Future Directions: Emerging Therapies in PV

Srdan Verstovsek, MD:In polycythemia vera, we have fulfilled one major unmet need, and that was what to do for patients that have polycythemia vera that are not responding to frontline therapy with hydroxyurea. The next is to see, is there a better way to even treat patients from the get-go from the beginning? Is there a better therapy than hydroxyurea for patients that need cytoreductive therapy and development of maybe ruxolitinib for frontline use, or novel forms of interferon for frontline use in a first-line setting? This is what I see in the next step in the field of polycythemia vera.

Of course, one would perhaps even explore combination therapies to have a better effect on the biology of the disease. Some even talk about elimination of the disease. Interferon in combination with ruxolitinib is being studied to see whether, with the two, we can control not just the signs and symptoms, but also increase the effect of each of these two medications on the malignant clone, the JAK2 V617F-positive cells that we can easily measure. These studies are underway.

In addition to ruxolitinib and ruxolitinib-based combination therapies, in Europe, in particular, there is an effort to develop what I call a super long-acting interferon, which is given under the skin as injection every 2 weeks or sometimes even every 4 weeks. That is quite a difference from the traditional interferon that is given three times a week. And the consequence of giving it less often, because the preparation is slow-release, is that there might be less of a toxicity that we know comes with interferon injections. About one-third of the patients that are given standard regular interferon drop out of the therapy within 1 year because of the side effects. And, average duration of the therapy with interferon is relatively short. With the new development with these slow-release interferons, we may expect in the future—and studies are underway—that the tolerance will decrease, and perhaps the benefit of the interferon therapy would be prolonged.

PV management has evolved over the last several years quite a bit. From looking at the red blood cell count as a target to realizing that there is much more there—there are other blood cell counts, there is the spleen, there are symptoms—we learned how to assess the benefit of therapy beyond just focusing on hematocrit. We developed new tools, questionnaires, for example, to assess the benefit properly, to assess the benefit in terms of quality of life in the particular setting. We developed tools to recognize who is not doing well in therapy. What are the criteria for a refractoriness, or how do we recognize intolerance, or how do we tell people to recognize what are the toxicities of therapies like hydroxyurea and the leg ulcers? So, the field is evolving very rapidly in the clinical arena, not just in the arena of biology where now we know the hyperactive JAK/STAT pathway is the culprit. We are further refining our ability to define the biological characteristics; for example, patients that don’t do well and have more aggressive disease as we are talking about developments in the clinical area.

Case 1:A Patient with Disease Progression on Hydroxyurea