Polycythemia Vera: An Update on Clinical Trials

Experts discuss clinical trial updates in polycythemia vera, including data from RESPONSE, RESPONSE-2, an international observational study of ruxolitinib, and REVEAL.

Srdan Verstovsek, MD, PhD: RESPONSE and RESPONSE-2 are 2 phase 3 studies, long-term studies that evaluated the role of ruxolitinib, a JAK inhibitor, in patients with polycythemia vera [PV] who were resistant, refractory, or intolerant to hydroxyurea. Hydroxyurea is the first-line choice in a great majority of the patients with PV. But about 20% to 25% of patients do not really do well. They are resistant or refractory and intolerant. They still need phlebotomy. In the RESPONSE study, for participation in that study, they needed to have a big spleen. In the RESPONSE-2 study, they did not have to have a big spleen. That was an additional factor to evaluate.

The goals of the therapies were in the second-line setting to compare ruxolitinib with best-available therapy, whatever the doctor wants to do, in achieving the control of the hematocrit, and then after that, also control of the spleen in the RESPONSE study, and control of the white blood cells and the platelets and the symptoms in all these studies. This is a challenge, because usually you need to have some time to assess these benefits. These are studies that took about a year to have a first glimpse in the response. The first study, the RESPONSE study, led to approval of ruxolitinib. The RESPONSE-2 study followed, of course, and now we have a 5-year follow-up to talk about from these 2 studies.

I would start ruxolitinib in patients who are suboptimally managed with hydroxyurea that have no good control of the red blood cell count, are still on phlebotomies, or have uncontrolled white cells or platelets, uncontrolled symptomatic splenomegaly, or general systemic symptoms. These are the factors we utilize to judge the benefit of any therapy in PV, particularly red blood cells, but other factors are important as well. If that is not achieved, or if patients have toxicities from hydroxyurea, then ruxolitinib is full-fledged choice for a second-line therapy.

We start with 10 mg twice a day, unlike in myelofibrosis, for which ruxolitinib is also approved. Here, everybody starts with 10 mg twice a day. We expect that two-thirds of the patients need more, from 10 mg twice a day; in a month or 2, you go to 15 mg, and then to 20 or 25 mg twice a day. Only 5% need less than 10 mg twice a day. For some reason, even that low dose is too much for them. But the expectation is to start ow and then go to higher. With that, you have excellent response.

In the first study, the RESPONSE study, about 60% of the patients had elimination of phlebotomy during the observation period, and the same happened in the RESPONSE-2 study. The spleen was very well controlled in patients with a big spleen on the RESPONSE study. Other benefits, controlling of white blood cells and platelets and the symptoms, were seen in most patients over a long period of time. After 5 years, we know that of those who responded, many of them are still responding. And there are no real major adverse effects. Remember, ruxolitinib in myelofibrosis, which was the first indication, was associated with anemia and thrombocytopenia as an adverse effect. These are benefits in PV. We don’t have major problems here. Occasional shortness of breath or diarrhea or a rash, which are low grade and go away on their own without need for dose adjustments. It’s effective over the long term without major adverse effects.

Ruben A. Mesa, MD: At ASH [American Society of Hematology Annual Meeting] there was a very nice international observation, real-world-evidence study from our colleagues in Europe looking at the use of ruxolitinib in patients with P [polycythemia] vera who had been resistant or intolerant to hydroxyurea. What they reported, in this ongoing observational phase 4 study in 352 patients with P vera, is that their experience was very similar to what has been reported in the RESPONSE-2 study. Namely, the therapy was very effective in decreasing the number of phlebotomies the patients needed or making the phlebotomy independent with better control of hematocrit. Overall they had a mean daily dose of around 21 mg of ruxolitinib, very consistent with that 10 mg twice-a-day dosing, and many individuals were able to remain subtly on that dose.

Adverse events that they had reported were modest but could include low-grade infections, some low-grade bleeding events, and a low rate of secondary neoplasms, the majority of which were cutaneous, which has been identified as 1 of the potential toxicities of JAK inhibition.

Presented at ASH as well, by my colleague Dr Brady Stein, were data with a trial that I’ve been 1 of the investigators on. The REVEAL study was a prospective observational study for patients with polycythemia vera on mortality and causes of death.

There have been over 2500 patients enrolled into this ongoing observational study. What they identified in terms of causes of death was a little surprising. For the causes of death, 72% had a known cause of death, and overall numbers of death is less than 10% of that overall cohort but still a significant number—250 or so individuals have passed away. A third of these individuals from thrombotic complications, broadly worded; 12% in solid tumors; bleeding in 6.3%; and 15.4% from a hematologic malignancy, assuming many of those potentially associated with P vera.

Looking at these data, they suggest that P vera–related causes of death are a higher percentage than one might expect overall, and that the 4-year mortality was greater than 10%, even though the mean age of enrollment was only 66 years of age. This helps reinforce the thinking that polycythemia vera is purely a benign disease for many individuals, which is probably inaccurate in that having an accurate diagnosis and effective therapy is important when we’re thinking about patients with polycythemia vera and look forward as more of these data from REVEAL to help guide us further in terms of refining our treatment algorithms.

Transcript edited for clarity.

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