Rampal Analyzes Ropeginterferon Data in Low-Risk Polycythemia Vera

Low-risk polycythemia vera (PV) is commonly managed with phlebotomy and aspirin. Raajit K. Rampal, MD, PhD, director of the Center for Hematologic Malignancies and the Myeloproliferative Neoplasms Program at Memorial Sloan Kettering Cancer Center, reviewed compelling data from the Low-PV trial (NCT03003325), noting that ropeginterferon alfa-2b (Besremi) reduced JAK2 allele burden and improved hematocrit control compared to standard therapy at a live event in Philadelphia, Pennsylvania. Rampal suggested these provocative results could potentially change the standard of care, though he acknowledged the challenges of interferon-related toxicity and the need for longer-term data.

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Targeted Oncology: What are some data of note in the Low-PV trial of ropeginterferon vs standard of care?

Raajit K. Rampal, MD, PhD: If we look at the absolute JAK2 allele burden change at month 12, it was reduced by 11.9 percentage points with ropeginterferon [compared] with standard therapy.¹ That's not a surprise. Looking at month 24, there continued to be a statistical difference in terms of hematocrit control [and in] the proportion of patients who had disease progression in the ropeginterferon vs the standard therapy arm. Now you're getting more profound changes in the JAK2 allele burden. You're getting about 23% reduction by mean and a 15% increase in the JAK2 allele burden in the patients treated with phlebotomy alone. This is really interesting. If this was 300 patients per arm, maybe this would completely change the standard of care; with 60 or so patients in each arm, it's a little bit difficult to extrapolate it. But it's also something that is hard to dismiss. There is some early evidence that you are perhaps modifying the disease.

Could you go into more detail about how the allele burden affects patients with PV?

We know that the allele burden, [depending on] if it's higher than 50% or less than 50%, absolutely associates with risk of disease progression, leukocytosis, risk of thrombosis and splenomegaly. Fifty percent has been studied as perhaps a line in the sand. Does preventing it or trying to reduce it earlier on attenuate the risk? Those data we don't have from this study, because this study is only about 3 or 4 years old. There are data from the high-risk population that do suggest that there is an event-free survival benefit. But do we have those data right now for these low-risk patients? We don't, however, it's hard to argue with these outcomes in terms of control of hematocrit and a reduction in the JAK2 burden.

One could make an argument that hydroxyurea [Hydrea] could achieve hematocrit control. It's not going to do anything to the JAK2 burden, but it would be easier and cheaper. Those are legitimate arguments. But to me, these data are highly suggestive. It's highly provocative.

What was the toxicity profile with ropeginterferon in this low-risk population?

In terms of safety, there were more adverse events with the ropeginterferon arm with pneumonitis, pruritus, fatigue, and other adverse events that we see commonly with interferons. These were not high-grade events. This is largely not higher than grade 1/2, some grade 3/4 neutropenia, but not frequent. But you can't ignore this; patients did have more adverse events with ropeginterferon therapy, and that is one of the caveats of how you use these data.

Can you describe the final results seen on this trial?

Essentially, more patients crossed over into the ropeginterferon arm, and about 16% of patients who were treated with ropeginterferon discontinued due to adverse events.² The protocol did specify the dosing, so in clinical practice, you can be much more judicious with the dosing, and you just have to have more patience. Whereas I believe this study prescribed that they had to go up [in dose], so that discontinuation rate might be something that could be reduced. So either way, I think it's very provocative.

Please discuss the quality-of-life data observed on the Low-PV trial.

This is a big thing, because a lot of these patients are highly symptomatic. Some don't care and they feel fine, but some are highly symptomatic. From this study, what was noted was that there was some association with improving quality of life and symptom profile, as the variant allele burden of the JAK2 went down. What's the real connection? I'm not sure. We can speculate, but...for example, many of the symptoms associated with the disease got better with ropeginterferon. Things like pruritus can certainly get worse with interferon. There's no question about that, but many symptoms did get better.¹

Is that because you have more consistent control of the disease vs somebody who's getting therapeutic phlebotomy and is going up and down? That may be the explanation. Maybe it is something more fundamentally biological, I don't know…. In somebody who's highly symptomatic, [you might] start cytoreductive therapy, but here at least, there's some evidence to say that you may benefit the patient from a symptomatic standpoint.

DISCLOSURES: Rampal has previously reported professional services and activities with AbbVie, American Society of Hematology, Boxer Capital, LLC, Chinese Academy of Medical Sciences, Cogent Biosciences, Inc., CTI BioPharma Corp., GlaxoSmithKline, Incyte, Jubilant Therapeutics Inc., MorphoSys AG, MPN Research Foundation, Noble Insights, PharmaEssentia, Protagonist Therapeutics, Inc., and Sumitomo Pharma.

REFERENCES:

1. Barbui T, Vannucchi AM, De Stefano V, et al. Ropeginterferon versus standard therapy for low-risk patients with polycythemia vera. NEJM Evid. 2023;2(6):EVIDoa2200335. doi:10.1056/EVIDoa2200335

2. Barbui T, Vannucchi AM, De Stefano V, et al. Ropeginterferon alfa-2b versus standard therapy for low-risk patients with polycythemia vera. final results of Low-PV randomized phase II trial. Blood. 2022;140(suppl 1):1797–1799. doi:10.1182/blood-2022-157255