Treatment Armamentarium for Polycythemia Vera


Centering discussion on polycythemia vera, Rami S. Komrokji, MD, and Pankit Vachhani, MD, share an in-depth review of cornerstone therapies in this setting.


Rami S. Komrokji, MD: Having said all of this setting the molecular background of the disease maybe we should zoom into particular diseases, polycythemia vera is a common one, the community oncologists and primary care physicians deal with polycythemia vera probably more than any of those diseases. Can you walk us through or tell us a little bit about how do you risk assess those patients? When do you start treatment, and what treatments are offered?

Pankit Vachhani, MD: Thank you, Dr Komrojki. The risk stratification in polycythemia vera is, at present, based on 2 factors which we routinely use. One is the age of the patient at the time when you are seeing the patient and that is a factor where we divide our patients into less than 60 years of age or more than 60 years of age. And then the second factor that we look into is history of prior thrombosis, venous or arterial. Once we take into these 2 factors, the presence of either one of these puts our patients at a higher risk of future thrombotic events. These patients get classified as high-risk PV patients. The absence of both factors, meaning a younger patient who has no history of thrombosis before the presentation that you are seeing the patient at, that person would be classified as a lower-risk PV patient. In terms of how we approach treatment, in terms of risk stratifying our patients and then subsequently treating, let me first start by saying that aspirate is supposed to be used for all our patients with polycythemia vera unless there is an absolute contraindication, so, aspirate for everyone. Then the second point to keep in mind, for example, based on the CYTO-PV study results, is that we should target a hematocrit of 45% or less across the board, low-risk, or high-risk patients. Where the additional point comes into play is the use of cytoreductive therapies, for example, hydroxyurea, interferon, or ruxolitinib, the 3 most commonly talked about ones. And there, what we say is that the cytoreductive therapies should be used all high-risk patients, in addition to that, of course, there are patients that fall into the low-risk category but may have excessive phlebotomy requirements to keep their hematocrit less than 45 or may be very symptomatic. Either those could be spleen-related symptoms or, let's say, bone pain, pruritus, concentration issues, and a wide variety of other symptoms. Even those patients would be worthy candidates for cytoreduction if just a hematocrit control is not enough. And finally, an additional point to keep in mind is that those patients with PV who have a worsening leukocytosis may also benefit from cytoreductive therapies since we know that patients who have a high white blood cell count are at a higher risk for thrombosis. These are the overall treatment approaches to summarize and put it in very simple words. Dr Komrojki, if you can take us through the NCCN [National Comprehensive Cancer Network] recommendations in terms of treatment for polycythemia vera and what the mechanisms of action are for the drugs that we talk about?

Rami S. Komrokji, MD: You highlighted important aspects of the management, the goal of the treatment, controlling hematocrit less than 45 as symptom directed. Maybe aspirin is a good treatment for most of those patients. The treatment is still based on disease risk, and as you said, sometimes we tailor that because some of the actors like leukocytosis are in risk models. We don't always act upon them, but it's very important. The NCCN guidelines have changed recently to incorporate some of the new drugs that were approved for P vera patient. To your point, obviously the decision to start treatment is based on disease risk. Obviously in P vera different from ET, all patients will need and baby aspirin to bring their hematocrit less than 45. Everybody is getting that. The question is, who gets cytoreductive therapy or not. And that's really based on the disease risk as you alluded. Those patients at higher of- risk of thrombotic events, obviously will get cytoreductive therapy. The first line choices historically had been Hydrea and nowadays the NCCN guidelines also include interferon-based therapies, whether it's the pegylated interferon or the newer approved ropeginterferon as well. And interestingly, the NCCN guidelines also recommend those or incorporate those in patients even with lower risk that historically we did not treat, because interferon-based treatment could alter the natural history. This is something new. In the NCCN guidelines, even lower risk group nowadays can be offered interferon-based therapy. In the higher risk group, obviously every patient needs a cytoreductive therapy. The choice, again, still hydrea could be very reasonable option, particularly for older the patients. Interferon based therapy is listed as an option. Then obviously there is the second line options. Ruxolitinib® is listed by the NCCN as a second line. Ruxolitinib® can sometimes be used in a first line in patients, as you alluded, that are symptomatic, that have spleen or constitutional symptoms. Pruritus could be really a symptom that impact the patient daily activities. I find ruxolitinib® very helpful in that setting. But in general, the major changes in the NCCN guidelines is integration of the interferon as first line therapy in the higher risk and they are second line. In the lower risk, for the first time, now we see that there is suggestion or option of using interferon-based therapy. Ruxolitinib® obviously is based as a second line therapy in the NCCN guidelines. Maybe I'll turn it back to you, since we have those 2 options that we historically did not have, the ruxolitinib and ropeg, to walk us through a little bit more of the data, mechanism of action. How do you see those agents?

Pankit Vachhani, MD: Ruxolitinib® is a JAK1 and JAK2 inhibitor. This was studied in 2 phase 3 open label clinical trials. RESPONSE was the phase 3 clinical trial evaluating ruxolitinib versus standard therapy for PV patients who had splenomegaly and had an inadequate response to just hydroxyurea. There the primary endpoint was the combination of hematocrit control at 32 weeks and a 35% spleen volume reduction. And ruxolitinib® was clinically and statistically significantly better compared to the standard therapy group. It was 21% versus 1% In fact, hematocrit control alone was achieved in 60% of the patients who got ruxolitinib®. And these achievements were very durable. RESPONSE-2 on the other hand, was also an open label phase 3 study. A very comparable study, much like the RESPONSE study that we talked about. But the difference here in RESPONSE-2 is that these patients were PV patients without splenomegaly. That resonates with many of our patients who we see in practice. And here in RESPONSE-2 hematocrit control was achieved in 62% of patients who received ruxolitinib® as opposed to 19% of patients who were on best available therapy. Definitely a great option both in splenomegaly patients or even otherwise. Interferon on the other hand, the interferon therapies have been around for decades. We don't fully understand how exactly they work in MPNs, but they have a wide variety of reasons as to why they may be working. They are immunomodulatory, they're anti-inflammatory, they have antiproliferative properties, and they also have selective anti MPN malignant clone related effects. We brought up a ropeginterferon® and it was studied in PEGINVERA, as well as the phase three PROUD-PV CONTINUATION-PV study. In the phase 3 PROUD-PV CONTINUATION-PV study, ropeginterferon® performed superior to the comparison arm at 36 months of follow up. The endpoint was met in 53% of patients versus only 38% of patients for hydroxyurea. What is important to highlight in addition, is that ropeginterferon® had a higher chance of achieving molecular response. So, 66% with ropeginterferon versus only 27% with hydroxyurea. And along that same vein, these responses of the molecular responses were maintained while those for hydroxyurea were lost with time. The results of the PROUD-PV CONTINUATION-PV study led to the approval first in the Europe, in 2019. But even the PEGINVERA trial, mainly form the basis of the US FDA approval of ropeginterferon® in a line agnostic fashion in the United States in 2021. We also have some additional novel agents, and we'll talk about these in the next section.

Transcript edited for clarity.

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