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

Research output: Contribution to journalArticlepeer-review

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
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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