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404 Aggressive Chemotherapy (CHOEP-14) and Rituximab or High-Dose Therapy (MegaCHOEP) and Rituximab for Young, High-Risk Patients with Aggressive B-Cell Lymphoma: Results of the MegaCHOEP Trial of the German High – Grade Non-Hodgkin Lymphoma Study Group (DSHNHL)

Oral and Poster Abstracts
Oral Session: Lymphoma: Chemotherapy, excluding Pre-Clinical Models - Non-Hodgkin Lymphoma: Therapy
Monday, December 7, 2009: 10:45 AM
208-210 (Ernest N. Morial Convention Center)

Norbert Schmitz1, Maike Nickelsen1*, Marita Ziepert2*, Matthias Haenel3*, Peter Borchmann, PD, Dr.4*, Andreas Viardot5*, Christina Nickenig6*, Martin Bentz, MD7, Christian Peschel, MD8, Lorenz Trümper9*, Markus Loeffler, Prof.2*, Michael Pfreundschuh10 and Bertram Glass, MD, PhD1*

1Hematology and Stem Cell Transplantation, ASKLEPIOS Klinik St. Georg, Hamburg, Germany
2Institute of Medical Informatics, Statistics and Epidemiology, Leipzig, Germany
3Departement of Internal Medicine III, Klinikum Chemnitz, Chemnitz, Germany
4First Department of Internal Medicine, University of Cologne, Cologne, Germany
5Internal Medicine III, Hematology, University Hospital Ulm, Ulm, Germany
6Medical Clinic III, University Hospital Munich Großhadern LMU, Munich, Germany
7II Medizinischen Klinik, Stadtisches Klinikum Karlsruhe, Karlsruhe, Germany
83rd Medical Department, Hematology and Oncology, Technische Universität München, München, Germany
9Hematology and Oncology, University of Göttingen, Göttingen, Germany
10University of Saarland, Homburg, Germany

Comparison of conventional chemotherapy with high-dose therapy followed by autologous stem cell transplantation (HDT/ASCT) administered to young, high-risk patients with aggressive B-cell lymphoma as part of first-line therapy gave conflicting results; none of the randomized studies used rituximab (R) in combination with conventional or HDT. In March 2003 we started a randomized phase III study for young (18-60 years), high-risk (age-adjusted IPI 2 or 3) patients with aggressive lymphoma. For patients with B-cell lymphomas this study compared 8 cycles of CHOEP-14 (CHOP + etoposide 300 mg/m² given every 2 weeks) with MegaCHOEP. The MegaCHOEP program used cyclophoshamide (1500 mg/m2 in cycle 1; 4500 mg/m2 in cycles 2 and 3; 6000 mg/m2 in cycle 4), doxorubicin (70 mg/m2 in all cycles), vincristine (2 mg, all cycles), etoposide (600 mg/m2 , cycle 1; 960 mg/m2 , cycles 2 and 3; 1480 mg/m2, cycle 4), and prednisone (500 mg, all cycles) to be administered every 21 days. Hematopoietic stem cells were harvested after cycles 1 and 2 and reinfused after HDT cycles 2, 3, and 4. Feasibility, safety, and efficacy of MegaCHOEP + / - R have been described (Glass et al. Blood 2006 and BMT 2006). The phase III study originally had four arms (8 x CHOEP – 14, 8 x CHOEP – 14 and 6 x R, MegaCHOEP, and MegaCHOEP and 6 x R). Treatment arms without R were closed in June 2004 because other studies (e.g the MInT study) had shown major improvement in outcome parameters when R was added to chemotherapy. The study continued comparing 8 x CHOEP – 14 and 6 x R (375 mg/m2) with MegaCHOEP and 6 x R (375 mg/m2). At the time of this analysis 346 patients (pts) had been recruited; 216 pts. (median age 48 years, LDH > N 97 %, stage III or IV 96%, ECOG > 1 35%) had been randomized until 07 / 07 and were available for this planned interim analysis ( 8 x CHOEP – 14 + 6 x R, n = 91; MegaCHOEP + 6 x R, n = 94; 8 x CHOEP – 14, n = 15; MegaCHOEP, n = 16). Major toxicities included mucositis, diarrhea, and infections all of which were significantly more frequent in the MegaCHOEP arm of the study. Treatment – related deaths occurred in 5 / 94 pts. ( 5.3%) in the MegaCHOEP arm and in 1 /  91 pts. (1.1 %) in the R – CHOEP arm (p = 0.211). Surprisingly, the 3 – year event – free survival ( EFS : time from randomization to either disease progression, no CR / CRu at the end of treatment, initiation of salvage therapy, relapse or death from any cause) was better after conventional than after HDT / ASCT: 71.0% after 8 x CHOEP-14 + 6 x R vs. 56.7 % after MegaCHOEP + 6 x R (p = 0.050). After a median observation time of 29 months the estimated 3-year overall survival  was 83.8 % after 8 x CHOEP – 14 + 6 x R and 75.3 % after MegaCHOEP + 6 x R (p = 0.142). Progression – free survival was 76.0 % after 8 x CHOEP – 14 + 6 x R and 64.6 % after MegaCHOEP + 6 x R (p = 0.119). A comparison of the rituximab-containing treatment arms (8 x CHOEP 14 + 6 x R and Mega CHOEP + 6 x R) with the chemotherapy – only arms (8 x CHOEP -14 and MegaCHOEP) revealed a 27.1 % difference in the 3-year EFS-rate ( p = 0.003 ) pointing to the unexpectedly high efficacy of R particularly in untreated, young, high-risk patients with aggressive B-NHL. These data were presented to the members of the study group and the data safety and monitoring committee who decided to stop the MegaCHOEP arm of the study. In conclusion, 8 x CHOEP -14 + 6 x R gave excellent results in young, high-risk patients with untreated aggressive B cell lymphoma. The 3-year EFS and OS are the best ever reported for this group of patients. MegaCHOEP + 6 x R was no better than aggressive conventional chemotherapy regarding any of the study endpoints; EFS (primary endpoint of the study) was significantly worse. Because of higher toxicity and inferior survival the MegaCHOEP arm was discontinued. HDT / ASCT has no role to play as part of first-line therapy for patients with high-risk aggressive B cell lymphoma if rituximab is combined with  aggressive conventional chemotherapy.

Disclosures: Schmitz: Roche: Honoraria, Research Funding. Nickelsen: Roche: Honoraria. Trümper: Roche: Honoraria, Research Funding. Pfreundschuh: Roche: Consultancy, Honoraria, Research Funding. Glass: Roche: Honoraria, Research Funding.

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