Previously reported results from the phase III ECHELON-1 trial suggested that replacing bleomycin with brentuximab vedotin in the standard ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) regimen could prolong modified progression-free survival (mPFS) in patients with advanced Hodgkin lymphoma (HL), with lower rates of pulmonary toxicity with the brentuximab vedotin combination (A+AVD) but no difference in overall survival. In an update published in Blood, ECHELON-1 investigators report that, after 3 years of follow-up, the benefits with A+AVD are sustained and consistent across risk subgroups.
Also, while A+AVD was associated with a higher rate of peripheral neuropathy and neutropenia compared with ABVD, these adverse events improved with longer follow-up in most patients, the authors, led by David Straus, MD, from Memorial Sloan Kettering Cancer Center in New York, wrote.
From November 19, 2012, through January 13, 2016, ECHELON-1 investigators randomized 1,344 patients with previously untreated, stage III or IV classic HL to receive up to 6 cycles of either ABVD (n=670) or A+AVD (n=664). The median age was 36 years (range = 18-83 years), 64% of patients in each group had stage IV disease, and 58% in each group had B symptoms.
Per study protocol, response was evaluated via PET at baseline, after 2 cycles of chemotherapy (PET2), after administration of the last dose of frontline therapy, and every 3 months during follow-up. Patients with a positive PET2 scan (defined as a Deauville score ≥4) could switch to alternative therapy at the treating physician’s discretion.
In the A+AVD arm, 89% were PET2-negative and 7% were PET2-positive; in the ABVD arm, PET2-negative and -positive rates were 86% and 9%, respectively.
After a median follow-up of 37.1 months (range = 0-66.9 months), the investigator-
assessed 3-year PFS rates among all patients, irrespective of PET2 status, were 83.1% and 76.0% in the A+AVD and ABVD arms, respectively (hazard ratio = 0.704; 95% CI 0.55-0.90; p=0.005). The PFS benefit was observed across subgroups, including in those younger than 60 years and across disease stages and International Prognostic Score (TABLE).
“A+AVD compares favorably to ABVD and PET-adapted strategies without requiring a change of therapy.”
—David Straus, MD
A+AVD was associated with “a predictable and manageable safety profile,” the authors reported . However, a total of 442 patients in the A+AVD arm had developed peripheral neuropathy, compared with 286 in the ABVD arm at the interim analysis. By 3-year follow-up, 78% of those in the A+AVD group had either complete resolution or improvement of peripheral neuropathy, compared with 83% in the ABVD group. The median time to complete resolution of peripheral neuropathy following the end of A+AVD or ABVD treatment was 28 weeks (range = 0-167 weeks) and 14 weeks (range = 0-188 weeks), respectively.
“This represents an 11% improvement for the A+AVD group and 8% for the ABVD group compared to 2-year follow-up results,” the researchers reported.
Incidence of febrile neutropenia also was higher in the A+AVD group (19% vs. 11%), but the investigators observed that the rate was reduced and comparable to ABVD among patients who received A+AVD with G-CSF primary prophylaxis beginning with cycle 1, “highlighting the importance of G-CSF primary prophylaxis for all patients treated with A+AVD.”
With 3 years of follow-up, the rates of secondary malignancies were 2.3% in the A+AVD arm and 3% in the ABVD arm, suggesting that “the risk of secondary malignancies with A+AVD does not exceed that with ABVD, although it is too early for a definitive conclusion,” the authors wrote, noting a potential limitation of this analysis.
No additional long-term toxicities were observed.
While the financial cost of A+AVD is higher than ABVD, “A+AVD compares favorably to ABVD and PET-adapted strategies without requiring a change of therapy based on interim PET assessment while eliminating exposure to bleomycin,” Dr. Straus and researchers concluded. “These data further support the advantages of A+AVD versus ABVD as frontline treatment of patients with advanced stage III or IV HL.”
Study authors report relationships with Millennium Pharmaceuticals, Seattle Genetics, and Takeda, which sponsored the trial.
Straus D, Długosz-Danecka M, Alekseev S, et al. Brentuximab vedotin with chemotherapy for stage III/IV classical Hodgkin lymphoma: 3-year update of the ECHELON-1 study. Blood. 2019. [Epub ahead of print]