Improved Progression-Free Survival With Brentuximab Vedotin Consolidation After Transplantation in Hodgkin Lymphoma
In the phase III AETHERA trial reported in The Lancet, Moskowitz et al found that brentuximab vedotin (Adcetris) consolidation therapy after autologous stem cell transplantation prolonged progression-free survival by 18 months vs placebo in patients with Hodgkin lymphoma at risk for relapse or disease progression.
In this double-blind trial, 329 patients from 78 sites in North America and Europe with unfavorable-risk relapsed or primary refractory classic Hodgkin lymphoma who had received autologous stem cell transplantation were randomly assigned between April 2010 and September 2012 to receive 16 cycles of 1.8 mg/kg of brentuximab vedotin (n = 165) or placebo (n = 164) given intravenously every 3 weeks, starting 30 to 45 days after stem cell transplantation. Randomization was stratified by best clinical response after completion of salvage chemotherapy (complete response vs partial response vs stable disease) and according to primary refractory Hodgkin lymphoma vs relapsed disease < 12 months and vs ≥ 12 months after completion of front-line therapy.The primary endpoint was progression-free survival on independent review in the intention-to-treat population.
The brentuximab vedotin group had a greater proportion of female patients and a lower proportion of male patients (54% vs 41% female; 46% vs 59% male) and a greater proportion of black patients (6% vs 1%; 93% vs 95% white, 1% vs 2% Asian). Otherwise, the two groups were generally balanced with regard to age, Eastern Cooperative Oncology Group performance status, number of prior systemic salvage therapies, receipt of more than one autologous stem cell transplantation, time from autologous stem cell transplantation to first study dose, front-line therapy, conditioning regimen, lymphoma status after front-line therapy, best response to salvage therapy after stem cell transplantation, pretransplantation positron-emission tomography status, extranodal involvement at pretransplantation relapse, and B symptoms after front-line therapy.
Improved Progression-Free Survival
After a median follow-up of 30 months, median progression-free survival on independent review was 42.9 months (95% confidence interval [CI] = 30.4–42.9 months) in the brentuximab vedotin group vs 24.1 months (95% CI = 11.5–not estimable) in the placebo group (hazard ratio [HR] = 0.57, P = .0013). Two-year progression-free survival was 63% vs 51%. Hazard ratios favored brentuximab vedotin in all subgroups analyzed and were significant among patients with partial response to salvage therapy, those with relapse < 12 months, those aged < 45 years, female patients, those with performance status of 1, those who received more than two prior systemic treatments, those with pre–stem cell transplantation extranodal involvement, and those with B symptoms after front-line therapy.
At the time of the progression-free survival analysis, interim analysis of overall survival showed no difference between the two groups, with death occurring in 17% vs 16% of patients (HR = 1.15, P = .6204). However, 72 (85%) of 85 patients in the placebo group who received treatment after disease progression received brentuximab vedotin, compared with 18% of patients in the brentuximab vedotin group. As noted by the authors, recent data have shown that retreatment with brentuximab vedotin can be beneficial in patients with relapsed/refractory disease. In addition, allogeneic stem cell transplantation was less common in the brentuximab vedotin group (12 vs 23 patients).
Adverse Events
The most frequent adverse events of any grade in the brentuximab vedotin group were peripheral sensory neuropathy (56% vs 16% in the placebo group), neutropenia (35% vs 12%), and upper respiratory infection (26% vs 23%). Grade ≥ 3 adverse events occurred in 56% vs 32% of patients, with the most common in the brentuximab vedotin group being neutropenia (29% vs 10%), peripheral sensory neuropathy (10% vs 1%), and peripheral motor neuropathy (6% vs 1%). Only one case of febrile neutropenia was observed in the brentuximab vedotin group. Growth factor support was required in 25% vs 11% of patients. Severe infection was observed in 7% vs 6%. Discontinuation of treatment due to adverse events occurred in 33% vs 6% of patients, with the most common causes in the brentuximab vedotin group being peripheral sensory and motor neuropathies.
The investigators concluded: “Early consolidation with brentuximab vedotin after autologous stem-cell transplantation improved progression-free survival in patients with Hodgkin’s lymphoma with risk factors for relapse or progression after transplantation. This treatment provides an important therapeutic option for patients undergoing autologous stem-cell transplantation.”
Craig H. Moskowitz, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author of The Lancet article.
The study was funded by Seattle Genetics and Takeda Pharmaceuticals International. For full disclosures of the study authors, visit www.thelancet.com.
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