Addition of Lenalidomide to Rituximab Consolidation Misses PFS End Point in Mantle Cell Lymphoma

The addition of lenalidomide (Revlimid) to rituximab (Rituxan) consolidation prior to bendamustine/rituximab induction did not significantly improve the primary end point of progression-free survival (PFS) in patients with mantle cell lymphoma (MCL), according to a presentation on results from the phase 2 NCTN E1411 trial (NCT01415752) during the 2022 American Society of Hematology (ASH) Annual Meeting. However, bendamustine/rituximab induction plus rituximab-based fixed duration consolidation could be a potential first-line approach based on a high complete response (CR) rate.

The 2-year PFS rate by overall treatment was 78% (95% CI, 66%-86%) for patients receiving bendamustine/rituximab plus rituximab consolidation, 78% (95% CI, 66%-86%) for those receiving bendamustine/rituximab with bortezomib (Velcade) plus rituximab consolidation, 80% (95% CI, 68%-88%) for patients receiving bendamustine/rituximab with lenalidomide and rituximab consolidation, and 91% (95% CI, 81%-96%) for those receiving bendamustine/rituximab with bortezomib plus lenalidomide and rituximab consolidation.

Additionally, the median PFS was 5.5 years (95% CI, 4.8-6.0), 6.9 years (95% CI, 4.0-not reached [NR]), 7.3 years (95% CI, 3.9-NR), and 6.9 years (95% CI, 5.5-8.0) in each respective cohort.

In terms of PFS by consolidation, the 2-year PFS rate was 78% (95% CI, 70%-84%) for patients receiving rituximab consolidation and 86% (95% CI, 79%-91%) for those receiving lenalidomide plus rituximab consolidation. Additionally, 87% and 84% of patients in each respective group experienced complete responses.

For patients over 60 years, the 2-year PFS rates were 81.2% for patients receiving bendamustine/rituximab with rituximab consolidation, 81.0% for those receiving bendamustine/rituximab plus bortezomib followed by rituximab consolidation, 81.2% for patients receiving bendamustine/rituximab followed by lenalidomide and rituximab consolidation, and 93.2% for patients receiving bendamustine/rituximab and bortezomib followed by lenalidomide plus rituximab consolidation. The median PFS in each respective arm was 6.0 years, 6.2 years, 5.7 years, and 7.7 years.

Investigators of the phase 2 E1411 trial randomly assigned patients with MCL to one of 4 treatment cohorts. In the first cohort, patients received an induction therapy consisting of 90 mg/m2 per day of bendamustine on days 1 and 2 plus 375 mg/m2 of rituximab on day 1 every 28 days for 6 cycles, followed by consolidation rituximab at 375 mg/m2 of every 8 weeks for 12 doses.

In the second cohort, patients received the same bendamustine-rituximab induction therapy plus 1.3 mg/m2 of bortezomib on days 1, 4, 8, and 11 intravenously or subcutaneously followed by the same rituximab consolidation.

In the third cohort, patients received bendamustine-rituximab followed by rituximab consolidation with 15 mg per day of lenalidomide on days 21 and 28 for 24 cycles.

In the fourth arm, patients received bendamustine-rituximab with bortezomib followed by lenalidomide plus rituximab consolidation.

The study aimed to assess PFS, the primary end point, for consolidation rituximab and lenalidomide/rituximab. Secondary end points for the trial included safety and toxicity.

Patients with untreated MCL, an ECOG performance status of 0 to 2, and adequate organ function were eligible to enroll on the trial. Patients were stratified by age and Mantle Cell Lymphoma International Prognostic (MIPI) measures.

In terms of accrual and patient demographics for consolidation, 276 of 361 patients were evaluable efficacy, which included 136 patients who received rituximab and 140 who received lenalidomide/rituximab. The overall median age of patients was 67 years, and 87% of patients were 60 years or older.

Overall, 40%, 31%, and 29% of patients overall had low, intermediate, and high MIPI scores, respectively. Additionally, 98% of patients had an ECOG performance status of 0 or 1.

Of the patients who received consolidation, 91 who were treated with rituximab and 95 who were treated with rituximab plus lenalidomide completed consolidation. For patients receiving lenalidomide plus rituximab, 15 discontinued treatments due to adverse effects (AEs), 11 discontinued due to progressive disease, and 2 discontinued due to death. In the rituximab arm, 22 patients discontinued due to progressive disease, 7 discontinued due to AEs, and 2 discontinued due to death.

The most common grade 3 or higher hematologic AE during consolidation was neutropenia occurring in 16, 12, 44, and 42 of patients and febrile neutropenia occurring in 1, 4, 5, and 5 patients receiving bendamustine/rituximab followed by rituximab consolidation, those receiving bendamustine/rituximab and bortezomib followed by rituximab consolidation, those receiving bendamustine/rituximab followed by rituximab and lenalidomide consolidation, and those receiving bendamustine/rituximab plus bortezomib followed by rituximab and lenalidomide consolidation, respectively.

Non-hematologic AES of grade 3 or higher that occurred during consolidation included rash in 4 patients, thromboembolic AEs in 3 patients, second treatment-related malignancies in 3 patients, fatigue in 9 patients, and diarrhea in 5 patients.

Reference

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 American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, Louisiana. Abstract 77.