Six, Not Eight Cycles of Bi-Weekly CHOP with Rituximab (R-CHOP-14) Is the Preferred Treatment for Elderly Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Results of the RICOVER-60 Trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL).
Authors: Pfreundschuh Michael , Kloess Marita , Schmits Rudolf , Zeynalova Samira , Lengfelder Eva , Franke Astrid , Steinhauer Hans , Reiser Marcel , Clemens Michael , Nickenig Christine , de Wit Martha , Hoffmann Martin , Mertelsmann Roland , Metzner Bernd , Ho Anthony , Truemper Lorenz , Eimermacher Hans , Mergenthaler Hans , Liersch Ruediger , Duehrsen Ulrich , Balleisen Leopold , Hartmann Frank , Poeschel Viola , Schmitz Norbert , Loeffler Markus 
Published: April 2020

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 without increasing toxicity compared to CHOP-21. In the RICOVER-60 trial, elderly patients (61–80 years, stages I–IV) were randomized to receive 6 or 8 cycles of CHOP-14 with or without 8 applications of 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. The primary endpoint was freedom from treatment failure (FFTF) with events defined as additional therapy, failure to achieve complete remission, progressive disease, relapse, or death. The trial was powered to show a 9% difference in FFTF rate after 3 years. Between 07/2000 and 06/2005, 1330 patients were recruited. A planned interim analysis was performed on 828 evaluable patients with CD20+ DLBCL (median age 68 years; IPI=1: 32%, IPI=2: 29%; IPI=3: 23%; IPI=4,5: 16%). As by intention to treat, there was no difference in FFTF between 6 (n=414) and 8 (n=413) cycles (p=0.23), but FFTF after R-CHOP-14 (n=414) was significantly better than after CHOP-14 (n=413) alone (p=0.000025). As the empirical p-value of the log rank test statistics for FFTF was considerably lower than the critical value for the interim analysis (pcrit=0.031), the formal criterion for stopping the trial according to the alpha spending function (O’ Brien and Fleming boundary) was met and the trial was stopped on June 17, 2005 with 50/1330 patients still under therapy. After a median observation time of 26 months, there was a trend for a better FFTF after 8 cycles of CHOP-14 (n=210) compared to 6 cycles (n=203; 58% vs. 53%; p=0.13), but this trend was neutralized after the addition of rituximab: 70% FFTF for both 6 (n=211) and 8 cycles R-CHOP-14 (n=203). The advantage of R-CHOP-14 over CHOP-14 with respect to overall survival after 26 months is not yet significant (74% vs. 78%; p=0.13). Excluding patients with stage I, the RICOVER-60 population is very similar to the one included in the GELA 98.5 trial; however, the projected 2.5-year survival rate for elderly stage II–IV patients after 6 x R-CHOP-14 (74%) compares favorably with 8 x R-CHOP-21 in the GELA trial (64%; Feugier et al. JCO 2005). The superiority of 6 x R-CHOP-14 over 8 x R-CHOP-21 is mostly due to the better 2.5-year survival of poor-prognosis patients (IPI=3,4,5: 64% in the RICOVER trial vs. 54% in the GELA trial). In conclusion, the results observed with 6 cycles of R-CHOP-14 in this largest randomized trial of DLBLC performed to date are the best ever reported for elderly patients with DLBCL. 6 x R-CHOP-14 should be considered as reference standard in future trials for elderly patients with DLBCL.