Optimal Frontline Hodgkin Lymphoma Treatment Requires Careful Consideration of Toxicities

Alison J. Moskowitz, MD

The addition of novel agents like brentuximab vedotin (Adcetris) to the Hodgkin lymphoma treatment arsenal has served to enhance the efficacy observed with mainstay chemotherapy regimens that are utilized in the frontline setting, according to Alison J. Moskowitz, MD, who added that the key to selecting the optimal approach for each patient will require consideration of baseline clinical factors, results from interim PET scans, and an assessment of associated toxicities.

“Our most important goal is to balance efficacy with toxicity. We certainly can use very strong, highly aggressive regimens in the frontline setting, but the overall benefit of using stronger regimens is not necessarily there if we end up causing toxicities down the road,” Moskowitz said. “The reason why we think about this so much in Hodgkin lymphoma is because this is a disease that often impacts young people who have multiple decades of life ahead of them. We want to be thinking about how to reduce their long-term toxicity.”

In an interview with OncLive^® during the 2021 Pan Pacific Lymphoma Conference, Moskowitz, medical oncologist and clinical director of the Lymphoma Inpatient Unit at Memorial Sloan Kettering Cancer Center, discussed recent developments made in the Hodgkin lymphoma paradigm, shared advice for optimal stratification, and spotlighted potential emerging prognostic markers that might further help to guide treatment decisions.

OncLive^®: What is the biggest recent advancement that has been made with regard to the frontline treatment of patients with Hodgkin lymphoma?

Moskowitz: My presentation centered around [the regimen of] doxorubicin, bleomycin, vinblastine, and dacarbazine [ABVD]; this is our most used regimen for [patients with] Hodgkin lymphoma. The main modification that has been made to [this approach] over time has been the introduction of PET-adapted therapy, as well as the incorporation of novel agents into treatment with ABVD. PET-adapted therapy is based upon the finding that an interim PET scan is prognostic in the frontline setting for Hodgkin lymphoma. Therefore, we know that we can use the response on that scan to modify therapy, which aids in reducing the toxicity of treatment and [helps us balance] that with efficacy.

The newer agents for Hodgkin lymphoma, such as brentuximab vedotin [Adcetris], and the anti–PD-1 agents nivolumab [Opdivo] and pembrolizumab [Keytruda], are working their way into the frontline treatment setting. Brentuximab vedotin is FDA approved for use in the frontline treatment [of patients with] stage III and stage IV disease in combination with doxorubicin, vinblastine, dacarbazine [AVD]. That [decision was] based [on data from] the large, randomized, phase 3 ECHELON-1 trial [NCT01712490], which included over 1300 patients. Brentuximab vedotin plus AVD [resulted in] an improvement in progression-free survival [PFS] vs standard ABVD. That has been one of the major changes in the frontline treatment for Hodgkin lymphoma.

What are some important considerations when combining brentuximab vedotin with AVD?

It is important to take into consideration the adverse effects [AEs] that we see with brentuximab vedotin plus AVD. This regimen is associated with a high rate of neutropenic fever, and so we must give growth factor with it. We do not tend to give growth factor with ABVD, and the use of growth factor with the brentuximab vedotin/AVD regimen does increase some of the AEs, and certainly the cost [of treatment].

The other important factor to consider is that because we are combining brentuximab vedotin with the vinblastine in this regimen, we see a fair amount of peripheral neuropathy. We now know from the follow-up [data that have been reported] from that study, that some of this peripheral neuropathy persists even 5 years out. At that point, we assume that some of these patients are going to have that [effect] for the rest of their life.

Because of these AEs that we tend to see with this regimen, and because brentuximab vedotin plus AVD is associated with a better PFS but not a huge benefit, I do tend to consider that regimen mostly for higher-risk patients. At this point, I tend to use the International Prognostic Score [in Hodgkin Lymphoma] to help guide which patients should receive ABVD vs brentuximab vedotin plus AVD. Usually, I tend to favor [the use of] brentuximab vedotin plus AVD in patients who have a score of 4 or more.

How do you stratify patients for treatment in clinical practice?

That’s a very important question in Hodgkin lymphoma: How do we [optimally] stratify patients for treatment? We currently use clinical factors to decide whether a patient has favorable or unfavorable disease, both in the early-stage and the advanced-stage setting. We also use interim PET scans to help guide therapy. However, we know that these frontline clinical factors, as well as interim PET scans, are not perfect. Although some of these factors predict whether [a patient] is going to do well [on a certain treatment], sometimes that is not the case.

Conversely, sometimes these factors predict that someone will do less well [on a treatment]. In that case, we [might] want to give them more intensive therapy, but maybe they do not really need that. Moving forward, we really need to figure out how to best stratify patients so that we are giving them the optimal treatment [choice] that is associated with the best chance of cure, [while minimizing] their toxicity.

Two things that are being looked at are metabolic tumor volume, as well as circulating tumor DNA [ctDNA]. Metabolic tumor volume is a way of using a patient's baseline PET scan to get a sense of their overall burden of disease. We know that traditionally, having disease bulk has been prognostic in Hodgkin lymphoma, and we have used that to help guide therapy. However, just looking at 1 mass may not be enough. Metabolic tumor volume [considers] the full patient and their full burden of disease, and that has been found to be prognostic in the frontline setting, at least when we look back on retrospective studies. It is very possible that this is a factor that should be used to help guide therapy in the future, either alone or possibly in combination with the clinical factors that we currently use.

Similarly, ctDNA appears to be better at predicting patient outcomes, or at least complementary to the interim PET scan, in the frontline setting. We really need more data from ongoing studies in this area to figure out how to use [these markers] to help guide therapy in the future.

How are checkpoint inhibitors being incorporated into frontline treatment?

[Checkpoint inhibitors] are not yet FDA approved [for use in the frontline setting]; they are still under investigation. However, some very exciting studies have already looked at the use of both nivolumab and pembrolizumab, either in combination with AVD-type therapy, or given sequentially with chemotherapy. The results look really promising.

One of the things that keeps coming to mind is that [we still see] pretty good [results] with our old school chemotherapy [approaches] that we have been using since the 1970s and 1980s. The question is, with these newer agents, does every patient need to receive rituximab [Rituxan]? Does every patient need to receive a checkpoint inhibitor in the frontline setting? The answer is probably no. However, some patients do need [these agents] and do benefit from them. I am hoping that in time, we will figure out who needs to receive these drugs early on and who do not.