A phase II study of continuous infusion of trimetrexate in patients with refractory acute leukemia.
Trimetrexate, a second-generation folate antagonist, is a potent inhibitor of dihydrofolate reductase with a broader spectrum of activity and different mechanism of entry and intracellular accumulation than methotrexate. Six patients with refractory or relapsed acute leukemia were treated with a 5-day continuous infusion of trimetrexate of 8 mg/m2/day after an initial loading dose of 4 mg/m2 to achieve a target plasma concentration of 0.2-0.5 microM. In 4 patients with peripheral blasts at study entry, transient decrease or disappearance of blasts was observed, although no decrease of bone marrow blasts occurred. Mucositis was dose-limiting and severe in 4 patients. Neutrophil and platelet nadirs occurred on day 5-12 postinfusion. Because of dose-limiting mucositis, this dose schedule of trimetrexate is not recommended for further studies in refractory acute leukemia. However, other dose schedules (24- to 72-hr infusions) and its use as a modulating agent with thiopurines or leucovorin in patients that are resistant to methotrexate should be explored.
Program of Molecular Pharmacology and Therapeutics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
A
A
Kheradpour
E
E
Berman
E
E
Göker
J T
JT
Lin
W P
WP
Tong
J R
JR
Bertino
D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D016597:Trimetrexate / Q000097:blood / Q000627:therapeutic use*
D016597:Trimetrexate