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Chairman of the Dutch Hematology Society Chairman of the HOVON CLL Group

Marinus van Oers Professor of Hematology/Head of the Department of Clinical Hematology, Academic Medical Center, University of Amsterdam, The Netherlands. Chairman of the Dutch Hematology Society Chairman of the HOVON CLL Group

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Chairman of the Dutch Hematology Society Chairman of the HOVON CLL Group

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  1. Marinus van OersProfessor of Hematology/Head of the Department of Clinical Hematology, Academic Medical Center, University of Amsterdam, The Netherlands • Chairman of the DutchHematology Society • Chairman of the HOVON CLL Group • Co-authored numerous papers in national and international peer-reviewed scientific journals • Principal investigator of theEORTC 20981 study • Prior Chairman of the Lymphoma Group of the Dutch Cancer Society • Prior board member of the Dutch Hemato-oncology Group Academic Medical Center

  2. Maintenance treatment in follicular lymphoma (FL): indications and considerations Marinus van Oers Academic Medical Center, University of Amsterdam, The Netherlands

  3. Rituximab maintenance therapy in FL: objectives Natural history of FL • Relapsing/remitting course • Duration of response (DR) to subsequent therapy diminishes

  4. Rituximab maintenance therapy in FL: objectives Natural history of FL • Relapsing/remitting course • Duration of response (DR) to subsequent therapy diminishes Objectives of rituximab maintenance therapy • Maintain remission, because prolonged remission predicts for improved overall survival (OS)1–3 • Improve response quality over time (partial response [PR]  complete response [CR]) • Eradicate minimal residual disease (MRD), thereby potentially increasing OS 1Gallagher C, et al. J Clin Oncol 1986;4:1470–802Weisdorf D, et al. J Clin Oncol 1992;10:942–73Montoto S, et al. Ann Oncol 2002;13:523–30

  5. Rituximab maintenance in follicular non-Hodgkin’s lymphoma (NHL): rationale • Maintenance treatment with cytotoxic agents or interferon alpha does not improve OS, but has considerable side effects and long term toxicity1 • Rituximab has minimal acute toxicity2 • There is no known cumulative toxicity2 • The CD20 persists on residual or recurrent lymphoma3 • Long half-life allows infrequent therapy while maintaining long-term exposure (in contrast to chemotherapy)3 1Rohatiner A, et al. Br J Cancer 2001;85:29–35 2Kimby E, et al. Cancer Treat Rev 2005;31:456–73 3Berinstein N, et al. Ann Oncol 1998;9:995–1001

  6. Rituximab maintenance studies in FL Maintenance after induction with single agent rituximab • SAKK 35/981 • Minnie Pearl2 Maintenance after induction with chemotherapy • ECOG 14963 Maintenance after induction with rituximab + chemotherapy • EORTC 209814 • GLSG5 1Ghielmini M, et al. Blood 2004;103:4416–23 2Hainsworth JD, et al. J Clin Oncol 2005;23:1088–95 3Hochster HS, et al. Blood 2005;106:106a (Abstract 349) 4van Oers MHJ, et al. Blood 2006;108:3295–301 5Forstpointner R, et al. Blood 2006;108:4003–8

  7. SAKK 35/98: study design • Phase III trial of rituximab maintenance therapy • 202 patients with previously untreated (n=64) or relapsed/refractory FL; 151 (51 previously untreated) patients randomised n=202 n=151 Observation R Rituximab375mg/m²weekly x 4 SD, PR, CR Prolonged treatment Rituximab 375mg/m² every 2 months x 4 PD off study R = rituximab SD = stable disease; PD = progressive disease Ghielmini M, et al. Blood 2004;103:4416–23

  8. SAKK 35/98 results • 52% response to induction rituximab • No increase in toxicity with rituximab maintenance versus observation *Patients randomised EFS = event-free survival Ghielmini M, et al. Blood 2004;103:4416–23

  9. ECOG 1496 study: rituximab maintenance after first line treatment of indolent NHL • Phase III trial of CVP ± rituximab maintenance therapy • 401 patients with previously untreated indolent NHL • 322 randomised • 237 (78%) with follicular histology R A N D O M I S E • Rituximab maintenance therapy • 375mg/m2 weekly x 4 • every 6 months x 4 PR, CR or stable CVP 6–8 cycles Observation ECOG = Eastern Cooperative Oncology GroupCVP = cyclophosphamide/vincristine/prednisone Hochster HS, et al.Blood 2005;106:106a (Abstract 349)

  10. ECOG 1496: progression-free survival (PFS) in FL 1.0 0.8 0.6 0.4 0.2 0 Median PFS: 61 months vs 15 months Probability MR (120) Observation (117) Log-rank one-sided p=0.0000003 HR: 0.4 (0.3–0.6) 0 1 2 3 4 5 6 Years from maintenance randomisation HR = hazard ratioMR = rituximab maintenance therapy Hochster HS, et al. Blood 2005;106:106a (Abstract 349)

  11. ECOG 1496: PFS at 3 years from randomisation CI = confidence interval; FLIPI = Follicular Lymphoma International Prognostic Index Hochster HS, et al. Blood 2005;106:106a (Abstract 349)

  12. ECOG 1496: OS in FL OS at 42 months from randomisation: 91% vs 75% 1.0 0.8 0.6 0.4 0.2 0 MR (120) Observation (117) Probability Log-rank one-sided p=0.03 HR: 0.5 (0.3–1.1) 0 1 2 3 4 5 6 Years from maintenance randomisation Hochster HS, et al. Blood 2005;106:106a (Abstract 349)

  13. ECOG 1496: conclusions • After successful induction, MR • delays disease progression, with more than half of patients remaining disease-free more than 4 years after completion of CVP • shows a strong trend towards improved OS for rituximab maintenance over observation at a median 3-year follow-up after randomisation Hochster HS, et al. Blood 2005;106:106a (Abstract 349)

  14. EORTC 20981: trial design • Phase III trial of CHOP ± rituximab, with or without MR • 465* patients with relapsed or refractory FL • 334 randomised to maintenance versus observation R A N D O M I S E R A N D O M I S E • MR • 375mg/m2 • Every 3 months to relapse or for 2 years R-CHOP x 6 CHOP x 6 Observation *474 patients randomised; nine excluded due to missing consent forms CHOP = cyclophosphamide/doxorubicin/vincristine/prednisone van Oers MHJ, et al. Blood 2006;108:3295–301

  15. EORTC 20981: patient characteristics at second randomisation (n=334) van Oers MHJ, et al. Blood 2006;108:3295–301

  16. EORTC 20981: rituximab maintenance prolongs PFS by more than 3 years 100 80 60 40 20 0 MR Median 51.5 months PFS (%) Observation Median 14.9 months Overall log-rank test: p<0.001 HR: 0.40 0 1 2 3 4 5 Years van Oers MHJ, et al. Blood 2006;108:3295–301

  17. Rituximab maintenance prolongs PFS irrespective of induction therapy PFS after CHOP (n=145) PFS after R-CHOP (n=189) 100 90 80 70 60 50 40 30 20 10 0 100 90 80 70 60 50 40 30 20 10 0 MR Median 51.8 months MR Median 42.2 months PFS (%) PFS (%) Observation Median 11.6 months Observation Median 23.0 months Overall log-rank test: p=0.004; HR: 0.54 Overall log-rank test: p<0.001; HR: 0.30 0 1 2 3 4 5 0 1 2 3 4 5 Years Years van Oers MHJ, et al. Blood 2006;108:3295–301

  18. MR significantly prolongs OS 100 90 80 70 60 50 40 30 20 10 0 MR 3 years 85.1% OS (%) Observation 3 years 77.1% Overall log-rank test: p=0.011 HR: 0.52 0 1 2 3 4 5 6 Years van Oers MHJ, et al. Blood 2006;108:3295–301

  19. Rituximab maintenance effect on OS: analysis by induction therapy OS after CHOP OS after R-CHOP 100 90 80 70 60 50 40 30 20 10 0 100 90 80 70 60 50 40 30 20 10 0 MR MR Observation OS (%) OS (%) Observation Overall log-rank test: p=0.073 HR: 0.52 Overall log-rank test: p=0.059 HR: 0.49 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Years Years van Oers MHJ, et al. Blood 2005;106:107a (Abstract 353) Updated in oral presentation

  20. Adverse events during maintenance: events with >2% reported grade 3-4 events (World Health Organization) 10 5 0 * Percent Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4 Neutropenia Infection Cardiac Pulmonary Skin *p=0.009 van Oers MH, et al. Blood 2006;108:3295–301

  21. EORTC 20981: conclusions • Rituximab maintenance therapy superior to observation for PFS • in the overall population • in subgroups (after R-CHOP/CHOP, after CR/PR) • Rituximab maintenance therapy improves OS • in the overall population • in subgroups longer follow-up required van Oers MHJ, et al. Blood 2006;108:3295–301 van Oers MHJ, et al. Blood 2005;106:107a (Abstract 353) Updated in oral presentation

  22. £/$ £/$ £/$ £/$ 0 0.5 1 1.5 2 The cost-effectiveness plane: EORTC 20981 analysis Incremental costs (£/$ CAD) Area of rejection Cost-effectiveness threshold Area of acceptance R-maintenance = 17,136/0.839 = $20,428 CAD/QALY gained Incremental drug benefit (QALYs) QALY = quality adjusted life years Maturi B, et al. Blood 2006;108:106a (Abstract 343)

  23. The German Lymphoma Study Group trial: study design R A N D O M I S E R A N D O M I S E Rituximabplus4 x FCM CR/PR MR* Advanced stage relapsed/refractory FL or MCL Observation only 4 x FCM CR/PR *4 x rituximab (375 mg/m2) at 3 and 9 months after induction MCL = mantle cell lymphomaFCM = fludarabine/cyclophosphamide/mitoxantrone Forstpointner R, et al. Blood 2004;104:3064–71

  24. MR after R-FCM improves DR in patients with FL and MCL FL MCL 1.00 0.75 0.50 0.25 0 1.00 0.75 0.50 0.25 0 MR (32/41)Median: not reached Observation (21/40)Median: 26 months Probability Probability MR (11/22) Median: 14 months Observation (2/25) Median: 12 months p=0.035 p=0.049 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Years Years Forstpointner R, et al. Blood 2006;108:4003–8

  25. Rituximab maintenance versus retreatment upon relapse

  26. Minnie Pearl Cancer Research Network: rituximab maintenance versus retreatment • Phase II randomised trial of MR versus retreatment at disease progression • 114 patients with relapsed/refractory indolent NHL following prior chemotherapy, 90 randomised R A N D O M I S E • Rituximab maintenance • 375mg/m2 qw x 4 • 6, 12 and 18 months Rituximab • 375mg/m2 • weekly x 4 PR, CR or stable • Rituximab retreatment • 375mg/m2 qw x 4 • Retreat if responsive disease for 3 months after each course Hainsworth JD, et al. J Clin Oncol 2005;23:1088–95

  27. MR achieves improved outcomes compared with retreatment *Subjective primary endpoint Hainsworth JD, et al. J Clin Oncol 2005;23:1088–95

  28. Rituximab retreatment after MR 58/106 (55%) still in response at end of 2 years maintenance Hainsworth JCO 2002;20:4261 Hainsworth JCO 2005;23:1088 35/58 progressed 4/58 died while still in remission 19/58 still in remission after 7 years

  29. MR versus retreatment: conclusions • The majority of patients who relapse after 2 years of MR remain sensitive to rituximab – can even be given MR again • Retreatment with rituximab, as a single agent, or in combination with chemotherapy, is a reasonable therapeutic option at the time of progression • A ongoing prospective phase III study (RESORT) also addresses quality of life and pharmacoeconomics Hainsworth JD, et al. Blood 2006;108:263b (Abstract 4723)

  30. MR schedules: all demonstrate significantly improved outcome 1Ghielmini M, et al. Blood 2004;103:4416–23; 2Hainsworth JD, et al. J Clin Oncol 2005;23:1088–95 3Hochster HS, et al. Blood 2005;106:106a (Abstract 349)4van Oers MHJ, et al. Blood 2006;108:3295–301; 5Forstpointner R, et al. Blood 2006;108:4003–8

  31. MR in FL: open questions • Role of rituximab maintenance after R-chemotherapy in first line (PRIMA study)

  32. MR in FL: open questions • Role of rituximab maintenance after R-chemotherapy in first line (PRIMA study) • Optimal rituximab maintenance regimen • schedule • duration

  33. MR in FL: open questions • Role of rituximab maintenance after R-chemotherapy in first line (PRIMA study) • Optimal rituximab maintenance regimen • schedule • duration • 2 years? • until relapse? • long term toxicity? • Ig levels/infections • CD20-negative relapse

  34. Ongoing trials of rituximab maintenance *One infusion every 2 months †One infusion every 3 months or four infusions at relapse

  35. Rituximab maintenance therapy: conclusions • Rituximab + chemotherapy induction and rituximab maintenance therapy is the standard in relapsed/refractory indolent NHL, where it confers a PFS and OS benefit

  36. Rituximab maintenance therapy: conclusions • Rituximab + chemotherapy induction and rituximab maintenance therapy is the standard in relapsed/refractory indolent NHL, where it confers a PFS and OS benefit • The benefit of rituximab maintenance is observed • after rituximab monotherapy, chemotherapy and rituximab immunochemotherapy • in previously untreated and relapsed/refractory patients • in MCL as well as FL • in patients with low-, intermediate- and high-risk FL

  37. Rituximab maintenance therapy: conclusions • Rituximab + chemotherapy induction and rituximab maintenance therapy is the standard in relapsed/refractory indolent NHL, where it confers a PFS and OS benefit • The benefit of rituximab maintenance is observed • after rituximab monotherapy, chemotherapy and rituximab immunochemotherapy • in previously untreated and relapsed/refractory patients • in MCL as well as FL • in patients with low-, intermediate- and high-risk FL • Rituximab maintenance appears to be safe, despite prolonged B-cell depletion

  38. Rituximab maintenance therapy: conclusions • Rituximab + chemotherapy induction and rituximab maintenance therapy is the standard in relapsed/refractory indolent NHL, where it confers a PFS and OS benefit • The benefit of rituximab maintenance is observed • after rituximab monotherapy, chemotherapy and rituximab immunochemotherapy • in previously untreated and relapsed/refractory patients • in MCL as well as FL • in patients with low-, intermediate- and high-risk FL • Rituximab maintenance appears to be safe, despite prolonged B-cell depletion • Rituximab maintenance therapy is a cost-effective treatment strategy for patients with FL

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