Ruxolitinib Patient Selection in Polycythemia Vera

Harry Erba, MD, PhD: The label for ruxolitinib in PV (polycythemia vera) is for patients with polycythemia vera who are either intolerant of, or resistant to, the effects of hydroxyurea. In my opinion, one of the groups that is probably best suited for consideration of ruxolitinib are patients who may not have been included in the RESPONSE Trial. And, those are patients who remain symptomatic from the disease, but not symptomatic from a direct effect of a high hematocrit. In other words, they’re not having microcirculatory events and are not symptomatic from a spleen. But, there a number of other symptoms that affect the quality of life for these patients, and hydroxyurea often doesn’t control those. One of the most devastating can be pruritus. Patients with persistent symptoms that are not controlled by hydroxyurea, I do think, would be appropriate candidates for ruxolitinib.

Patients who are continuing to require phlebotomy even though they’re on hydroxyurea, now, that’s been the standard of care for decades. As I said, when patients were randomized to best available therapy, what did the doctor do with their patient? They kept them on phlebotomy and hydroxyurea, and an aspirin, because that’s what we have done. We haven’t had an alternative. Now we do.

The question is, is it worth taking that alternative? Many people would say we’ve been doing this for years without ruxolitinib, why change? And, I think one of the most important reasons to change—this has to do with talking to your patients about how the disease affects them—is that the continued requirement for phlebotomy, despite using hydroxyurea, actually does lead to symptoms that I think we underestimate. Not just the inconvenience of coming in, not just the initial consequence of phlebotomy and maybe orthostasis or multiple venous phlebotomies, but, really, the iron deficiency symptoms need to be considered. And so, in patients who are well managed on hydroxyurea, don’t need phlebotomy, or if they’re on hydroxyurea needing phlebotomy, I would switch to ruxolitinib in order to be able to carefully give those patients iron, so that they don’t have those symptoms of iron deficiency.

Most of my experience with ruxolitinib has come from patients with symptom burden—I really think that’s the real benefit of this drug—and specifically, one patient I’ve had with polycythemia vera who had been managed with phlebotomy and hydroxyurea. However, when she came to see me, she continued to have night sweats, she continued to have pruritus, and most importantly, she was having aches and pains in her body. And, she was a long-distance runner, and she wanted to continue to exercise. I started her on ruxolitinib and her arthralgias, and bone pain, and pruritus went away. It completely changed her quality of life. Her fatigue didn’t quite go away. Her energy level didn’t quite get back to what she wanted. It was at that point we recognized, well, she was still iron deficient. So, very cautiously, while on ruxolitinib to maintain the hemoglobin and hematocrit in the normal range, she started back on multivitamins with low-dose iron, and her iron stores came up and she felt remarkably better.

In this disease, polycythemia vera, it’s very difficult to predict which patients are going to progress to myelofibrosis or acute leukemia. I have not actually been able to find any clinical features, either in the literature or in my own patient population, which can predict this. And, it doesn’t necessarily have to be something that occurs after decades of having the disease. I’ve seen patients in their early 20s have a diagnosis of PV and within 6 months, a diagnosis of acute myeloid leukemia. I don’t know why. I don’t know what was specific about that patient. We can define risk factors for the major complication that we’re trying to prevent in PV, which is thromboembolic events, but I haven’t been able to define risk factors for patients who are going to progress to myelofibrosis or acute leukemia. The only exception to that would be some very old studies from the Polycythemia Vera Study Group where patients received chemotherapy or phosphorous 32, and those patients seem to have a higher risk of progression to advanced stage of the disease.

From the RESPONSE Trial, it is very difficult to say that ruxolitinib does reduce the risk of thromboembolic events compared to best available therapy. There are no data that say that in polycythemia vera. The study was small, only 110 patients in each arm. The study primary endpoint was 32 weeks with only an 80-week follow-up, so a very short period of time. So, at this point, numerically, there were fewer thromboembolic events with ruxolitinib than best available therapy. I don’t believe that was statistically significant, and further follow-up would be needed.

What’s going to compromise our ability though to be able to see if there’s a difference between best available therapy and ruxolitinib is the fact that, in the RESPONSE Trial, all the patients have come off of best available therapy, and most of them have switched over to ruxolitinib. We don’t have a control group. So, I don’t think we’re ever going to, from a study such as this one, have a satisfactory answer as to whether ruxolitinib decreases the risk of thromboembolic events compared to other therapies.

A Patient with Disease Progression on Hydroxyurea

Case 1: