Management of Myeloproliferative Neoplasms - Episode 9

Ruxolitinib's Role in Treating Polycythemia Vera


Harry P. Erba, MD, PhD: If a patient is progressing, we can now use ruxolitinib. Let’s step back and ask the question, Rami, why? Why is it important? Why is JAK2 an important target in polycythemia vera?

Rami Komrokji, MD: As we discussed earlier, the JAK/STAT pathway overactivation, whether it’s from a mutation or ligand overactivation, is the hallmark for all those diseases. The EPO (erythropoietin) signaling is obviously the JAK/STAT pathway. In the majority of patients with polycythemia vera, the mutation is there and the pathway is overactivated, so it makes sense to test the JAK2 inhibitors in that setting. In addition, we also see common features of those diseases. In polycythemia vera, patients had splenomegaly or pruritis and other things; ruxolitinib has proven to be very effective in patients with myelofibrosis, and it could be utilized for those patients.

Based on all of that, there obviously had been a randomized clinical trial in patients who are resistant or intolerant to Hydrea (hydroxyurea) where they randomized to best available therapy versus ruxolitinib. The primary endpoint was a composite endpoint of spleen and the hematocrit control. That was defined on the study based on eligibility for phlebotomy. The study showed that it met the primary endpoint, the composite one. It showed better control or a higher rate of complete hematological responses. That’s the benefit. Regarding patients who had required multiple phlebotomies, I think their hematocrit control was better. From my view in clinical practice, there is really benefit for symptom control as Srdan was indicating. If patients have splenomegaly or pruritus, you don’t get that control with the best available therapy. When you look more into the study, it was obviously not powered to look at things like thrombotic events. It looked like they were less common, but that was not the aim of the study by any means.

A very important point I think Srdan raised is looking at secondary malignancies. It also looked like they were less common, but it was not aimed to look at that. There are so many benefits of this agent or a rationale to use it in terms of hitting goals, the biology, the control, and the side effects. I think what we lack a little bit would be the long-term use of this medication, somebody who is 25 and put on ruxolitinib for 20 or 30 years. We don’t have data on that. That’s what I tell my younger patients sometimes, that I don’t have long-term data on the safety.

Harry P. Erba, MD, PhD: In the RESPONSE trial, you’re right, they had to have both palpable splenomegaly and a large spleen by MRI and there was also a phlebotomy requirement, so it was a composite endpoint. But then, there was RESPONSE-2, where you didn’t have to have splenomegaly. What I took note of is that the rate of hematocrit control as well as the number of phlebotomies, however you look at that, was better with ruxolitinib compared to best available therapy. The responses were almost identical to those responses in RESPONSE-1. And again, in RESPONSE-2, there were fewer thrombotic events. Although the numbers are quite low, there were fewer thrombotic events over this period of time in the ruxolitinib arm. Maybe it had to do with the complete hematologic remissions. Maybe it is the control of the white blood cell count.

Srdan Verstovsek, MD, PhD: One salient point here, which is obvious but maybe not officiated by community physicians, is that this is not a spleen drug. You don’t have to have a big spleen for the drug to work. It’s the same in myelofibrosis. Almost all the studies had a requirement for myelofibrosis patients to have a big spleen. The RESPONSE study that led to approval of ruxolitinib in PV had the requirement for big spleen. But you pointed out that the follow-up study, RESPONSE-2, did not mandate it. In fact, they were excluding patients with big spleens. That’s a second-line PV study, and response in control of the symptoms and blood cell count was the same as in patients with big spleen. Big spleen, yes or no, in PV it doesn’t even matter. Activity is there for the symptoms and the blood cell count.

Transcript Edited for Clarity