 100 mg/m2 sc, d1-d4 x 2.25 x 2.4 x 1.5 R-ACVBP Doxo: 16.7 CPM: 250 Rituximab: 125 R-CHOP

  22. 0 2 4 6 10 14 24 Wks LNH 03-2B study New DLBCL Age 18-59 aaIPI 1 MTX R-IFM-VP16 Ara-C R-ACVBP 14 R 4 IT-MTX 0 3 6 9 12 15 18 21 Wks • 380 patients have been included: • 196 (R-ACVBP) and 184 (R-CHOP) • Pathological review: 344 patients (91%) • Median follow-up: 44 months • Analyses are on an intent-to-treat basis. R-CHOP 21 *No radiotherapy in both arms ClinicalTrials.gov: NCT00140595

  23. R-ACVBP (vs R-CHOP in DLBCL < 60 aaIPI = 1)ORR 92% vs 88% • 3-Year Progression-Free Survival: • R-ACVBP (n = 196), 87% • R-CHOP (n = 183), 73% • p = 0.0015 • HR = 0.482 • 3-Year Overall Survival: • R-ACVBP (n = 196), 92% • R-CHOP (n = 183), 84% • p = 0.0071 • HR = 0.439 Recher et al, ASH 2010.

  24. Toxicity (grade ≥ 3) R-ACVBP R-CHOP Toxic deaths: 5/196 (2.6%) in the R-ACVBP arm vs 3/184 (1.6%) in the R-CHOP arm Recher et al, ASH 2010.

  25. Beyond R-CHOP-21 in younger patients with DLBCL • R-ACVBP • R-EPOCH • R-CHOP-14 • Auto SCT in first remission • R-CHOP + novel agents • Epratuzumab • Bortezomib • Lenalidomide • Enzastaurin • Azacitidine

  26. What Clinicians Want to KnowA Live CME Event Addressing the Most Common Questions and Controversies in the Current Clinical Management of Select Hematologic CancersSunday, June 5, 20117:00 PM – 9:30 PMChicago, Illinois Moderator Neil Love, MD Faculty Sergio Giralt, MDJohn P Leonard, MD Lauren C Pinter-Brown, MD Antonio Palumbo, MDSusan M O’Brien, MDProfessor Michael Hallek

  27. What schedule of R maintenance do you use?

  28. What Clinicians Want to KnowA Live CME Event Addressing the Most Common Questions and Controversies in the Current Clinical Management of Select Hematologic CancersSunday, June 5, 20117:00 PM – 9:30 PMChicago, Illinois Moderator Neil Love, MD Faculty Sergio Giralt, MDJohn P Leonard, MD Lauren C Pinter-Brown, MD Antonio Palumbo, MDSusan M O’Brien, MDProfessor Michael Hallek

  29. Do you use interim PET scans in diffuse large B-cell lymphoma?

  30. What Clinicians Want to KnowA Live CME Event Addressing the Most Common Questions and Controversies in the Current Clinical Management of Select Hematologic CancersSunday, June 5, 20117:00 PM – 9:30 PMChicago, Illinois Moderator Neil Love, MD Faculty Sergio Giralt, MDJohn P Leonard, MD Lauren C Pinter-Brown, MD Antonio Palumbo, MDSusan M O’Brien, MDProfessor Michael Hallek

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