Lenalidomide-Rituximab or Lenalidomide-Rituximab-Bendamustine in Patients with Relapsed/Refractory Follicular Lymphoma: Priimary Analysis of the Randomized Phase II HOVON110/Rebel Trial

Introduction The R² regimen (lenalidomide-rituximab) is effective in treatment-naive and relapsed/refractory follicular lymphoma (R/R FL). Combining R² with bendamustine (R²B) is feasible (Stevens WBC et al., Hemasphere 2020) and hypothesized to deepen remission and prolong event-free survival (EFS) compared to historic controls. We performed a randomized phase II trial of R² and R²B, aiming at identifying the most promising arm to take forward to a randomized phase III trial.

Methods In the multicenter, prospective, randomized, non-comparative phase II part of the HOVON110/ReBeL study (Dutch Clinical Trial Register NTR3028), patients (pts) with FL relapsed after ≤5 prior therapies were randomized 1:1 to R² (Arm A) or R²B (Arm B). Stratification factors used 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). Arm A pts received 6 cycles of R² q28 days (lenalidomide 20 mg day 1-21, rituximab 375 mg/m² day 1); Arm B pts 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, pts 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. Arms A and B were separately evaluated for efficacy and toxicity. Co-primary endpoints were CT-based CR rate according to Cheson 2007 criteria at end of induction (EOI) and incidence of severe toxicities (ST), defined as grade ≥ 3 non-hematological toxicity, specified grade 4 hematologic toxicity (neutropenia lasting ≥ 7 days despite GCSF, febrile neutropenia, thrombocytopenia) or non-lymphoma related death. An event for event-free survival was defined as induction failure, progression, relapse or death from any cause. PET-CT was performed before and after induction. Central pathology and blinded central PET-CT review (Lugano classification) were performed.

Results Between 2014 and 2019, 92 of 150 planned pts were randomized. The trial was stopped early because of slow accrual. Two pts (1 in each arm) were ineligible. Baseline characteristics were comparable between Arms A/B in terms of gender and median age (64/62 years). Most pts had stage III/IV disease (85%/80%), an intermediate/high risk FLIPI score (78%/89%) and had undergone 1 prior treatment (75%/76%; range 1-5).

For pts in arms A/B, 80%/76% completed all 6 induction cycles and 41%/43% completed 8 cycles of RM. Main reasons for discontinuation during induction were progressive disease (PD) (n=4 per arm) and toxicity or other reasons in 5/7 patients. Severe toxicity (ST) occurred in 3 pts in arm A (6.8%; 2 fatal pneumonia cases) and in 6 pts in arm B (13.0%; no fatalities), while 43%/66% of pts experienced any grade 3-4 AE (2%/7% grade 4). These comprised mainly skin toxicity, infections and gastrointestinal toxicity. In the R²B arm, 1 pt had Pneumocystis carinii pneumonia during RM.

Based on intention to treat (ITT) and local CT assessment (efficacy co-primary endpoint), 16% of R² and 22% of R²B treated pts 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 a median follow-up of 48 months (mo), EFS was 39% and 61%; median EFS was 24.6 mo and not reached (NR). Importantly, median time to next treatment (TTnT) was 9.2 mo and NR. There were 7 second primary malignancies (SPM) in 5 pts in Arm A) and 5 SPM in 4 pts in Arm B). Overall survival was excellent in both arms with 72% and 91% of pts alive at 48 months. Causes 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.

Conclusions This randomized non-comparative phase II trial of R² and R²B in R/R FL patients showed high CT-based OR rates and PET-CT CMR rates, but low CT-based CR rates for both treatments. At a median FU of 48 months, 39% of R² treated patients and 61% of R²B treated patients were still alive and in remission; this compares favorably with historic real world controls (Batlevi et al, Blood Cancer J 2020). 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 III trials.

Kersten:Roche: Honoraria, Research Funding; Mundipharma: Research Funding; BMS/Celgene: Honoraria, Research Funding; Kite, a Gilead Company: Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria; Miltenyi Biotec: Honoraria; Adicet Bio: Honoraria. Dreyling:Abbvie: Research Funding; Bayer: Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead/Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Lilly/Loxo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Linton:Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy; Beigene: Consultancy; Kite/Gilead: Consultancy; BMS/Celgene: Consultancy. Tonino:Roche: Honoraria; Incyte: Honoraria; Takeda: Honoraria. Chamuleau:Gilead: Research Funding; Abbvie: Honoraria; Genmab: Research Funding; BMS/Celgene: Honoraria, Research Funding; Novartis: Honoraria; Roche: Honoraria. McKay:Abbvie, AstraZeneca, Beigene, Celgene/BMS, Epizyme, Gilead/Kite, Incyte, Janssen, Recordati Rare Diseases, Roche, Takeda: Consultancy; Gilead/Kite, Incyte, Janssen: Speakers Bureau. Pettitt:Napp: Other: Grant and non financial support; AstraZeneca: Other: Grant and non financial support; Chugai: Other: Grant, personal fees and non financial support; GSK/Novartis: Other: Grant and non financial support; Roche: Other: Grant, personal fees and non financial support, Research Funding; Gilead: Other: Grant, personal fees and non financial support; BMS/Celgene: Other: Grant and non financial support, Research Funding. Minnema:Bristol Myers Squibb: Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Medscape: Speakers Bureau. Doorduijn:Eli Lilly/Loxo: Honoraria, Membership on an entity's Board of Directors or advisory committees.