A New First-line Regimen for Advanced Hodgkin Lymphoma?

Nancy A. Melville

June 10, 2022

Patients with advanced classical Hodgkin lymphoma treated with first line brentuximab vedotin (Adcetris) plus chemotherapy showed substantial improvements in overall survival compared with those receiving standard chemotherapy, new research shows.

Over a follow-up of 6 years, patients on brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD) had a 41% lower risk of death vs those who got the standard doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) regimen.

"This is the first head-to-head study to show an overall survival advantage of A+AVD over [standard chemotherapy] in classical Hodgkin lymphoma, and that is a major, significant finding," first author John Radford, MD, of the University of Manchester and the Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK, told Medscape Medical News. "Based on these data, A+AVD should be considered a preferred first-line treatment option for patients with previously untreated stage 3 or 4 classical Hodgkin lymphoma."

Previous results from the phase 3 ECHELON-1 study, published in January 2018 in the New England Journal of Medicine, found a long-term progression-free survival benefit with first-line A+AVD compared with ABVD.

The latest results, presented today at the 2022 European Hematology Association (EHA) Annual Meeting in Vienna, highlight the 6-year follow-up data.

In the open-label trial, Radford and colleagues randomized 1334 patients with stage III or IV Hodgkin lymphoma to first-line treatment with the antibody drug conjugate brentuximab vedotin plus chemotherapy (A+AVD, n = 664) or the standard regimen (ABVD, n = 670).

Overall, patients in the A+AVD arm showed a significantly reduced risk of death compared with patients receiving the ABVD regimen (hazard ratio [HR], 0.59).

Over a median follow-up of 73 months (6.1 years), overall survival events were significantly lower in the A+AVD arm compared with the ABVD group (39 vs 64, respectively). The estimated overall survival rates were 93.9% in the A+AVD arm and 89.4% in the ABVD arm (P = .009).

Importantly, the overall survival benefit was consistent across a variety of patient subgroups, including those with stage III (HR, 0.86) and stage IV disease (HR, 0.48) at diagnosis as well as those who were PET-negative (HR, 0.58) or PET-positive at cycle 2 (HR, 0.16), and those younger than age 60 years (HR, 0.51) or 60 and older (HR, 0.83).

The overall survival benefit with A+AVD remained consistent in a multivariable analysis when adjusting for baseline demographic and disease factors (HR, 0.53).

The rate of progression-free survival benefit at 6 years also remained significantly better in the A+AVD group (82.3% vs 74.5%; HR, 0.68).

The authors noted two other benefits for those receiving A+AVD: the use of subsequent therapy was less common and patients had fewer subsequent malignancies — 23 secondary malignancies in the A+AVD arm compared with 32 in the ABVD arm.

This study, alongside findings from other A+AVD trials, "represents a potential milestone, showing that chemotherapy in combination with an antibody drug conjugate may be producing something over and above chemotherapy alone," Radford said. 

In terms of safety, no new signals emerged, with the two arms demonstrating similar long-term safety profiles.

Overall, treatment-emergent peripheral neuropathy occurred in significantly more patients in the A+AVD group (67% vs 43% in the ABVD arm at 2 years); however, symptoms continued to resolve or improve among 86% of patients receiving A+AVD and 87% receiving ABVD.

"We do know that peripheral neuropathy is more frequent after A+AVD, but this largely resolves, and while a few patients are left with some numbness, most recover," Radford said.

The numbers of pregnancies were higher among female patients in the A+AVD group (n = 49) vs the ABVD group (n = 28), as were live births, but no stillbirths were reported.

"This is especially important because the median age of presentation in this study was 35 to 36, so people may be still planning families at that age and the risks of sterility are a major concern," Radford said.

The study received funding from Takeda Development Center Americas, Inc., Lexington, MA, and Seagen Inc., Bothell, Washington. Radford reported financial relationships with Takeda, ADC Therapeutics, Kite Pharma, and AstraZeneca

EHA 2022, the European Hematology Association Annual Meeting: Abstract S200. Presented June 10, 2022.

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