Rituximab-CHOP Versus CHOP with or without Maintenance Rituximab in Patients 60 Years of Age or Older with Diffuse Large B-Cell Lymphoma (DLBCL): An Update.

To address early and late treatment failures in DLBCL in patients age 60 and greater, we performed a prospective 2 x 2 randomized trial to determine the impact of the addition of rituximab to standard CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy during induction with a second randomization to maintenance rituximab (MR) or observation. From 2/98 to 7/01, 632 previously untreated patients were randomized to 6–8 cycles of rituximab (R)-CHOP (n=318) or CHOP (n=314). Rituximab 375 mg/M(2) was administered 7 and 3 days prior to cycle 1 and 2 days before cycles 3, 5, and 7. Responding patients (n=415) were randomized to MR 375 mg/M(2) weekly every 6 months x4 (n=207) or observation (n=208). The primary endpoint was time-to-treatment failure (TTF), and all p-values were two-sided. After ineligibility exclusion (76 pathology, 10 other), there were 267 R-CHOP and 279 CHOP patients with 178 observation patients and 174 MR patients. This report is based upon 95% information for induction and 75% information for MR. The base-line characteristics were balanced for age and prognostic factors. For all patients treated, granulocytopenia occurred in 12% (23) of MR patients vs 4% of observation patients (p=0.0008). This difference was significant in patients treated with CHOP (p=0.03) but not R-CHOP (p=0.12). Overall response rates were not different for R-CHOP (79%) versus CHOP induction (76%) (p=0.92). In induction therapy with a median follow-up of 3.5 years, time-to-treatment failure (TTF) favored R-CHOP (53% at 3 yrs) (p=0.04, HR=0.78, 95% CI [0.61,0.99]) versus CHOP (46% at 3 yrs). There was no significant difference in overall survival (OS) according to induction therapy (p=0.18). Maintenance rituximab significantly prolonged the TTF (p=0.009, HR=0.63, 95% CI [0.44,0.90]), but there was not a significant impact on OS (p=0.85). The TTF was prolonged with MR after CHOP (p=0.0004) but not after R-CHOP (p=0.81). In the patients reaching the second randomization to MR, the 2-year TTF was 77%, 79%, 74%, and 45% for R-CHOP, R-CHOP + MR, CHOP + MR, and CHOP, respectively (p<0.0001). The induction therapy results were influenced by maintenance treatment. A secondary analysis was performed to remove the effect of maintenance treatment on the induction comparisons of TTF and OS. R-CHOP alone resulted in a 36% reduction in the risk of treatment failure (p=0.003, HR=0.64,95% CI [0.47,0.85]) with an estimated 3-year TTF of 52% for R-CHOP vs 39% for CHOP. Survival was also longer after R-CHOP induction alone (p=0.05, HR=0.72, 95% CI [0.52,1.00]) compared to CHOP alone with an estimated 3-year OS of 67% for R-CHOP and 58% for CHOP. The addition of rituximab as induction or maintenance to CHOP chemotherapy improves the TTF in patients aged 60 and older. With the addition of rituximab as induction therapy or as maintenance therapy, the improvement in TTF suggests an additive rather than a synergistic effect of rituximab with CHOP in DLBCL.