Brentuximab vedotin prolongs the post-transplant progression-free survival in hard-to-treat Hodgkin’s lymphoma patients

Data from the phase III, randomized, multi-center AETHERA study, comparing brentuximab vedotin with placebo in 327 Hodgkin’s lymphoma (HL) patients at risk of relapse following an autologous stem cell transplantation (ASCT), demonstrate that patients receiving brentuximab vedotin as consolidation therapy immediately after ASCT had a significantly longer progression-free survival (PFS) as compared to patients receiving placebo (median PFS 43 vs. 24 months, HR[95%CI]: 0.57[0.40-0.81]; p= 0.001). These data form an important breakthrough, given the slow progress in the development of new therapeutic options for these hard-to-treat HL patients over the last 20 years. As such, brentuximab vedotin has the potential to become the new standard of care for HL patients undergoing ASCT to reduce the risk of disease relapse or progression.

For the past 20 years, high-dose therapy plus autologous stem cell transplant (ASCT) has been the standard of care for patients with chemosensitive relapsed/refractory HL, providing a cure for approximately 50% of patients. Despite optimization of salvage chemotherapy, supportive care, and patient selection, improvements in outcomes post-ASCT have plateaued, likely due to disease progression in patients with pre-salvage therapy risk factors. The majority of patients with multiple risk factors will progress post-ASCT and novel therapy is urgently needed. Brentuximab vedotin is an anti-CD30 antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE) and has an objective response rate of 75% in relapsed or refractory HL.

In the AETHERA trial, a total of 329 HL patients was treated with an ASCT after which they were randomized between brentuximab vedotin (1.8 mg/kg q3wk) and best supportive care (BSC) or placebo and BSC for up to 16 cycles. Patients with disease progression were to discontinue study therapy and could request unblinding. These patients were then able to receive subsequent brentuximab vedotin on another clinical trial or on-label, if available.The primary endpoint of the study was PFS, while additional objectives included overall survival (OS) and safety.

The trial achieved its primary endpoint and demonstrated a significant increase in PFS per independent review with a HR of 0.57 (95%CI: 0.40-0.81) and a p-value of 0.001. The median PFS was 43 months with brentuximab vedotin and 24 months with placebo, translating into a 2-year PFS rate of 63% with brentuximab vedotin and 51% with placebo. This PFS benefit seen with brentuximab vedotin was consistent across all pre-specified subgroups, including primary refractory patients (N=196), patients who relapsed within 12 months of frontline therapy (N=107) and patients with extranodal disease (N=26) who relapsed after 12 months. Patients in both arms of the study who experienced disease progression received a variety of subsequent therapies. In the brentuximab vedotin arm 16% received subsequent brentuximab vedotin as compared to 85% of the progressive patients in the placebo arm. This high rate of cross-over in the placebo arm will make it difficult to see a difference in OS in this study, according to the investigators. At the time of presentation, the OS data were still immature, but no statistically significant difference was seen between both arms (HR: 1.15; p= 0.62).

Of note, the investigators underlined that the patient population in this trial was at a very high risk of relapse or disease progression after ASCT with over half of the patients having at least 3 known risk factors for relapse (relapsed within 12 months or refractory to frontline therapy, best response or partial response or stable disease to the most recent salvage therapy, extranodal disease at pre-ASCT relapse, B symptoms at pre-ASCT relapse and two or more prior salvage therapies). This further underlines the potential of brentuximab vedotin in this setting.

The most common adverse events associated with brentuximab vedotin included upper respiratory tract infection (26%), fatigue (24%) and peripheral sensory neuropathy (23%). The most common adverse events in the placebo arm were upper respiratory tract infection (23%), fatigue (18%), peripheral sensory neuropathy (16%), cough 16%) and neutropenia (12%).

In summary, the outcome of AETHERA is an important milestone as it demonstrates that early consolidation treatment with brentuximab vedotin in patients at risk of relapse after an ASCT can result in a substantial improvement in PFS. Given these positive results, the investigators suggested that brentuximab vedotin could soon become the standard of care for HL patients who undergo an ASCT.


Moskowitz CH, Nadamanee A, Masszi T, et al. The AETHERA trial: results of a randomized, double-blind, placebo-controlled phase 3 study of Brentuximab Vedotin in the treatment of patients at risk of progression following autologous stem cell transplant for Hodgkin’s Lymphoma. Presented at ASH 2014; Abstract 673.

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