TY - JOUR
T1 - 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
AU - Karp, Judith E.
AU - Giles, Francis J.
AU - Gojo, Ivana
AU - Morris, Lawrence
AU - Greer, Jacqueline
AU - Johnson, Bonny
AU - Thein, Mya
AU - Sznol, Mario
AU - Low, Jennifer
PY - 2008/1
Y1 - 2008/1
N2 - 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.
AB - 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.
KW - Fludarabine
KW - Myeloproliferative disorders
KW - Rbonucleotide reductase
KW - Refractory acute leukemia
KW - Triapine
UR - http://www.scopus.com/inward/record.url?scp=36048952046&partnerID=8YFLogxK
U2 - 10.1016/j.leukres.2007.05.003
DO - 10.1016/j.leukres.2007.05.003
M3 - Article
SN - 0145-2126
VL - 32
SP - 71
EP - 77
JO - Leukemia Research
JF - Leukemia Research
IS - 1
ER -
