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439 R-CHOP Versus R-FC Followed by Maintenance with Rituximab Versus Interferon-Alfa: Outcome of the First Randomized Trial for Elderly Patients with Mantle Cell LymphomaClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 624. Lymphoma - Therapy with Biologic Agents, excluding Pre-Clinical Models: Mantle Cell and T Cell Lymphoma - Targeted Antibody and Small Molecule Approaches
Monday, December 12, 2011: 10:30 AM
Ballroom 20A (San Diego Convention Center)

J.C. Kluin-Nelemans1, E. Hoster2*, J. Walewski, MD3, S. Stilgenbauer, M.D.4, C. H. Geisler5, C. Gisselbrecht, MD6, U. Vehling-Kaiser, MD7*, J. K. Doorduijn, MD8*, M. Trneny, MD9, B. Coiffier, MD10, R. Forstpointner, MD11*, H. Tilly, MD12, L. Kanz, MD13*, M. Szymczyk, MD14*, O. Hermine, MD, PhD15, W. Klapper, MD16*, W. Hiddemann, MD17, M. Unterhalt, PhD18* and M. H. Dreyling, MD18

1Department of Hematology, University Medical Center Groningen, Groningen, Netherlands
2Internal Medicine, Klinikum der Universität München , Munich, Germany
3Department of Lymphoproliferative Diseases, Maria Sklodowska-Curie Memorial Institute and Cancer Center, Warsaw, Poland
4Internal Medicine, University of Ulm, Ulm, Germany
5Department of Hematology, Rigshospitalet, Copenhagen, Denmark
6Hospital Saint Louis, Institut Hematologie, Paris, France
7Hemat-oncol. Praxis, Landshut , Germany
8Hematology, Erasmus Medical Center, Rotterdam, Netherlands
9First Dept. of Medicine, Charles Univ. General Hosp., Prague, Czech Republic
10Departement d'Hematologie, Centre Hospitalier Lyon-Sud, Pierre-Benite Cedex, France
11Campus Grosshadern , Klinikum der Universität München , Munich, Germany
12Centre Henri Becquerel, Rouen, France
13Dept. of Medicine II, University of Tubingen, Tubingen, Germany
14Department of Lymphoproliferative Diseases , Maria Sklodowska-Curie Memorial Institute and Cancer Center, Warszawa, Poland
15Hematology, Hopital Necker, Paris, France
16Department of Haematopathology and Lymph Node Registry, UK-SH Kiel, Kiel, Germany
17Department of Medicine III, Laboratory for Leukemia Diagnostics, Munich, Germany
18Department of Internal Medicine III, University Hospital Munich, Munich, Germany

Introduction. The prognosis of elderly patients with mantle cell lymphoma (MCL) is poor. Despite R-CHOP, only low rates of complete remissions (CR) are obtained and almost all patients relapse. Median overall survival (OS) used to be far below 5 years. Within the European MCL Network we performed a randomized intergroup trial to investigate both whether a fludarabine-containing induction regimen could improve the CR-rate, and whether maintenance with rituximab could prolong remission duration.

Methods. Patients with stage II-IV MCL >60 yrs not eligible for high-dose therapy were randomized between either 8 x R-CHOP-21 (day 1: rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2, max 2 mg and day 1-5 prednisone 100 mg) or 6 x R-FC-28 (rituximab 375 mg/m2 day 1, fludarabine 30 mg/m2 + cyclophosphamide 250 mg/m2, both iv day 1-3). Responding (CR, CRu, PR) patients underwent a second randomization between maintenance with rituximab one dose every 2 months or interferon-alfa (IFN; regular IFN weekly 3x3 MIU or pegylated IFN 1x1 μg/kg), both given until progression. 

First randomisation for induction therapy - R-CHOP vs R-FC: Between Jan 2004 and Oct 2010, 560 patients were entered; 457 were evaluable for response to induction. Median age was 70 yrs, 70% male, 83% stage IV, 41% intermediate and 50% high-risk MIPI. Whereas CR rates after R-FC and R-CHOP were similar (38 vs 34% CR, 52 vs 50% CR/CRu, respectively), the overall response rate was lower after R-FC (78% vs 87%; p=0.0508). Progressive disease was more frequent during R-FC (15% vs 5%). Of note, median OS was significantly inferior after R-FC (40 vs 64 months; p=0.0072). More patients died after initial progression (14% vs 4%) or in first remission (11% vs 3%) in the R-FC arm compared to R-CHOP. Hematologic grade 3-4 toxicities were more frequent during R-FC, especially thrombocytopenia (40% vs 17%). Non-hematologic grade 3-4 toxicity was rare (below 7% each), except neutropenic fever (12% R-FC; 18% R-CHOP) and infections (16% R-FC; 14% R-CHOP).

Second randomisation for maintenance therapy - Interferon-alpha vs Rituximab: From the responding patients, 310 underwent the second randomization. Sixty-one percent of patients had a CR/CRu upon induction therapy. Fifty-eight percent had received R-CHOP induction. Rituximab maintenance almost doubled the remission duration compared with IFN (at 4-yrs 57% vs 26% in remission; HR 0.54, 0.35-0.87; p=0.0109). Overall survival did not differ between both maintenance arms (p=0.17). However, the subcohort of R-CHOP-treated patients showed a significant advantage after rituximab maintenance (4-yr OS 87% vs 57% after IFN; p=0.0061). Hematologic grade 3-4 toxicity was higher in the IFN arm (leukocytopenia 33% vs 16%; thrombocytopenia 15% vs 6%); non-hematologic grade 3-4 toxicity was rare, except for infections (8% IFN; 7% rituximab). R-FC followed by rituximab resulted in the highest infection rate (CTC grades 1-4: 50%), whereas all other combinations (R-CHOP followed by rituximab or IFN, and R-FC followed by IFN) ranged between 25-35%. Patients in CR/CRu or PR after induction who did not receive any maintenance for various reasons, mainly based upon patient’s decisions or ongoing cytopenia after induction (n = 104), had a poor outcome (median remission duration 18 months).

Conclusions. Induction therapy with R-FC is discouraged for elderly patients with MCL, whereas R-CHOP induction followed by rituximab maintenance should be considered the new standard for elderly MCL patients, to which new regimens need to be compared.

Disclosures: Off Label Use: rituximab maintenance for mantle cell lymphoma. Geisler: Roche: Consultancy, Research Funding; Celgene: Consultancy; GSK: Consultancy. Tilly: Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Hiddemann: Roche Pharma: Honoraria, Research Funding. Dreyling: Roche: Research Funding, Scientific advisory board, Speakers Bureau.

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