Emerging Therapies for Polycythemia Vera

Transcript:

Ruben Mesa, MD: The therapies for PV have evolved quite a bit over the last several years. We look back over 10 years ago, and not even aspirin was indicated in these patients because of the concern that it might increase the risk of hemorrhage. Randomized studies clearly showed that a low-dose baby aspirin was beneficial. Next, it was shown, in the CYTO-PV study, that a tight control of the hematocrit of under 45%—and keeping that as a strict ceiling—was an important goal for decreasing the risk of thrombosis or bleeding.

Finally, the availability of targeted therapy JAK inhibition with ruxolitinib has been very impactful. Ever since the discovery of the JAK2 mutation, it was identified that inhibitors of JAK2 would likely be very impactful, in particular with polycythemia vera, given its prevalence. But, the ability of that therapy to impact not only the counts—where other cytoreductive therapies have been limited, such as hydroxyurea—but also to control splenomegaly symptoms and vascular events is really, very favorable and has made a big impact.

Srdan Verstovsek, MD, PhD: Traditionally, in the United States, hydroxyurea has been a first choice as a cytoreductive therapy for patients with PV who had a high risk of thrombosis, and it does work well in many patients—but not in all. And the question is whether or not this particular agent, which is a chemotherapy, is even safe long-term, particularly when it’s given to patients who are younger. Attempts are being made to challenge the position of hydroxyurea as a frontline therapy by comparing it to interferon. Interferon is a biological agent; it’s injectable. There are studies underway, which were recently presented in a preliminary fashion at the American Society of Hematology meeting in December of 2016. It is not quite clear, yet, whether or not interferon can be better than hydroxyurea in a frontline setting based on its known toxicity profile. But, the studies are underway. Alternatives would be to entertain the possibility of developing ruxolitinib, a JAK inhibitor, as a frontline therapy for patients with PV, which potentially might be better with Hydrea [hydroxyurea]. We will certainly endorse such a study to prove that ruxolitinib has value in the frontline setting.

Jamile M. Shammo, MD: Some of the novel therapies being developed are biological agents that have various, or different, mechanisms of action. So, there’s interest in developing an MDM2 or TP53 inhibitor, for example, at Memorial Sloan Kettering Cancer Center, for people who have PV that is resistant or intolerant to Hydrea or Jakafi [ruxolitinib]. Combination therapies that add other drugs to ruxolitinib—things like heat shock protein, for example—are being evaluated. And also, HDAC inhibitors are being evaluated in the same way they were for myelofibrosis. PI3K delta inhibitors are also being evaluated in this patient population. So, all these are very interesting concepts and novel clinical trials that I think are reasonable approaches for a patient population that haven’t responded to anything we currently have in the clinic.

Ruben Mesa, MD: There are promising combinations for patients with polycythemia vera using ruxolitinib as a base, given its benefit. The most interesting combination is the 2 agents that really are the most active in polycythemia vera—ruxolitinib and interferon. Both agents have, potentially, complementary value. Interferon may have an anti-clonal effect that may be complementary to the effects of ruxolitinib. There are other therapies potentially in development, including nutlin inhibitors and other kinds of novel pathway inhibitors, that will be of interest. If I were a patient with polycythemia vera, I’d be very hopeful for all of these advances that are occurring.

Transcript Edited for Clarity