Data-informed Treatment Sequencing in Polycythemia Vera
A review of available treatments, treatment selection, and treatment sequencing for patients with PV as informed by clinical trial data.
Prithviraj Bose: Treatment for PV. So PV is, as we just discussed, first, when you see a patient with PV, you're asking yourself, is this a low-risk patient or a high-risk patient. And generally when we use the word risk, we are talking about risk for thrombosis, again, just to be clear on that. So a low-risk patient is typically today still treated with phlebotomy and aspirin for the most part. Although there is definitely very interesting data for ropeginterferon alfa-2b approved by the FDA in November 2021 in low-risk PV as well, besides the better-known data in high-risk PV. But generally the paradigm in low-risk PV is no drugs, no cytoreductive drugs, but just phlebotomy and aspirin. Now for high-risk patients, the paradigm is cytoreductive therapy and aspirin. Now, at least in my practice, if I'm doing cytoreductive therapy, I don't want to also be doing phlebotomies because the whole idea of cytoreductive therapy in my mind is to be able to eliminate phlebotomy, to suppress that myeloproliferation so that phlebotomies are no longer needed. In fact, there is some data out of Spain that if you are on hydroxyurea and still needing three or more phlebotomies a year, that suggests of course, more proliferative disease and actually was correlated with the higher risk of thrombosis in those patients. So that is sort of a guiding principle for me that if I'm using cytoreductive therapy, I would like to minimize phlebotomy if not eliminate it altogether. Now regarding the different therapies, so I alluded to ropeginterferon alfa-2b in low risk because there is data for that and this agent actually has a broad label in the United States. It is for anybody with PV. So it's not line specific, but most of the discussion of cytoreductive therapy, as you can imagine, is in high-risk PV where we have mostly used hydroxyurea over decades. The leukemogenic risk, quote unquote, of hydroxyurea has never been proven. It is by and large a very safe drug and an effective drug in getting the counts down and removing that need for phlebotomies. However, there are patients, I think about 20%, who over time will develop resistance or intolerance to hydroxyurea. In my experience, more intolerance than resistance, but definitely we can see both. And what we know is that resistance to hydroxyurea is actually correlated with worse overall survival. So that's a big deal. Intolerance too can be, especially if it's getting leukopenic, the patient becoming leukopenic at the minimum dose you need to control their hematocrit or symptoms or whatever it is that you're trying to control. If the patient gets leukopenic, that's another bad sign. So up to 20% of patients, I think, can become hydroxyurea resistant or intolerant. And it is these patients in whom I would typically use ruxolitinib that is approved since it has been since December 2014 for exactly this, that is hydroxyurea failures. So a second line, I would call it. And so that's typically what I use in the second line after hydroxyurea failure. And now with ropeginterferon alfa-2b approved, like I said earlier, one could be starting with ropeginterferon alfa-2b. And of course, the second line still for me would be ruxolitinib in that, in a setting of not being able to achieve one's goals in the first line setting. And what are the goals? The goal in PV is first and foremost to get the hematocrit under 45% and keep it constantly there, keep it stable under 45%. And then also I like to control the white blood cells, patients are symptomatic. So it's important to control those. So a bit of a more holistic view, but I think the less than 45% is the most critical one. And then I would say the white cells as well, because of the things we discussed that white cells could be related to, and obviously symptoms and spleen sort of round out the picture. Now, just a couple of other points. The overarching goal here is to prevent thrombosis. That's why we are doing what we are doing. And then also it would be nice to be able to delay progression to myelofibrosis or transformation to AML. And a lot of the research is in that area. So just very quickly, ruxolitinib was approved based on the response and response to trials. Won't go into the details, but basically the end points were spleen volume reduction, hematocrit control, complete hematologic response, total symptom score, all of which were very significantly in favor of ruxolitinib as opposed to the control, which was best available therapy in both of these trials. But reducing thrombosis was actually a safety endpoint, not an efficacy endpoint, but that's a commonly asked question because that's really the overall goal here. And recently we have a study called the MAGIC-PV study. This was at ASH 2022. And that actually showed in a prospective randomized way in the second line setting that ruxolitinib was superior to best available therapy for thrombosis-free survival. So that's something really important, I think, that came out at this last ASH meeting. Moving over to ropeginterferon alfa-2b, that was approved on the basis of a relatively small phase two study called PEG-INVERA, but more data I think comes from the PROUD and continuation PV studies, which were larger, which combined were a larger phase three study against hydroxyurea in high-risk patients with PV. These were patients who had had hydroxyurea for a short duration or were a treatment naive high-risk PV patients and ropeginterferon alfa-2b was compared to hydroxyurea. And just to very quickly summarize, in the first year, ropeginterferon alfa-2b actually was not superior. In fact, hydroxyurea was better on multiple fronts, but as you went along over the years, and we now have six years of follow-up, ropeginterferon alfa-2b got better and better in terms of hematologic response, molecular response, pretty profoundly, especially for molecular beating hydroxyurea or best available therapy. Important to note that the patients who were on HU in the first year mostly remained on HU after the first year was over and the continuation phase began. So it was for the most part a ropeg versus hydroxyurea study. I alluded to this drug in low-risk PV before, that was a separate study called the Low-PV study, where it was ropeg versus phlebotomy, essentially, and ropeg was superior at one year and two years. So those are I think the big trials in this space. I'll go back to ruxolitinib for a moment and just note that another very interesting thing from the MAGIC study is that the allele burden reduction over time was better for ruxolitinib than best available therapy. And those who had the allele burden reduction actually had a better event-free survival. So sort of challenging the notion that why should I worry about the allele burden or why should I care to check it? Perhaps we are entering a new era where we're increasingly being able to correlate allele burden reduction with actual clinically relevant hard outcomes. So some of this- I think is for the future, but some interesting, you know, let's say insights provided by the MAGIC study.
