Dose reduction of coadministered 6-mercaptopurine decreases myelotoxicity following high-dose methotrexate in childhood leukemia.

High-dose methotrexate (HDM) given concurrently with oral 6-mercaptopurine (6 MP) may be followed by myelotoxicity, which may necessitate treatment interruption and thus interfere with the efficacy of the treatment of childhood acute lymphoblastic leukemia (ALL). Through inhibition of purine de novo synthesis and enhancement of the bioavailability, HDM may increase the incorporation into DNA of 6-thioguanine nucleotides, the cytotoxic metabolites of 6 MP.A total of 26 children diagnosed 3/1996-4/2001 with ALL received five courses of HDM (5 g/m(2)/24 h with leucovorin rescue) at 8 weeks intervals during their first year of maintenance therapy with oral methotrexate (20 mg/m(2)/week) and 6MP (75 mg/m(2)/day). The dose of oral 6MP was reduced to a median of 51% (75% range: 39-62%, maximum 74%) of the standard dose from 2 weeks prior to until 2 weeks after HDM, because the previous HDM had led to a thrombocyte nadir < or =60 x 10(9)/l and/or a neutrophil nadir < or =0.7 x 10(9)/l. The 6MP dose reductions raised the median thrombocyte nadir following HDM from 46 x 10(9)/l (range: 6-214) to 133 x 10(9)/l (range: 21-305; P<0.001) and the median neutrophil nadir from 0.5 x 10(9)/l (range: 0.0-1.4) to 0.9 x 10(9)/l (range: 0.2-3.2; P<0.001). The effect of 6MP dose reductions was not significantly related to risk group, gender, age, or thiopurine methyltransferase genotype. With 6MP dose reductions, the median duration of treatment interruption following HDM was reduced from 8 to 0 days (P < 0.001). The reduction of 6MP dosage during HDM can significantly reduce the risk of severe myelotoxicity and prevent treatment interruptions.