A randomized phase II study of standard-dose versus high-dose rituximab with BEAM in autologous stem cell transplantation for relapsed aggressive B-cell non-hodgkin lymphomas: long term results

Abstract

High-dose rituximab (HD-R) combined with carmustine, cytarabine, etoposide and melphalan (BEAM) and autologous stem cell transplant (ASCT) was effective and tolerable in a single-arm prospective study of relapsed aggressive B-cell non-Hodgkin lymphoma (R-NHL). We performed a randomized phase 2 study comparing HD-R versus standard-dose rituximab (SD-R) in R-NHL. Ninety-three patients were randomized to HD-R (1000 mg/m² ) (n = 42) or SD-R (375 mg/m² ) (n = 51) administered on post-transplant days +1 and +8, using a Bayesian adaptive algorithm. The 2 treatment arms were balanced in regards to patient demographic and clinical characteristics. At a median follow-up of 7·92 years, the 5-year disease-free survival (DFS) and overall survival (OS) were 40% and 48%, respectively. We found no statistically significant differences between HD-R and SD-R in 5-year DFS (36% vs. 43%; P = 0·205) and OS (43% vs. 52%; P = 0·392). In multivariate analyses, only disease status before ASCT [residual disease versus complete remission (CR)] (hazard ratio [HR] 1·79, 95% confidence interval [CI]: 1·08-2·95) and number of prior treatments received (>2 vs. ≤2 lines of treatment) (HR 1·89, 95% CI: 1·13-3·18) were associated with worse DFS and OS. Patients who had SCT while in CR or who received ≤2 lines of treatment prior to SCT had better 5-year OS (57% vs. 35%; P = 0·02 and 54% vs. 30%, P = 0·001, respectively) in both arms. No differences in engraftments or adverse events were noted in the 2 arms. When combined with BEAM and ASCT in relapsed aggressive B-cell NHL, HD-R provided no DFS or OS advantage over SD-R. In patients who have been exposed to rituximab in the frontline or salvage setting, the addition of rituximab in the peri-transplant setting remains controversial.

Keywords: autologous transplant; carmustine, cytarabine, etoposide and melphalan; non-Hodgkin lymphoma; rituximab.

Figure 1. Consort diagram showing the flow of participants at each stage of the randomized trial

Abbreviations: BEAM, carmustine, etoposide, cytarabine, and melphalan; HD-R, high-dose rituximab; SD-R, standard-dose rituximab. *Patients with unclassified grade 3 follicular lymphoma but with high-grade pathologic and/or clinical features were considered aggressive B-cell lymphomas.

Figure 2

Survival of patients after autologous stem cell transplantation (n=93). (A) Disease-free survival (DFS) of all study patients. (B) Overall survival (OS) of all study patients. (C) DFS by study arm. (D) OS by study arm.

Figure 3. Survival of patients after autologous stem cell transplantation according to significant predictive factors (n=93). (A–B) Disease-free survival (DFS) and overall survival (OS) by disease status prior to transplant. (C–D) DFS and OS by number of prior lines of treatment

Abbreviations: CR/CRu, complete remission/complete remission unconfirmed; PR/SD, partial response/stable disease.