A phase II study of 5-azacitidine for patients with primary and post-essential thrombocythemia/polycythemia vera myelofibrosis.

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.