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

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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-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

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Janus Kinase 1
Primary Myelofibrosis
Safety
Splenomegaly
Janus Kinase 2
Essential Thrombocythemia
INCB018424
STAT3 Transcription Factor
Philadelphia Chromosome
Polycythemia Vera
Mutation
Maximum Tolerated Dose
Sweat
Pruritus
Thrombocytopenia
Fatigue
Weight Loss

ASJC Scopus subject areas

  • Medicine(all)

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

In: New England Journal of Medicine, Vol. 363, No. 12, 16.09.2010, p. 1117-1127.

Research output: Contribution to journalArticle

Verstovsek, S, Kantarjian, H, Mesa, RA, Pardanani, AD, Cortes-Franco, J, Thomas, DA, Estrov, Z, Fridman, JS, Bradley, EC, Erickson-Viitanen, S, Vaddi, K, Levy, R & Tefferi, A 2010, 'Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis', New England Journal of Medicine, vol. 363, no. 12, pp. 1117-1127. https://doi.org/10.1056/NEJMoa1002028
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. / Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. In: New England Journal of Medicine. 2010 ; Vol. 363, No. 12. pp. 1117-1127.
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AU - Verstovsek, Srdan

AU - Kantarjian, Hagop

AU - Mesa, Ruben A.

AU - Pardanani, Animesh D

AU - Cortes-Franco, Jorge

AU - Thomas, Deborah A.

AU - Estrov, Zeev

AU - Fridman, Jordan S.

AU - Bradley, Edward C.

AU - Erickson-Viitanen, Susan

AU - Vaddi, Kris

AU - Levy, Richard

AU - Tefferi, Ayalew

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N2 - 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.)

AB - 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.)

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