Phase 2B trial of aminopterin in multiagent therapy for children with newly diagnosed acute lymphoblastic leukemia.
OBJECTIVE
Aminopterin offers advantages over the related antifolate, methotrexate, including greater potency, complete bioavailability, and more consistent accumulation and metabolism by patients' blasts. This current trial was done to document the toxicity of the aminopterin within a multiagent therapeutic regimen for children with newly diagnosed ALL.


METHODS
Patients at high risk of relapse were non-randomly assigned to therapy including oral aminopterin 4 mg/m(2), in two doses 12 h apart, in place of methotrexate 100 mg/m(2) in four divided doses.


RESULTS
Thirty-two patients, 22 with pre-B ALL and ten with T-lineage ALL, have been treated with aminopterin, with median follow up of 40 months. Hematologic, mucosal and hepatic toxicity has been tolerable and reversible. There have been no toxic deaths among patients in remission. During weekly AMT therapy, higher mean neutrophil counts were observed among patients who were wild type for polymorphisms in methylene tetrahydrofolate reductase and methionine synthase reductase.


CONCLUSIONS
Aminopterin can be safely incorporated in multiagent therapy for patients with ALL, in place of systemic methotrexate, without causing excessive toxicity. These results support a larger trial comparing the efficacy and toxicity of aminopterin and methotrexate in therapy for patients with ALL.
Cole
Peter D
PD
Pediatric Hematology/Oncology, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School/UMDNJ, 195 Little Albany Street, New Brunswick, NJ 08901, USA. pcole@aecom.yu.edu
Drachtman
Richard A
RA
Masterson
Margaret
M
Smith
Angela K
AK
Glod
John
J
Zebala
John A
JA
Lisi
Stacey
S
Drapala
Drew-Anne
DA
Kamen
Barton A
BA
D000293:Adolescent; D000630:Aminopterin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000931:Antidotes / Q000627:therapeutic use; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001847:Bone Diseases / Q000139:chemically induced; D002648:Child; D002675:Child, Preschool; D062787:Drug Overdose; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D005334:Fever / Q000150:complications / Q000209:etiology; D005493:Folic Acid Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005767:Gastrointestinal Diseases / Q000139:chemically induced / Q000150:complications; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use; D020258:Neurotoxicity Syndromes / Q000150:complications; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics; D012008:Recurrence; D016896:Treatment Outcome
D000931:Antidotes; D000964:Antimetabolites, Antineoplastic; D005493:Folic Acid Antagonists; D000630:Aminopterin; D002955:Leucovorin; D008727:Methotrexate