Treatment Regimens to Be Refined in Hodgkin Lymphoma

Nancy L. Bartlett, MD

The phase III ECHELON-1 trial demonstrated a superior progression-free survival (PFS) with brentuximab vedotin (Adcetris) plus the AVD regimen of doxorubicin, vinblastine, and dacarbazine (A+AVD) compared with standard ABVD (AVD plus bleomycin) in patients with advanced-stage Hodgkin lymphoma.¹ Because the regimen showed an increase in adverse events (AEs), Nancy L. Bartlett, MD, said that tolerability and age should be considered in selecting an appropriate regimen for patients.

There are several treatment regimens for these patients, noted Bartlett, including ABVD; BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone), and the addition of brentuximab vedotin to AVD. A+AVD was FDA approved for frontline treatment in March 2018 based on the findings from the phase III ECHELON-1 trial, which indicated a 23% reduction in the risk of progression, death, or starting new therapy with A+AVD versus ABVD. In the North American subgroup analysis, investigators observed an 11.7% benefit in PFS at 2 years.²

Though A+AVD demonstrated a statistically significant improvement in PFS, Bartlett explained that it is best suited for high-risk patients with stage IV disease and an International Prognostic Score (IPS) of 4 to 7. As physicians look to the future, Bartlett explained that the challenge will lie in equating a regimen’s efficacy to its tolerability.

OncLive: What are the commonly used regimens for patients with advanced-stage Hodgkin lymphoma?

In an interview with OncLive^® during the 2018 State of the Science Summit™ on Hematologic Malignancies, Bartlett, a professor of medicine in the Division of Oncology, Koman Chair in Medical Oncology, Siteman Cancer Center, Washington University School of Medicine, discussed factors in treatment decisions for patients with advanced-stage Hodgkin lymphoma.Bartlett: For patients with stage III/IV Hodgkin lymphoma I discussed [the available therapies] for patients under 60 and over 60, because there are different approaches for those 2 age groups. For patients under 60, there are 3 options to use. The most standard option is from the RATHL trial, where patients get 2 cycles of ABVD. If they have a negative interim PET scan, then they get 4 cycles of AVD, which eliminates bleomycin. Bleomycin is an agent that is associated with a lot of toxicity.

A second option for high-risk patients is to start with a more aggressive regimen, known as escalated BEACOPP, and give 2 cycles of that. If patients have a negative PET scan, then you can de-escalate to ABVD for 4 cycles. Patients had very favorable results with that regimen. There was a 4-year PFS of over 90%, which is better than what we have seen with anything else.

The third option is a newer option, which is ABVD plus brentuximab vedotin. That came out of a very large randomized trial comparing ABVD to A+AVD, in which A+AVD looked very favorable. There was a statistically significant improvement in PFS with A+AVD—it was 77% for ABVD and 82% for A+AVD. There is still room for improvement there. We were a little bit disappointed that the A+AVD wasn't better.

Are you using A+AVD in practice?

What ongoing trials are showing promise?

What is the biggest unmet need in Hodgkin lymphoma?

With these additive agents, is there any hope of de-escalating therapy?

For patients over the age of 60, giving the combination of A+AVD is really too toxic. We didn't see improvement in that group. One option is to give sequential therapies such as brentuximab vedotin for 2 cycles. Then, 6 cycles of AVD with no bleomycin and 4 more doses of brentuximab vedotin. Alternatively, you can use AVD in that over-60 age group, but you definitely do not want to give bleomycin to that population. I am only using it in the highest-risk patients, so those who have an IPS of 4 to 7 and patients who have stage IV disease. That is where the highest benefit was seen. I have not incorporated it for some of the reasons that have been mentioned, including financial toxicity, neurotoxicity, and myelosuppression for, really, a modest improvement in PFS. For the low- or intermediate-risk patients, I continue to use ABVD and then eliminate bleomycin after 2 cycles. The next trial for these advanced-stage patients, which is being developed by cooperative groups, is a randomized trial comparing A+AVD with AVD plus the PD-1 inhibitor nivolumab (Opdivo). That should hopefully open in the late first quarter of 2019. It has been very active in refractory patients, so that's one option. At some point, we may be using AVD plus brentuximab plus nivolumab. That will add financial toxicity, as well. We still struggle with the toxicities in Hodgkin lymphoma. The outcomes are looking very good. We are curing over 80% of patients with advanced-stage disease and over 90% of patients with early-stage disease with their first-line of therapy. We also have very good treatments for patients with relapsed disease. Most studies show survival in the 95% to 99% range. The challenge is continuing to get those very good results with less toxicity. That has been one of the issues with A+AVD. Though it did improve things a little bit, it wasn't less toxicity; in fact, it was more toxicity. That is a good question, and we are all a bit nervous about that. In early-stage disease, physicians are doing some de-escalation therapy. They are going down to 3 cycles of treatment and giving a few doses of brentuximab vedotin and nivolumab. There is a lot of work going on in that area. Three or 4 cycles of ABVD is very well tolerated, so most of us do not think there is a reason that we need to go down below that.

References

1. Connors J, 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 or IV hodgkin lymphoma (HL): the phase 3 echelon-1 study. In: Proceedings from the 2017 ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, Georgia. Abstract 6.
2. Ramchandren R, Advani R, Ansell S, et al. Brentuximab vedotin (BV) plus chemotherapy in patients with newly diagnosed advanced stage Hodgkin lymphoma (HL): North American results. J Clin Oncol. 2018;36(suppl; abstr 7541). doi: 10.1200/JCO.2018.36.15.