Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin’s Lymphoma

Abstract

BACKGROUND Brentuximab vedotin is an anti-CD30 antibody–drug conjugate that has been approved for relapsed and refractory Hodgkin’s lymphoma. METHODS We conducted an open-label, multicenter, randomized phase 3 trial involving patients with previously untreated stage III or IV classic Hodgkin’s lymphoma, in which 664 were assigned to receive brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) and 670 were assigned to receive doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). The primary end point was modified progression-free survival (the time to progression, death, or noncomplete response and use of subsequent anticancer therapy) as adjudicated by an independent review committee. The key secondary end point was overall survival. RESULTS At a median follow-up of 24.9 months, 2-year modified progression-free survival rates in the A+AVD and ABVD groups were 82.1% (95% confidence interval [CI], 78.7 to 85.0) and 77.2% (95% CI, 73.7 to 80.4), respectively, a difference of 4.9 percentage points (hazard ratio for an event of progression, death, or modified progression, 0.77; 95% CI, 0.60 to 0.98; P = 0.03). There were 28 deaths with A+AVD and 39 with ABVD (hazard ratio for interim overall survival, 0.72 [95% CI, 0.44 to 1.17]; P = 0.19). All secondary efficacy end points trended in favor of A+AVD. Neutropenia occurred in 58% of the patients receiving A+AVD and in 45% of those receiving ABVD; in the A+AVD group, the rate of febrile neutropenia was lower among the 83 patients who received primary prophylaxis with granulocyte colony-stimulating factor than among those who did not (11% vs. 21%). Peripheral neuropathy occurred in 67% of patients in the A+AVD group and in 43% of patients in the ABVD group; 67% of patients in the A+AVD group who had peripheral neuropathy had resolution or improvement at the last follow-up visit. Pulmonary toxicity of grade 3 or higher was reported in less than 1% of patients receiving A+AVD and in 3% of those receiving ABVD. Among the deaths that occurred during treatment, 7 of 9 in the A+AVD group were associated with neutropenia and 11 of 13 in the ABVD group were associated with pulmonary-related toxicity. CONCLUSIONS A+AVD had superior efficacy to ABVD in the treatment of patients with advanced-stage Hodgkin’s lymphoma, with a 4.9 percentage-point lower combined risk of progression, death, or noncomplete response and use of subsequent anticancer therapy at 2 years. (Funded by Millennium Pharmaceuticals and Seattle Genetics; ECHELON-1 ClinicalTrials.gov number, NCT01712490; EudraCT number, 2011-005450-60.)

Current considerations in AYA Hodgkin lymphoma

“…More recently, brentuximab vedotin (BV), an anti‐CD30 antibody‐drug conjugate that is highly active in the relapsed/refractory setting, was also tested in advanced stage patients. The ECHELON study compared ABVD to BV plus AVD (BV+AVD) in patients with advanced stage disease (Connors et al , ) (Table ). The trial demonstrated modest improvement in modified PFS, with an absolute difference of 4·9 percentage points (HR for an event of progression, death, or modified progression, 0·77, CI; 0·6–0·98, P = 0·04) with BV+AVD as compared with ABVD without difference in OS with short follow‐up.…”

Doxorubicin, vinblastine, dacarbazine and lenalidomide for older Hodgkin lymphoma patients: final results of a German Hodgkin Study Group (GHSG) phase‐I trial

“…Similarly, recent results of the ECHOLON‐1 study of BV combined with AVD showed the well‐known effect of treatment intensification in older HL patients (Connors et al , ). The intensified A+AVD regimen had increased severe toxicity in older patients including febrile neutropenia in more than one third of the patients (37%) (Connors et al , ). In accordance with previous results using ABVD, this suggests that AVD might not be the ideal chemotherapy‐backbone for simultaneous combination to novel substances in older HL patients (Böll et al , ; Evens et al , ).…”

Current treatment paradigms for advanced stage Hodgkin lymphoma

“…This was an unblinded study and therefore potentially prone to bias in this respect. With a median follow‐up of 2 years there was a 4·9% difference in modified PFS in favour of the AVD‐BV group with no difference in 2‐year EFS or OS (Connors et al , ). A higher incidence of grade 3–4 peripheral neuropathy and febrile neutropenia was reported in the BV+AVD group but the myelosuppression could be mitigated by the use of prophylactic granulocyte colony‐stimulating factor.…”