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 × CHOEP – 14, 8 × CHOEP – 14 and 6 × R, MegaCHOEP, and MegaCHOEP and 6 × 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 × CHOEP – 14 and 6 × R (375 mg/m2) with MegaCHOEP and 6 × 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 availabel for this planned interim analysis ( 8 × CHOEP – 14 + 6 × R, n = 91; MegaCHOEP + 6 × R, n = 94; 8 × 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 × CHOEP-14 + 6 × R vs. 56.7 % after MegaCHOEP + 6 × R (p = 0.050). After a median observation time of 29 months the estimated 3-year overall survival was 83.8 % after 8 × CHOEP – 14 + 6 × R and 75.3 % after MegaCHOEP + 6 × R (p = 0.142). Progression – free survival was 76.0 % after 8 × CHOEP – 14 + 6 × R and 64.6 % after MegaCHOEP + 6 × R (p = 0.119). A comparison of the rituximab-containing treatment arms (8 × CHOEP 14 + 6 × R and Mega CHOEP + 6 × R) with the chemotherapy – only arms (8 × 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 × CHOEP -14 + 6 × 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 × 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.
Schmitz:Roche: Honoraria, Research Funding. Nickelsen:Roche: Honoraria. Trümper:Roche: Honoraria, Research Funding. Pfreundschuh:Roche: Consultancy, Honoraria, Research Funding. Glass:Roche: Honoraria, Research Funding.
Asterisk with author names denotes non-ASH members.