Phase III Trial of 2-Weekly CHOP with Rituximab for Aggressive B-Cell Non-Hodgkin’s Lymphoma in Elderly Patients.

Treatment results in elderly patients (> 65 yrs) with aggressive Non-Hodgkin lymphoma (NHL) are associated with a lower complete response (CR) rate and a worse survival (OS). Efforts have been made to improve the outcome by adding Rituximab to standard CHOP chemotherapy or by intensifying CHOP from 21 days to 14 days intervals (2-weekly CHOP, CHOP14). The Dutch HOVON and the Scandinavian Nordic groups have performed a prospective, multi-center, randomized phase III trial to compare 8 cycles of CHOP14 chemotherapy with or without 6 administrations of Rituximab (R-CHOP14), supported by G-CSF in previously untreated, older patients with intermediate or high-risk B-cell NHL. Inclusion criteria were mantle cell lymphoma, follicular lymphoma grade III or diffuse large B-cell lymphoma; intermediate or high age adjusted IPI score; CD20-positive NHL; age greater than 65 yrs. The target number was 400 patients to be accrued in 5 years based on an expected increase in failure free survival with hazard ratio HR=0.70. Based on a planned interim analysis the Data and Safety Monitoring Board stopped the trial because of a significant difference for primary endpoints. At final analysis 243 of 261 patients were eligible and evaluable. The median follow up was 20 months (range 3–46). The median age was 72 years (range 65–85 years), 80 % had DLBCL, 60 % had intermediate-high/high age-adjusted IPI score, 65 % had increased serum LDH. 64% of patients completed the planned treatment, while 22% went off treatment because of toxicity, of which 2 % was cardiovascular. 14% of patients experienced CTC grade 3–4 infections.

The number of patients who went off treatment because of toxicity was 15 % in those aged < 70 and increased with age up to 38 % in those over 75 yrs. After 3–4 cycles 16 % of the patients in the R-CHOP arm achieved a CR(u) as compared to 12 % with CHOP14; after 8 cycles the difference was 66 % vs 46 %. Overall response (PR+CRu) was 92 % and 83 %, respectively. Overall survival (OS) by Cox regression analysis adjusted for aaIPI and diagnosis was better with R-CHOP14 than with CHOP14 (relative hazard ratio HR=0.69, 95 % CI 0.46-1.05, p=0.09). The primary endpoint Failure free survival (FFS) was better in the R-CHOP14 arm (38 failures: 9 non-responders, 29 relapses, FFS2yr =55%)) than in the CHOP14 arm (65 failures: 20 non-responders, 45 relapses, FFS2yr =33%) with hazard ratio HR=0.60 (P=0.007). In the subgroup of DLBCL, FFS2yr was 62 %, while log-rank OS (p=0.05) and FFS (p=0.004) were both superior with R-CHOP14. These data indicate that in an elderly population (median age 72 yrs) with highly aggressive NHL, the CHOP14 regimen is tolerable and achievable in > 60 % of patients, and that the addition of Rituximab improves CR rate, OS and FFS.