Tolerability With Brentuximab Vedotin Treatment in Hodgkin Lymphoma

Craig Moskowitz, MD

Professor

Physician-in-Chief, Oncology Service Line

Don Soffer Clinical Research Center

University of Miami Sylvester Comprehensive Cancer Center

Miami, FL

[Read Part 1]

Targeted Oncology: When looking at toxicities leading to death reported in the ECHELON-1 trial (NCT01712490), how do we know that pulmonary fibrosis toxicity reported in patients receiving frontline ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) for Hodgkin lymphoma isn’t related to receiving bleomycin?

CRAIG MOSKOWITZ, MD: [The toxicity] happens late. [Older physicians have seen] patients die from bleomycin. It never happens early. It's unusual to die from bleotoxicity in patients who just get ABVD unless they are older, and we don't give bleomycin to patients who are older than 60 years anymore.

But in a younger patient who dies from pulmonary toxicity who received ABVD, a lot of times they have relapsed, and they've also had radiation therapy, and maybe BCNU [carmustine] as part of an [autologous stem cell transplant], so it's hard to tease out. But older patients, in effect, there was a study [North American Intergroup E2496 Trial; NCT00003389] that…compared ABVD with Stanford V [mechlorethamine, doxorubicin hydrochloride, vinblastine, vincristine, bleomycin, etoposide and prednisone], and that was a negative study.¹ In that study, the elderly cohort had an 18% death rate, and the majority was from bleomycin. So what we learned from that is that when you're older than 60 years, you probably shouldn't get bleomycin. ­

But in the younger patients, it's very rare. You'd have to probably have some other underlying genetic abnormality to die from bleotoxicity when you're young.

What else stands out concerning the safety and survival outcomes of the ECHELON-1 trial comparing ABVD with BV-AVD (brentuximab vedotin [Adecetris], doxorubicin, vinblastine, and dacarbazine)?

Looking at deaths on treatment in the ECHELON-1 trial, it's hard for me to understand. The most common secondary malignancy in the groups of patients with ABVD was large cell lymphoma,² which makes me think they already had large cell lymphoma, [but] it was just misdiagnosed, so I don't think anything of [those data], other than the fact that more patients who got ABVD died from Hodgkin lymphoma [or its complications].

I don't think there's a difference in secondary malignancies. I also don't think there is much of a difference with safety. There is more pulmonary toxicity with ABVD and there's more neurotoxicity with BV-AVD, and [for physicians] who don't use a lot of BV, you need to know that if [the patient] can't button their shirt or zip their fly or write a check, you probably need to reduce the dose of brentuximab. I always ask patients, “Can you button this button on your shirt?” If you can't button this button because of neuropathy, it's always grade 2, and [BV] has to be reduced to 0.9 mg/kg. If it's worse than that, you have to drop BV.

How do these therapies impact pregnancy and fertility?

We take care of a lot of young women and a lot of young women are pregnant with Hodgkin lymphoma…. The patients are always undertreated, but there's no difference in the pregnancy rate with BV-AVD and ABVD, which is key.²

I don't necessarily know the sperm data with BV-AVD. All the men [used] a sperm bank anyway, but the female pregnancy rate [of partners of men treated for Hodgkin lymphoma] is pretty good.

What dose modifications are required for patients with peripheral neuropathy with BV?

When we see somebody with [peripheral neuropathy related to] BV-AVD, and I think our chief complaint that we get is the patients have bone pain from pegfilgrastim [Neulasta]. The patients are young, and that's their chief complaint. And then when we tell them we can change them to G-CSF [granulocyte-colony stimulating factor]. I usually give G-CSF on day 6 through 10, and if the counts are too high, we can reduce it by a day, and if it's still too high, we can give 3 doses. They don't always say yes, because they don't want to self-inject. But that's by far the biggest complaint that we have, which is much different than, for example, nivolumab [Opdivo]-AVD or pembrolizumab [Keytruda]-AVD.

What immunotherapy agents are being investigated in combination with chemotherapy for Hodgkin lymphoma?

There was a huge national study [SWOG S1826 study; NCT03907488] comparing BV-AVD versus nivolumab-AVD. That study was done, and was powered for nivolumab-AVD to be 5% better than BV-AVD. It's important to think about that in a couple of ways. First, it's a United States study, so it's mandated that the patients who get BV get growth factors.

When patients who receive BV-AVD get growth factors…it's 5% better. It's probably at 84% at 5 years. Those are probably the [most significant] data with BV-AVD.³

That means we're asking nivolumab-AVD to be at 89% for advanced stage Hodgkin lymphoma at 5 years. If it's not at 89%, it's going to be a negative study. Now, of course, there are secondary end points with toxicity and whatnot, but the primary end point is efficacy, and efficacy has to be 5% better with that program.

There are many different adverse events [AEs] between these 2 programs. BV-AVD causes neuropathy, and it causes cytopenias.⁴ Nivolumab-AVD causes immune-related AEs, [and] thyroid dysfunction in about 15% of patients, which I don't [worry] about so much, but it's annoying.⁵

Rash is not easy. Rash is a real [issue] with pembrolizumab and nivolumab when combined with chemotherapy. They also get this gastrointestinal discomfort syndrome, which is hard to explain. It's not benign, even though it's outpatient treatment, but we'll see what happens when the study is reported. [I have heard] that there will be some toxicity data that's going to be reported [later this year at the International Conference on Malignant Lymphoma] out in Lugano, [Switzerland].

This study is the [SWOG S1826 study]. We [at the University of Miami] put 18 patients on, and all our patients have done well. The first 12 patients all got BV-AVD; although it's supposed to be random. I think there is 1 patient who [responded] and that patient got BV-AVD.

Merck is doing an industry-sponsored study…comparing pembrolizumab-AVD versus ABVD, and I don't know if that's being done in the United States all that much, but it’s being done quite a bit in Europe.

The phase 2 data with pembrolizumab-AVD look quite good.⁶ The phase 2 data with nivolumab-AVD last had been updated in 2019.⁷ At that point, the results were decent. Now, we have been championed a program called pembrolizumab-GVD [gemcitabine, vinorelbine, and liposomal doxorubicin], which is a study that Alison J. Moskowitz, MD, and I wrote before I left Memorial Sloan Kettering Cancer Center, and we brought that [to the University of Miami], in patients with relapsed Hodgkin lymphoma. That's one of the best treatments we've ever given, and it's phenomenal. It has a litany of AEs, but it's outpatient and it's pretty well tolerated.⁸

_REFERENCES

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_{6. Allen PB, Savas H, Evens AM, et al. Pembrolizumab followed by AVD in untreated early unfavorable and advanced-stage classical Hodgkin lymphoma. Blood. 2021;137(10):1318-1326. doi:10.1182/blood.2020007400}

_{7. Ramchandren R, Domingo-Domènech E, Rueda A, et al. Nivolumab for newly diagnosed advanced-stage classic hodgkin lymphoma: safety and efficacy in the phase II CheckMate 205 study. J Clin Oncol. 2019;37(23):1997-2007. doi:10.1200/JCO.19.00315}

_{8. Moskowitz AJ, Shah G, Schöder H, et al. Phase II trial of pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin as second-line therapy for relapsed or refractory classical Hodgkin lymphoma. J Clin Oncol. 2021;39(28):3109-3117. doi:10.1200/JCO.21.01056}