Brentuximab Vedotin and Chemotherapy in Classical HL

Siddhartha Ganguly, MD, FACP:Most recently, brentuximab vedotin is now approved for up-front treatment in patients with stage III and stage IV classic Hodgkin lymphoma, in combination with chemotherapy.

Historically we have been treating stage III, stage IV, or advanced, patients’ classic Hodgkin lymphoma with ABVD [doxorubicin, bleomycin, vinblastine, dacarbazine], 4 drugs. But there have been some issues with ABVD, especially the bleomycin-related pulmonary toxicity. By giving also ABVD, 75% of the patients do get cure in the long term, but 25% patients eventually do relapse, and the only way we can salvage those patients would be by an autologous stem cell transplantation. And unfortunately only 50% of them can be salvaged with autologous stem cell transplantation.

Patients who have relapsed after ABVD or relapsed after autologous transplantation options are limited. There is an unmet need to improve upon this ABVD and make it safer, and we have a lot of patients who are now being treated with ABVD and cured but have long-term consequences from this combination chemotherapy. Think about a 22-year-old young man, or a woman, who got treated for stage IV classic Hodgkin lymphoma with ABVD and now they are in their 30s or 40s, in the prime age. They’re cured of the cancer but cannot climb a flight of stairs or take part in daily activities because of advanced interstitial pulmonary fibrosis. Some of them could also be fatal. We have been always looking for a safer approach, and maybe even superior efficacy, for treatment of advanced classic Hodgkin lymphoma.

The ECHELON-1 trial is a large multicenter trial that randomized patients with advanced Hodgkin lymphoma in a 1-to-1 fashion where 1 arm, the treatment arm, received brentuximab vedotin, or Adcetris, and the bleomycin was omitted. We called that treatment arm A-AVD [Adcetris, doxorubicin, vinblastine, dacarbazine]. Note, we omitted the B [bleomycin] from here. That was compared with the standard-of-care arm with ABVD and given for 6 cycles and then they were monitored. Subsequently we looked for the primary outcome as modified progression-free survival, which was defined by either progression, death, or some other event that required some additional treatment by the treating physician. Hence this modified progression-free survival is slightly different from the progression-free survival that we usually use in our research trials. The secondary outcomes were overall survival, adverse events, etc.

At the end of the treatment the modified progression-free-survival was clearly superior in patients [who] received A-AVD compared with ABVD, by around 5%. The overall survival was not different, and there were many reasons. One is the length of follow-up was not long enough, and No. 2, patients who relapsed after ABVD were allowed to receive other alternative therapy that affected the overall survival.

In that ECHELON-1 trial, because of that pivotal trial, NCCN [National Comprehensive Cancer Network] Guidelines have now accommodated A-AVD, or brentuximab vedotin in combination with chemotherapy as a category 2b level of evidence, especially in patients who you doubt they may have underlying lung disease or they have a high risk for relapse; or for elderly patients I use this combination often in my practice.

Dr Galal, in your experience, can you explain some other modalities like relapsed-refractory combination treatment with brentuximab vedotin with bendamustine or PD-1 [programmed cell death protein 1] inhibitors like nivolumab? What do you prefer to use in your patients who are older, in your practice, with classic Hodgkin lymphoma?

Ahmed Galal, MD, FRACP, MSc:There is a category 2b for the NCCN Guidelines, and there’s category 2a for patients who cannot receive bleomycin or cannot receive other chemotherapeutic agents. Elderly patients who would have contraindication for the chemotherapy might benefit from a combination of brentuximab vedotin with a bendamustine. So it has these 2 categories in them.

Category 2b implies that the evidence is lowering quantity or quality, and that there’s no uniform consensus there. It depends on the clinical scenario when we decide to use this agent in combination with chemotherapy. This is the current, generally, for NCCN Guidelines. But the category 2a means that it’s a lower quality of evidence, but there is consensus of using it in this kind of population.

The combinations elderly patients have intolerance to, multiagent chemotherapy, have been tested, and the agent like bendamustine that’s been used frequently in non-Hodgkin lymphoma is quite active in Hodgkin lymphoma as well, and in combination with brentuximab it has been tested and used. And although it does have a lot of adverse effects, however, this population, if they are fit and can tolerate the chemotherapy, they might benefit from that. Alternatively, we can use the dacarbazine in combination with brentuximab vedotin in this kind of older population with very good effectiveness and outcome, with minimal adverse effects compared with the bendamustine and brentuximab. It opened the arena for better therapy and much more effective therapy for this population.

Also, the checkpoint inhibitor was used in Hodgkin lymphoma effectively and shown to have a good response rate. In combination with brentuximab vedotin in the CheckMate trial, it did show the effectiveness. Now it’s been sort of recommended in this elderly population again, which data [relate] very well to the checkpoint inhibitor like the nivolumab or pembrolizumab, to be used in combination with brentuximab vedotin with very good outcomes and tolerance.

Transcript edited for clarity.