Mitigating Peripheral Neuropathy Is Still Focus of Ongoing Research in Hodgkin Lymphoma

Five-year follow-up data from the pivotal phase 3 ECHELON-1 trial (NCT01712490) suggest that peripheral neuropathy is not a prohibitive toxicity for the majority of patients with newly diagnosed stage III/IV Hodgkin lymphoma who receive brentuximab vedotin (Adcetris) plus doxorubicin, vinblastine, and dacarbazine (A+AVD), explained Mendel Goldfinger, MD. However, further studies are needed to determine whether vinblastine could be omitted from the brentuximab vedotin–containing regimen to mitigate some of the risk for peripheral neuropathy.

Findings from the 5-year analysis, which were presented virtually during the 2020 American Society of Hematology Annual Meeting and Exposition, showed that treatmentemergent peripheral neuropathy completely resolved in 84% of patients treated with A+AVD and 86% of patients treated with AVD plus bleomycin (ABVD). The median time to complete resolution of peripheral neuropathy was 30 weeks and 16 weeks, respectively.

Moreover, the majority of patients with ongoing peripheral neuropathy had low-grade events, explained Goldfinger.

“Neuropathy [is] the major toxicity of brentuximab vedotin, and the majority of patients [who develop neuropathy] are young. It [is] concerning that we are going to cure them [of their Hodgkin lymphoma] but [leave them with] neuropathy that could be a lifelong debilitating issue,” said Goldfinger.

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on hematologic malignancies, Goldfinger, director of the HematologyOncology Montefiore Network Program at Montefiore Medical Center and an assistant professor at the Albert Einstein College of Medicine, discussed some of the key points of the ECHELON-1 trial data.

OncLive^®: Why has A+AVD become the new standard of care for patients with stage III/IV Hodgkin lymphoma?

Goldfinger: ECHELON-1 was a large phase 3 trial [conducted] in many countries at many centers in patients with advanced Hodgkin lymphoma to try to change [what had been the standard of care] for more than a decade. The standard [arm] was ABVD, which more than 600 patients received, and the other half of patients received AVD with brentuximab vedotin, which was substituted for bleomycin. 

For a long time, we had tried to get away from bleomycin because it is known to cause short- and long-term toxicity, potentially. We also looked at ways to improve efficacy. 

ECHELON-1 nicely showed at 2, 3, and 4 years that the A+AVD arm had much better progression-free survival [(PFS) rates] compared with ABVD. In addition, the toxicity of bleomycin [was absent].

There was initial concern about peripheral neuropathy, which is an adverse effect that we see more with brentuximab vedotin. However, the good news was that [with longer follow-up], the majority of patients’ neuropathy subsided over time. The vast majority of patients who had sustained neuropathy had very low-grade neuropathy. 

Clearly, this was a large trial that was able to change the standard of care for advanced-stage Hodgkin lymphoma. The community has accepted [A+AVD] as the new standard [for this patient population].

Did A+AVD decrease the need for salvage therapy compared with ABVD?

It’s always been challenging to demonstrate survival benefits in Hodgkin lymphoma because we get another chance at [treatment] if our patient doesn’t do well and recurs. However, even though we could salvage patients, that requires an additional year of chemotherapy or an autologous stem cell transplant with high-dose chemotherapy. [Chemotherapy] by itself has short- and long-term complications. Therefore, even though some patients don’t do well with ABVD, we can salvage the majority of them, but at a very big price. 

[ECHELON-1] showed that not only do the short-term data look better with A+AVD, but the reason the data look better is that we get it right the first time. A subgroup of these patients who would have likely required additional therapy can be cured [with A+AVD].

All subgroups except for patients from Asia benefitted from the A+AVD regimen compared with ABVD. Why might that be?

It’s a great question. This trial wasn’t statistically powered to look at that subgroup [of patients from Asia]; however, subsequent studies will have to look into that with more detail. In general, we try to look at subgroups [to determine] whether we can study [those patients] in more detail later on. Is it the disease biology? Is it the pharmacokinetics of the drugs? These are questions that will have to be answered in subsequent trials.

Could you speak to the PFS benefit observed in patients independent of PET2 status and in patients younger than 60 years?

ECHELON-1 was not what we would call a PET-adapted approach. Patients did get a PET scan after 2 cycles [of A+AVD or ABVD], but as long as they were not progressing, they continued on their assigned treatment regimen. 

The data demonstrated that even the patients who had a Deauville score of 4, which we routinely consider for treatment escalation or switch to a different therapy, had benefit with A+AVD vs ABVD. It wasn’t as pronounced as in the patients [with lower Deauville scores], but clearly there was benefit. 

One point that should be made is that a minority of patients had a positive PET scan after 2 [cycles of therapy]. 

Additionally, the study doesn’t give clear guidance as to whether we should do an [interim] PET scan after 2 cycles. When using A+AVD, my personal approach has been to [do] the interim PET scan to make sure the patient is heading in the right direction. The vast majority of patients will have a negative PET with a Deauville score of 3 or less. If they do have a Deauville score of 4, there is not clear guidance.

Clearly, the [ECHELON-1] study showed a benefit [with A+AVD] compared with ABVD. However, whether [we should] change the treatment course at that point is a case-by-case [decision]. Data are emerging that the delta comparing the baseline PET scan with the repeat PET scan does matter. That’s usually a question of tumor boards with colleagues. 

As far as age [as a stratification point], the data were striking. Hodgkin lymphoma [affects] a heterogeneous group of patients. There is bimodal distribution [between] younger and older [patients]. Clearly the benefit [of A+AVD] was there for the young patients as well.

Does peripheral neuropathy remain a concern with A+AVD? How could this toxicity potentially be prevented?

As oncologists, we deal with [the risk of neuropathy] with other drugs as well. As the data [from ECHELON-1] mature, we see that the vast majority of patients’ neuropathy disappears. [Patients with] remaining neuropathy have low-grade toxicity. 

Another point is that studies are currently ongoing to [answer] this question: If we omit vinblastine, which is another microtubal inhibitor that can cause neuropathy, can we minimize toxicity and maximize efficacy? Boston investigators have published some early reports [with that approach]. The data look good, but they are not ready for prime time. We will have to wait for the full study to mature. Going forward, we believe there will be ways to try to mitigate this toxicity even further.

How is peripheral neuropathy currently mitigated in practice?

The key is to ask the patient all the time about [whether they are experiencing] neuropathy and whether we need to dose-reduce [brentuximab vedotin]. Generally, [A+AVD] is a curative therapy, so we try to keep going [with treatment]. The biggest tip that I have found to be helpful is to see whether the neuropathy gets better in week 2, prior to [initiating] therapy [in that cycle].

[If it does,] then I know we are going in the right direction. If a patient still has [neuropathy] on day 14 or day 28 prior to starting the next dose, and it hasn’t gotten better than [it was] the week before, there are good guidelines on how to grade [the neuropathy] and dose-reduce if needed. I honestly haven’t had a patient whose neuropathy has not gotten better as they got closer to the next dose, but [if it hasn’t gotten better,] that is usually a warning sign that we should consider dose reduction.

Is the addition of granulocyte colony-stimulating factor (G-CSF) warranted with A+AVD and what is your approach to navigating that decision?

[The ECHELON-1] investigators learned early on that without G-CSF support, a number of neutropenic patients had neutropenic sepsis and [eventual] death. Once the G-CSF support was added, that was no longer an issue. I give patients long-acting G-CSF with pegfilgrastim [Neulasta] with each therapy. It is basically [given] on day 2 and day 16 in whatever formulation [of pegfilgrastim] is available in the clinic. I’ve seen clinicians give [pegfilgrastim] once a cycle; my approach has been to give it with each treatment.

Can A+AVD be sequentially administered for elderly patients with Hodgkin lymphoma?

Certainly, we have bimodal distribution in Hodgkin lymphoma. An elderly population of patients who get this disease have not historically been well represented in the data. A+AVD could be very toxic for these patients. 

A small but practical study was published in the Journal of Clinical Oncology that gives good guidance. [In it,] patients get 2 cycles of single-agent brentuximab vedotin, followed by 6 cycles of AVD, followed by 4 more cycles of brentuximab vedotin. This approach has multiple benefits. [Brentuximab vedotin] is better tolerated as it is sequenced. The vast majority of patients [on the study] did well in terms of remission. Personally, using this regimen [allows me to have] the ability to test what my patients can tolerate. I’ve had patients who haven’t finished a full course of treatment, but I was able to learn as I was sequencing how much they could tolerate.

The downside [of this approach] is that it takes a long time to get through [a cycle]. However, the results are good, and it is among the biggest contributors [to the Hodgkin lymphoma armamentarium], specifically for elderly patients with Hodgkin lymphoma who have not historically been well represented in the literature.

What efforts are underway to improve A+AVD as a treatment for patients with advanced-stage Hodgkin lymphoma?

We have other incredibly effective agents in Hodgkin lymphoma, including immunotherapy. Checkpoint inhibitors have shown really good responses in the relapsed/ refractory setting. A clinical trial is looking at A+AVD compared with a checkpoint inhibitor plus AVD. It will be a number of years before we have the readout of that trial. 

Another remaining question that I alluded to earlier: Can we omit vinblastine or decrease the amount of vinblastine that we give to mitigate neuropathy? We will have to answer that question in ongoing clinical trials. 

The addition of G-CSF was a game-changer. We have to wonder, if we had [given G-CSF with A+AVD] from the get-go, whether the data would have looked even better than they do. The real-world data might be slightly better than the data from the trial because we are learning how to manage toxicities.

Reference

1. Straus DJ, Dlugosz-Danecka M, Connors JM, et al. Brentuximab vedotin with chemotherapy for patients with previously untreated, stage III/IV classical Hodgkin lymphoma: 5-year update of the ECHELON-1 study. Blood. 2020;136(suppl 1):26-28. doi:10.1182/blood-2020-137089