Background: The use of the anti-CD30 antibody drug conjugate, Brentuximab vedotin (Bv) has not been established as first line therapy for Hodgkin lymphoma (HL) in children or adolescents. We compared the efficacy and safety of Bv with doxorubicin, vincristine, etoposide, prednisone and cyclophosphamide (Bv-AVE-PC) to the standard pediatric dose intensive regimen ABVE-PC, inclusive of bleomycin.
Methods: This multicenter randomized, open-label phase 3 study enrolled patients 2-21 years (yrs) with previously untreated HL, stages IIB + bulk, IIIB, IVA, IVB (NCT02166463). Patients were randomized to 5 cycles of either ABVE-PC or Bv-AVE-PC given every 21 days with granulocyte colony-stimulating factor support. Centrally reviewed PET-CT after 2 cycles (iPET) defined slow responding lesions (SRL) by 5-point score (PS) >3. Involved site radiotherapy (ISRT) was given to bulky mediastinal adenopathy and SRL. The primary objective was EFS.
Results:
600 participants were enrolled across 153 Children’s Oncology Group institutions from March 2015 to August 2019; 587 were eligible. Median age was 15.6 yrs (range 3.4-22). Patient and disease characteristics were balanced across study arms. Stage distribution: 20.6% IIB-bulk; 19.3% IIIB; 28.5% IVA; 31.7% IVB.
At a median follow-up of 42.1 mos (0.1-80.9), 3-year EFS (95%CI) by intent-to-treat analyses was 92.1% (88.4, 94.7) with Bv-AVE-PC vs. 82.5% (77.4, 86.5) with ABVE-PC (HR 0.41 (0.25, 0.67), p=0.0002). Cumulative incidence of relapse was 7% with Bv-AVE-PC and 17% following ABVE-PC. iPET+ rates were comparable (ABVE-PC 19% vs. Bv-AVE-PC 18%, p=0.8), but iPET+ patients who received Bv-AVE-PC had a significantly higher 3yr-EFS (90.7%) compared to ABVE-PC (68.3%) (HR 0.28 [0.10, 0.76]). As-treated ISRT receipt did not differ (ABVE-PC 55.7% vs. Bv-AVE-PC 52.7%, p=0.69). No difference was noted in grade 3/4 adverse events; myelosuppression, reflected in a 32% incidence of > grade 3 febrile neutropenia, did not differ by arm (p=0.67). Only 19% of patients experienced > grade 2 neuropathy by the Balis pediatric neuropathy scale, with no difference between arms (p=0.86).
Conclusion: Bv with AVE-PC in a dose intensive regimen has superior efficacy to ABVE-PC for pediatric patients with high-risk HL. A 9.6% improvement in EFS was achieved with no increase in toxicity and with fewer patients receiving RT compared to prior pediatric trials for high-risk HL.