Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis

Fabio P.S. Santos, Hagop M. Kantarjian, Nitin Jain, Taghi Manshouri, Deborah A. Thomas, Guillermo Garcia-Manero, Debra Kennedy, Zeev Estrov, Jorge Cortes, Srdan Verstovsek

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179 Scopus citations

Abstract

Few treatment options exist for patients with myelofibrosis (MF), and their survival is significantly shortened. Activating mutation of the JAK2 tyrosine kinase (JAK2V617F) is found in approximately 50% of MF patients. CEP-701 is a tyrosine kinase inhibitor that inhibits JAK2 in in vitro and in vivo experiments. We conducted a phase 2 clinical study of CEP-701 in 22 JAK2V617F-positive MF patients (80 mg orally twice daily), and 6 (27%) responded by International Working Group criteria (clinical improvement in all cases): reduction in spleen size only (n = 3), transfusion independency (n = 2), and reduction in spleen size with improvement in cytopenias (n = 1). Median time to response was 3 months, and duration of response was more than or equal to 14 months. No improvement was seen in bone marrow fibrosis or JAK2 V617F allele burden. Phosphorylated STAT3 levels decreased from baseline in responders while on therapy. Eight patients (36%) experienced grade 3 or 4 toxicity, and 6 (27%) required dose reduction. Main side effects were myelosuppression (grade 3 or 4 anemia, 14%; and thrombocytopenia, 23%) and gastrointestinal disturbances (diarrhea, any grade, 72%; grade 3 or 4, 9%; nausea, grade 1 or 2 only, 50%; vomiting, grade 1 or 2 only, 27%). In conclusion, CEP-701 resulted in modest efficacy and mild but frequent gastrointestinal toxicity in MF patients. The study was registered at http://clinicaltrials.gov as NCT00494585.

Original languageEnglish (US)
Pages (from-to)1131-1136
Number of pages6
JournalBlood
Volume115
Issue number6
DOIs
StatePublished - Feb 11 2010
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Santos, F. P. S., Kantarjian, H. M., Jain, N., Manshouri, T., Thomas, D. A., Garcia-Manero, G., Kennedy, D., Estrov, Z., Cortes, J., & Verstovsek, S. (2010). Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. Blood, 115(6), 1131-1136. https://doi.org/10.1182/blood-2009-10-246363