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

Open access
Verstovsek, Srdan, Kantarjian, Hagop, Mesa, Ruben A., Pardanani, Animesh D., Cortes-Franco, Jorge, Thomas, Deborah A., Estrov, Zeev, Fridman, Jordan S., Bradley, Edward C., Erickson-Viitanen, Susan, Vaddi, Kris, Levy, Richard, Tefferi, Ayalew·2010·New England Journal of Medicine
DOI 10.1056/nejmoa1002028
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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−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. (Funded by Incyte; ClinicalTrials.gov number, NCT00509899.)

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Authors
Verstovsek, S., Kantarjian, H., Mesa, R. A., Pardanani, A. D., Cortes-Franco, J., Thomas, D. A., Estrov, Z., Fridman, J. S., Bradley, E. C., Erickson-Viitanen, S., Vaddi, K., Levy, R., & Tefferi, A.
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2010-09-16
Volume
363
Issue
12
Pages
1117-1127
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa1002028
OpenAlex
W2123633897
Cited by
1,164
References
0
FWCI
53.13
Type
journal article
Language
en
Open access
bronze

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