Ruxolitinib for Relapsed/Refractory or Hydroxyurea-Intolerant Polycythemia Vera Patients

Srdan Verstovsek, MD:Once we engage in a therapy of polycythemia vera with cytoreductive therapy, and hydroxyurea being, usually, the first choice, we should be looking at several factors in a particular patient beyond just control of red blood cell count. We are talking here about controlling five factors. This would be red blood cells, white blood cells, platelets, symptoms, and spleen. Patients may have a controlled red blood cell count and have a very bad quality of life, or an enlarged spleen that is causing trouble, or they may have progressive increase of white cells or platelets. So, more than one way of looking at a benefit of any cytoreductive therapy really looks at these five factors, controlling of the blood cell count, all three lines, skin and symptoms. Hydroxyurea may not achieve that in many patients. I’m talking about perhaps 20% to 25% of patients being either resistant or intolerant to hydroxyurea. New development relatively recently in the United States and Europe led to the approval of a new medication called ruxolitinib for patients that are intolerant or refractory to hydroxyurea, which would then mean that this is a second-line therapy for patients who do not do well on hydroxyurea.

The important aspect of development of ruxolitinib is to understand real benefits in a modern era. Looking at these five factors that I mentioned, two studies were done so far. One of them is widely known, it’s called the RESPONSE study, where patients that were refractory or intolerant to hydroxyurea and still in need of therapy, still requiring phlebotomy, and having enlarged spleen were randomized prospectively between best available therapy, meaning whatever the doctor wants you to do or ruxolitinib. And, in this fashion, looking at it particularly as a primary goal of using the spleen and controlling the red blood cell count, controlling the hematocrit, there was a significant difference on the part of ruxolitinib, which is the best available therapy.

We also looked beyond that. We looked at control. The white cells, and platelets, and symptoms, and all the aspects of the polycythemia vera were very well controlled in a majority of the patients on ruxolitinib, where there’s hardly anybody on best available therapy arm. So, that led to approval of ruxolitinib, a spectrum of benefits. More recently, 3 months ago, there was announcement of another study called the RESPONSE-2 study, where similar design was implemented. Patients intolerant or refractory to hydroxyurea in need of therapy with polycythemia vera, requiring phlebotomy but without a big spleen, were tested in the same way, in a prospective randomized study. Ruxolitinib was the best available therapy and the results were almost identical to the first study. There was much better control of red blood cell count, white cells, and platelets, and symptoms where there’s the best available therapy arm. So, now we have two large prospective studies confirming benefit of ruxolitinib in second-line patients after hydroxyurea in polycythemia vera.

Hydroxyurea is a relatively very well tolerated and effective first-line therapy for patients with polycythemia vera. After a quarter of the patients with hydroxyurea therapy developed resistance or intolerance, they need something else. They need a better therapy that would control their symptoms and signs, and this is particularly important for the patients that are really resistant to hydroxyurea. They do have a more aggressive disease. They have more symptoms, a bigger spleen. They tend to transform more to myelofibrosis and acute myeloid leukemia, and have a shorter life expectancy.

There are not too many options. Interferon is one of the options, but it does not work in many patients. It does cause many side effects. Even with the advent of new long-acting interferons, the results do not support long-term use of those medications. And, other traditional medications that we have been using in this setting, alkylating agents like busulfan, melphalan, chlorambucil, radioactive phosphorus, are known to be leukemogenic, meaning increase in the risk of transformation to acute myeloid leukemia. So, there was a clear need for a new therapy that would be developed which is safe and perhaps biologically targeting what is abnormal in PV. And, ruxolitinib has fulfilled that role. It is targeting the hyperactive JAK/STAT pathway. With that, it does diminish very quickly the number of cells in blood. It does diminish very quickly the spleen that may be enlarged in these patients. And what I see in my patients—I have treated many patients—quality of life markedly improved within a couple of weeks in many patients that don’t have good options. So, now we have a complete picture of controlling all blood cell counts, spleen, and symptoms in patients with PV after hydroxyurea. This is where the real role for ruxolitinib is.

Case 1:A Patient with Disease Progression on Hydroxyurea