Six vs. Eight Cycles of Bi-Weekly CHOP-14 with or without Rituximab for Elderly Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Results of the Completed RICOVER-60 Trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL).
Authors: Pfreundschuh Michael , Kloess Marita , Zeynalova Samira , Lengfelder Eva , Franke Astrid , Reiser Marcel , Steinhauer Hjalmar , Clemens Michael , Nickenig Christina , de Wit Maike , Metzner Bernd , Hensel Manfred , Mergenthaler Hans-Guenther , Liersch Ruediger , Duehrsen Ulrich , Balleisen Leopold , Engelhardt Monika , Poeschel Viola , Schubert Joerg , Truemper Lorenz , Schmitz Norbert , Loeffler Markus 
Published: October 2019

Abstract
Interval reduction from 3 (CHOP-21) to 2 weeks (CHOP-14; Pfreundschuh et al., Blood, 2004) and the addition of rituximab to CHOP-21 (R-CHOP-21; Coiffier et al., NEJM, 2002) improved outcome in elderly patients with DLBCL to a similar extent compared to CHOP-21. In the RICOVER-60 trial, elderly patients (61–80 years) were randomized to receive 6 or 8 cycles of CHOP-14 with or without rituximab given on days 1, 15, 29, 43, 57, 71, 85, and 99. Radiotherapy was planned to sites of initial bulk and/or extranodal involvement. Between 07/2000 and 06/2005, 1222 patients with CD20+ DLBCL and informed consent were recruited and evaluable (median age 68 years; IPI=1: 30%, IPI=2: 28%; IPI=3: 26%; IPI=4,5: 16%). The primary endpoint was event-free survival (EFS) with events defined as additional therapy, failure to achieve complete remission, progressive disease, relapse, or death. As by intention to treat, the 3-year EFS rate was 47% after 6×CHOP-14 (n=307), 53% after 8×CHOP-14 (n=305), 66% after 6×R-CHOP-14 (n=306), and 63% after 8×R-CHOP-14 (n=304). Regarding time-to-event data, we found a relevant interaction term (RR 1.4, p=0.068) between treatment contrasts and performd according to the protocol single-arm comparisons using 6×CHOP-14 without rituximab as the reference arm instead of a 2×2 factorial analysis. The p-values for the univariate log-rank tests of the improvement in EFS over 6×CHOP-14 were p=0.036 for 8×CHOP-14, and p<0.001 for 6×R-CHOP-14 and 8×R-CHOP-14, respectively. After a median observation time of 34.5 months, the estimated 3-year overall survival (OS) rates were 68% for 6×CHOP-14, 66% for 8×CHOP-14, 78% for 6×R-CHOP-14, and 72% for 8×R-CHOP-14. The p-values for the univariate log-rank tests of the OS improvement over 6×CHOP-14 were p=0.836 for 8×CHOP-14, p=0.018 for 6×R-CHOP-14 and p=0.260 for 8×R-CHOP-14. In a multivariate analysis using 6×CHOP-14 without rituximab as the reference and adjusting for the stratification variables (elevated LDH, advanced stage III&IV, ECOG performance state >1, bulky disease, >1 extranodal site, and age >70), both rituximab arms had a significantly improved EFS (6×R-CHOP-14: relative risk [RR]=0.51, p<0.001; 8×R-CHOP-14: RR 0.54, p<0.001; 8×CHOP14: RR 0.76, p=0.017). However, in the multivariate analysis for OS adjusting for the stratification variables, only the OS after 6×R-CHOP-14 (RR 0.63; p=0.003), but not after 8×R-CHOP-14 (RR=0.78; p=0.102) was significantly better than the OS after 6×CHOP-14. In summary, only 6 cycles of R-CHOP-14 significantly improved both EFS and OS over 6×CHOP-14, while 8×R-CHOP-14 did so only with respect to EFS. The reasons for the less favorable OS after 8×R-CHOP-14 compared to 6×R-CHOP-14 will be analyzed and discussed. The results after 6 cycles of R-CHOP-14 in this largest randomized trial of DLBLC performed to date are the best reported for elderly patients with CD20+ DLBCL. 6×R-CHOP-14 should be considered as reference standard in future trials for elderly patients with DLBCL.