Rhodes Evaluates Toxicity Concerns With ABVD and Brentuximab Vedotin in cHL

Joanna M. Rhodes, MD, MSCE

Director, Lymphoma Program

Rutgers Cancer Institute

Assistant Professor of Medicine

Rutgers Robert Wood Johnson Medical School

New Brunswick, NJ

CASE SUMMARY

• A 49-year-old man presented with asymptomatic cervical nodes developing over several months and was initially evaluated by his primary care physician, who recommended observation.
• Subsequently, enlargement of nodes prompted referral to hematologist for evaluation.
• Physical examination: supraclavicular, right neck, right axillary, and right groin masses
• Social history: No tobacco use, occasional alcohol use
• Family history: unremarkable
• The patient is diagnosed with stage IIIA classical Hodgkin lymphoma (cHL).

PEERS & PERSPECTIVES IN ONCOLOGY: Based on findings from the RATHL trial (NCT00678327), what are the adverse event (AE) challenges of chemotherapy in patients with cHL?

RHODES: We know that BEACOPP [bleomycin, etoposide phosphate, doxorubicin, cyclophosphamide, vincristine sulfate (Oncovin), procarbazine hydrochloride, and prednisone] can be challenging. The etoposide [can be] terrible for blood cell counts. There are issues with fertility. We are seeing that there are higher rates of neutropenia with escalated BEACOPP compared with ABVD [doxorubicin hydrochloride (Adriamycin), bleomycin, vinblastine, and dacarbazine].¹ There were less lung toxicity and pneumonitis, comparatively less venous thromboembolism, fewer [vascular events], and [slightly] fewer grade 3 or 4 events when you go from ABVD to AVD [doxorubicin hydrochloride, vinblastine, and dacarbazine]. This is demonstrating that less chemotherapy, if it’s not worse for outcomes, is probably the better and kinder thing to do for our patients.

Why does it matter that we talk about ABVD vs AVD? [There was] an oral presentation in the past year trying to understand long-term lung function.² We worry a lot about the effect of bleomycin as we’re giving the drug. This is demonstrating long term that we are seeing decrements in DLCO [diffusing capacity of the lungs for carbon monoxide].... Over time, it’s challenging when you think about a 26-year-old patient who’s 6 years out from their ABVD and what that means for them when they’re 40, 50, 60 years old. And maybe they pick up vaping…or they do something they weren’t doing before. This is challenging, and this was based on data from RATHL [showing] there’s a very significant difference between lung function in patients who did get de-escalated therapy vs stayed on ABVD for 6 cycles.

Although some patients do have improvement, the improvement seems to stagnate after 1 year.² What you’re stuck with 1 year after bleomycin for lung function seems to be what you’re stuck with for a longer period. I’ll be intrigued to see how they do 10, 15, and 20 years later, because that’s important, and I hope to get to see it.

What toxicity concerns were there for BV-AVD (brentuximab vedotin [Adcetris] plus AVD) compared with ABVD in findings from the ECHELON-1 trial (NCT01712490)?

The phase 3 ECHELON-1 study was a very large 1300-patient trial for patients with stage III and IV disease, not stage IIB, [comparing] BV-AVD vs ABVD. [They received] ABVD for 6 cycles. This was not PET adapted, even though they did check PET/CT scans at cycle 2. For patients who had a true Deauville score of 5, they could come off study and do other treatments. The primary end point was modified progression-free survival that was published back in 2017.³

One of the things we think about is whether there are secondary malignancies. A breakdown of secondary solid tumors was similar between the 2 groups [14 in each].⁴

But interestingly, there were more secondary hematologic malignancies in patients with ABVD [n = 17] vs BV-AVD [n = 9]. This was an early data cutoff, about 10 years [after treatment] when we think about secondary malignancies, but we’re starting to see some differences. I’ll be interested to see how this plays out long term. There were a fair number of gastrointestinal cancers, some lung cancers, dermatologic cancers, different non-Hodgkin lymphomas, as well as some acute myeloid leukemia, myelodysplastic syndrome, and acute promyelocytic leukemia. Clearly, there are going to be some differences in the long term.

What other AEs are of concern with BV?

At least in my limited experience, I’ve not seen a lot of cardiac dysfunction.… Peripheral neuropathy gets better over time, very similar to vincristine, although perhaps on a more protracted timeline, and there were no differences in fertility, which is important.

The AE that has come up most frequently is peripheral neuropathy.³ There is neutropenia, but because we don’t have bleomycin in the mix, we can ensure that we can give growth factor in these patients without worsening lung toxicity, which is important [Table³].

[We need to know whether] we are getting an overall survival benefit but also making patients miserable. It’s important that the majority of patients see either improvement or complete resolution of their peripheral neuropathy. I’m sure we’ve all given vincristine to someone, and [they] have long-term peripheral neuropathy that slowly gets better. Nerves…don’t like to regenerate, and nothing we do makes them [recover faster]. This, at least to me, is reassuring for patients. Looking long term, there isn’t a lot of grade 2 or grade 3; the majority of it is grade 1 [Figure 1⁴].

What is the role of dose reduction of BV for peripheral neuropathy?

This is an important point. For R-CHOP [rituximab (Rituxan), cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone], we gave 1.4 mg/m² of vincristine, and we probably [caused severe peripheral neuropathy] with that, then we started maxing it out at 2 mg. In my practice, I dose-reduce vincristine, despite the fact that for diffuse large B-cell lymphoma, it is a curative-intent treatment.

But it’s important to point out that you can dose-reduce BV and have the same outcomes. Reducing it to 0.9 mg/kg [ for grade 2] and for grade 3 [Figure 2⁵]—I think about this a lot, because when we grade AEs in CTCAE [Common Terminology Criteria for Adverse Events], we are not neurologists. No one has [monofilament tests] in their office.

Neurosurgeons have an entire [set] of filaments sitting there that are nice and sterile. We don’t do this [test]. But grade 2 peripheral neuropathy means that you have neuropathy that is making you unable to do your instrumental activities. Grade 3 is very severe; you are basically in your chair and can’t do very much. So it’s important to think about dose reduction early and know that outcomes are not sacrificed by dose-reducing early.

In the ECHELON-1 trial, patients did dose-reduce even though it was blinded,³ and there have been several real-world series that have looked at dose reductions in real-world settings, which is probably more important because those are the patients you’re seeing in your office who may or may not have been clinical trial candidates. I find that reassuring to demonstrate that outcomes are great even if you dose reduce.^6,7

Is there a dose density threshold of BV where you would expect peripheral neuropathy?

To my knowledge, there isn’t a cycle at which this happens or a specific dose at which this happens, although that’s a great point and something to think about. It has to do with the patient’s underlying neurologic function. But neurotoxicity is often very unpredictable. At least in the data we know from BV in relapsed disease, cycles 6 to 8 are when most patients would see it with the 1.8-mg/kg dose.⁸ It’s more challenging because we’re also giving it with vinblastine, which also has some neurotoxicity, and so the combination may make it more unpredictable.

I’m finishing treatment for a [patient at] cycle 6, and I have not dose-reduced anything, and she tells me she’s fine. Then I have patients who at cycle 2 are starting to feel it, and [this is true] at very similar age ranges, whether they’re young or old. It’s more challenging, but it [requires] making sure that you’re mindful of it and perhaps dose-reducing even earlier than when you would normally do it for other drugs.

_REFERENCES

_{1. Johnson P, Federico M, Kirkwood A, et al. Adapted treatment guided by interim PET-CT scan in advanced Hodgkin’s lymphoma. N Engl J Med. 2016;374(25):2419-2429. doi:10.1056/NEJMoa1510093}

_{2. Phillips EH, Kirkwood AA, Hague C, et al. Bleomycin affects lung function for at least 5 years after treatment for Hodgkin lymphoma - data from the international, randomised phase 3 RATHL trial. Blood. 2023;142(suppl 1):612. doi:10.1182/blood-2023-185818}

_{3. Connors JM, Jurczak W, Straus DJ, et al; ECHELON-1 Study Group. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med. 2018;378(4):331-344. doi:10.1056/NEJMoa1708984}

_{4. Ansell SM, Radford J, Connors JM, et al; ECHELON-1 Study Group. Overall survival with brentuximab vedotin in stage III or IV Hodgkin’s lymphoma. N Engl J Med. 2022;387(4):310-320. doi:10.1056/NEJMoa2206125}

_{5. Adcetris. Prescribing information. Seagen Inc; 2023. Accessed May 17, 2024. https://tinyurl.com/vpnv5mnb}

_{6. Steiner RE, Hwang SR, Khurana A, et al. Impact of cumulative dose of brentuximab vedotin on outcomes of frontline therapy for advanced-stage Hodgkin lymphoma. Blood Adv. 2023;7(24):7485-7493. doi:10.1182/bloodadvances.2023010700}

_{7. Bowers JT, Anna J, Bair SM, et al. Brentuximab vedotin plus AVD for Hodgkin lymphoma: incidence and management of peripheral neuropathy in a multisite cohort. Blood Adv. 2023;7(21):6630-6638. doi:10.1182/bloodadvances.2023010622}

_{8. Yi JH, Kim SJ, Kim WS. Brentuximab vedotin: clinical updates and practical guidance. Blood Res. 2017;52(4):243-253. doi:10.5045/br.2017.52.4.243}