First-Line Bendamustine-Rituximab-Based Induction Followed By Rituximab ± Lenalidomide Consolidation for MCL: Phase 2 Trial Results

According to phase 2 results, lenalidomide did not significantly improve the primary endpoint of progression free survival (PFS) when added to rituximab as consolidation of bendamustine-rituximab-based induction as initial mantle cell lymphoma (MCL) therapy.

Lenalidomide did not significantly improve the primary endpoint of progression free survival (PFS) when added to rituximab as consolidation of bendamustine-rituximab-based induction as initial mantle cell lymphoma (MCL) therapy, according to phase 2 results to be presented at the 2022 ASH Annual Meeting by Mitchell R Smith, MD, The Follicular Lymphoma Foundation, Washington, DC, et al.

Based on prior research, bendamustine-rituximab is commonly used in MCL treatment and bortezomib and lenalidomide have activity against MCL. The randomized phase 2 NCTN trial E1411 tested whether progression-free survival (PFS) is prolonged by addition of bortezomib (1.6 mg/m2 SC/IV days 1, 8) to bendamustine-rituximab (bendamustine-bortezomib-rituximab vs bendamustine-rituximab) induction and/or by addition of lenalidomide (15 mg/d days 1-21/28) to rituximab (lenalidomide-rituximab vs rituximab) consolidation. Previous reports from ASCO 2021 indicated no significant benefit of addition of bortezomib to bendamustine-rituximab.

As a first step, this trial randomized 373 patients into induction between 2012–16, stratified by MIPI (low v intermediate v high) and age (<60 v ≥60). Randomization was to 1 of 4 arms: A) Bendamustine-rituximab induction x 6 followed by rituximab x 2 years, B) Bendamustine-bortezomib-rituximab followed by rituximab, C) Bendamustine-rituximab followed by lenalidomide-rituximab, or D) Bendamustine-bortezomib-rituximab followed by lenalidomide-rituximab.

Progression-free survival was calculated from study registration (including induction + consolidation). The 2-year PFS and median PFS (years) for the 4 individual arms were bendamustine-rituximab and rituximab (80.7%, 6.0), bendamustine-bortezomib-rituximab with rituximab (82.8%, 6.6), bendamustine-rituximab with lenalidomide-rituximab (83.3%, 7.8), and bendamustine-bortezomib-rituximab with lenalidomide-rituximab (94.2%, 7.7).

Eligible patients included in this study had untreated MCL, ≥ age 18 (amended from ≥60 when S1106 for < 65 closed), ECOG PS 0-2 and adequate hematologic and organ function. Step two demonstrated that patients without progressive disease during induction proceeded to consolidation rituximab vs lenalidomide-rituximab.

For the endpoint of PFS from the start of consolidation, patients were stratified by induction strategy (bendamustine-rituximab vs bendamustine-bortezomib-rituximab) for the pooled analysis of lenalidomide-rituximab vs rituximab. During step 2, 290 eligible treated consolidation 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.

Of the 293 patients that registered to consolidation, the efficacy population was 276 (17 patients were either ineligible or not treated). The planned number of consolidation treatment cycles were completed in 95 of 140 (67.9%) lenalidomide-rituximab vs 90 of 136 (66.2%) rituximab. Of the 119 PFS events (57 lenalidomide-rituximab; 62 rituximab), 29 are death without progressive disease (PD), 40 with PD have died, and 50 are alive post-PD.

The noted grade ≥ 3 toxicities from this study were 87% with lenalidomide-rituximab vs 64.1% with rituximab. The largest adverse effects were neutropenia (58.9% vs 19.7%), with febrile neutropenia being the most common (6.8% vs 3.5%).

The only non-hematologic grade ≥ 3 toxicity measured in less than 5% of patients was lung infection/pneumonitis/upper respiratory infection (9.6% vs 4.2%). There were also 3 potentially treatment-related deaths.

Dr. Smith and colleagues concluded, “Each treatment arm was tolerable and deliverable to the majority of patients. The high [complete response] rate and [median progression free survival] of 6+ years from start of [bendamustine-rituximab]-based induction + [rituximab]-based fixed duration consolidation support this approach for 1st-line MCL therapy in individuals not appropriate for more intensive approaches, and as a platform for broader clinical trials.”

- Written by: Amber Denham

Source:

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. Abstract presented at: ASH Annual Meeting; Dec 10-13, 2022; New Orleans, LA, and virtual. Abstract 77.