The treatment of childhood acute lymphoblastic leukemia based on the pharmacokinetics of methotrexate in serum and cerebrospinal fluid
Muchi, H.; Ijima, H.; Karube, T.
Nihon Ketsueki Gakkai Zasshi Journal of Japan Haematological Society 48(6): 1397-1408
1985
ISSN/ISBN: 0001-5806 PMID: 3867213 Document Number: 248520
Three regimens against childhood acute lymphoblastic leukemia were compared, and the concentrations of methotrexate in serum and cerebrospinal fluid were measured in order to determine the optimal dose scheduling of methotrexate. Repeated intravenous infusions of an intermediate dose (150 mg/m2) and intrathecal injection of the drug prevented central nervous system leukemia as well as other extramedullary diseases in standard risk group without cranial irradiation. Toxicity to the central nervous system was minimum. Prophylactic irradiation and intermediate doses (150 mg and 500 mg/m2) methotrexate without leukovorin rescue were given to prevent early relapse in central nervous system and to prolong the complete remission duration in high risk group. Both cranial irradiation and central nervous system disease appear to increase the level of methotrexate in the cerebrospinal fluid by increasing the blood-brain barrier permeability and/or decreasing the clearance of the drug from the central nervous system. When 500 mg/m2 methotrexate was infused, its level in the cerebrospinal fluid was 3.24 .times. 10-7 M, which was equal to the level by infusion of 150 mg/m2 after cranial irradiation. It was concluded that intermediate-dose methotrexate without leukovorin rescue was safe and considerably effective for the prevention of relapses. Infusions of 500 mg/m2 methotrexate without cranial irradiation and 150 mg/m2 methotrexate after cranial irradiation appear to be the optimal dose schedules for the treatment of childhood acute lymphoblastic leukemia.