title: A phase II trial of sequential ribonucleotide reductase inhibition in aggressive myeloproliferative neoplasms.
abstract: Myeloproliferative neoplasms are a varied group of disorders that can have prolonged chronic phases, but eventually accelerate and can transform into a secondary acute myeloid leukemia that is ultimately fatal. Triapine is a novel inhibitor of the M2 subunit of ribonucleotide reductase. Sequential inhibition of ribonucleotide reductase with triapine and an M1 ribonucleotide reductase inhibitor (fludarabine) was noted to be safe, and led to a 29% complete plus partial response rate in myeloproliferative neoplasms. This article reports the findings of a phase II trial of triapine (105 mg/m(2)/day) followed by fludarabine (30 mg/m(2)/day) daily for 5 consecutive days in 37 patients with accelerated myeloproliferative neoplasms and secondary acute myeloid leukemia. The overall response rate was 49% (18/37), with a complete remission rate of 24% (9/37). Overall response rates and complete remissions were seen in all disease subsets, including secondary acute myeloid leukemia, in which the overall response rate and complete remission rate were 48% and 33%, respectively. All patients with known JAK2 V617F mutations (6/6) responded. The median overall survival of the entire cohort was 6.9 months, with a median overall survival of both overall responders and complete responders of 10.6 months. These data further demonstrate the promise of sequential inhibition of ribonucleotide reductase in patients with accelerated myeloproliferative neoplasms and secondary acute myeloid leukemia. This study was registered with clinicaltrials.gov (NCT00381550).
authors.affiliation: jzeidner@jhmi.edu / mmcdevi1@jhmi.edu.
authors.forename: Joshua F
authors.initials: JF
authors.lastname: Zeidner
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Blackford
authors.forename: B Douglas
authors.initials: BD
authors.lastname: Smith
authors.forename: Ivana
authors.initials: I
authors.lastname: Gojo
authors.forename: Steven D
authors.initials: SD
authors.lastname: Gore
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Levis
authors.forename: Hetty E
authors.initials: HE
authors.lastname: Carraway
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Greer
authors.forename: S Percy
authors.initials: SP
authors.lastname: Ivy
authors.forename: Keith W
authors.initials: KW
authors.lastname: Pratz
authors.forename: Michael A
authors.initials: MA
authors.lastname: McDevitt
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009196:Myeloproliferative Disorders / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D011725:Pyridines / Q000008:administration & dosage / Q000627:therapeutic use*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D013882:Thiosemicarbazones / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011725:Pyridines; D013882:Thiosemicarbazones; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone; D012264:Ribonucleotide Reductases; D014740:Vidarabine; C024352:fludarabine