Lenalidomide Plus Rituximab for Relapsed or Refractory Diffuse Large B-Cell, Follicular and Transformed Lymphoma: Final Data Analysis of a Phase 2 Trial

Background: We have previously reported the favorable safety and efficacy of lenalidomide plus rituximab in relapsed or refractory (R/R) aggressive B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL), grade 3 follicular lymphoma (FLG3) and transformed lymphoma (TL) (Wang et al, Leukemia 2013). Here we report results of the final data analysis of this phase 2 trial after an extended follow-up.

Methods: Patients with R/R DLBCL, FLG3 and TL were enrolled in this single arm trial. Lenalidomide (20 mg daily) was administered orally on days 1-21 of each 28-day cycle, and rituximab (375 mg/m² weekly) was administered intravenously during the first cycle only. Treatment was continued with dose-reduction allowance until disease progression, stem-cell transplantation or severe toxicity. The primary endpoint was overall response rate (ORR), and the secondary endpoint was survival. Analysis was by intention to treat.

Results: In total, 45 patients were enrolled, with 32 DLBCL, 4 FLG3 and 9 TL. 29 were male and 16 were female. The median age was 66 years (range 23-84). Median ECOG PS was 1 (range 0-3). 41 patients (91.1%) were stage 3-4. Median number of prior lines of therapy was 3 (range 1-4). The median follow-up time was 9.8 months (range 0.8-77.7). Overall, 10 patients (22.2%) achieved CR, and 5 patients (11.1%) achieved PR, with an ORR of 33.3%. An additional 11 patients (24.4%) achieved SD. The ORR was 28.1% for DLBCL, 25.0% for FLG3, and 55.6% for TL. In Chi-square test, lower IPI score (0-2) was associated with higher ORR (P = 0.043). Patients with fewer prior lines of therapy tended to respond better (P = 0.118). In multivariate logistic regression, lower IPI was predictive of better ORR (P = 0.023). Median time to initial and best response was 1.8 months (range 0.8-2.1) and 1.8 months (range 0.8-20.1), respectively. Median duration of response was 10.2 months (95% CI 0.0-24.7). The median progression-free survival (PFS) was 3.7 months (95% CI 1.8-5.6), and the median overall survival (OS) was 10.8 months (95% CI 6.5-15.1). The 6- and 12-month PFS rates were 22.5% and 11.3%, respectively. The 1-, 2- and 5-year OS rates were 43.5%, 38.9% and 15.4%, respectively. Median OS was 50.3 months (95% CI 42.8-57.8) in responders and 6.6 months (95% CI 4.0-9.1) in non-responders (P < 0.001). In multivariate Cox regression, lower IPI was significantly predictive of longer OS (HR = 0.323, 95% CI = 0.157-0.668, P = 0.002) and showed a clear trend in predicting longer PFS (HR = 0.495, 95% CI 0.234-1.048, P = 0.066). Gender, Ki67 at registration and number of prior lines of therapy were not predictive of PFS or OS.

Conclusions: Lenalidomide plus rituximab is an efficacious treatment regimen for relapsed or refractory aggressive B-cell lymphoma. IPI is strongly predictive of ORR and OS in this setting. Ki-67 and number of prior lines of therapy are not predictive of ORR, PFS or OS.