David J. Straus, MD, Memorial Sloan Kettering Cancer Center, New York, NY, discusses the 3-year follow-up results from the ECHELON-1 trial comparing brentuximab vedotin with chemotherapy versus chemotherapy alone for the treatment of patients with stage 3/4 classical Hodgkin lymphoma, presented at the 2019 ASCO Annual Meeting.

David J. Straus, MD: The ECHELON-1 trial was a postspective, randomized trial in 1334 patients, who were randomized to either standard chemotherapy with ABVD or with AVD plus brentuximab vedotin.

Brentuximab vedotin is an antibody-drug conjugate which, as a single-agent, has approximately twice the activity of any other conventional chemotherapy agent. This trial tested its incorporation in frontline treatment.

The trial was for adult patients with Stage III and IV classical Hodgkin lymphoma. The primary endpoint was the 2-year modified progression-free survival.

This was reported at the American Society of Hematology meeting in December 2017, and published simultaneously in the "New England Journal of Medicine."

The difference in the modified progression-free survival at two years between the two arms was five percent in favor of brentuximab vedotin plus AVD. This was statistically significant and led to the approval of brentuximab vedotin plus AVD for initially diagnosed patients with Stage III and IV Hodgkin lymphoma.

This trial updates this to 3 years. Most recurrences of Hodgkin lymphoma occur within the first 2 to 3 years, so this gives additional follow-up.

This difference did hold up, and it actually increased somewhat. At 3 years, the modified progression-free survival was 83% for the brentuximab vedotin plus AVD, and 76% for ABVD, a difference of approximately 7%, with a p-value, I believe, of 0.005.

There were a number of findings in this trial which I think are of interest for clinical practice. First of all, there is, in subset analyses of different risk groups, a forest plot shows an advantage for the brentuximab vedotin plus AVD regimen as compared to ABVD in all groups except those in the older age group.

The brentuximab vedotin plus AVD does get rid of bleomycin, which is a toxicity of which is very problematic and is higher in older patients.

As part of the trial, interim PET/CT scans were performed after 2 cycles of treatment in both arms.

There have been studies that showed that with ABVD, patients who were interim PET-positive had a much worse outcome. There was a very widely known study of Dr. Gallamini that showed that patients who were interim PET-positive had about an 80% relapse rate.

In this trial, we found that patients on the ABVD who were interim PET-positive had about a 50% relapse rate, where those in the brentuximab vedotin plus AVD arm had around 30% relapse rate. This trial showed that interim PET was not necessary, since it didn't change treatment.

While the overall results for the A+AVD arm were 83%, it was close to 70% for the PET-positive, not really significantly different. One addition of this trial to the treatment considerations are getting rid of the interim PET, since it doesn't really change treatment.

I was involved in several trials in newly diagnosed Hodgkin lymphoma using interim PET to tailor treatment, including one that I chaired in early-stage Hodgkin lymphoma. The problem is that PET-negative patients, which are the majority, this shows a good outcome. It's a very powerful tool.

The problem is what to do with the PET-positive patients. BEACOPP was used in several trials, including the ones that I participated in. Because of its toxicity, and because it did not really improve things that much, it's not clear that that is the right answer.

With the 3-year results of the ECHELON-1 trial, if you use brentuximab vedotin plus AVD, you can just proceed with 6 cycles. You do not have to worry about interim PET being positive.

The second thing is the toxicities. The toxicities are somewhat different for the 2 regimens. Bleomycin in the ABVD regimen is the most serious toxicity that can cause delays in treatment, and even fatalities. The brentuximab vedotin plus AVD gets rid of this.

There is more febrile neutropenia in the brentuximab vedotin plus AVD arm, however, prophylactic use of growth factor reduces this from 20% to 10%, which is about the same rate of febrile neutropenia with R-CHOP, which is widely used for non-Hodgkin lymphoma.

The other thing is the peripheral neuropathy, which is higher in the brentuximab vedotin plus AVD arm than ABVD. However, a follow-up up to 3 years shows that most of this peripheral neuropathy, sensory neuropathy, is resolved by 3 years.

Roughly 17% of patients with brentuximab vedotin plus AVD have residual grade 1 or 2 neuropathy. The rest resolves with time, ABVD, around 6%. This problem of peripheral neuropathy does decrease with time.

There is still a little bit more residual grade 1 and 2 in patients with BV+AVD as compared to ABVD, but this is not a big difference.

In summary, we think that brentuximab vedotin plus AVD is a good treatment choice, particularly for patients with adverse risk factors. The patients in whom you do not want to expose to bleomycin and its risks of toxicity, and even rarely, mortality, and that by using this regimen, it gets rid of the necessity for doing interim PET, which can be a problem.