Lenalidomide in Combination with Bendamustine for Patients with Chemorefractory Hodgkin Lymphoma: Final Results of the Leben Multicenter Phase 1/2 Study
Authors: Pinto Antonello , Pavone Vincenzo , Angrilli Francesco , Saggese Mariangela , Crisci Stefania , Patti Caterina , Zinzani Pier Luigi , D'Arco Alfonso Maria , Cavalieri Elena , Guarini Attilio , Spina Michele , Carlino Daniela , Falorio Simona , Morelli Emanuela , Arcamone Manuela , Frigeri Ferdinando , De Chiara Annarosaria , De Filippi Rosaria , Corazzelli Gaetano 
Published: October 2019

Abstract
Background
Improving strategies for patients (pts) with relapsed/refractory (R/R) Hodgkin lymphoma (HL) who fail stem cell transplantation (SCT) or are unsuitable for the procedure remains an essential need. Lenalidomide and bendamustine are active and well tolerated as single agents in recurrent HL, with overall response rates (ORR) of 30% to 53% [Fenhinger, 2012; Corazzelli, 2012; Moskowitz, 2012].These agents independently frame different targets on tumor and microenvironment cells and may cooperate to override disturbed immunologic pathways and circumvent drug resistance in HL. In a Bayesian, multi-center, open label phase 1/2 study, we investigated for safety and efficacy the combination of continuous lenalidomide with weekly bendamustine (ClinicalTrials.gov # NTC01412307).
Methods
The study aimed at defining the optimal daily dose of continuous lenalidomide (10, 15, 20 or 25 mg) as combined, in a 28-day cycle, to weekly fixed-dose bendamustine (60 mg/m2; d 1, 8, 15). The dose-finding algorithm proceeded in cohorts of 3 pts, based on anticipated efficacy and toxicity pairs of probability (Thall & Cook, Biometrics 2004). Trade-offs between response [Cheson 2007 criteria] and dose-limiting toxicity [CTCv3.0 grade (G) >3 lasting >2 weeks] were assessed after 2 cycles (day +56) and pts were planned to receive up to 6 total courses, unless progression or unacceptable toxicity occurred. ORR and progression-free survival (PFS) were additional endpoints.
Results
Thirty-six pts (69% male) with a median age of 31 yrs (r 19-75) were enrolled. The median number of prior therapies was 4 (r 1-9) and the median time from upfront treatment was 24 mo.s (r 7-118). Twenty-six pts (72%) had primary refractory disease after ABVD, 16 pts (44%) failed prior SCT [single (n=7) or tandem (n=3) ASCT, tandem ASCT/alloSCT (n=6)]. Fifteen pts (42%) had previously received a median of 5 cycles (r 2-8) of brentuximab vedotin (BV) and 3 pts were already given bendamustine (>3 courses). Overall, 23 pts (64%) were refractory to most recent therapy. Eff/Tox trade-offs at cycle 2 showed that 73% of pts had response w/o toxicity, 19% had no response w/o toxicity, 6% had response with toxicity and 2% had no response with toxicity. With such Eff/Tox profiles, the study algorithm did not prompt any dose escalation for lenalidomide after the first 18 pts and the initial dose level (10 mg) was adopted for the expansion phase. A total of 156 LeBen cycles were administered, and pts received a median of 4 courses (r 1-6). Overall, 16 cycles were delayed due to G3/G4 thrombocytopenia (n=6), G4 neutropenia (n=3), G3 pneumonia (n=3), G3 respiratory infection (n=2), G2 phlebitis (n=1), G2 supraventricular arrhythmia (n=1). Two patients discontinued treatment, while in PR and CR after 4 courses, due to protracted (>2 weeks) thrombocytopenia. No G4 extra-hematological toxicity was observed. The complete response (CR) rate was 44% (16/36) with an ORR of 75% (27/36; 95% CI, 59-86). Notably, substantial CR and PR rates were achieved after LeBen regardless of primary refractoriness, SCT and BV failure (Table). Most CRs (14/16) were obtained within the first 4 cycles; 6 responders (4 CRs and 2 PRs) underwent SCT. Median PFS was 3.2 mo.s (r 1.5-5.4) for pts with progressive (PD) or stable disease (SD) and 11.4 mo.s (r 4-31) for those achieving CR/PR. Median overall survival for the entire cohort was 24 mo.s. Overall, complete responders (including 6 pts consolidated with SCT) had a 2-year disease-free survival of 41% (median, 14.3 mo.s).
Conclusions
The innovative schedule of the Leben combination is safe, yields high response rates in heavily pretreated and primary refractory HL pts, including SCT and BV failures, and steps over the 'single agent' activity of its components. Due to its immunomodulatory potential the Leben platform is amenable to further upgrading through lenalidomide maintenance, combination with immune checkpoint inhibitors and BV.
Table 1. Efficacy results Responsesno. (%) All pts Refractory to upfront therapy Refractory to most recent therapy Failure after SCT Failure after ASCT Failure after AlloSCT Failure after BV Failure after SCT and BV Failure after bendamustine No BV (n=36) (n=26) (n=23) (n=16) (n=10) (n= 6) (n=15) (n=8) (n=3) (n=21) CR 16 (44) 11 (42) 8 (35) 8 (50) 6 (60) 2 (33) 5 (33) 3 (37) 0 11 PR 11 8 9 4 2 2 4 2 0 7 SD 2 2 2 1 0 1 1 1 1 1 PD 7 5 4 3 2 1 5 2 2 2 CR+PR 27 (75) 19 (73) 17 (74) 12 (75) 8 (80) 4 (66) 9 (60) 5 (62) 0 18 (86)

Disclosures
Pinto: Takeda, Celgene, Roche, TEVA: Honoraria; Takeda: Research Funding. Zinzani:Takeda: Membership on an entity's Board of Directors or advisory committees; J&J: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.