Moskowitz Weighs Benefits, Challenges With A+AVD in Hodgkin Lymphoma

Craig Moskowitz, MD

The addition of brentuximab vedotin (Adcetris) to chemotherapy has slightly improved outcomes for patients with advanced-stage Hodgkin lymphoma, so the challenge is deciding which patients will benefit from this regimen versus the traditional 4-drug cocktail of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).

In the ECHELON-1 study, an international phase III trial, patients were randomized to receive either ABVD or brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD). The initial data, presented at the 2017 ASH Annual Meeting, demonstrated a 5% improvement in median progression-free survival (PFS) with A+AVD. In the subgroup analysis of the trial, which examined the outcomes in North American patients, the PFS advantage was about 10%.

This minor PFS advantage with A+AVD has led to some controversy in the field, according to Craig Moskowitz, MD, with some investigators positing that the benefit of A+AVD may not outweigh the massive cost of the regimen compared with the standard of care.

Despite this, investigators plan to evaluate the use of A+AVD in combination with the checkpoint inhibitor nivolumab (Opdivo) in a phase II trial that is currently recruiting patients (NCT03712202).

OncLive: Could you speak to the use of PET-adapted therapy in advanced-stage Hodgkin lymphoma?

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Moskowitz, physician-in-chief, Oncology Service Line, Sylvester Comprehensive Cancer Center, University of Miami Health System, discussed the role of PET imaging in the treatment of patients with Hodgkin lymphoma, weighed the pros and cons of A+AVD, and spoke to where future research is headed in the space.Moskowitz: In general, for standard therapy for patients with advanced-stage Hodgkin lymphoma, we coined the term PET-adapted therapy. What that means is that the patients have a pre-treatment PET scan to determine stage, and then after 2 cycles of upfront therapy, which typically consists of ABVD, we do a PET scan. Based on criteria, if that PET scan is positive or negative, we drop bleomycin and we give 4 months of AVD. That is seen in about 80% of patients. In 20% of patients, the PET scan is not what we want it to be, so we change therapy to what we call escalated BEACOPP.

What treatment strategies are under investigation?

This is all based upon 2 treatment programs. One is a randomized trial that was published in the New England Journal of Medicine about 1 year ago called the RATHL study. In that trial, about 78% of patients who have a negative PET scan at interim re-staging are cured. [This is] good, but not great. About two-thirds of patients who have a positive PET scan and change therapies have done well. We now know that if you just continue your treatment that you were on originally, and if the PET scan was positive and you didn't change therapy, about 40% of patients would be cured if that therapy was continued. Therefore, changing therapy is important. However, since the majority of patients maintain the therapy they were on, still having 20% to 25% of patients not doing well is unfavorable. There is room for improvement. There is some evidence that [pre-treatment metabolic tumor volume] can predict outcome. Future studies will look into that.The results of the ECHELON-1 study were presented a couple of years ago and were subsequently published in the New England Journal of Medicine. This randomized trial was in patients with stage III and IV disease and compared ABVD versus a new regimen called A+AVD. Investigators substituted brentuximab vedotin for bleomycin. In that study, there was a 5% difference in 2-year PFS in favor of the A+AVD. The results are very controversial. Does this mean we should give 100 patients this new regimen to benefit 5 patients? The answer to that is no.

What is the role of checkpoint inhibitors in these patients?

What is your take-home message to your colleagues?

Economically, ABVD is basically free. We charge for chemotherapy administration; the drugs have been around forever. A+AVD costs about $250,000 annually. As such, one has to look at the program carefully to determine which patients should receive which treatments. I give A+AVD to about 40% of my patients with stage III and stage IV disease.There was a phase II study in which investigators combined nivolumab with AVD and showed that the majority of patients did well by achieving remission. At a short-term follow-up, it seems as though everyone is doing OK. There is also going to be the Intergroup study, which is opening at the end of next month. We will anticipate this at Sylvester Comprehensive Cancer Center.In general, it is important to remember that early-stage Hodgkin lymphoma is more common than advanced-stage disease. Early-stage disease happens in about 55% of patients. I like to divide Hodgkin lymphoma into 5 silos. We divide them into [several stages]: favorable early stage, unfavorable early stage, unfavorable early stage without tumor bulk, unfavorable early stage with tumor bulk, favorable advanced stage, and unfavorable advanced stage. Luckily for the patients, the least favorable subgroups are the most uncommon. The 2 most common are unfavorable early stage without tumor bulk and favorable advanced-stage disease.

What we try to do is to treat appropriately based on whatever silo they fall into, whether that is standard therapy or an emerging option in a research program. The aforementioned study of nivolumab plus AVD will likely be for patients with moderately unfavorable and unfavorable advanced-stage Hodgkin lymphoma.

Connors JM, Jurczak W, Straus DJ, et al. Brentuximab vedotin plus doxorubicin, vinblastine, dacarbazine (A+AVD) as frontline therapy demonstrates superior modified progression-free survival versus ABVD in patients with previously untreated stage III Hodgkin lymphoma (HL): the phase 3 Echelon-1 study. Blood. 2017;130(6). bloodjournal.org/content/130/Suppl_1/6.