Abstract Topic: 17. Hodgkin lymphoma - Clinical
Background: Lenalidomide and nivolumab each have single agent activity in relapsed Hodgkin lymphoma (HL) and large B-cell lymphoma (LBCL) with potential for additive or synergistic activity. The immunomodulatory properties of this combination may salvage response to prior adoptive cellular therapy.
Aims: The objectives of this multicenter, open label, phase 1/2 study were to establish the recommended phase 2 dose (RP2D) of nivolumab and lenalidomide, and to assess the toxicity and preliminary efficacy of the combination in patients with relapsed HL and LBCL.
Methods: Adult patients with relapsed LBCL ineligible for or relapsed following autologous transplant (ASCT) or relapsed HL with ≥ 2 prior lines of therapy were eligible. Nivolumab 240 mg IV every 2 weeks for cycles 1-4 (28-day cycle) and 480 mg IV every 4 weeks beginning cycle 5 was given for up to 12 cycles. Lenalidomide was given orally once daily days 1-21 according to prespecified dose levels and continued until progression.
Results: Thirty-six patients signed informed consent and were treated, including 10 patients in the phase I cohort, 10 patients in the phase Ib HL cohort, and 16 patients in the phase II LBCL cohort. Dose limiting toxicity (DLT) occurred in 2/4 patients at dose level 1 (lenalidomide 15 mg) and included grade 3 rash and grade 3 generalized weakness. Six patients were treated at dose level -1 (lenalidomide 10 mg) with no DLT and thus 10 mg lenalidomide was selected as the RP2D. The most common adverse events (AE) included diarrhea (44%), rash (42%), and hypothyroidism (25%). Grade ≥ 3 AE included SARS CoV2 infection (11%), fatigue (8%), pulmonary embolism (3%), and Stevens-Johnson Syndrome (SJS) (3%).
Baseline characteristics for the phase Ib HL cohort included median age 28.5 (range 19-43), male sex in 9/10 patients, classical HL in 9 and nodular lymphocyte predominant HL in 1 patient, prior brentuximab vedotin in 8/10 patients, prior ASCT in 5/10, prior PD-1 inhibitor in 1/10, and a median of 3 prior lines of treatment (range 2-9). The overall response rate (ORR) was 70% including 30% complete response (CR). The median progression free survival (PFS) and overall survival (OS) were not reached (PFS depicted in Figure). Two patients completed 12 cycles of nivolumab and remain on lenalidomide treatment at data cut-off. Reasons for discontinuation included AE (SJS) in 1 patient, disease progression in 4 patients, and alternative treatment in 3 patients. In total 6 patients (2 from phase I and 4 from phase 1b) with HL underwent consolidative ASCT (n=2) or allogeneic transplant (allo-HCT) (n=4) directly following discontinuation of study treatment, and all 6 remain alive and relapse-free at data cut-off.
Baseline characteristics for the phase 2 LBCL cohort included a median age 62, male sex in 12/16 patients, and a median of 4 prior lines of treatment (range 2-5). Fourteen patients had previously received CAR-T therapy and 3 had prior ASCT. The ORR was 37%, including 12% CR. The median PFS was 2.6 months with a median OS of 12.3 months. Both patients with CR received CAR-T as the most recent prior treatment and responses were ongoing beyond 12 months; an additional patient with a partial response underwent allo-HCT and remains alive and relapse-free.
Summary/Conclusion: The combination of nivolumab and lenalidomide has an acceptable toxicity profile and a high response rate in HL, including utilization as salvage prior to consolidative transplant. In LBCL, while the ORR to the combination of nivolumab and lenalidomide is similar to lenalidomide monotherapy, two patients with prior CAR-T treatment achieved sustained responses beyond 12 months.
Keywords: Diffuse large B cell lymphoma, Hodgkin’s lymphoma, CAR-T