R-ICE Versus R-DHAP in Relapsed Patients with CD20 Diffuse Large B-Cell Lymphoma (DLBCL) Followed by Stem Cell Transplantation and Maintenance Treatment with Rituximab or Not: First Interim Analysis on 200 Patients. CORAL Study.

Salvage chemotherapy followed by high dose therapy (HDT) and autologous stem cell transplantation (ASCT) is the standard of treatment for chemosensitive relapses in diffuse large B cell lymphoma. Improvement of salvage chemotherapy was suggested with the association rituximab, Ifosfamide, etoposide, carboplatinum, R-ICE. What is the optimal chemotherapy regimen and can we reduce the post ASCT relapses rate? The ongoing CORAL trial was designed to answer these questions. DLBCL CD 20+ in first relapse or pts refractory after first line therapy were randomized between rituximab plus DHAP and R-ICE. Stratification was made on centers, prior rituximab exposure and refractory/<12months relapses. Responding patients received HDT (BEAM) and ASCT and were randomized between observation and maintenance with rituximab one injection every 2 months for 1 yr. Over 400 pts have been randomized in 11 countries since 2003. The planned interim analysis was performed on the 200 first pts with a minimum follow up of 1 yr. Six pts did not receive any treatment. Intent to treat analysis was made on 194 pts (100 R ICE arm, 94 R DHAP arm): median age 55 yrs.; 86 relapses >12months, 108 refractory/early relapses; 97 pts with prior exposure to rituximab; Stage 3-4 107 pts; elevated LDH 88 pts; secondary IPI 0–1 112 pts; sIPI 2-3 63pts. The two arms were well balanced. In the prior rituximab cohort exposure more pts had refractory disease and adverse prognostic factors. However, at inclusion patients characteristics were not significantly different in the stratified subgroups. The overall response rate was 68%, with 41% complete remission rate. Toxicity was similar to what is expected with intensive therapy, 72 SAE were reported with 12 deaths during the initial salvage regimens. In univariate analysis factors significantly affecting response rate (p<.0001) were: refractory/relapse < 12 months 52% vs 88%, secondary IPI >1 54% vs 77% and prior exposure to rituximab 54% vs 82%. In a logistic regression model only refractory/early relapse and secondary IPI remain significant for response rate. Intent to treat 2 yrs EFS and OS were 50% (CI 42–57%) and 69% (CI 61–75%) respectively. Only 107 pts in this prospective study received, per protocol ASCT. For patients transplanted, 2 yrs EFS was 75% (CI 63–84%) with OS 89%. Two yrs EFS was affected by: prior treatment with rituximab, 34% vs 66% (p=.0001); refractory/early relapse 36% vs 68% (p <.0001); secondary IPI 2–3: 39% vs 0–1: 56% (p=.03). After ASCT 104 pts were randomized between observation and rituximab. Only 17% events occurred so far without unexpected toxicity, preventing to give results between the different arms according to Data Safety Monitoring Board.

Conclusion: Salvage chemotherapy incorporating rituximab provide a high 82% response rate in pts not previously treated with rituximab. Patients who refractory to upfront rituximab-based chemotherapy have a poor response rate and prognosis. The study is on going to include 240 pts in the second randomisation for the EFS primary endpoint.