title: 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.
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/m(2)/day over 4 h followed by fludarabine daily x 5 (24 patients, fludarabine 15-30 mg/m(2)/dose); (B) Triapine 200 mg/m(2) over 24h followed by 5 days of fludarabine 30 mg/m(2)/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/m(2) followed by fludarabine 30 mg/m2 daily x 5 is active in refractory myeloid malignancies and warrants continuing study for patients with aggressive MPD.
authors.affiliation: Leukemia Program, Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231-1000, USA. jkarp2@jhmi.edu
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
authors.forename: Ivana
authors.initials: I
authors.lastname: Gojo
authors.forename: Lawrence
authors.initials: L
authors.lastname: Morris
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Greer
authors.forename: Bonny
authors.initials: B
authors.lastname: Johnson
authors.forename: Mya
authors.initials: M
authors.lastname: Thein
authors.forename: Mario
authors.initials: M
authors.lastname: Sznol
authors.forename: Jennifer
authors.initials: J
authors.lastname: Low
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D009196:Myeloproliferative Disorders / Q000188:drug therapy; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000178:diet therapy*; D011725:Pyridines / Q000008:administration & dosage*; D012008:Recurrence; D013882:Thiosemicarbazones / Q000008:administration & dosage*; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D011725:Pyridines; D013882:Thiosemicarbazones; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone; D014740:Vidarabine; C024352:fludarabine