Safety and Efficacy of INCB018424, a JAK1 and JAK2 Inhibitor, in Myelofibrosis
| العنوان: | Safety and Efficacy of INCB018424, a JAK1 and JAK2 Inhibitor, in Myelofibrosis |
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| المؤلفون: | Ruben A. Mesa, Zeev Estrov, Srdan Verstovsek, Jordan S. Fridman, Edward C Bradley, Richard S. Levy, Jorge Cortes-Franco, Kris Vaddi, Animesh Pardanani, Ayalew Tefferi, Hagop M. Kantarjian, Susan Erickson-Viitanen, Deborah A. Thomas |
| المصدر: | New England Journal of Medicine. 363:1117-1127 |
| بيانات النشر: | Massachusetts Medical Society, 2010. |
| سنة النشر: | 2010 |
| مصطلحات موضوعية: | Adult, Male, STAT3 Transcription Factor, medicine.medical_specialty, Ruxolitinib, Gastroenterology, chemistry.chemical_compound, hemic and lymphatic diseases, Internal medicine, Nitriles, medicine, Humans, Myelofibrosis, Myeloproliferative neoplasm, Aged, Aged, 80 and over, Janus kinase 2, Dose-Response Relationship, Drug, biology, Janus kinase 1, business.industry, Anemia, Janus Kinase 1, General Medicine, Janus Kinase 2, Middle Aged, TG101348, medicine.disease, Pathophysiology, Pyrimidines, Pacritinib, chemistry, Primary Myelofibrosis, Mutation, biology.protein, Cancer research, Cytokines, Pyrazoles, Female, business, Biomarkers, Spleen, Hepatomegaly, medicine.drug |
| الوصف: | 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.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.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.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.) |
| تدمد: | 1533-4406 0028-4793 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b553579ecb4fa7a20ab1727e9e6217e3Test https://doi.org/10.1056/nejmoa1002028Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b553579ecb4fa7a20ab1727e9e6217e3 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15334406 00284793 |
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