Brentuximab Vedotin After Autologous Stem Cell Transplantation in High-Risk Hodgkin Lymphoma: Implications of the AETHERA Trial


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Stephen M. Ansell, MD, PhD

For the first time, a randomized controlled trial has shown that the use of a single agent reduced the rate of relapse or disease progression after autologous stem cell transplant for Hodgkin lymphoma.

—Stephen M. Ansell, MD, PhD

Hodgkin lymphoma is generally thought to be a malignancy with a favorable prognosis. Overall, approximately 80% of patients will have durable, long-term remissions with initial chemotherapy. Some patients, however, demonstrate evidence of disease progression, and these patients usually receive salvage chemotherapy followed by autologous stem cell transplantation. Although patients can be cured with this approach, at least 50% of patients subsequently progress, and many of these patients are not cured despite the use of novel treatment approaches and allogeneic stem cell transplantation. Therefore, a strategy to prevent progression of disease in patients undergoing an autologous stem cell transplant could significantly impact the outcome of this population of patients.

Review of Study Findings

As recently reported in The Lancet and reviewed in this issue of The ASCO Post, Dr. Moskowitz and colleagues tested whether such a strategy would be successful by performing a randomized, double blind, placebo-controlled, phase III trial in patients at high risk for disease progression after an autologous stem cell transplant.1 Patients were defined as having high-risk disease if they had failed to achieve a complete remission with initial chemotherapy, had evidence of disease progression within the first year after initial treatment, or had extranodal involvement at the time of disease progression (even if the period was longer than 1 year). To test whether brentuximab vedotin (Adcetrix) could prolong progression-free survival in unfavorable-risk, relapsed or primary refractory classic Hodgkin lymphoma, patients were randomized to receive 16 cycles of brentuximab vedotin at a dose of 1.8 mg/kg or a placebo. The therapy was infused every 3 weeks, starting 4 to 6 weeks after the autologous stem cell transplant.

A total of 329 patients were enrolled in this clinical trial, and after a median follow-up of 30 months, the median progression-free survival on independent review was 42.9 months in the brentuximab vedotin group compared with 24.1 months in the placebo group. This was a statistically significant difference, and the 2-year progression-free survival was also significantly different, with 63% of patients progression-free in the brentuximab vedotin group vs 51% in the placebo group. In all the subgroups analyzed, the hazard ratios favored brentuximab vedotin use in comparison to placebo. At the time of the report, however, the overall survival analysis showed no difference between the two groups.

Adverse events were obviously greater in the brentuximab vedotin–treated group, with neuropathy and neutropenia significantly more frequent in the brentuximab vedotin patients. One-third of patients discontinued brentuximab vedotin due to adverse events compared with 6% who discontinued therapy in the placebo group. The overall conclusion of the study was that early consolidation with brentuximab vedotin after stem cell transplantation improved progression-free survival in patients with high-risk Hodgkin lymphoma.

Challenging the Standard of Care

The findings of this study are significant in that, for the first time, a randomized controlled trial has shown that the use of a single agent reduced the rate of relapse or disease progression after autologous stem cell transplant for Hodgkin lymphoma. The findings challenge the assumption that the standard of care in patients with Hodgkin lymphoma after transplantation is observation with best supportive care until the disease progresses or relapses.

The fact, however, that overall survival is not impacted as yet by the use of brentuximab vedotin does bring to question whether it is required to administer brentuximab vedotin in the post-transplant setting or whether a similar outcome could be achieved if patients are treated with brentuximab vedotin at the time of disease progression. In this trial, it is likely that patients in the placebo arm will subsequently receive brentuximab vedotin at the time of disease progression, and therefore demonstrating a survival advantage between the two arms will be extremely difficult.

Furthermore, multiple new agents that have significant activity in Hodgkin lymphoma, including immune checkpoint inhibitors, histone deacetylase inhibitors, and immune modulatory drugs, are now available. The use of these agents in patients who have undergone a previous autologous stem cell transplant for Hodgkin lymphoma will further complicate the analysis to determine whether patients do better overall with the use of a maintenance approach after transplant.

For many Hodgkin lymphoma patients, however, remaining in remission without evidence of progression of their high-risk disease is an important factor in treatment decisions. The data from this trial confirm that the use of brentuximab vedotin decreases the rate of disease progression and relapse, and therefore the addition of brentuximab vedotin after transplant will be an attractive option for many patients at risk for disease progression. The increased rate of side effects will need to be balanced against the concern for disease relapse in making a decision to use maintenance therapy after transplant.

In closing, the results of this trial are extremely encouraging, confirming that we continue to make progress in maintaining remissions for patients with Hodgkin lymphoma and may be decreasing the number of patients who subsequently progress. The hope for the future is that the use of novel agents in patients with Hodgkin lymphoma will further improve the number of patients who are cured of this disease and do not require additional therapy for disease relapse. ■

Disclosure: Dr. Ansell received research funding from Seattle Genetics, Bristol-Myers Squibb, and Celldex Therapeutics.

Reference

1. Moskowitz CH, Nademanee A, Masszi T, et al: Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse Lancet. March 18, 2015 (early release online).

 


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In the phase III AETHERA trial reported in The Lancet, Craig H. Moskowitz, MD, of Memorial Sloan Kettering Cancer Center, and colleagues found that brentuximab vedotin (Adcetris) consolidation therapy after autologous stem cell transplantation prolonged progression-free survival by 18 months vs...


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