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

Research output: Contribution to a Journal (Peer & Non Peer) › Article › peer-review

102 Citations (Scopus)

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
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
Publication status	Published - Jan 2008
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Fludarabine
Myeloproliferative disorders
Rbonucleotide reductase
Refractory acute leukemia
Triapine

Access to Document

10.1016/j.leukres.2007.05.003

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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

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

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.",

keywords = "Fludarabine, Myeloproliferative disorders, Rbonucleotide reductase, Refractory acute leukemia, Triapine",

author = "Karp, \{Judith E.\} and Giles, \{Francis J.\} and Ivana Gojo and Lawrence Morris and Jacqueline Greer and Bonny Johnson and Mya Thein and Mario Sznol and Jennifer Low",

year = "2008",

month = jan,

doi = "10.1016/j.leukres.2007.05.003",

language = "English",

volume = "32",

pages = "71--77",

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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

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 a Journal (Peer & Non Peer) › Article › peer-review

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 - https://www.scopus.com/pages/publications/36048952046

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 -

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