Ruxolitinib Shows Promise in Polycythemia Vera

Ruxolitinib, a JAK1/2 inhibitor approved by the FDA for the treatment of myelofibrosis, also has activity in another myeloproliferative neoplasm, polycythemia vera, according to two reports from the phase III RESPONSE trial presented at the American Society of Clinical Oncology (ASCO) and the European Hematology Association (EHA) annual meetings.

The drug demonstrated improved hematocrit control and reduction in spleen size in patients with polycythemia vera who were resistant or intolerant to hydroxyurea, as reported by Srdan Verstovsek, MD, PhD, of the MD Anderson Cancer Center in Houston, Texas,at the 2014 ASCO Meeting in Chicago, and Alessandro M. Vannucchi, MD, of the University of Florence in Italy, at the 2014 EHA Congress.

In the RESPONSE trial, 222 patients with hydroxyurea-resistant or -intolerant polycythemia vera were randomized to either twice-daily 10 mg ruxolitinib (n=110, median age 62, 60% male) or best available treatment (BAT; n=112, median age 60, 71% male). BAT was identified as monotherapy, consisting of one of the following: hydroxyurea, interferon/pegylated interferon, anagrelide, pipobroman, immunomodulatory drugs, or observation. Therapy could be changed in case of lack of response or BAT-related toxicity requiring drug discontinuation, the researchers noted.

At week 32 of the trial, 77 percent of patients in the ruxolitinib arm met at least one component of the primary endpoint:

  • 60 percent had achieved hematocrit control without phlebotomy
  • 38 percent saw a ≥35 percent reduction in spleen size

In the BAT group, on the other hand, only 21 percent and 1 percent of patients achieved these endpoints, respectively.

Furthermore, complete hematologic remission (defined as maintaining hematocrit control without phlebotomy, a platelet count >400 x 109/L, and a white blood cell count >10 x 109/L) was seen by 23.6 percent (p=0.0034) of ruxolitinib patients – compared with 8.9 percent of BAT patients. Out to week 48, 88.5 percent of ruxolitinib patients had maintained this remission, and 91 percent had maintained hematologic response.

“Ruxolitinib is a JAK1 and JAK2 inhibitor that functions as an inhibitor of the tyrosine kinase site of the activated JAK1/2, meaning it does not hamper function of the protein while at rest and is not specific for the mutated JAK2V617F protein. Rather, it functions against both mutated and wild-type protein,” Dr. Vannucchi explained to ASH Clinical News.

Polycythemia vera is a myeloproliferative neoplasm characterized by erythrocytosis. Its symptoms include pruritus, along with severe burning pain in the hands or feet accompanied by skin discoloration. It can cause cardiovascular complications resulting from thrombosis or hemorrhage, and treatment options are limited. Hydroxyurea is the current first choice for cytoreduction; however, many patients become resistant or intolerant to this therapy, according to the researchers.

“Because JAK signaling is essential for erythropoiesis and platelet production, anemia and thrombocytopenia are the most common toxicities of the drug,” Dr. Vannucchi noted, but overall ruxolitinib was well-tolerated, with 1.8 percent and 5.5 percent of patients experienced grade 3 or 4 anemia and thrombocytopenia, respectively. “Thrombocytopenia is also the dose-limiting toxicity of ruxolitinib,” Dr. Vannucchi added.

Dr. Verstovsek observed that, “in the RESPONSE trial, most of the observed cytopenias were resolved with dose adjustments, and most of these adjustments were only required in the first eight weeks. Most patients maintained their dose for the remainder of the study, with a median dose of approximately around 25 mg per day, which was consistent with the twice-daily 10 mg starting dose.”

The exposure-adjusted rates of serious adverse events per 100 patient-years were comparable in both arms (15.3 ruxolitinib and 13.7 BAT), Dr. Verstovsek and colleagues pointed out, but fewer patients in ruxolitinib experienced a thromboembolic event. “The rate in the ruxolitinib arm is also lower than what would be expected in a high-risk [polycythemia vera] population,” he added.


  • Verstovsek S, Kiladjian J-J, Griesshammer M, et al. Results of a prospective, randomized, open-label phase 3 study of ruxolitinib (RUX) in polycythemia vera (PV) patients resistant to or intolerant of hydroxyurea (HU): the RESPONSE trial. Abstract presented at: 2014 ASCO Annual Meeting; June 3, 2014; Chicago, IL.
  • Vannucchi M. Ruxolitinib proves superior to best available therapy in a prospective, randomized, phase 3 study (RESPONSE) in patients with polycythemia vera resistant to or intolerant of hydroxyurea. Abstract presented at: 19th Congress of the European Hematology Association; June 14, 2014; Milan, Italy.