Brentuximab Vedotin Plus Bendamustine for Pediatric Patients with Relapsed/Refractory Hodgkin Lymphoma: A Multi-Institution Retrospective Analysis

Background: Pediatric patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL) are often curable through a combination of salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT). Complete response (CR) to salvage treatment prior to HSCT is associated with superior outcomes, therefore optimal salvage treatments need to be identified. Brentuximab vedotin (BV), an antibody-drug conjugate combining an anti-CD30 murine/human chimeric monoclonal antibody covalently linked by an enzyme cleavable peptide to monomethyl auristatin E, and bendamustine, a fusion hybrid molecule containing the purine analogue fludarabine and the alkylating nitrogen mustard, are novel agents that have demonstrated potency as single-agent therapies for patients with R/R HL. Recently, the combination of BV and bendamustine proved to be highly active in adults with R/R HL. However, safety and efficacy data for pediatric patients are lacking.

Patients and Methods: We performed a multi-institution retrospective review of pediatric patients with R/R HL <21 years of age treated with BV/bendamustine. Patients received BV (1.8mg/kg) on Day 1 with bendamustine (90mg/m²) on Days 1 and 2 of 3-week cycles. Response was assessed utilizing Lugano criteria. Twenty-nine patients with a median age of 16 years (range 10 to 20 years) were identified across 3 institutions. Ten patients were classified as having refractory disease and 19 with relapsed disease, with 14/19 patients having relapsed less than a year from the completion of initial therapy. Twenty-one patients received BV/bendamustine as first line salvage therapy. Eight patients (28%) previously received radiation therapy (RT), 4 patients (14%) received prior BV and 4 patients (14%) had ASCT as part of prior therapy.

Results: Patients received a median of 3 cycles of BV/bendamustine (range 2-7). Overall, 18 (62%) patients achieved a CR (95%CI: 42 to 79%). An objective response (OR) was observed in 23 patients (ORR 79%) (95%CI: 60 to 92%). Notably, response rates were comparable among patients with relapsed (CR/ORR: 63/79%) or refractory (CR/ORR: 60/80%) disease. Among responders, 15 (65%) achieved best response within 2 cycles. CR and OR rates in patients receiving BV/bendamustine as first-line salvage therapy versus second-line salvage or greater was 67/81% and 50/75%, respectively. The most common grade 3 or 4 toxicities were hematologic (neutropenia (n=13), anemia (n=4), thrombocytopenia (n=4)). Three patients experienced grade 3 infusion reactions. Two patients proceeded with BV/bendamustine following desensitization protocols and 1 patient continued therapy with single-agent bendamustine. Sixteen patients received a consolidative transplant following BV/bendamustine (13 autologous, 3 allogeneic), 5 patients received consolidative RT, and 10 patients received post-transplant consolidation with BV. For the entire cohort, the 3-year post-BV/bendamustine event-free and overall survival was 65% (95%CI: 46 to 85%) and 89% (95%CI: 74 to 100), respectively.

Conclusions: Combination therapy with BV/bendamustine for pediatric patients with R/R HL compares favorably with currently accepted salvage regimens in terms of response and tolerability. These results support evaluation of this regimen in a multi-center prospective clinical trial.