Safety and Efficacy of INCB018424, a JAK1 and JAK2 Inhibitor, in Myelofibrosis

By S. Verstovsek, H. Kantarjian, R. Mesa, A. Pardanani, J. Cortes-Franco, D. Thomas, Z. Estrov, J. Fridman, E. Bradley, S. Erickson-Viitanen and 3 more. New England Journal of Medicine, 2010

1,143 citations recorded by the source corpus.

Background Myelofibrosis is a Philadelphia chromosome–negative myeloproliferative neoplasm associated with cytopenias, splenomegaly, poor quality of life, and shortened survival. About half of patients with myelofibrosis carry a gain-of-function mutation in the Janus kinase 2 gene (JAK2 V617F) that contributes to the pathophysiology of the disease. INCB018424 is a potent and selective Janus kinase 1 (JAK1) and JAK2 inhibitor. Methods We conducted a phase 1–2 trial of INCB018424 in patients with JAK2 V617F–positive or JAK2 V617F–negative primary myelofibrosis, post–essential thrombocythemia myelofibrosis, or post–polycythemia vera myelofibrosis. Results A total of 153 patients received INCB018424 for a median duration of more than 14.7 months. The initial dose-escalation phase established 25 mg twice daily or 100 mg once daily as maximum tolerated doses, on the basis of reversible thrombocytopenia. A dose-dependent suppression of phosphorylated signal transducer and activator of transcription 3 (STAT3), a marker of JAK signaling, was demonstrated in patients with wild-type JAK2 and in patients with the JAK2 V617F mutation. We studied additional doses and established that a 15-mg twice-daily starting dose, followed by individualized dose titration, was the most effective and safest dosing regimen. At this dose, 17 of 33 patients (52%) had a rapid objective response (≥50% reduction of splenomegaly) lasting for 12 months or more, and this therapy was associated with grade 3 or grade 4 adverse events (mainly myelosuppression) in less than 10% of patients. Patients with debilitating symptoms, including weight loss, fatigue, night sweats, and pruritus, had rapid improvement. Clinical benefits were associated with a marked diminution of levels of circulating inflammatory cytokines that are commonly elevated in myelofibrosis. Conclusions INCB018424 was associated with marked and durable clinical benefits in patients with myelofibrosis for whom no approved therapies existed.

Subfields: Genetics, Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/34c2219878a2fa9ce97a143faf7a759dbfb36d85

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In Genetics

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Citations in the corpus

• Modulation of Innate and Adaptive Immune Responses by Tofacitinib (CP-690,550) (2011, background): “Other JAK inhibitors being studied in the setting of autoimmune disease include the JAK3 inhibitors VX-509 and WYE-151650, the JAK1/ JAK2 inhibitors INCB028050 and INCB018424, and the JAK3/ Spleen tyrosine kinase inhibitor R348 (12, 13, 17, 24, 25) (ClinicalTrials.”
• JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age (2015, background): “Roxolitinib can have side effects, including anemia and thrombocytopenia (33, 63), in humans who have myelofibrosis.”
• Cellular Senescence: A Translational Perspective (2017, background): “syndrome, without affecting their underlying hematological condition as manifested by clonal myeloproliferation assays (Verstovsek et al., 2010).”