title: A phase II study of 5-azacitidine for patients with primary and post-essential thrombocythemia/polycythemia vera myelofibrosis.
abstract: Myelofibrosis (MF; primary or post-essential thrombocythemia/polycythemia vera) is incurable clonal myeloproliferative disorder, with no effective treatment. Epigenetic changes play an important role in cancer pathogenesis through transcriptional silencing of critical tumor suppressor genes. We conducted a phase-II study to evaluate the activity of DNA methyltransferase inhibitor, 5-azacitidine, in patients with MF. Thirty-four patients (76% previously treated) received 5-azacitidine at 75 mg/m(2) subcutaneously daily for 7 days, every 4 weeks. Twelve (35%) patients had abnormal cytogenetics and 19 (70%) of 27 evaluable patients had JAK2(V617F) mutation. Responses occurred in 8 (24%) patients after a median of 5 months (range, 3-10). Partial response occurred in 1 (3%) patient (duration 22+ months) and clinical improvement in 7 (21%) patients (median duration 4 months; range, 2-8.5). Myelosuppression was the major adverse effect, with grade 3-4 neutropenia in 10 (29%) patients. Global DNA methylation assessed by the long interspersed nucleotide element (LINE) bisulfite/pyrosequencing assay decreased from 53% pretherapy to 44% on day 14 (P=0.0014) and returned to 50% at the end of the first 28-day cycle (P=0.016). 5-azacitidine is relatively well tolerated and results in induction of global hypomethylation in patients with MF, but results in limited clinical activity.
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA.
authors.forename: A
authors.initials: A
authors.lastname: Quintás-Cardama
authors.forename: W
authors.initials: W
authors.lastname: Tong
authors.forename: H
authors.initials: H
authors.lastname: Kantarjian
authors.forename: D
authors.initials: D
authors.lastname: Thomas
authors.forename: F
authors.initials: F
authors.lastname: Ravandi
authors.forename: S
authors.initials: S
authors.lastname: Kornblau
authors.forename: T
authors.initials: T
authors.lastname: Manshouri
authors.forename: J E
authors.initials: JE
authors.lastname: Cortes
authors.forename: G
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: S
authors.initials: S
authors.lastname: Verstovsek
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001374:Azacitidine / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D019175:DNA Methylation; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D011087:Polycythemia Vera / Q000188:drug therapy*; D055728:Primary Myelofibrosis; D013920:Thrombocythemia, Essential / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D053614:Janus Kinase 2; D001374:Azacitidine