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110 Alternating Courses of 3x CHOP and 3x DHAP Plus Rituximab Followed by a High Dose ARA-C Containing Myeloablative Regimen and Autologous Stem Cell Transplantation (ASCT) Is Superior to 6 Courses CHOP Plus Rituximab Followed by Myeloablative Radiochemotherapy and ASCT In Mantle Cell Lymphoma: Results of the MCL Younger Trial of the European Mantle Cell Lymphoma Network (MCL net)Clinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: Lymphoma - Chemotherapy, excluding Pre-Clinical Models: Aggressive Non-Hodgkin Lymphoma Therapy
Sunday, December 5, 2010: 4:45 PM
Auditorium - 320 (Orange County Convention Center)

Olivier Hermine, MD, PhD1*, Eva Hoster2*, Jan Walewski3, Vincent Ribrag, MD4*, Nicole Brousse5*, Catherine Thieblemont, MD6, Reda Bouabdallah7*, Stephan Stilgenbauer, MD8, Pierre Feugier, MD, PhD9*, Roswitha Forstpointner, MD2*, Corinne Haioun, MD, PhD10, Michael Kneba, MD, PhD11, Mathias Hänel12, Rene-Olivier Casasnovas13*, Jürgen Finke, MD14, Michael Hallek, MD15*, Hannes Wandt, MD16*, Andre Bosly, MD, PhD17, Wolfram Klapper, MD11*, Christian Gisselbrecht, MD18, Bertrand Coiffier, MD, PhD19, Wolfgang Hiddemann, MD, PhD2, Michael Unterhalt, MD, PhD2* and Martin H. Dreyling, PhD2

1Necker Hospital, Paris, France
2Department of Internal Medicine III, University Hospital Munich, Munich, Germany
3Department of Lymphoproliferative Diseases, Maria Sklodowska-Curie Memorial Institute and Cancer Center, Warsaw, Poland
4Service d'hématologie-oncologie, Institut Gustave Roussy, Villejuif
5Pathology, Necker Hospital, Paris, France
6Hospital Saint-Louis, Paris, France
7IPC, Marseille, France
8University of Ulm, Ulm, Germany
9Service d'Hématologie, Hôpital Adultes de Brabois, Vandoeuvre Les Nancy, France
10Hematology, Hôpital Henri Mondor, Créteil, France
11Campus Kiel, 2nd Dept. of Internal Medicine, Univ. of Schleswig-Holstein, Kiel, Germany
12GMMG, Germany
13Department of Hematology, University Hospital, Dijon, France
14Dept. of Medicine 1, Hem.-Onc., Universitatsklinikum Freiburg, Freiburg, Germany
15Department of Internal Medicine I, University of Cologne, Cologne, Germany
165. Medizinische Klinik, Klinikum Nürnberg, Nürnberg, Germany
17Hematology, UCL Mont Godinne, Yvoir, Belgium
18Hospital Saint Louis, Paris, France
19Centre Hospitalier Lyon-Sud, Pierre-Benite, France

Background: Mantle Cell Lymphoma (MCL) has been characterized by poor long term prognosis with a median survival of only 3 to 4 years. However, outcome has improved during the last decades. In its first randomized trial, the MCL net demonstrated that myeloablative consolidation followed by ASCT resulted in a significant prolongation of PFS in advanced stage MCL (Dreyling et al Blood 2005). Recent phase II studies suggested that the addition of rituximab to CHOP like chemotherapy and/or high dose ARA-C may significantly improve remission rates and PFS. A French phase II trial using sequential R-CHOP/R-DHAP followed by ASCT showed an overall response rate of 95% with a CR rate of 61% translating into a median EFS of 83 months and a 75% survival rate at 5 years (Delarue et al ASH 2008).

Methods: To evaluate the potential superiority of a high dose ARA-C containing regimen, the MCL net initiated a randomized trial comparing 6 courses of CHOP plus Rituximab followed by myeloablative radiochemotherapy (12 Gray TBI, 2x60mg/kg Cyclophosphamide) and ASCT (control arm A) versus alternating courses of 3x CHOP and 3x DHAP plus Rituximab followed by a high dose ARA-C containing myeloablative regimen (10 Gray TBI, 4x1,5 g/m2 Ara-C, 140mg/m2 melphalan) and ASCT (experimental arm B). Patient eligibility criteria included previously untreated MCL stage II-IV up to the age of 65 years. Histological diagnosis was confirmed by a central pathology review board. The primary end point time to treatment failure (TTF) was monitored continuously by a sequential procedure based on a one sided triangular test. Stable disease after induction, progression or death from any causes, were considered as treatment failure. Sample size was calculated to detect a hazard ratio of 52% for arm B with a power of 95%. Randomization was stopped as soon as a significant difference was observed between the two arms.

Results: From July 2004 to May 2010, 497 patients were randomized in 4 countries (Germany, France, Poland, Belgium). The 391 patients evaluable for the primary analysis (19 no MCL, 87 not yet documented) displayed similar characteristics in both treatment arms: median age 55 vs 56 years, male 78% vs 79%, stage IV 85% vs 79%, B symptoms 43% vs 33%, ECOG >2 5% vs 5%, elevated LDH 37% vs 38%, and MIPI low/int/high risk 61%/25%/14% vs 62%/23%/15%, respectively. After induction overall response was similarly high in both arms (A: 90% vs B: 94%; p=0.19) and CR rate and combined CR/CRu rate were significantly higher in arm B (26% vs 39%; p=0.012 and 41% vs 60%; p=0.0003). The number of patients transplanted was similar in both arms (72% vs 73%) and after transplantation overall response and CR rates were comparable in both arms (97% vs 97% and 63% vs 65%, respectively). After a median follow up of 27 months, patients in arm B experienced a significantly longer TTF (49 months vs NR; p=0.0384, hazard ratio 0.68) mainly due to a lower number of relapses after CR/CRu/PR (20% vs 10%), whereas the rate of ASCT-related deaths in remission was similar in both arms (3% vs 4%). Although CR rate after ASCT was comparable in both arms, remission duration (RD) after ASCT was superior in Arm B (48m vs NR; p=0.047). Interestingly, for patients in CR after ASCT, RD after ASCT was also presumably superior in arm B (51 months vs NR; p=0.077). At the time of analysis overall survival was similar in both arms with medians not reached and 79% vs. 80% survival rates at 3 years (p=0.74). Safety after induction was comparable in both arms except for an increased grade 3/4 hematological toxicity (Hb 8% vs 28%, WBC 48% vs 75%, platelets 9% vs 74%, respectively), an excess of renal toxicity (creatinine grade 1/2: 8% vs 38%, grade 3/4: none vs 2%), and more frequent grade 1/2 nausea and vomiting in arm B. Toxicities of both conditioning regimen were similar, except for higher grade 3/4 mucositis (43% vs. 61%) in Arm B, and higher grade 1/2 liver toxicity and constipation in Arm A.

Conclusions: High dose ARA-C in addition to R-CHOP+ASCT increases significantly complete response rates and TTF without clinically relevant increase of toxicity. Therefore, induction regimen containing high dose ARA-C followed by ASCT should become the new standard of care of MCL patients up to 65 years.

Disclosures: Walewski: Roche: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Stilgenbauer: Amgen: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Research Funding. Feugier: roche: Consultancy, Honoraria. Bosly: Roche: Membership on an entity’s Board of Directors or advisory committees. Gisselbrecht: Roche: Research Funding.

*signifies non-member of ASH