IS THERE A ROLE FOR RITUXIMAB IN IS THERE A ROLE FOR RITUXIMAB IN MAINTENANCE TREATMENT IN NON- MAINTENANCE TREATMENT IN NON- FOLLICULAR INDOLENT LYMPHOMAS? FOLLICULAR INDOLENT LYMPHOMAS? YES! YES! Anton Hagenbeek, M.D., Ph.D. Anton Hagenbeek, M.D., Ph.D. Academic Medical Center Academic Medical Center Department of Hematology Department of Hematology University of Amsterdam University of Amsterdam Amsterdam, The Netherlands Amsterdam, The Netherlands E-mail: a.hagenbeek@amc.uva.nl E-mail: a.hagenbeek@amc.uva.nl
NON-FOLLICULAR INDOLENT LYMPHOMAS (WHO CLASSIFICATION 2008) - Small lymphocytic lymphoma Lymphoplasmacytic lymphoma / Waldenström - Extranodal marginal zone lymphoma of MALT type - Nodal marginal zone lymphoma - Splenic B-cell marginal zone lymphoma - Mantle cell lymphoma (?) -
BACKGROUND CONSIDERATIONS BACKGROUND CONSIDERATIONS ON THE ROLE OF RITUXIMAB ON THE ROLE OF RITUXIMAB MAINTENANCE MAINTENANCE • No (large) randomized trials in non-follicular No (large) randomized trials in non-follicular indolent NHL indolent NHL • Non-follicular indolent NHL are included in Non-follicular indolent NHL are included in several (positive!) trials with mainly follicular several (positive!) trials with mainly follicular NHL patients NHL patients • No reason to believe that R-maintenance would No reason to believe that R-maintenance would not benefit CD20-positive non-follicular indolent benefit CD20-positive non-follicular indolent not NHL NHL • We all induce these patients with R-chemo We all induce these patients with R-chemo anyway anyway
BACKGROUND CONSIDERATIONS BACKGROUND CONSIDERATIONS ON THE ROLE OF RITUXIMAB ON THE ROLE OF RITUXIMAB MAINTENANCE (CONT’D) MAINTENANCE (CONT’D) Thus: Thus: I defend the statement that results from R- I defend the statement that results from R- maintenance studies represent results to maintenance studies represent results to be expected in the subgroup of non- be expected in the subgroup of non- follicular indolent NHL! follicular indolent NHL!
THE EVIDENCE THE EVIDENCE 1. R-maintenance in first remission follicular NHL R-maintenance in first remission follicular NHL 1. - PRIMA study - PRIMA study ≥ 2 R-maintenance in ≥ 2. R-maintenance in 2 nd nd remission follicular NHL remission follicular NHL 2. - EORTC 20981 - EORTC 20981
RITUXIMAB MAINTENANCE FOR 2-YEARS SIGNIFICANTLY IMPROVES THE OUTCOME OF PATIENTS WITH UNTREATED HIGH TUMOR BURDEN FOLLICULAR LYMPHOMA AFTER RESPONSE TO IMMUNOCHEMOTHERAPY: RESULTS OF THE PRIMA STUDY G. Salles, J.V. Catalano, P. Feugier, F. Offner, R. Bouabdallah, D. Caballero, P. G. Salles, J.V. Catalano, P. Feugier, F. Offner, R. Bouabdallah, D. Caballero, P. Brice, L. Moller Pedersen, C. Haioun, D. Belada, A. Delmer, D. Simpson, H. Tilly, S. Brice, L. Moller Pedersen, C. Haioun, D. Belada, A. Delmer, D. Simpson, H. Tilly, S. Leppa, P. Soubeyran, A. Hagenbeek, O. Casasnovas, I. Tanin, C. Ferme, M. Gomes Leppa, P. Soubeyran, A. Hagenbeek, O. Casasnovas, I. Tanin, C. Ferme, M. Gomes Da Silva, C. Sebban, R. Pettengell, J. Estell, G. Milone, A. Sonnet, A. Lopez- Da Silva, C. Sebban, R. Pettengell, J. Estell, G. Milone, A. Sonnet, A. Lopez- Guillermo, J-F. Seymour, L. Xerri Guillermo, J-F. Seymour, L. Xerri from France, Australia, Belgium, Spain, Denmark, Czech Republic, New Zealand, from France, Australia, Belgium, Spain, Denmark, Czech Republic, New Zealand, Finland, the Netherlands, Thailand, Portugal, United Kingdom, Argentina Finland, the Netherlands, Thailand, Portugal, United Kingdom, Argentina on behalf of the PRIMA investigators on behalf of the PRIMA investigators Gilles Salles Gilles Salles Gilles Salles Gilles Salles Hospices Civils de Lyon Hospices Civils de Lyon Hospices Civils de Lyon Hospices Civils de Lyon & Université Claude Bernard, Lyon, France & Université Claude Bernard, Lyon, France & Université Claude Bernard, Lyon, France & Université Claude Bernard, Lyon, France EHA Barcelona, June 2010 EHA Barcelona, June 2010
PRIMA: STUDY DESIGN INDUCTION MAINTENANCE Rituximab maintenance 375 mg/m 2 Registration Registration every 8 weeks Immunochemotherapy for 2 years ‡ High 8 x Rituximab tumor burden + CR/CRu Random 1:1* untreated Random 1:1* 8 x CVP or PR follicular 6 x CHOP or lymphoma 6 x FCM Observation ‡ PD/SD PD/SD off study off study * Stratified by response after induction, regimen of chemo, and geographic region * Stratified by response after induction, regimen of chemo, and geographic region Frequency of clinical, biological and CT-scan assessments identical in both arms ‡ Frequency of clinical, biological and CT-scan assessments identical in both arms ‡ Five additional years of follow-up Five additional years of follow-up
PATIENT DISPOSITION Patients registered: N = 1217 * * 15 pts in 3 sites closed 15 pts in 3 sites closed Patients evaluable (N = 1202)* prematurely prematurely n I d R-CHOP R-CVP R-FCM 9 pts did not receive chemo 9 pts did not receive chemo u N = 885 N = 272 N = 45 c 147 pts withdrew during or at 147 pts withdrew during or at t o i the end of induction (failure the end of induction (failure n to respond; toxicity) Randomized Randomized Randomized to respond; toxicity) N = 769 N = 222 N = 28 28 pts failed to be 28 pts failed to be randomized randomized Patients randomized: ‡ 1 pt died during the ‡ 1 pt died during the N = 1018 ‡ randomization process randomization process M a n i Rituximab Observation t e N = 505 N = 513 n a n c e
PRIMARY ENDPOINT (PFS) MET AT THE PLANNED INTERIM ANALYSIS Rituximab maintenance significantly reduced the risk of progression by 50% 1.0 1.0 82% 82% Rituximab maintenance Progression-free rate Progression-free rate 0.8 0.8 N=505 0.6 0.6 Observation 66% 66% N=513 0.4 0.4 stratified HR=0.50 stratified HR=0.50 95% CI 0.39; 0.64 0.2 95% CI 0.39; 0.64 0.2 p <.0001 p <.0001 0 0 0 0 6 6 12 12 18 18 24 24 30 30 36 36 Time (months) Time (months) Patients at risk Patients at risk 505 472 443 336 230 103 18 513 469 411 289 195 82 15
CONSISTENT RESULTS ACROSS SECONDARY ENDPOINTS Time to next Time to next Time to next Time to next anti-lymphoma treatment chemotherapy treatment anti-lymphoma treatment chemotherapy treatment Rituximab Rituximab 1.0 1.0 1.0 1.0 maintenance maintenance 0.8 0.8 0.8 0.8 Event-free rate Event-free rate Event-free rate Event-free rate 0.6 0.6 0.6 0.6 HR = 0.61 HR = 0.61 HR = 0.60 HR = 0.60 Observation Observation Observation Observation 0.4 0.4 0.4 0.4 p = 0.0003 = 0.0003 p = 0.0011 = 0.0011 p p 0.2 0.2 0.2 0.2 0 0 0 0 0 0 6 12 18 24 30 36 0 0 6 12 18 24 30 36 0 0 6 12 18 24 30 36 Time (months) Time (months) Time (months) Time (months) Patients at risk Patients at risk 505 483 453 349 235 103 18 505 484 457 351 243 108 19 513 487 447 327 218 87 15 513 492 454 332 225 91 17
SAFETY DURING RITUXIMAB MAINTENANCE 100 100 80 80 Observation (n = 508) Observation (n = 508) Rituximab maintenance (n = 501) Rituximab maintenance (n = 501) Patients (%) Patients (%) 60 60 40 40 52 20 20 37 35 23 22 16 4 4 4 4 <1 <1 <1 <1 <1 0 0 Grade ≥2 Grade ≥2 Any adverse Grade 3/4 Grade 3/4 Grade 3/4 Any adverse Grade 3/4 Grade 3/4 Grade 3/4 infections infections event adverse events neutropenia infections event adverse events neutropenia infections
SUMMARY • Rituximab maintenance for 2 years significantly improved • Rituximab maintenance for 2 years significantly improved PFS for patients with previously untreated FL who PFS for patients with previously untreated FL who responded to induction with chemotherapy plus rituximab responded to induction with chemotherapy plus rituximab • Benefits of rituximab maintenance seen in all major sub- • Benefits of rituximab maintenance seen in all major sub- groups groups • Consistent improvements in secondary endpoints including • Consistent improvements in secondary endpoints including EFS, TNLT, TNCT, ORR and CR rate at the end of EFS, TNLT, TNCT, ORR and CR rate at the end of maintenance maintenance • Safety of maintenance was consistent with the known • Safety of maintenance was consistent with the known safety profile of rituximab, with no new or unexpected safety profile of rituximab, with no new or unexpected findings findings • Additional follow-up will allow evaluation of a possible • Additional follow-up will allow evaluation of a possible effect on overall survival effect on overall survival
THE EVIDENCE THE EVIDENCE 1. R-maintenance in first remission follicular NHL R-maintenance in first remission follicular NHL 1. - PRIMA study - PRIMA study ≥ 2nd remission follicular NHL R-maintenance in ≥ 2. R-maintenance in 2nd remission follicular NHL 2. - EORTC 20981 - EORTC 20981
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