Polycythemia Vera: Ruxolitinib Trial Data

Harry P. Erba, MD, PhD: You make a very good point. Until recently, for decades our management of PV has been aspirin, hydroxyurea, and phlebotomy; we didn’t have anything else. Worrying about where hematocrit is and symptoms and all these things, we didn’t really have any other tools. People didn’t want to use interferon, but there are better-tolerated interferons and more data coming, and now there’s ruxolitinib. Srdan, I’m going to turn to you to review the data for ruxolitinib in PV patients.

Srdan Verstovsek, MD, PhD: You set the stage very well, and only now do we have a good reason to review our practice and see how well we are doing with hydroxyurea. In the retrospective chart review studies, a number of which have been done, 20% to 25% of patients are not benefiting and should be candidates for something else. We have the opportunity to introduce ruxolitinib as the JAK1/2 inhibitor that Ruben mentioned as an alternative in these people who are not responding well.

There were 2 studies that led to its approval. First there was the RESPONSE study, then REPSONSE-2. They should be looked at together. They clearly describe the value of ruxolitinib in this setting well. The first study, RESPONSE, was for patients who did not do well on hydroxyurea, required phlebotomy, and had a big spleen. They were randomized between the ruxolitinib and control arm, which in the majority of cases was hydroxyurea by itself, because that’s the evidence of not having many other choices.

The RESPONSE-2 study was a copy of that study, so patients were refractorily resistant to Hydrea [hydroxyurea] with the need for phlebotomy, but without a big spleen. The benefits are easy to understand: there was a significant difference in ability to control the red blood cell count. Without going through the numbers themselves, the majority of people had controlled hematocrit on the ruxolitinib and a minority on the control arms.

In the study that requires a big spleen, the spleen was significantly reduced with ruxolitinib and not with the control arm. When we look beyond just the red blood cell count in the spleen, we also look at the control of the white blood cells, the platelets, and the symptoms. This is how I look at the benefit to any therapy: There are 5 factors that are built into the guidelines for what the response should be or how to assess response. That should be control of the red blood cells, white blood cells, platelets, spleen, and symptoms.

We talk about primary goals: eliminating phlebotomy, normalizing the hematocrit at 45%, controlling myeloproliferation as Dr Shammo described, white blood cells and platelets to the extent possible. Then for the quality-of-life issues, control the big spleen that may be symptomatic and general systemic symptoms. These are the benefits of the new therapies we cherish, and ruxolitinib is now an option in the second-line setting.

Harry P. Erba, MD, PhD: How often do you have to adjust the dose of the ruxolitinib? We at the Duke Cancer Institute start at 10 mg twice daily. How do you do that? What do you use to adjust the dose?

Srdan Verstovsek, MD, PhD: For myelofibrosis, you’re right: the starting dose for every PV patient is suggested to be 10 mg twice a day, and the expectations are that you would go up. About 65% of patients need to increase: from 10 mg, you go to 15 mg twice a day, then to 20 mg twice a day, and even some patients need 25-mg-plus a day. It’s all adjusted based on the need to control the blood cell count and the symptoms that we described.

Only about 5% of patients need less than 10 mg twice a day, and that would be because of too much myelosuppression. This is where we simplify things for patients when looking at the numbers because other nonhematologic toxicities are rare. There are some, but they’re not common. The guidelines would be to look at the blood cell count and optimize the dose to derive those benefits and control the symptoms, spleen, and blood cell count to the maximum.

Harry P. Erba, MD, PhD: I have a question. Ruben, I need your help on this. I see the data from the RESPONSE trials showing superiority in terms of decreased phlebotomy requirements, better erythroid control, and reduction of splenic volume in RESPONSE. The goal of therapy in PV is to prevent thrombotic events. Is there any evidence that, by switching to ruxolitinib, you may prevent thrombotic events?

Ruben A. Mesa, MD, FACP: In short, yes. The studies were not powered with thrombosis as a primary end point, but there have clearly been many fewer thrombotic events on the ruxolitinib arm versus the best alternative therapy arm. There’s good mechanistic reason to believe that that is true. First, there was better, more consistent control of counts as well as likely improvement in inflammation and other aspects that might create a pro-inflammatory milieu.

I’m mindful that, for patients who are inadequately controlled with supplemental phlebotomies on other medical therapy, they’re going to be spending a good amount of their time above the target hematocrit of 45%. Every time you phlebotomize them for their hematocrit of 49%; how long have they been above 45%? Maybe they’ve been above 45% since the last time you phlebotomized them; we don’t know. It’s an uneven control of the hematocrit. There are multiple mechanistic reasons why stable control with a JAK inhibitor like ruxolitinib is probably superior for thrombosis prophylaxis.

Harry P. Erba, MD, PhD: Krisstina, the primary end point of RESPONSE was at 32 weeks, and we’re talking about a disease that in patients who had similar life expectancies to age and gender-match control. What do we know about long term? Are there longer-term data from the RESPONSE trial about tolerability and durability of these responses?

Krisstina Gowin, DO: Absolutely. We see at 156 weeks that these responses—hematologic, splenic, and symptom responses—were sustained, and patients maintained activity on the ruxolitinib. The RESPONSE data have certainly given us another option to treat patients, particularly if they have had progressive disease on first-line therapy, and it has been a valuable contribution to our therapeutic armamentarium.