1 / 40

Optimal use of rituximab in aggressive NHL

Optimal use of rituximab in aggressive NHL. Professor Michael Pfreundschuh. International Prognostic Index (IPI). Patients of all ages Risk factors Age >60 years PS 2 – 4 LDH level Elevated Extranodal involvement >1 site Stage (Ann Arbor) III-IV

latham
Download Presentation

Optimal use of rituximab in aggressive NHL

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Optimal use of rituximab in aggressive NHL Professor Michael Pfreundschuh

  2. International Prognostic Index (IPI) Patients of all ages Risk factorsAge >60 years PS 2–4 LDH levelElevated Extranodal involvement>1 site Stage (Ann Arbor)III-IV Patients 60 years (age-adjusted)PS 2–4 LDHElevated StageIII-IV Shipp N Engl J Med 1993;329:987

  3. DLBCL: overall survival 100 80 IPI 0–1 60 Patients (%) 40 IPI 2–3 IPI 4–5 20 p<0.001 0 0 1 2 3 4 5 6 7 8 Year Adapted from Armitage and Weisenburger. J Clin Oncol. 1998;16:2780.

  4. Rituximab in first-line treatment of aggressive NHL

  5. Rituximab plus CHOP versus CHOP in elderly patients with DLBCL GELA phase III trial (n=399) Cyclophosphamide 750mg/m² Doxorubicin 50mg/m² Vincristine 1.4mg/m² Prednisone 40mg/m²/day x 5 days 3 weeks 8 cycles R-CHOP 375mg/m² Coiffier B, et al. N Engl J Med 2002;346:235–43 Feugier P, et al. J Clin Oncol 2005 23:4117–26

  6. GELA- LNH 98.5 trial planned interim analysis: initial data R-CHOP CHOP p value (n=169) (n=159) Median 1-year EFS (%) 69 49 <0.0005 OS (%) 83 68 <0.01 Coiffier B, et al. Blood 2000;96:223a (Abstract 950)

  7. GELA-LNH 98.5 5-year follow-up: overall survival 100 80 60 40 20 0 Rituximab plus CHOP 58% Overall survival (%) CHOP 45% p<0.007 0 1 2 3 4 5 6 7 Years Feugier P, et al. J Clin Oncol 2005;23:4117–26

  8. GELA-LNH 98.5 5-year follow-up: progression-free survival 100 80 60 40 20 0 PFS excludes late deaths not related to lymphoma or treatment Rituximab plus CHOP 54% Progression-free survival (%) CHOP 30% p<0.00001 0 1 2 3 4 5 6 7 Years Feugier P, et al. J Clin Oncol 2005;23:4117–26

  9. GELA-LNH 98.5: 5-year EFS in low-aaIPI patients (aaIPI 0/1) 100 80 60 40 20 Rituximab plus CHOP 63% Event-free survival (%) CHOP 34% p=0.0008 0 1 2 3 4 5 6 7 Years Feugier P, et al. J Clin Oncol 2005;23:4117–26

  10. GELA-LNH 98.5: 5-year EFS in high-aaIPI patients (aaIPI 2/3) 100 80 60 40 20 0 Rituximab plus CHOP 41% Event-free survival (%) CHOP 27% p=0.004 0 1 2 3 4 5 6 7 Years Feugier P, et al. J Clin Oncol 2005;23:4117–26

  11. CHOP ECOG 4494 phase III trial: study design Stratified by IPI CR/PR; induction Stratified by IPI (0–1 vs 2–4) 1 2 3 4 5 6 7 8 Cycle R A N D O M I S E D R A N D O M I S E D MR every6 months x 2 years Rituximab Observation 1 2 3 4 5 6 7 8 Cycle (n=415) (n=632) Habermann T, et al. Blood 2004;104:40a (Abstract 127)

  12. ECOG 4494: R-CHOP versus CHOP weighted analysis to remove the effect of maintenance FFS 1.0 0.8 0.6 0.4 0.2 0 R-CHOP Probability CHOP HR=0.64 p=0.003 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 Years from induction randomisation OS 1.0 0.8 0.6 0.4 0.2 0 R-CHOP Probability HR=0.72 p=0.05 CHOP 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 Years from induction randomisation Habermann T, et al. Blood 2004;104:40a (Abstract 127)

  13. Rituximab plus CHOP for DLBCL in British Columbia (BC): study aim • March 1, 2001: BC Cancer Agency implemented a new policy recommending R-CHOP for all patients with advanced stage DLBCL in BC • Population-based retrospective analysis over a 3-year interval (1/9/99 – 31/8/02) • Compare outcomes • 18 months prior to rituximab policy (pre-rituximab) versus • 18 months following rituximab policy (post-rituximab) Sehn LH, et al. J Clin Oncol 2005;23:5027–33

  14. CHOP  rituximab in British Columbia: overall survival by treatment era and age (≥60 vs <60 years) ≥60 years (n=170) <60 years (n=122) 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 Post-rituximab Post-rituximab Pre-rituximab Probability of survival Probability of survival Pre-rituximab p=0.0003 p=0.02 0 1 2 3 4 5 0 1 2 3 4 5 Years Years Sehn LH, et al. J Clin Oncol 2005;23:5027–33

  15. 6 x CHOP-14 + 36 Gy (Bulk, E) CD20+ DLBCL 61–80 years IPI I-V (n=828) RANDOMISATION 2 x 2 factorial design 8 x CHOP-14 + 36 Gy (Bulk, E) 6 x CHOP-14 + 36 Gy (Bulk, E) + 8 x rituximab 8 x CHOP-14 + 36 Gy (Bulk, E) + 8 x rituximab RICOVER 60: trial design Pfreundschuh et al., Blood 2005;106 (Abstract 13)

  16. RICOVER 60: response to therapy 6 Cycles 8 Cycles p CR/CRu (%) 76 78 0.432 Progressive disease (%) 7 7 0.985 CHOP-14 R-CHOP-14 p CR/CRu (%) 73 81 0.008 Progressive disease (%) 9 6 0.102 Pfreundschuh et al., Blood 2005;106 (Abstract 13)

  17. RICOVER 60 interim analysis: freedom from treatment failure (FFTF) *Median 26 months follow-up Pfreundschuh et al., Blood 2005;106 (Abstract 13)

  18. RICOVER 60: time to treatment failure 6 cycles vs 8 cycles CHOP-14 vs R-CHOP-14 100 80 60 40 20 0 100 80 60 40 20 0 p=0.23 p=0.000025-crit* = 0.031 70% 64% 62% Failure-free survival (%) Failure-free survival (%) 57% 8 x (R)-CHOP-14(n=415) 6 x (R)-CHOP-14(n=413) 6/8 x R-CHOP-14(n=414) 6/8 x CHOP-14(n=414) 0 5 10 15 20 25 30 35 40 45 0 5 10 15 20 25 30 35 40 45 Months Months Pfreundschuh et al., Blood 2005;106 (Abstract 13)

  19. RICOVER 60: survival 6 cycles vs 8 cycles CHOP-14 vs R-CHOP-14 p=0.284 p=0.088 100 80 60 40 20 0 100 80 60 40 20 0 78% 78% 77% 76% Surviving (%) Surviving (%) 6 x (R)-CHOP-14(n=415) 8 x (R)-CHOP-14(n=413) 6/8 x R-CHOP-14(n=414) 6/8 x CHOP-14(n=414) 0 5 10 15 20 25 30 35 40 45 0 5 10 15 20 25 30 35 40 45 Months Months Pfreundschuh et al., Blood 2005;106 (Abstract 13)

  20. Elderly DLBCL: survival Historical perspective (I): stages I–IV 100 80 60 40 20 0 78% 72%* 58%* Surviving (%) 8 x R + 6/8 x CHOP-14 (n=414) 6 x CHOP-14* (n=172) 6 x CHOP-14* (n=176) 0 5 10 15 20 25 30 35 40 45 Months *Pfreundschuh et al., Blood 2004;104:634–41 Pfreundschuh et al., Blood 2005;106 (Abstract 13)

  21. Elderly DLBCL: survival Historical perspective (II): stages II–IV 100 90 80 70 60 50 40 30 20 10 0 74% 64%* Surviving (%) 55%* 8 x R + 6/8 x CHOP-14n=414 8 x R-CHOP-21*n=202 8 x CHOP-21*n=197 0 5 10 15 20 25 30 35 40 45 50 55 60 Months * Feugier P, et al. J Clin Oncol 2005 23:4117–26 Pfreundschuh et al., Blood 2005;106 (Abstract 13)

  22. RICOVER 60: conclusions • R-CHOP-14 superior to CHOP-14 • Trend in favour of 8 x CHOP-14 over 6 x CHOP-14 • - disappears after rituximab • 8 x R+ 6/8 x CHOP-14: best results in elderly to date • 8 x R + 6 x CHOP-14: reference for future trials Pfreundschuh et al., Blood 2005;106 (Abstract 13)

  23. MInT: trial design 6 x CHOP-like + 30–40 Gy (Bulk, E) CD20+ DLBCL 18–60 years IPI 0,1 Stages II–IV, I with bulk (n=823) Randomisation 6 x CHOP-like + rituximab + 30–40 Gy (Bulk, E) Pfreundschuh M, et al. Proc Am Soc Clin Oncol 2005 (Abstract 6529)

  24. MInT: time to treatment failure 1.0 0.8 0.6 0.4 0.2 0 80% R-Chemo 61% Probability Chemo p=0.00 00 00 00 7 0 5 10 15 20 25 30 35 40 45 50 Months Median observation time: 22 months Pfreundschuh M, et al. Proc Am Soc Clin Oncol 2005 (Abstract 6529)

  25. MInT: overall survival 1.0 0.8 0.6 0.4 0.2 0 95% R-Chemo 86% Chemo Probability Lymphoma-associated deaths: Chemo: 42 R-Chemo: 13 p=0.0002 0 5 10 15 20 25 30 35 40 45 50 Months Median observation time: 23 months Pfreundschuh M, et al. Proc Am Soc Clin Oncol 2005 (Abstract 6529)

  26. MInT: time to treatment failure R-CHOEP vs CHOEP R-CHOP vs CHOP 1.0 1.0 R-CHOEP (n = 181) 82.9% .9 .9 80.4% .8 R-CHOP (n = 197) .8 .7 65.1% .7 55.3% .6 .6 Probability .5 Probability .5 CHOP (n = 197) CHOEP (n = 180) .4 .4 .3 .3 .2 .2 P < 0.00000005 P = 0.0006 .1 .1 0.0 0.0 0 5 10 15 20 25 30 35 40 45 50 0 5 10 15 20 25 30 35 40 45 50 Months Months Pfreundschuh M, et al. Proc Am Soc Clin Oncol 2005 (Abstract 6529)

  27. MInT: time to treatment failure R-CHOP vs R-CHOEP CHOP vs CHOEP 1.0 R-CHOP (n = 197) 1.0 82.9% .9 .9 .8 65.1% .8 80.4% .7 .7 CHOEP (n = 180) .6 .6 Probability Probability CHOP (n = 187) 55.3% .5 .5 R-CHOEP (n = 181) .4 .4 .3 .3 .2 .2 P = 0.67 P = 0.04 .1 .1 0.0 0.0 0 5 10 15 20 25 30 35 40 45 50 0 5 10 15 20 25 30 35 40 45 50 Months Months Pfreundschuh M, et al. Proc Am Soc Clin Oncol 2005 (Abstract 6529)

  28. MInT: overall survival for (R)-CHOP versus (R)-CHOEP Very favourable (IPI=0, no bulk) Less favourable(IPI=1 and/or bulk) 100% R-CHOP 95.8% 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 R-CHOP R-CHOEP 92.8% 95.1% R-CHOEP Probability Probability p=0.65 p=0.26 0 5 10 15 20 25 30 35 40 45 50 0 5 10 15 20 25 30 35 40 45 50 Months Months Pfreundschuh M, et al. Proc Am Soc Clin Oncol 2005 (Abstract 6529)

  29. Rituximab in first-line treatment of aggressive NHL: conclusions • 8 cycles of rituximab plus chemotherapy is the standard of care for DLBCL patients irrespective of age or risk factors • confirmed in a community-based study • Addition of 8 cycles of rituximab to dose intensified strategies allows a reduction in the number of cycles of CHOP • may reduce toxicity, particularly cardiotoxicity

  30. Rituximab in relapsed/refractory aggressive NHL

  31. Rituximab plus ICE for relapsed/refractory CD20+ DLBCL • Median days to complete three cyclesR-ICE: 45 (35–59) vs 37 with ICE • 10/34 (29%) patients completed R-ICE in 35 days • 28/34 (83%) sufficient PBPC harvest vs 80/92 (87%) ICE Kewalramani T, et al. Blood 2004;103:3684–8

  32. R-ICE for relapsed/refractory CD20+ DLBCL PFS 1.0 0.8 0.6 0.4 0.2 0 R-ICE (n=34) Proportion progression-free ICE (n=92;historical controls) p=0.25 0 20 40 60 80 100 120 Months from ASCT Kewalramani T, et al. Blood 2004;103:3684–8

  33. Rituximab + EPOCH in relapsed aggressive NHL: protocol MabThera 375 mg/m2i.v. day 1Doxorubicin15 mg/m2 c.i.v. days 2–4 Etoposide 65 mg/m2 c.i.v. days 2–4Vincristine 0.5 mg c.i.v. days 2–4 Cyclophosphamide 750 mg/m2 i.v. day 5Prednisone 60 mg/m2 p.o. days 1–14 MabThera Doxorubicin Etoposide Vincristine Cyclophosphamide Prednisone 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Days Updated from Jost et al. Proc Am Soc Clin Oncol. 2001;21:290a. Abstract 1157.

  34. Patients (%) (n=50) ORR 64 CR 26 PR 38 Rituximab + EPOCHin relapsed aggressive NHL: response • Stem cell harvest in 18 of 27 patients (67%) under 60 years Updated from Jost et al. Proc Am Soc Clin Oncol. 2001;21:290a. Abstract 1157.

  35. CORAL trial of R-ICE versus R-DHAP SD/PD Off R A N D O M I S E R-ICE x 3 R A N D O M I S E R x 6 BEAM CD20+ DLBCL Relapsed/refractory + ASCT PR/CR Stratification: rituximab-naive versus previous rituximab R-DHAP x 3 Obs 400 patients needed

  36. Rationale for rituximab in vivo purging and consolidation • Rituximab in vivo purging can eliminate residual lymphoma cells, a major cause of relapse, from stem cell harvests, without adversely affecting the yield or function of stem cells • Rituximab can also be used as consolidation therapy post-transplant to eliminate residual malignant cells and reduce the likelihood of relapse

  37. In vivo purging with rituximab prior to ASCT • B-NHL patients (n=27) received rituximab plus DexaBEAM therapy prior to ASCT • 16 months post HDT: • 95% overall survival • 77% progression-free survival Flohr T, et al. Bone Marrow Transplant 2002;29:796–75

  38. Rituximab after HDT/ASCT CY BCNU/VP/CY Rituximab* Rituximab* Harvest† ASCT 42 days 6 months Time *375mg/m2 weekly x 4†CD34-enriched and in-vitro antibody purged Horwitz SM, et al. Blood 2004;103:777–83

  39. Rituximab after autologous transplantation:event-free survival 120 100 80 60 40 20 0 120 100 80 60 40 20 0 All patients Recurrent DLBCL Event-free survival (%) Event-free survival (%) n=35 n=21 0 1 2 3 4 5 0 1 2 3 4 5 Years Years Horwitz S, et al. Blood 2004;103:777–83

  40. Rituximab for treatment of relapsed/refractory aggressive NHL: conclusions • Adding rituximab to salvage chemotherapy improves the response to chemotherapy and therefore can improve patient outcome • In vivo purging with rituximab prior to ASCT may impact progression-free and overall survival • Rituximab consolidation post-ASCT may impact event-free survival providing further patient benefit

More Related