Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis

Srdan Verstovsek, Hagop Kantarjian, Ruben A. Mesa, Animesh D. Pardanani, Jorge Cortes-Franco, Deborah A. Thomas, Zeev Estrov, Jordan S. Fridman, Edward C. Bradley, Susan Erickson-Viitanen, Kris Vaddi, Richard Levy, Ayalew Tefferi

Research output: Contribution to journalArticlepeer-review

791 Scopus citations

Abstract

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-posi t i ve 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. (Funded by Incyte; ClinicalTrials.gov number, NCT00509899.)

Original languageEnglish (US)
Pages (from-to)1117-1127
Number of pages11
JournalNew England Journal of Medicine
Volume363
Issue number12
DOIs
StatePublished - Sep 16 2010

ASJC Scopus subject areas

  • Medicine(all)

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