Lenalidomide-rituximab or lenalidomide-rituximab-bendamustine were associated with less severe toxicity than expected in patients with relapsed/refractory follicular lymphoma, according to a phase 2 trial.

Marie José Kersten, MD, PhD, University of Amsterdam, Amsterdam, Netherlands and colleagues conducted a multicenter, prospective, randomized, non-comparative phase 2 part of the HOVON110/ReBeL study, and sought to identify the most promising arm in order to progress to a randomized phase 3 trial.

In a presentation at the 2022 American Society of Hematology (ASH) Annual Meeting & Exposition, data from the phase 2 trial indicated that usage of regimens of lenalidomide-rituximab (R²) or lenalidomide-rituximab-bendamustine (R²B) were associated with less severe toxicity than expected in patients with relapsed/refractory follicular lymphoma (R/R FL), therefore supporting additional examination of R² combinations in randomized phase 3 trials.

In this trial, patients with FL relapsed after ≤5 prior therapies were randomized 1:1 to R² (arm A) or R²B (arm B). Stratification factors employed were FLIPI score (0-2 vs 3-5), number of prior treatments (1 vs 2-5), prior bendamustine use and relapse during rituximab maintenance (RM).

Those in the arm A group received 6 cycles of R² q28 days (lenalidomide 20 mg day 1-21, rituximab 375 mg/m² day 1). Those in the arm B group received 6 cycles of R²B q28 days (lenalidomide 20 mg day 3-21, rituximab 375 mg/m² day 1, bendamustine 90 mg/m2 day 1,2).

In both arms, patients with partial or complete remission (PR/CR) received 2 years of RM treatment, once every three months. Subcutaneous rituximab was allowed. Thrombosis prophylaxis was advised during induction; antimicrobial prophylaxis with valaciclovir and cotrimoxazole was mandatory in arm B.  Patients in arms A and B were separately assessed for efficacy and toxicity.

Co-primary endpoints were CT-based CR rate at end of induction (EOI) and incidence of severe toxicities (ST).  Results revealed that between 2014 and 2019, 92 of 150 planned patients were randomized. Due to slow accrual, the trial was halted early. 2 patients (1 in each arm) were classified as ineligible. Baseline characteristics were comparable between arms A/B in terms of gender and average age (64/62 years).

The majority of the patients had stage 3/4 disease (85%/80%), an intermediate/high risk FLIPI score (78%/89%) and had undergone 1 prior treatment (75%/76%; range 1-5). With regard to patients in arms A/B, 80%/76% completed all 6 induction cycles and 41%/43% finished 8 cycles of RM. Primary reasons for discontinuation during induction were progressive disease (PD) (n=4 per arm) and toxicity or other reasons in 5/7 patients.

Three patients in arm A (6.8%; 2 fatal pneumonia cases) experienced severe toxicity (ST) and STs occurred in 6 patients in arm B (13.0%; no fatalities). Additionally, 43%/66% of patients respectively experienced any grade 3-4 AE (2%/7% grade 4) which primarily included skin toxicity, infections and gastrointestinal toxicity. In the R²B arm, one patient was diagnosed with pneumocystis carinii pneumonia during RM.

Based on intention to treat (ITT) and local CT evaluation (efficacy co-primary endpoint), 16% of R² and 22% of R²B treated patients achieved a CR at EOI; the overall response rate (ORR) was 70% and 72%, respectively. The complete metabolic remission rate (CMR) by central PET-CT review at EOI was 48% and 54%.

At an average follow-up of 48 months, event free survival (EFS) was 39% and 61%; average EFS was 24.6 mo and not reached (NR). Significantly, average time to next treatment (TTnT) was 9.2 mo and NR. Overall survival was excellent in both arms with 72% and 91% of patients still alive at 48 months. Documented reasons of death during the study were progression of FL (n=8) and toxicity (n=3) in Arm A; FL (n=3), toxicity (n=1) and suicide (n=1) in Arm B.

The researchers indicated that findings from this randomized non-comparative phase 2 trial of R² and R²B in R/R FL patients demonstrated high CT-based OR rates and PET-CT CMR rates, but low CT-based CR rates for both treatments.

“Both regimens were associated with less severe toxicity than expected (pre-set acceptability threshold of 20% ST), supporting further investigation of R² combinations in randomized phase 3 trials,” concluded Kersten and colleagues.

Source:

Kersten MJ, Dreyling M, Linton K et al. Lenalidomide-Rituximab or Lenalidomide-Rituximab-Bendamustine in Patients with Relapsed/Refractory Follicular Lymphoma: Primary Analysis of the Randomized Phase 2 HOVON110/Rebel Trial. Presented at the 2022 American Society of Hematology Annual Meeting; December 10-13; New Orleans, LA. Abstract 950.