A Phase I study of the novel ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine®) in combination with the nucleoside analog fludarabine for patients with refractory acute leukemias and aggressive myeloproliferative disorders

Judith E. Karp*, Francis J. Giles, Ivana Gojo, Lawrence Morris, Jacqueline Greer, Bonny Johnson, Mya Thein, Mario Sznol, Jennifer Low

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

83 Scopus citations

Abstract

Triapine® is a potent ribonucleotide reductase (RR) inhibitor that depletes intracellular deoxyribonculeotide pools, especially dATP. We designed a Phase I trial of Triapine followed by the adenosine analog fludarabine in adults with refractory acute leukemias and aggressive myeloproliferative disorders (MPD). Two schedules were examined: (A) Triapine 105 mg/m2/day over 4 h followed by fludarabine daily × 5 (24 patients, fludarabine 15-30 mg/m2/dose); (B) Triapine 200 mg/m2 over 24 h followed by 5 days of fludarabine 30 mg/m2/day (9 patients). Complete and partial responses (CR, PR) occurred in Schedule A (5/24, 21%), with CR occurring at the 2 highest fludarabine doses (2/12, 17%). In contrast, no CR or PR occurred in Schedule B. Four of the 5 responses occurred in patients with underlying MPD (4/14, 29%). Drug-related toxicities included fever and metabolic acidosis. Triapine 105 mg/m2 followed by fludarabine 30 mg/m2 daily × 5 is active in refractory myeloid malignancies and warrants continuing study for patients with aggressive MPD.

Original languageEnglish (US)
Pages (from-to)71-77
Number of pages7
JournalLeukemia Research
Volume32
Issue number1
DOIs
StatePublished - Jan 2008

Keywords

  • Fludarabine
  • Myeloproliferative disorders
  • Rbonucleotide reductase
  • Refractory acute leukemia
  • Triapine

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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