High‐dose bendamustine plus brentuximab combination is effective and has a favourable toxicity profile in the treatment of refractory and relapsed H odgkin lymphoma

Abstract

Introduction: The management of patients with refractory or relapsed Hodgkin lymphoma (HL), especially after autologous stem cell transplantation (ASCT), remains controversial. Bendamustine has demonstrated efficacy in several lymphoproliferative disorders, but limited data are available regarding the schedule in patients with HL, in particular its dosage and the possible combinations for a synergistic effect. Brentuximab vedotin is a CD30-directed antibody-drug conjugate, currently approved for the treatment of relapsed or refractory HL. The objective of this retrospective observational trial was to evaluate efficacy and safety of salvage cytotoxic regimens in patients with refractory and/or relapsed HL. Three different regimens were evaluated. Methods: From May 2011 to December 2016, 32 consecutive patients (19 M/13 F) with a median age of 31.7 years (range, 16-73) received a salvage regimen after failure of ASCT. Patients were by chance assigned to one of these 3 arms: standard dose bendamustine (90 mg/sqm) days 1 and 2 plus standard DHAP schedule (every 4 weeks) × 3 cycles (Arm A, n = 10 cases), brentuximab single agent 1.8 mg/kg (every 3 weeks) × 4 to 8 cycles (Arm B, n = 11 cases), high dose bendamustine (120 mg/sqm) days 1 and 2 plus brentuximab 1.8 mg/kg (day 3) × 4 to 6 cycles (Arm C, n = 11 cases). Each cycle in arm C was repeated every 28 days, and growth factor support was systematically administered, in association with antimicrobial prophylaxis. The treatment efficacy in each arm was evaluated according to Revised Response Criteria for Malignant Lymphoma by Cheson et al. Any adverse event occurred was recorded and classified for type and grade using NCI-CTCAE criteria (v 4.0). Results: In arm A, the overall response rate (ORR) was 40% (4/10 patients), with 4 (40%) complete remission (CR) and 6 (60%) progressive disease (PD). Hematological toxicity was grade 3 thrombocytopenia in 4 patients (40%) and bone marrow aplasia in 1 patient (10%); extrahematological toxicity was gastrointestinal toxicity of grade 2 in 6 patients (60%) and grade 1 in 3 patients (30%). In arm B, ORR was 63.6% (7/11 patients), with 5 (45%) CR, 2 (18%) partial response (PR), and 4 (36%) PD. Hematological toxicity was grade 2 neutropenia in 4 patients (36%), extrahematological toxicity was grade 3 neuropathy in 2 patients (18%). In arm C, ORR was 100% (11/11 patients), with 11 CR followed by SCT (second autologous transplant, 6 cases; and haploidentical transplant, 5 cases) with persistence of complete remission in all patients at a median follow-up of 33.4 months (range, 12-60). Hematological toxicity was grade 3 thrombocytopenia in 4 patients (36.3%); extrahematological toxicities were increase of transaminase (grade 2) in 3 patients (27%) and cytomegalovirus (CMV) reactivation in 2 patients (18%), treated successfully with valganciclovir. Three patients had fever during infusion at first cycle, together with a skin rash, managed with corticosteroid injections, and a successful antihistamine plus corticosteroid prophylaxis in the next cycles of treatment. Conclusions: High-dose bendamustine plus brentuximab has shown relevant efficacy and a relatively good safety profile in a setting of heavily pretreated patients with HL. Adequate monitoring of CMV reactivation is recommended. This combination could be considered as a bridge to second autologous or allogenic SCT. However, these results should be validated by controlled and prospective studies involving larger number of patients. (Figure Presented).