Lenalidomide in Combination with Bendamustine for Patients with Chemorefractory Hodgkin Lymphoma: Final Results of the Leben Multicenter Phase 1/2 Study

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.

Optimizing outcomes in relapsed/refractory Hodgkin lymphoma: a review of current and forthcoming therapeutic strategies

“…193 Recently, the efficacy of lenalidomide-bendamustine combination was evaluated in a phase I/II study, with 75% ORR and 44% CRs independently of previous autoSCT. 200 Panobinostat, Vorinostat, Mocetinostat, and Entinostat regulate several oncogenic pathways by inhibiting histone deacetylase (HDAC). Panobinostat (40 mg t.i.w.…”

“…Several novel agents had shown promising results, but their development was delayed or stopped with the appearance of the impressive results obtained with BV and checkpoint inhibitors. The potential role of such targeted agents in rr-cHL, including mTOR inhibitors, lenalidomide, histone deacetylase inhibitors (HDACi), and JAK inhibitors, as well as inhibitors of the B-cell receptor (BCR) pathway, 189–210 and details of major clinical trials of these agents are summarized in Table 3.…”

“…193 Recently, the efficacy of lenalidomide-bendamustine combination was evaluated in a phase I/II study, with 75% ORR and 44% CRs independently of previous autoSCT. 200…”

Treatment of Hodgkin Lymphoma – New and Developing Therapies and Their Potential Role in Standard of Care

“…(95% CI 59-88) and a CR of 44% was achieved. 121 A phase II study of lenalidomide in combination with temsirolimus has also shown promising results in patients with relapsed or refractory Hodgkin lymphoma (ORR of 80%). 122 Investigations of lenalidomide in combination with other agents, such as pembrolizumab (NCT02875067) and nivolumab (NCT03015896), are currently underway.…”

Current strategies for salvage treatment for relapsed classical Hodgkin lymphoma

“…Overall, patients in CR had a 2-year disease-free survival of 41% (median 14.3 months). 55 The HDAC inhibitor, panobinostat, has also been studied for the treatment of rel 24,35,40,42,45,46 Novel approaches in treatment in elderly patients with rel/ref HL are necessary. [58][59][60] Role of allogeneic stem cell transplantation in relapsed HL Prior to development of novel agents, an alloHCT was the only curative option and could still benefit a subgroup of patients in rel/ref HL, such as patients who relapsed after HDT/ASCT or refractory disease to multiple lines of therapy.…”