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Brentuximab vedotin stalled Hodgkin’s lymphoma progression after autologous HSCT
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SAN FRANCISCO — Brentuximab vedotin safely and effectively stalled disease progression in patients with Hodgkin’s lymphoma when administered early after autologous hematopoietic stem cell transplantation, according to results of the phase 3 AETHERA study presented at the ASH Annual Meeting and Exposition.
“We’ve been transplanting Hodgkin’s lymphoma now for almost 30 years, and unfortunately, the PFS is fairly stable, between 40% and 55%,” Craig H. Moskowitz, MD, clinical director of the division of hematologic oncology at Memorial Sloan Kettering Cancer Center and a HemOnc Today Editorial Board member, said during a press briefing. “In fact, we’ve done a host of randomized clinical trials in all of the aggressive lymphomas … comparing A vs. B, and all of these studies are negative.”
Craig H. Moskowitz
The analysis included 329 patients with a median age of 32 years (range, 18-76), 53% of whom were male.
All patients received best supportive care plus 1.8 mg/kg brentuximab vedotin (Adcetris, Seattle Genetics; n=165) or placebo (n=164) every 3 weeks after undergoing autologous HSCT. This represents the first placebo-controlled, randomized study in Hodgkin’s lymphoma, Moskowitz said.
A substantial proportion of patients in each arm had previously received two or more systemic salvage therapies (brentuximab vedotin, 43%; placebo, 48%).
Further, 60% of patients in the brentuximab vedotin arm and 59% of patients in the placebo arm had refractory disease.
Patients received a median of 15 cycles of study treatment, and 49% of patients received the complete 16 cycles.
Treatment discontinuation occurred due to progressive disease (28%), adverse events (19%), patient decision (5%) or investigator decision (˂1%).
Median follow-up was 24.4 months (range, 0-43). Fifty patients had died by this time, eight of whom died before disease progression.
Sixty-five percent of patients in the brentuximab vedotin arm achieved 2-year PFS, compared with 45% of patients in the placebo arm. Brentuximab vedotin significantly prolonged PFS compared with placebo according to investigator review (HR=0.5; 95% CI, 0.36-0.7).
“Relapses almost never happen after 2 years in Hodgkin’s lymphoma,” Moskowitz said. “If you’re in remission at 2 years after stem-cell transplant for Hodgkin’s lymphoma, you are likely to be cured. The bottom line is there was a 20% difference in PFS at 2 years. This has never been seen in patients with relapsed, refractory lymphoma, let alone Hodgkin’s lymphoma.”
Eighty-five percent of the patients who received placebo crossed over to treatment with brentuximab vedotin at the time of relapse, which diminished the likelihood for a survival difference between the arms, Moskowitz said.
When calculating OS, researchers considered five risk factors including primary refractory disease, a lack of complete response to salvage chemotherapy, disease outside of the lymph node system, active symptoms at time of relapse and heavy pretreatment. Approximately half of the patients had at least three of these risk factors, which researchers have previously demonstrated is associated with only a 25% likelihood of being cured with an autologous transplant.
Researchers calculated a 0.92 HR (95% CI, 0.45-1.88) for OS with brentuximab vedotin for patients with at least three of these risk factors.
More patients in the brentuximab vedotin arm experienced peripheral neuropathy of any grade (67% vs. 19%) or which was grade 3 or higher (13% vs. 1%). Eighty-five percent of patients who experienced peripheral neuropathy on study treatment experienced resolution or improvement of the adverse event, and the median time to resolution or improvement was 23.4 weeks.
Brentuximab vedotin also was associated with greater rates of dose delays (9% vs. 3%) and dose reductions (32% vs. 3%).
“Once this study is published, for patients who meet the study eligibility criteria — including those with a remission duration of less than 1 year, disease outside of the lymph node system or primary refractory disease — in my opinion, this is going to be the standard of care.”
For more information:
Moskowitz CH. Abstract #673. Presented at: ASH Annual Meeting and Exposition; Dec. 6-9, 2014; San Francisco.Perspective
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Jeremy Slade Abramson, MD
The majority of patients with Hodgkin’s lymphoma are cured with initial therapy. However, a significant minority will relapse. Among those patients, only approximately half of patients may be cured with the standard therapy, which is high-dose chemotherapy with autologous stem cell transplant. This is a disease that typically affects younger people, often in their teenage years and early 20s, so cure of this disease ensures decades of remaining life expectancy. We’re therefore particularly focused on improving the outcomes and cure rates for young patients with Hodgkin’s lymphoma.The clinical trial that was performed was specifically looking at patients who relapsed after standard initial therapy and proceeded to salvage chemotherapy followed by high-dose chemotherapy with autologous stem cell rescue. This clinical trial looked at adding the novel targeted therapy brentuximab vedotin to this treatment. This drug, when given to patients with relapsed disease who relapse after autologous transplant, has a response rate of approximately 75%, which garnered it FDA approval in that population. However, those were all patients who went to an autologous transplant and then relapsed. What if we used that drug earlier in the course and prevent those patients from relapsing in the first place?
The study randomly assigned patients to receive brentuximab vedotin consolidation immediately after autologous stem cell transplant vs. no further therapy. Though follow-up is limited, there were fewer relapses in patients treated with brentuximab vedotin, suggesting a higher cure rate for these patients. An OS advantage has not been demonstrated, but follow-up is still quite short, and relapsing patients in the control arm likely received brentuximab vedotin at the time of their recurrence. What this study shows is that we can improve the outcome in patients who go to high-dose chemotherapy with stem cell support by incorporating a novel targeted therapy, and this creates a new standard of care for treating these young patients with relapsed disease.
Perspective
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Brad S. Kahl, MD
This is the first study that has shown a significant benefit for a post-transplant strategy in any kind of aggressive lymphoma. With the AETHERA trial, the big question is: Is the application of the maintenance brentuximab vedotin just delaying the inevitable relapse, so the patients will still relapse — just later — or, has the brentuximab taken patients who are destined to relapse and turned them into a cured patient? We don’t know the answer to that question, and that will become apparent with more time.Click Here to Manage Email Alerts