Bendamustine-Rituximab Followed by Rituximab ± Lenalidomide for Mantle Cell Lymphoma
The optimal therapy for mantle cell lymphoma (MCL) has not yet been determined. Bendamustine-rituximab (BR) is most commonly used to date, and rituximab consolidation is often added post-BR although randomized supporting data is lacking. The randomized phase 2 NCTN trial E1411 tested whether progression-free survival (PFS) is prolonged by the addition of bortezomib (V) (1.6 mg/m2 SC/IV days 1, 8) to BR (BVR vs BR) induction and/or by the addition of lenalidomide (L) (15 mg/d days 1–21/28) to rituximab (LR vs R) consolidation.
Although the prior 2021 report showed no significant benefits of V to BR, at the 64th American Society of Hematology Annual Meeting and Exposition, Mitchell R Smith, MD, presented, “Randomized Phase 2 Trial of First-Line Bendamustine-Rituximab (BR)-Based Induction Followed By Rituximab (R) ± Lenalidomide (L) Consolidation for Mantle Cell Lymphoma ECOG-ACRIN E1411,” findings on the efficacy and toxicity of LR vs R consolidation.
“There’s a high initial response to therapy but unfortunately continuous relapse patterns, suggesting that we’re not curing this disease,” Dr Smith said. “In 2011, when this trial was designed, the strategy was to use a less-intense, nontransplant approach for patients over the age of 60 and at that time, bendamustine rituximab was a relatively standard induction, and it still is. Bortezomib was an active agent that had been approved for relapsed mantle cell, and so we asked the question in induction of whether the addition of bortezomib to BR would be effective.”
Between 2012 to 2016, a total of 373 patients were randomized into step 1 (induction), stratified by MIPI and age. Patients who met the criteria were randomized to one of four arms: BR induction x 6 followed by R x 2 years, BVR followed by R, BR followed by LR, or BVR followed by LR. Inclusion criteria consisted of having untreated MCL, aged ≥18 years, ECOG performance status of 0–2, and adequate hematologic and organ function.
Patients without progressive disease (PD) during induction proceeded to step 2 (consolidation) R vs LR. For step 2, 290 eligible patients were required to provide 89.4% statistical power to demonstrate a 37.4% reduction in the hazard ratio, using stratified log-rank test with a 10% 1-sided alpha.
The groups had similar demographics: median age 67 (range 42–90), 73% men, ECOG performance status of 0–1 98%, and MIPI low/intermediate/high of 40%/31%/29%.
Of 293 patients that registered to consolidation, 17 were ineligible or not treated leaving an efficacy population of 276 patients. All planned number of consolidation treatment cycles were completed in 95 (67.9%) of 140 LR vs 90 (66.2%) of 136 R; off-treatment reasons were PD 11 vs 22, adverse events 15 vs 7, and other 19 vs 17, respectively.
Estimated PFS at 2 years was 85.8% LR (95% CI 78.6–90.7) vs 77.7% R (95% CI 69.5–84.0) (one-sided stratified log-rank P = .416).
“There’s no statistically significant difference, 2-year PFS appears higher in the LR arm but it was not maintained and it did not reach statistical significance,” Dr Smith said.
Of the 119 PFS events (57 LR; 62 R), 29 were death without PD, 40 with PD died, and 50 were alive post-PD. Median PFS follow-up was 5.8 years, median PFS estimated in the pooled arms was 6.1 years from step 2 registration.
The 2-year PFS and median PFS (years) for the 4 individual arms were BR-R (80.7%, 6.0), BVR-R (82.8%, 6.6), BR-LR (83.3%, 7.8), and BVR-LR (94.2%, 7.7). The 2-year and median PFS in each arm, starting from study registration, after limiting the analysis to those patients over 60 years of age (87%), results were BR-R (81.2%, 6.0), BVR-R (81.0%, 6.2), BR-LR (81.2%, 5.7), and BVR-LR (93.2%, 7.7).
Grade ≥3 toxicities were 87.0% LR vs 64.1% R and included neutropenia 58.9% vs 19.7%, febrile neutropenia 6.8% vs 3.5%, and lung infection/pneumonitis/URI 9.6% vs 4.2%, and three potentially treatment-related deaths (MI and invasive SCC on LR, MDS on R).
Data from 64 unique patients with second malignancies (19 patients had >1 second malignancy) were BR-R (17), BVR-R (21), BR-LR (23), and BVR-LR (34).
“In conclusion, the question of consolidation of adding lenalidomide to rituximab in E1411 was achievable and tolerable but did not meet the primary endpoint of increased 2-year PFS, did not improve overall or complete response or median PFS, but also did not generate any unexpected toxicities,” Dr Smith said.
Further follow-up will continue as more than half of the patients remain alive and without progression.
Smith MR, Jegede O, Martin P, et al. Randomized Phase 2 Trial of First-Line Bendamustine-Rituximab (BR)-Based Induction Followed By Rituximab (R) ± Lenalidomide (L) Consolidation for Mantle Cell Lymphoma ECOG-ACRIN E1411. Presented at: 64th ASH Annual Meeting and Exposition; December 10-13, 2022. Abstract 77.
