The U.S. Food and Drug Administration approved ruxolitinib (Jakafi? oral tablets, Incyte Corporation) for the treatment of intermediate and high risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis.
Myelofibrosis is a progressive, potentially life-threatening blood cancer with limited treatment options. Patients with myelofibrosis suffer a high disease burden characterized by bone marrow failure, enlarged spleen (splenomegaly) and debilitating symptoms including fatigue, severe itching (pruritus), night sweats, bone pain, and early satiety (a feeling of fullness), leading to impaired quality of life. The enlarged spleen and debilitating symptoms of myelofibrosis are linked to dysregulated signaling in the Janus kinase (JAK) pathway.[3,4]
Results of two randomized controlled trials in patients with intermediate or high risk myelofibrosis comparing ruxolitinib to placebo (Study 1) or to best available therapy (Study 2) were the basis of approval.
Study 1 was a double-blind, randomized, placebo-controlled study allocating 309 patients (1:1) to either ruxolitinib (15-20 mg orally twice daily) or placebo. Fifty percent of patients had primary myelofibrosis, 31% post-polycythemia vera myelofibrosis and 18% post-essential thrombocythemia myelofibrosis. Study 2 was an open-label trial allocating 219 patients (2:1) to either ruxolitinib (15-20 mg orally twice daily) or best available therapy. Fifty-three percent of patients had primary myelofibrosis, 31% post-polycythemia vera myelofibrosis, and 16% post-essential thrombocythemia myelofibrosis. The ruxolitinib starting dose in both trials was based on the entry platelet counts.
Reduction in spleen volume
Ruxolitinib treatment in both trials continued as long as the patients continued to benefit or until unacceptable toxicity. The primary endpoint was a comparison of the proportion of patients in the two arms who achieved a ?35% reduction in spleen volume (by CAT scan or MRI) after 24 weeks (Study 1) or after 48 weeks of treatment (Study 2).
Both randomized trials achieved their pre-specified primary endpoints. In Study 1, 42% versus 1% of patients on the ruxolitinib and placebo arms, respectively, experienced a ? 35% reduction of spleen volume at 24 weeks (p<0.0001, Chi-square and Fisher?s exact test). In Study 2, 29% versus 0% of patients on the ruxolitinib and best available therapy arms, respectively, experienced a ? 35% reduction of spleen volume at 48 weeks (p<0.0001, Cochran-Mantel-Haenszel test).
Reduction of a total symptom score
The key secondary endpoint for Study 1 was to determine the difference between the proportion of patients on ruxolitinib versus placebo who experienced ?50% reduction of a total symptom score. This symptom score evaluated abdominal discomfort, pain under left ribs, night sweats, itching, bone/muscle pain and early satiety at 24 weeks compared to baseline. The percentage of patients who achieved a ?50% reduction of the total symptom score at 24 weeks was 46% versus 5% on the ruxolitinib and placebo arms, respectively (p<0.0001, Chi-square test).
The key secondary endpoint on Study 2 was to determine the difference between the two arms in the proportion of patients who achieved a ?35% reduction in spleen volume (by CAT scan or MRI) at 24 weeks of treatment. A ?35% reduction in spleen volume occurred in 32% of the patients on the ruxolotinib arm and 0% on the best available therapy arm (p <0.0001, Chochran-Mantel-Haenszel test). At the time of approval, 75% of the patients on Study 1 and 67% on Study 2 who achieved a ?35% reduction in spleen volume maintained this reduction in spleen volume.
Adverse drug reactions
The most common adverse drug reactions observed in ?1% of the patients treated with ruxolitinib included thrombocytopenia, anemia, bruising, dizziness and headache. Adverse drug reactions (grade 3 or greater) increased on the ruxolitinib arm compared to the placebo arm in Study 1 were thrombocytopenia (13% versus 1%) and anemia (45% versus 19%). Similar results were observed in Study 2.
The recommended starting dose of ruxolitinib is 20 mg orally twice daily for patients with a platelet count >200 X 109/L and 15 mg orally twice daily for patients with a platelet count between 100 and 200 X 109/L.
?Today?s FDA approval of Jakafi has the potential to transform the way we treat myelofibrosis,? said Srdan Verstovsek, M.D., Ph.D., Associate Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center and the principal investigator of the COMFORT-I pivotal trial. ?In this Phase III clinical trial, we observed significant reductions in spleen size and significant improvements in symptoms. Importantly, these benefits were achieved early on, most within a month, and tended to be durable during treatment. In contrast, most of the patients who received placebo saw their spleens increase and their symptoms worsen.?
 Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113:2895-2901.
 Mesa RA, Niblack J, Wadleigh M, et al. The burden of fatigue and quality of life in myeloproliferative disorders (MPDs): an international internet-based survey of 1179 MPD patients. Cancer. 2007;109:68-76.
 Levine RL, Pardanani A, Tefferi A, Gilliland DG. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer. 2007;7:673-683.
Vannucchi AM, Guglielmelli P, Tefferi A. Advances in understanding and management of myeloproliferative neoplasms. CA Cancer J Clin. 2009;59:171-191.