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

Program: Oral and Poster Abstracts
Type: Oral
Session: 623. Mantle Cell, Follicular, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological II
Hematology Disease Topics & Pathways:
Biological therapies, Non-Biological therapies, Chemotherapy, Combination therapy, Therapies, Immunotherapy, Adverse Events, Monoclonal Antibody Therapy
Monday, December 12, 2022: 4:45 PM

Marie José Kersten, MD, PhD1, Martin Dreyling, MD2, Kim M. Linton3*, Dana Chitu, PhD4*, Sanne Tonino5*, Marcel Kap, BSc6*, Roberto D Liu, BSc7*, Martine E.D. Chamuleau, MD, PhD8, Hein P.J. Visser, MD9*, Eva De Jongh, MD10*, Erik WAF Marijt, MD, PhD11, Maria B.L. Leijs, MD12,13*, Yavuz M. Bilgin, MD PhD14*, Jan Dürig, MD15*, Pamela McKay, MBChB, FRCP, FRCPath16*, Tjeerd J.F. Snijders, MD PhD17*, Andrew Pettitt, PhD, FRCPath18,19*, Monique C. Minnema, MD, PhD20, Gabriele Prange-Krex, MD21*, Maria Cuijpers, MD22*, Lara H. Böhmer, MD23*, Lidwine W. Tick, MD, PhD24, Axel Florschütz25*, Matthijs Silbermann26*, Rob Fijnheer27*, Aart Beeker28, Nelleke Tolboom, MD29*, Cristina Mitea, MD30*, Anne IJ Arens, MD31*, Gerben JC Zwezerijnen, MD32*, Wolfram Klapper33*, Sarah E. Coupland, MBBS, PhD34*, Daphne de Jong, MD, PhD35*, Jeanette K. Doorduijn, MD, PhD36 and Josée M. Zijlstra, MD PhD37

1Amsterdam University Medical Centers, Location University of Amsterdam; Cancer Center Amsterdam, Amsterdam, Netherlands
2Department of Medicine III, Klinikum Der Universitaet Muenchen-Campus Grosshadern, Munich, Germany
3Division of Cancer Sciences, University of Manchester and the Christie Hospital, Manchester, United Kingdom
4HOVON Data Center, Erasmus MC Cancer Institute, Department of Hematology, Rotterdam, Netherlands
5Dept of Hematology, Lymmcare, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
6HOVON Data center, Dept. of Hematology, ErasmusMC Cancer Institute, Rotterdam, Netherlands
7Amsterdam UMC, University of Amsterdam, Amsterdam, NLD
8Amsterdam UMC, Vrije Universiteit Amsterdam, department of Hematology, Cancer Center Amsterdam, Amsterdam, Netherlands
9Hematology, Medisch Centrum Alkmaar, Alkmaar, NLD
10Department of Hematology, Albert Schweitzer Hospital, Dordrecht, Netherlands
11Hematology, Leiden University Hospital, Leiden, Netherlands
12Maasstad Ziekenhuis, Rotterdam, Netherlands
13Maasstad Ziekenhuiis, Rotterdam, Netherlands
14Department of Internal Medicine, Admiraal de Ruijter Hospital, Goes, Netherlands
15Department of Hematology, Essen University Hospital, Essen, Germany
16Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
17Medisch Spectrum Twente, Enschede, Netherlands
18The Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool, United Kingdom
19University of Liverpool, Liverpool, United Kingdom
20Department of Hematology, University Medical Center, Utrecht, Netherlands, Utrecht, Netherlands
21Gemeinschaftspraxis Mohm/Prange-Krex, Dresden, Germany
22Viecuri Medical Centre, Venlo, NLD
23Department of Hematology, Haga Teaching Hospital, The Hague, Netherlands
24Maxima Medical Center, Veldhoven, NLD
25Hematology, Klinikum Dessau, Dessau, Germany
26Ter Gooi Hospital, HILVERSUM, NLD
27Meander Medical Center, Department of Internal Medicine, Amersfoort, Netherlands
28Spaarne Ziekenhuis, Hoofddorp, Netherlands
29Nuclear Medicine, University Medical Center Utrecht, Utrecht, Netherlands
30Nuclear Medicine, Maastricht University Medical Center, Maastricht, Netherlands
31Radboud University Medical Center, Nijmegen, NLD
32Department of Radiology and Nuclear Medicine, Amsterdam UMC, Location VUmc, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, Netherlands
33University Hospital Schleswig-Holstein, Campus Kiel, Kiel, DEU
34Pathology, University of Liverpool, Liverpool, GBR
35Amsterdam UMC, Vrije Universiteit Amsterdam, department of Pathology, Cancer Center Amsterdam, Amsterdam, Netherlands
36Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
37Department of Hematology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands, Amsterdam, Netherlands

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.

Disclosures: 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: BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead/Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Lilly/Loxo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy; Bayer: Research Funding; Abbvie: Research Funding. 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.

*signifies non-member of ASH