Relapsing DLBCL patients respond to rituximab-based Rx

ATLANTA-Interim results of an international phase III study show that rituximab (Rituxan)-based salvage chemotherapy results in high response rates in patients with CD20-positive relapsed/refractory diffuse large B-cell lymphoma (DLBCL) allowing for stem-cell transplantation.

Christian Gisselbrecht, MD, PhD, of the Institut Hematologie, Hpital Saint Louis, Paris, presented preliminary results from the GELA-sponsored Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) at ASH 2007 (abstract 517).

The standard of care in relapsing CD20-positive DLBCL is salvage chemotherapy, followed by autologous stem-cell transplantation (ASCT) in responding patients. Choice of salvage regimen varies, however. DHAP (dexamethasone, ara-C, and cisplatin) has been the most widely used, but a higher remission rate was achieved in a phase II trial of ICE (ifosfamide, carboplatin, etoposide) (Blood 103:3684-3688, 2004).

When the present study was initiated in 2002, Dr. Gisselbrecht noted, it was not known which salvage regimen was best, and whether rituximab could improve outcomes following ASCT. CORAL is a multicenter, multinational trial designed to address these questions, with a planned enrollment of at least 400 patients.

Patients with CD20-positive relapsed/refractory DLBCL were randomized to receive three cycles of treatment with either ICE or DHAP, both combined with rituximab (R-ICE or R-DHAP).

Responding patients received high-dose therapy consisting of BEAM (BCNU, etoposide, ara-C, and melphalan) and ASCT. They then underwent a second randomization to maintenance therapy with six cycles of rituximab 375 mg/m2 administered every 2 months or observation only. Stratification was according to center, prior first-line rituximab therapy, and whether patients were refractory or had relapsed within the last 12 months.

Interim results reported by Dr. Gisselbrecht were based on an intent-to-treat (ITT) analysis of 194 patients (100 R-ICE, 94 R-DHAP) with a minimum follow-up of 12 months.

The overall response rate was 68%, including a 41% complete remission rate. In rituximab-nave patients, the response rate was 82% vs 54% in those who had received prior rituximab (P < .0001).

By univariate analysis, factors predictive of response included prior rituximab exposure or none (54% vs 82%); secondary IPI score [≤ 2 vs > 1] (77% vs 54%); and relapse less than 12 months after diagnosis (88% vs 52%). However, logistic regression revealed that only secondary IPI > 1 and early relapse remained significant predictors of response.

ITT 2-year event-free survival (EFS) was 50%, and 2-year overall survival (OS) was 69%. Prognostic factors for EFS included prior treatment with rituximab vs no rituximab (34% vs 66%, P < .0001); failure from diagnosis < 12 months vs ≥ 12 months (36% vs 68%, P < .0001); and age-adjusted IPI 2-3 vs 0-1 (39% vs 56%, P = .0084).

For the 107 patients who received ASCT, the 2-year EFS was 75% and OS 89%. Of these transplanted patients, 104 were randomized to maintenance rituximab therapy or observation and are still being followed for outcomes. The number of events to date have been limited (17%), precluding subgroup analysis.

Toxicity on both treatment arms was similar, Dr. Gisselbrecht reported, with 72 serious adverse events reported and 12 deaths during the initial salvage regimens.

In conclusion, Dr. Gisselbrecht said, rituximab-based salvage chemotherapy results in a high response rate for patients with relapsing DLBCL not previously treated with rituximab. Such salvage therapy, however, is less effective in patients who fail upfront rituximab-based therapy in less than 12 months.

The high (50%) dropout rate for patients eligible for transplantation and subsequent second randomization is also challenging, Dr. Gisselbrecht said.

The CORAL study will continue to enroll up to 240 patients in the second randomization for analysis of the EFS primary endpoint. In addition, genomic studies are in progress to better predict outcomes and select therapy in relapsing and refractory patients.