Since the times of Vaquez and Osler over one hundred years ago phlebotomy has been has been a mainstay of treatment in Polycythemia vera (PV) and for more than fifty years, cytoreductive agents have been added to achieve hematocrit control in patients at high risk for thrombosis. Thus PV has lagged behind other hematologic malignancies in the implementation of novel and targeted drug therapy. This has changed recently with the development of novel therapies for this disease, a number of which have received regulatory approval internationally.
Ruxolitinib has been approved as second line therapy for PV patients intolerant of or resistant to hydroxyurea on the basis of the RESPONSE trial. In this study 222 patients were randomized to receive ruxolitinib or best available therapy (BAT) in the second line setting. At 5 years 60% of the ruxolitinib patients versus 19% of the BAT patients maintained hematocrit control without need for phlebotomy. Reduction in spleen volume was also more frequent among ruxolitinib patients (89 vs. 49%). There were decreases in JAK2 V617F allele burden in both groups but complete molecular remissions were rare. Importantly, herpes zoster infections occurred among ruxolitinib treated patients.
Interferon has become an important drug in the treatment of PV with the publication of interim and final results of a number of studies of pegylated versions of interferon. The Myeloproliferative Disorders Research Consortium (MPD-RC) 112 and MPD-RC 111 randomized studies previously treated and untreated patients respectively. Good clinical responses with manageable toxicity were attained and further follow up is awaited. The 3 year results of the combined PROUD-PV and CONTINUATION-PV, randomized, phase 3 trials comparing ropeginterferon (a novel, long-acting, mono-pegylated proline interferon) to hydroxyurea in newly diagnosed PV patients show improved complete haematological response and reduced JAK2 V617F allele burden with ropeginterferon. The drug is also under study in patients with low-risk PV in whom hematocrit levels at or below 45% compared with those who received monthly phlebotomy alone were more common according to interim findings from the ongoing LOW-PV trial.
Novel agents for PV include MDM2 inhibitors, nutlins. MDM2, an inhibitor of TP53 is up-regulated in PV CD34+ cells and exposure to a nutlin induced TP53 and selective stem cell depletion in preclinical models. Early trials of idasanutlin, an oral MDM2 antagonist demonstrated a 58% overall response rate and median duration of response of 16.8 months in high-risk PV patients after failing prior therapy. Idasanutlin is being evaluated in a multinational phase 2 trial.
A unique approach to controlling the hematocrit in PV by targeting iron metabolism is currently in early testing. Hepcidin is the major physiologic regulator of iron metabolism. PTG-300 is a first-in-class synthetic hepcidin mimetic that is in phase 2 clinical trial development. The agent reduces iron available for erythropoiesis and in a preliminary study was able to maintain the hematocrit at <45% without need for phlebotomy in a small number of PV patients all of whom were previously phlebotomy dependent.
These novel agents and others will likely change treatment paradigms in PV.
