Dr Raajit Rampal Discusses Disease Modification and Emerging Therapies in Polycythemia Vera


Raajit Rampal, MD, PhD, of Memorial Sloan Kettering Cancer Center, discusses the potential of a disease-modifying therapy in polycythemia vera, treating high-risk vs low-risk patients, and emerging therapies in the pipeline.

Achieving a disease-modifying therapy for polycythemia vera might require adjusting the end points in a study needed for a drug to be approved, said Raajit Rampal, MD, PhD, hematologic oncologist, associate attending physician, Memorial Sloan Kettering Cancer Center.


Currently, there are no disease-modifying treatments in polycythemia vera, but it is being explored. What might such a therapy look like?

If we talk about disease modification, the first question is, what do you mean by disease modification? I think, what we would want is for our patients to live the longest and fullest life, free of the symptoms or burdens of their disease. To me, that is the sort of working definition of disease modification. From there, one can try to come up with biological definitions of things like depleting the stem cell, which are important things. But keeping this on a patient level, what we want for our patients [is a life free of disease burden]. How do we think about therapies that address those issues?

Part of it is a regulatory conundrum in the sense that studies have to meet certain end points for drugs to get approved, but the way we study the drugs is relative to the definitions of the end points that make the drugs successful. In many cases, [the end point is asking] are you controlling the hematocrit adequately? That's one of the major things in polycythemia vera. But in order to really try to get at the question of disease modification, we've got to think about changing the end points of our studies to reflect that.

What are the things that are going to best correlate with the idea that you aren't keeping patients free of the catastrophic consequences of their disease, like blood clots, like [disease] turning into leukemia or myelofibrosis? Are you controlling the patient's symptoms to an adequate degree? Those are the things that I think are fundamental. But we've got to change the end points of our studies to really get at that.

How do treatments differ between patients with high-risk and low-risk polycythemia vera?

Right now, the paradigm is that in patients who are low risk, we treat people with aspirin and phlebotomy to keep the hematocrit level under 45%, and if they're high risk, we put them on a therapeutic intervention like Hydrea [hydroxyurea] or ropeginterferon or pegylated interferon. That's the current paradigm. If patients are having lots of phlebotomies or they're having symptoms, then it's reasonable to think about putting them on a therapy.

Coming back to the idea that with newer data, that paradigm may need to change, in the sense that there is some data that [show] treating the low-risk patients with things like ropeginterferon might make a difference, in terms of controlling their blood counts, maybe controlling for a disease progression.

I think that there needs to be more data in this space. Is this really the right approach? I mean, this has been the historic approach, this has been the paradigm that everybody follows. But it begs the question, is that really the right approach? As we have more active agents in this space, I think we've got to refine our questions and focus on those questions.

Is there anything specific of interest in the pipeline that might change how polycythemia vera is treated?

There is this drug rusfertide, a hepcidin memetic, which in phase 2 studies has shown promise in helping patients become phlebotomy independent, which is an important end point. Phlebotomy is not a bit of a benign thing; I think that's an important thing for everyone to realize. People become iron deficient [with too many phlebotomies]. Iron deficiency can cause symptoms, things like restless leg syndrome, and there is data that long-term phlebotomies and becoming iron deficient may lead to or be associated with things like pulmonary hypertension. Thinking of phlebotomy as a benign intervention and using medications as not a benign intervention is perhaps the wrong way to be thinking about this.

These medications like rusfertide that could make a difference there. And there is more and more emerging data with ruxolitinib, and it's absolutely a highly effective drug to treat polycythemia vera. The question is, how deep of a response? Does it have the ability to potentially change the disease course in some patients? Is introducing it early in the disease, rather than as a second-line agent after Hydrea, potentially beneficial in the long term? These questions remain unanswered, but at least we have the drug, and these questions are being studied.

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