A phase II trial of sequential ribonucleotide reductase inhibition in aggressive myeloproliferative neoplasms
Joshua F. Zeidner,
Judith E. Karp,
Amanda L. Blackford,
B. Douglas Smith,
Ivana Gojo,
Steven D. Gore,
Mark J. Levis,
Hetty E. Carraway,
Jacqueline M. Greer,
S. Percy Ivy,
Keith W. Pratz,
Michael A. McDevitt
Affiliations
Joshua F. Zeidner
Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD
Judith E. Karp
Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD
Amanda L. Blackford
Department of Oncology Biostatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD
B. Douglas Smith
Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD
Ivana Gojo
Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD
Steven D. Gore
Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD
Mark J. Levis
Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD
Hetty E. Carraway
Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD
Jacqueline M. Greer
Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD
S. Percy Ivy
National Cancer Institute, Bethesda, MD
Keith W. Pratz
Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD
Michael A. McDevitt
Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD;Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
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/m2/day) followed by fludarabine (30 mg/m2/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).
