Hydroxyurea Resistant Polycythemia Vera - Episode 4
Ruben A. Mesa, MD:This individual, I would say, has demonstrated clear resistance to hydroxyurea based on current European LeukemiaNet criteria, as well as some degree of intolerance. They would be a candidate for targeted therapy, and ruxolitinib is specifically indicated for individuals in this setting. He would be very consistent with the types of individuals recruited onto the clinical trials for ruxolitinib in hydroxyurea-resistant or hydroxyurea-intolerant patients.
Ruxolitinib has been very effective for patients with polycythemia verain particular, individuals with the phenotype like this patient, with problematic polycythemia vera—and that has a variety of manifestations: a good control of the hematocrit in those who have failed hydroxyurea by resolution of need for phlebotomy through control of erythrocytosis; improvements in splenomegaly, when it has been present; improvement in disease-associated symptoms—in particular, difficult symptoms such as pruritus, night sweats, etc. It has also been demonstrated, compared with best alternative therapy, to have a significant impact on decreasing the risk of thrombosis or bleeding, which are, again, key goals for us as we manage patients with polycythemia vera.
Targeted therapy with JAK inhibition, with ruxolitinib, in patients with polycythemia vera seems to have a strong impact on decreasing the risk of thrombosis and bleeding. And we believe that may be from a variety of factors. It has good control of myeloproliferation, a control of accounts, which has been long recognized as a goal of therapy. We do believe that there may be some other positive benefits from this line of therapy in decreasing that risk. Ruxolitinib is a JAK1 and JAK2 inhibitor. It helps to decrease inflammation associated with polycythemia vera. That inflammatory state is probably conducive to the development of thrombosis and bleeding. That may be helpful, as well. In addition, the individuals are more active. They feel better. They’re walking around more, and that probably has an additional level of benefit in terms of decreasing that disease associated morbidity from inactivity.
The management of polycythemia vera has really evolved over the last several years. Throughout much of my career, we only had the options of phlebotomy, aspirin, and hydroxyurea. During these last several years, we have realized that, with phlebotomy or cytoreduction, we need to be stricter than we used to be. Through the CYTO-PV study, it was recognized that we clearly have to keep the hematocrit under 45% to decrease that risk of thrombosis and bleeding.
We’ve recognized the value of aspirin. In the past, aspirin was felt to be contraindicated, as it maybe increases the risk of hemorrhage. It was demonstrated that low-dose aspirin is both beneficial and safe to use. And finally, we have clearly seen the strong benefit of JAK inhibition with ruxolitinib in this group of patients. Indeed, after the discovery of theJAK2V617F mutation in patients with polycythemia vera, it was speculatedeven from that time in 2005—that if we had an inhibitor of JAK2, it would be very effective for polycythemia vera, given the overrepresentation and overactivity of the JAK/STAT pathway in these patients.
Polycythemia vera still has unmet needs. We still are trying to identify whether or not there’s a role for targeted therapy earlier in the disease. Should it be used in the frontline setting? And there are ongoing efforts to try to identify whether or not that should be the case. We are still trying to figure out why it is that patients progress. Are there other ways that we can make that progression less likely to occur? We do recognize that individuals, even with effective targeted therapy, have improvement in their symptoms but not complete resolution. So, our group has been very active in looking at nonpharmacologic complementary approaches to try to help these patients further, whether that’s through physical activity, yoga, meditation, etc to manage some of the chronic symptoms they can have with this difficult disease.
In polycythemia vera, many exciting things are going on. In the arena of targeted therapy, I think the key question is, should we be using these therapies earlier, even in a select group of individuals, to try to have a greater likelihood of them not progressing in the future? There are also investigations going on with other agentsthe Nutlin inhibitors, interferons, or others—and single-agent approaches, or perhaps combination approaches that involve ruxolitinib as part of that therapy, that I think are very exciting and may lead us to deeper levels of control of the disease.
Transcript edited for clarity.