Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis

Animesh D Pardanani, R. R. Laborde, T. L. Lasho, C. Finke, Kebede Begna, A. Al-Kali, William Hogan, Mark R Litzow, A. Leontovich, M. Kowalski, Ayalew Tefferi

Research output: Contribution to journalArticle

151 Citations (Scopus)

Abstract

JAK-STAT is a rational drug target in myelofibrosis (MF) given its association with JAK2/MPL mutations and aberrant inflammatory cytokine expression. We conducted a Phase 1/2 trial of CYT387, a potent JAK1/2 inhibitor, in patients with high- or intermediate-risk primary or post-polycythemia vera/essential thrombocythemia MF. Pre-planned safety and efficacy analysis has been completed for the initial 60 patients. In the dose-escalation phase (n=21), the maximum-tolerated dose was 300 mg/day based on reversible grade 3 headache and asymptomatic hyperlipasemia. Twenty-one and 18 additional patients were accrued at two biologically effective doses, 300 mg/day and 150 mg/day, respectively. Anemia and spleen responses, per International Working Group criteria, were 59% and 48%, respectively. Among 33 patients who were red cell-transfused in the month prior to study entry, 70% achieved a minimum 12-week period without transfusions (range 4.7->18.3 months). Most patients experienced constitutional symptoms improvement. Grade 3/4 adverse reactions included thrombocytopenia (32%), hyperlipasemia (5%), elevated liver transaminases (3%) and headache (3%). New-onset treatment-related peripheral neuropathy was observed in 22% of patients (sensory symptoms, grade 1). CYT387 is well tolerated and produces significant anemia, spleen and symptom responses in MF patients. Plasma cytokine and gene expression studies suggested a broad anticytokine drug effect.

Original languageEnglish (US)
Pages (from-to)1322-1327
Number of pages6
JournalLeukemia
Volume27
Issue number6
DOIs
StatePublished - Jun 2013

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Primary Myelofibrosis
Safety
Headache
Anemia
Spleen
Cytokines
Essential Thrombocythemia
Polycythemia Vera
Maximum Tolerated Dose
Peripheral Nervous System Diseases
Transaminases
N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide
Thrombocytopenia
Pharmaceutical Preparations
Gene Expression
Mutation
Liver

Keywords

  • JAK2V617F
  • myeloproliferative
  • polycythemia
  • thrombocythemia

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. / Pardanani, Animesh D; Laborde, R. R.; Lasho, T. L.; Finke, C.; Begna, Kebede; Al-Kali, A.; Hogan, William; Litzow, Mark R; Leontovich, A.; Kowalski, M.; Tefferi, Ayalew.

In: Leukemia, Vol. 27, No. 6, 06.2013, p. 1322-1327.

Research output: Contribution to journalArticle

Pardanani, AD, Laborde, RR, Lasho, TL, Finke, C, Begna, K, Al-Kali, A, Hogan, W, Litzow, MR, Leontovich, A, Kowalski, M & Tefferi, A 2013, 'Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis', Leukemia, vol. 27, no. 6, pp. 1322-1327. https://doi.org/10.1038/leu.2013.71
Pardanani, Animesh D ; Laborde, R. R. ; Lasho, T. L. ; Finke, C. ; Begna, Kebede ; Al-Kali, A. ; Hogan, William ; Litzow, Mark R ; Leontovich, A. ; Kowalski, M. ; Tefferi, Ayalew. / Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. In: Leukemia. 2013 ; Vol. 27, No. 6. pp. 1322-1327.
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