Phase II trial of oral aminopterin for adults and children with refractory acute leukemia

Peter D. Cole, Richard A. Drachtman, Angela K. Smith, Sarah Cate, Richard A. Larson, Douglas S. Hawkins, John Holcenberg, Kara Kelly, Barton A. Kamen

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20 Scopus citations

Abstract

Purpose: To determine the antileukemic activity of weekly oral aminopterin in patients with refractory acute leukemia; to describe the pharmacodynamic properties of aminopterin; and to contrast the intracellular metabolism of aminopterin and methotrexate by patients' blasts in vitro. Experimental Design: Forty-six patients were enrolled in three strata: children with acute lymphoblastic leukemia (ALL), adults with ALL, and patients with acute myeloid leukemia (AML). Aminopterin was given weekly, in two doses of 2 mg/m 2, 12 hours apart. Limited sampling pharmacokinetic analysis was done during the first week of therapy. Accumulation of [3H]aminopterin and [3H] methotrexate by leukemic blasts was studied in vitro. Results: Six of 22 children with ALL (27%; 95% confidence interval, 8-47%) had clinically significant responses. None of those with AML and only two of 11 adults with ALL had responses meeting protocol definitions, although peripheral blast counts tended to decrease with therapy in all groups. Mucosal toxicity was minimal, even with limited use of leucovorin rescue. Complete bioavailability of aminopterin was confirmed, with a mean area under the curve of 0.52 ± 0.03 μmol hour/L after oral dosing. No relationship between aminopterin pharmacokinetics and response was seen. In vitro, aminopterin showed more consistent metabolism by leukemic blasts to polyglutamates than methotrexate. Lineage-specific differences in the pattern of intracellular antifolylpolyglutamates were observed. Conclusions: Weekly oral aminopterin has significant activity among children with refractory ALL. With greater cellular accumulation and metabolism, more reliable bioavailability than methotrexate, and tolerable toxicity at this dose and schedule, aminopterin deserves further study as a potent alternative to methotrexate.

Original languageEnglish (US)
Pages (from-to)8089-8096
Number of pages8
JournalClinical Cancer Research
Volume11
Issue number22
DOIs
StatePublished - Nov 15 2005

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Cole, P. D., Drachtman, R. A., Smith, A. K., Cate, S., Larson, R. A., Hawkins, D. S., Holcenberg, J., Kelly, K., & Kamen, B. A. (2005). Phase II trial of oral aminopterin for adults and children with refractory acute leukemia. Clinical Cancer Research, 11(22), 8089-8096. https://doi.org/10.1158/1078-0432.CCR-05-0355