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

doi:10.1016/j.leukres.2007.05.003

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

School of Medicine

Research output: Contribution to journal › Article › peer-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 language	English (US)
Pages (from-to)	71-77
Number of pages	7
Journal	Leukemia Research
Volume	32
Issue number	1
DOIs	https://doi.org/10.1016/j.leukres.2007.05.003
State	Published - Jan 2008

Keywords

Fludarabine
Myeloproliferative disorders
Rbonucleotide reductase
Refractory acute leukemia
Triapine

ASJC Scopus subject areas

Hematology
Oncology
Cancer Research

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Karp, J. E., Giles, F. J., Gojo, I., Morris, L., Greer, J., Johnson, B., Thein, M., Sznol, M., & Low, J. (2008). 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. Leukemia Research, 32(1), 71-77. https://doi.org/10.1016/j.leukres.2007.05.003

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. / Karp, Judith E.; Giles, Francis J.; Gojo, Ivana et al.
In: Leukemia Research, Vol. 32, No. 1, 01.2008, p. 71-77.

Research output: Contribution to journal › Article › peer-review

Karp, JE, Giles, FJ, Gojo, I, Morris, L, Greer, J, Johnson, B, Thein, M, Sznol, M & Low, J 2008, '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', Leukemia Research, vol. 32, no. 1, pp. 71-77. https://doi.org/10.1016/j.leukres.2007.05.003

Karp JE, Giles FJ, Gojo I, Morris L, Greer J, Johnson B et al. 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. Leukemia Research. 2008 Jan;32(1):71-77. doi: 10.1016/j.leukres.2007.05.003

Karp, Judith E. ; Giles, Francis J. ; Gojo, Ivana et al. / 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. In: Leukemia Research. 2008 ; Vol. 32, No. 1. pp. 71-77.

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abstract = "Triapine{\textregistered} 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.",

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