What is the role of JAK inhibitors in the treatment of polycythemia vera (PV)?

Updated: Aug 20, 2019
  • Author: Srikanth Nagalla, MBBS, MS, FACP; Chief Editor: Koyamangalath Krishnan, MD, FRCP, FACP  more...
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Answer

Ruxolitinib (Jakafi), a Janus-associated kinase (JAK1/JAK2) inhibitor, was approved by the FDA in December 2014 for the treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea. Approval was based on data from the phase III RESPONSE trial. In this trial, patients treated with ruxolitinib demonstrated superior hematocrit control and reductions in spleen volume compared with best available therapy. A greater proportion of patients on the ruxolitinib treatment arm achieved complete hematologic remission (ie, hematocrit control and lowered platelet count and WBC). Hematologic adverse reactions are prevalent with ruxolitinib (incidence > 20%) and include thrombocytopenia and anemia. [30]

Ruxolitinib had initially been approved in the United States in 2011 for patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis, and post–essential thrombocythemia myelofibrosis.

Another JAK inhibitor, fedratinib (Inrebic), was approved in August 2019 for adults with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF). Efficacy of fedratinib was investigated in JAKARTA (NCT01437787), a double-blind, randomized, placebo-controlled trial in 289 patients with intermediate-2 or high-risk MF, post-polycythemia vera MF, or post-essential thrombocythemia MF with splenomegaly. Patients were randomized to receive either fedratinib 500 mg (N=97), 400 mg (n=96), or placebo (n=96) once daily for at least 6 cycles.

The primary efficacy outcome was the proportion of patients achieving a reduction of 35% or greater from baseline in spleen volume at the end of cycle 6 measured by MRI or CT with a follow-up scan 4 weeks later. Of the 96 patients treated with the recommended dose (400 mg) of fedratinib, 35 (37%) achieved a 35% or greater reduction in spleen volume, compared with 1 of 96 patients who received placebo (p< 0.0001). The median duration of spleen response was 18.2 months for the fedratinib 400 mg group. In addition, 40% of patients who received 400 mg experienced a 50% or greater reduction in myelofibrosis-related symptoms, whereas only 9% of patients receiving placebo experienced a decline in these symptoms. [31]


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