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).

Figures

Figure 1.

Kaplan-Meier overall survival curves for (A) the entire study population, (B) patients who achieved complete remission (CR) versus those who did not, and (C) responders versus non-responders. Comparisons between response groups (B–C) are based on a landmark analysis, where overall survival was measured from day 42 of treatment until death or last known follow-up, and response group was based on patients’ status on day 42. Patients who died before day 42 (n=5) were excluded from these analyses. P values are from Cox proportional hazards models that adjusted for patients’ age and gender. CR: complete remission; PR: partial remission; HI: hematologic improvement; SD: stable disease; NR: no response.