Triapine and cytarabine is an active combination in patients with acute leukemia or myelodysplastic syndrome

Yee, Karen; Cortes, Jorge; Ferrajoli, Alessandra; Garcia‐Manero, Guillermo; Verstovšek, Srđan; Wierda, William G.; Thomas, Deborah A.; Faderl, Stefan; King, Ivan; O’Brien, Susan; Jeha, Sima; Andreeff, Michael; Cahill, Ann; Sznol, Mario; Giles, Francis J.

doi:10.1016/j.leukres.2005.12.013

Cited by 49 publications

(37 citation statements)

References 40 publications

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“…Methemoglobinemia has not been reported as a common toxicity in other studies investigating 3-AP in advanced leukemia [7,8,20]. In a prior phase I trial of 3-AP and cytarabine, DLTs included grade 4 sensorimotor peripheral neuropathy, grade 4 mucositis and grade 3 hyperbilirubinemia occurring at the 800 mg/m 2 dose level of cytarabine.…”

Section: Discussionmentioning

confidence: 99%

“…The dose and schedule of both drugs in that trial was different from that utilized in our trial. In that study, 3-AP was administered at a fixed dose of 105 mg/m 2 , given as a 6 h infusion, daily for 5 days, while cytarabine was administered in a dose range of 100 to 800 mg/m 2 , given over 18 h, daily for 5 days [20]. It is possible that this difference in dose and schedule may have contributed to the differences in the spectrum of toxicities observed.…”

Section: Discussionmentioning

confidence: 99%

“…In another recent phase I study of 3-AP in leukemia, only 1 of 25 patients had documented methemoglobinemia [8]. None of these trials [7,8,20] incorporated routine monitoring of met-Hg levels; therefore it is possible that the incidence of this toxicity may have been underestimated.…”

Section: Discussionmentioning

confidence: 99%

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Phase I study of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) in combination with high dose cytarabine in patients with advanced myeloid leukemia

et al. 2008

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SummaryPurpose-This Phase I dose escalation study was based on the hypothesis that the addition of 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) to cytarabine would enhance cytarabine cytotoxicity. The primary objective of the study was to establish the maximum tolerated dose of 3-AP when given in combination with a fixed dose of cytarabine.Experimental design-Twenty-five patients with relapsed or refractory myeloid leukemia were enrolled to three dose levels of 3-AP. Cytarabine was administered as a 2 h infusion at a fixed dose of 1,000 mg/m 2 /day for 5 consecutive days. Escalating doses of 3-AP as a 2 h infusion were administered on days 2 through 5. The 3-AP infusion preceded the start of the cytarabine infusion by 4 h.Results-In general, the toxicities observed with the combination were similar to the expected toxicity profile for cytarabine when utilized as a single agent at this dose and schedule. However, two of three patients developed dose-limiting methemoglobinemia at the highest 3-AP dose studied (100 mg/m 2 ). Transient reversible methemoglobinemia was documented in 11 of 15 patients enrolled at the 75 mg/m 2 dose level. Objective evidence of clinical activity was observed in four patients.Conclusions-The combination of 3-AP and cytarabine given on this schedule is feasible in advanced myeloid leukemia. The recommended Phase II dose is 75 mg/m 2 /day of 3-AP on days 2-5 given prior to cytarabine administered at a dose of 1,000 mg/m 2 /day over 5 consecutive days. Methemoglobinemia is a common toxicity of this combination and requires close monitoring.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Phase I study of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) in combination with high dose cytarabine in patients with advanced myeloid leukemia

et al. 2008

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“…[79][80][81][82][83][84] The success of Fe chelators as potential anti-tumor agents is marked by the entry of Triapine ® into phase I and II clinical trials alone or in combination with a range of chemotherapeutics. 85,86 In fact, recent results with this agent have shown that it can successfully reduce white blood cell counts by 50% in leukemia patients. 87 A structurally different ligand known as Tachpyridine is also currently in pre-clinical development with the National Cancer Institute.…”

Section: Iron As Possible Therapeutic Strategy For Cancer Treatmentmentioning

confidence: 99%

Tuning Cell Cycle Regulation with an Iron Key

Yu¹,

Kovačević²,

Richardson³

2007

Cell Cycle

216

190

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“…These data were used as a springboard for development of a "second generation" Phase I trial of Triapine 105 mg/m 2 followed immediately by escalating doses of an 18-hr ara-C infusion daily × 5 days in patients with refractory or relapsed, ara-C-resistant AML, and high-risk myelodsyplasia (MDS). 24 This sequential combination yielded CRs in 4/31 (13%) patients, with 2 CRs exceeding 1 year.…”

Section: Introductionmentioning

confidence: 88%

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

et al. 2008

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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 105mg/m 2 /day over 4 hours followed by fludarabine daily × 5 (24 patients, fludarabine 15-30 mg/m 2 /dose); B.To whom correspondence should be addressed: Judith E. Karp, MD, Sidney Kimmel Cancer Center at Johns Hopkins, 1650 Orleans Street, CRB Room 289, Baltimore, Maryland 21231-1000, Phone: 410-502-7726, Fax: 410-614-1005.edu. Current affiliation:Yale University School of Medicine, New Haven, CT Current affiliation: Genentech, South San Francisco, CA Contributions: J.E. Karp contributed to concept and design; performed research; collected, interpreted and analyzed data; wrote the paper; provided intellectual content and provided study material/patients. F.J. Giles, I. Gojo, and L.E. Morris performed research; collected, interpreted and analyzed data; provided intellectual content; and provided study material/patients. J. Greer and M. Thein collected and/ or assembled data. M. Sznol contributed to concept and design and provided intellectual content. J. Low contributed to data analysis and provided intellectual content.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access

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Triapine and cytarabine is an active combination in patients with acute leukemia or myelodysplastic syndrome

Cited by 49 publications

References 40 publications

Phase I study of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) in combination with high dose cytarabine in patients with advanced myeloid leukemia

Phase I study of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) in combination with high dose cytarabine in patients with advanced myeloid leukemia

Tuning Cell Cycle Regulation with an Iron Key

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

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