Aaron Gerds, MD, MS: For patients with polycythemia vera [PV] who do need cytoreduction, meaning lowering of the blood counts or control of blood counts with a medication, there are 2 top-line choices. One is hydroxyurea, the other is interferons as a class. Typically in polycythemia vera these days, we’re talking about ropeginterferon. Hydroxyurea has been around for a very long time, kind of grandfathered in as a standard of care treatment. It was the center of a lot of clinical trial work back in the ’70s and into the ’80s with the polycythemia vera study group. But there’s never been a high-risk study done where high-risk patients were positive, never were [randomly assigned] between hydroxyurea and phlebotomy alone. So, unfortunately, we’ll never have that information. Nonetheless, the benefit from keeping them adequate under 45 is quite clear in high-risk patients. I don’t think anyone debates that to any degree. And since hydroxyurea has been proven to be an effective method of keeping the hematocrit under 45 with very manageable [adverse] effects and a well-known toxicity profile, we can endorse that based on this historical context alone. Interferons have been tested in a number of different formulations, starting with regular interferon, pegylated interferon, and now ropeginterferon. And in more recent times, we look to 2 key trials with interferons. One is the [phase 3] MPNRC 112 study [NCT01259856], which is a randomized controlled trial in high-risk PV and ET [essential thrombocythemia]…pitting hydroxyurea versus pegylated interferon and the more recent [phase 3] PROUD-PV trial [NCT01949805] where in the upfront setting high-risk patients were treated either with hydroxyurea or ropeginterferon. And so this is prospective randomized phase 3 data that establishes interferon as a frontline therapy for high risk, polycythemia vera. There is also randomized phase 2 data for polycythemia vera. A low-risk polycythemia vera, although it’s tough to know what direction to go with this because the data isn’t really large enough to detect thrombosis differences between the different treatment arms. But certainly it does provide a viable option in a symptomatic patient who may benefit from site of reductive therapy in the low-risk setting. Again, hydroxyurea is often included in this setting as well, just because of its track record and again, [it’s] well-defined toxicity profile.

The NCCN [National Comprehensive Cancer Network] guidelines have categories for their recommendation. There’s category 1, 2A, 2B and 3. So all recommendations in the guidelines are to 2A unless otherwise noted. So if you don’t see a category attached with a recommendation, it’s assumed that it’s a 2A, and we point out ones that aren’t 2A. Category 1 is based on high level.... And there’s uniform consensus within the panel that the treatment is appropriate. So they’re kind of the top of the peak there, if you will. So, very good, well done prospective randomized phase 3 trials. Ideally, in a more common disease, there’ll be multiple randomized phase 3 trials, all pointing in the same direction that go into that recommendation. Category 2A is based on lower evidence. It could be a single randomized trial or a large number of phase 2 trials. But there still is uniform consensus among the panel to make that recommendation. 2B has a similar level of evidence but…there’s a little less consensus, that it’s not uniform. So the number of votes is not quite meeting that threshold to make it a category 2A. The difference between the 2A and 2B is a 85% vote. To go from 2A to 2B, you have to say 85% of the panel says, yep, this is an appropriate treatment. And…based on this data, we push it forward. A category 3 is based on any level of evidence, whether we’re talking case reports, anecdote, what have you, or even randomized phase 3 trials. But there is major disagreement on whether or not to recommend this. So it relies heavily on the vote, but also has the influence of evidence. But it’s really all about the consensus. Preferred versus other recommendations versus useful different sets of circumstances helps give levels of preference to different agents. [With] preferred intervention, the interventions are based on superior efficacy, safety, and evidence, and affordability, when appropriate. Kind of gives you additional options. Other inventions can be maybe somewhat less efficacious, may be more toxic. Maybe the data is not quite as mature. It’s a good therapy to consider, but not…top tier. Then [there are those that are] useful in [certain] circumstances. That type of label implies why we may want to use that. So in rare instances or certain circumstances, you might want to choose one drug over the other. Historically, interferons have been useful in some circumstances because we thought its best efficacy was in maybe younger patients or patients who may get pregnant at some point, or you want to avoid hydroxyurea. But over time, as the data has developed, particularly for ropeginterferon, that category preference has changed. It’s gone from useful in circumstances to other recommended to edging on a preferred agent. So you can see how a particular agent has climbed the ladder of preference over time as more data and more consensuses has been generated.

Certainly the guidelines just don’t want to give you a single recommendation [to use] this drug and then not give you support thereafter, because none of these drugs are home runs. They’re not perfect agents. They’re not going to be perfect in every situation. They’re not going to be without [adverse] effects. And there are some patients whose counts aren’t under good control with these drugs. So we definitely want to give additional options. The simple way to think about it is you start with either hydroxyurea or interferons, and then if that’s not working, switch to an alternative agent. So if you start out hydroxyurea, interferons could be considered a second-line therapy. If you start on interferons, hydroxyurea could be considered a second-line therapy. There’s also the added agent in the second line setting of ruxolitinib. Ruxolitinib is a JAK inhibitor. It is FDA-approved to treat polycythemia vera after hydroxyurea. That’s what the label says on it, and [it] has continued to show impressive data in terms of controlling counts. And now, with the MAJIC-PV trial, event-free survival improvement over other options. And so certainly [for] patients who have been on hydroxyurea who either are having [adverse] effects that limit its use or are not getting their counts under control, we have a relatively low threshold for switching over to ruxolitinib at this point in time. So those are the major 3 options available in the second line, either hydroxyurea or interferons, as well as a ruxolitinib.

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