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Follicular Lymphoma Transformed Lymphoma Diffuse Large B-Cell Lymphoma John P. Leonard, M.D. Richard T. Silver Distinguished Professor of Hematology and.

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Presentation on theme: "Follicular Lymphoma Transformed Lymphoma Diffuse Large B-Cell Lymphoma John P. Leonard, M.D. Richard T. Silver Distinguished Professor of Hematology and."— Presentation transcript:

1 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

2 Copyright © 2011 Research To Practice. All rights reserved. Interest in Topics Related to the Treatment of Patients with FL (Percent Responding 9 or 10) 30% 32% 33% 34% 35% 52% 0%10%20%30%40%50%60% Treatment of relapsed FL Rituximab maintenance Initial therapy for patients >70 yo Watch and wait vs rituximab monotherapy Initial therapy for patients <70 yo New agents/regimens

3 Copyright © 2011 Research To Practice. All rights reserved. 31% 35% 36% 38% 48% 0%10%20%30%40%50%60% Radioimmunotherapy R-CHOP alternatives Post-transplant relapse Cell origin biomarkers/risk New agents/regimens Therapy for relapsed DLBCL Interest in Topics Related to the Treatment of Patients with DLBCL (Percent Responding 9 or 10)

4 Copyright © 2011 Research To Practice. All rights reserved. What is your usual induction regimen for an otherwise healthy 60-year-old patient who requires initial systemic treatment for FL? 3% 5% 8% 24% 9% 21% 9% 1% 20% 0%5%10%15%20%25%30% Other FCR Rituximab monotherapy R-CVP BR (B at 90 mg/m 2 d1, d2 q3wk) BR (B at 90 mg/m 2 d1, d2 q4wk) BR (B at 120 mg/m 2 d1, d2 q3wk) BR (B at 120 mg/m 2 d1, d2 q4wk) R-CHOP

5 Copyright © 2011 Research To Practice. All rights reserved. Do you generally recommend R maintenance after R-chemotherapy?

6 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

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 Bendamustine-Rituximab CHOP-Rituximab FollicularWaldenströms Marginal zone Small lymphocytic Mantle cell RR StiL NHL StiL NHL Bendamustine 90 mg/m 2 day 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) B-R (n = 260)CHOP-R (n = 253) (no. of pts) p-value Alopecia–+++< Paresthesias1873< Stomatitis1647< Skin (erythema)4223= Allergic reaction (skin) 4015= Infectious complications 96127= Sepsis18=

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

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

12 Randomized Trial of Rituximab Versus Watch-and-Wait in Stage II-IV Asymptomatic Nonbulky Follicular Lymphoma: Study Design Ardeshna et al. ASH 2010; abstract 6. Arm A Watch-and-Wait Arm B Rituximab 375 mg/m 2 /week × 4 Arm C Rituximab 375 mg/m 2 /week × 4375 mg/m 2 q 2 months × 12 Eligibility criteria: Stage II-IV FL Grade 1-3a Asymptomatic ECOG PS 0/1 Low tumor burden RANDOMIZERANDOMIZE (n = 187) (n = 84) (n = 192) Primary endpoint: time to initiation of new therapy

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. Response at 25 months Arm A (N = 187) Arm B (N = 84) Arm C (N = 192) ORR8%53%79% CR/CRu4%40%70% PR4%13%9% Initiated new treatment44%23%10% HR for median TTNT 0.37 (34 months) No treatment at 3 years48%80%91% 3-year PFS33%60% 81% (P < vs. A) 3-year OS95% (no significant difference) Safety Serious adverse events14625

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

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

16 PRIMA: Study design PD/SD off study Rituximab maintenance 375 mg/m 2 every 8 weeks for 2 years Observation CR/CRu PR Random 1:1* Immunochemotherapy 8 x Rituximab + 8 x CVP or 6 x CHOP or 6 x FCM High tumor burden untreated follicular lymphoma INDUCTIONMAINTENANCE Registration * 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 months follow-up Salles GA et al. Proc ASH 2010;Abstract Observation n = 513 R Maintenance n = yr progression-free survival (PFS) 58%75% Hazard ratio (95% CI) 0.55 ( ) p-value<0.0001

18 Safety during rituximab maintenance Observation n = 508 Rituximab n = 501 Any adverse event35%52% Grade 2 infections22%37% Grade 3/4 adverse events16%23% Grade 3/4 neutropenia<1%4% Grade 3/4 infections<1%4% Salles GA et al. Proc ASH 2010;Abstract 1788.

19 FIT Study Schema First-line therapy with chlorambucil, CVP, CHOP, CHOP-like, fludarabine combination, or rituximab combination INDUCTION 90 Y-ibritumomab (n = 207) Rituximab 250 mg/m 2 IV on day 7 and day Y-ibritumomab 14.8 MBq/kg (0.4 mCi/kg) [max 1184 MBq (32 mCi)] on day 0 CONSOLIDATION NR PD CR/CRu or PR Not eligible RANDOMIZATIONRANDOMIZATION RANDOMIZATIONRANDOMIZATION No further treatment (n = 202) CONTROL Start of study 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: weeks after last dose of induction Patients with previously untreated FL Hagenbeek et al, ASH 2010.

20 Cumulative Percentage 90 Y-ibritumomab Control N F 90 Y-ibritumomab Control At risk: PFS from Time of Randomization (Months) Overall PFS for Treatment Groups 90 Y-ibritumomab: n = 207 Median PFS: 49 mo Control: n = 202 Median PFS: 15 mo The 5-year overall PFS was 29% in the control arm compared with 47% in the 90 Y-ibritumomab arm HR = 1.95 (95% CI: 1.52 – 2.50); P < With permission from Hagenbeek et al, ASH 2010.

21 R-ACVBP (vs R-CHOP in DLBCL < 60 aaIPI = 1) Increased dose-intensity (mg/ m 2.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/m 2 ; d1-d5 –Ritux: 375 mg/m 2 ; d1 –Doxo: 75 mg/m 2 ; d1 –CPM: 1200 mg/m 2 ; d1 –Vindesine: 2 mg/m 2 ; d1 & d5 –Bleomycin 10 mg; d1 & d5 –Methotrexate (IT) 15 mg; d1 –G-CSF 5 µg/kg/d; d6-d13 Methotrexate –3 g/m 2 ; d1-d15 R-Ifosfamide-VP16 –Ritux: 375 mg/m 2 ; d1 –Ifosfamide: 1.5g/m 2 ; d1 –VP16: 300 mg/m 2 ; d1 Ara-C –100 mg/m 2 sc, d1-d4 x 2.25x 2.4x 1.5 Doxo: 37,5CPM: 600Rituximab: 187 Doxo: 16.7CPM: 250Rituximab: 125 R-ACVBP R-CHOP

22 LNH 03-2B study *No radiotherapy in both arms ClinicalTrials.gov: NCT R R-ACVBP 14 R-CHOP 21 Wks MTXR-IFM-VP16Ara-C Wks 4 IT-MTX New DLBCL Age aaIPI 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.

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

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 Copyright © 2011 Research To Practice. All rights reserved. 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, :00 PM – 9:30 PM Chicago, Illinois Faculty Sergio Giralt, MD John P Leonard, MD Lauren C Pinter-Brown, MD Moderator Neil Love, MD Antonio Palumbo, MD Susan M OBrien, MD Professor Michael Hallek

27 Copyright © 2011 Research To Practice. All rights reserved. What schedule of R maintenance do you use?

28 Copyright © 2011 Research To Practice. All rights reserved. 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, :00 PM – 9:30 PM Chicago, Illinois Faculty Sergio Giralt, MD John P Leonard, MD Lauren C Pinter-Brown, MD Moderator Neil Love, MD Antonio Palumbo, MD Susan M OBrien, MD Professor Michael Hallek

29 Copyright © 2011 Research To Practice. All rights reserved. Do you use interim PET scans in diffuse large B-cell lymphoma?

30 Copyright © 2011 Research To Practice. All rights reserved. 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, :00 PM – 9:30 PM Chicago, Illinois Faculty Sergio Giralt, MD John P Leonard, MD Lauren C Pinter-Brown, MD Moderator Neil Love, MD Antonio Palumbo, MD Susan M OBrien, MD Professor Michael Hallek


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