Influence of methylene tetrahydrofolate reductase polymorphisms and coadministration of antimetabolites on toxicity after high dose methotrexate

Background and objective: Through interruption of maintenance treatment with 6-mercaptopurine (6MP), toxicity after high-dose methotrexate (HDMTX) may compromise the efficiency of the treatment of children with acute lymphocytic leukaemia (ALL). We investigated the influence of polymorphisms in the methylene tetrahydrofolate reductase (MTHFR) gene and coadministration of antimetabolites on post-HDMTX toxicity. Methods: Toxicity was retrospectively analysed after 656 HDMTX courses administered to 88 paediatric ALL patients at a single treatment centre. Results: High-dose methotrexate with high-intensity co-treatment (6MP 75 mg/m(2)/d + MTX 20 mg/m(2)/wk) was found associated with increased odds of haematological toxicity (OR's: 3.47-7.88; P's: < 0.001), hepatic toxicity (OR = 6.91; P < 0.001), hospitalization with fever (OR = 2.2; P = 0.004) and interruption maintenance treatment (OR = 15.9; P < 0.001) compared to HDMTX with low-intensity co-treatment (6MP 25 mg/m(2)/d). Addition of cytarabine to the low-intensity co-treatment increased the odds of neutropenia (OR = 3.51; P = 0.002), thrombocytopenia (OR = 6.56; P < 0.001), hepatic toxicity (OR = 3.84; P = 0.012) and interruption of maintenance treatment (OR = 4.25; P = 0.002). Alterations in 6MP dose were associated with significant changes in toxicity. Dose reduction reduced the odds of haematological toxicity (OR's: 0.22-0.34; P's: < 0.001-0.020), while dose increase increased the odds of haematological toxicity (OR's: 2.72-7.42; P's: 0.006-0.027), fever (OR = 2.65; P = 0.037) and interruption of maintenance treatment (OR = 3.04; P = 0.032). No convincing associations were found between the MTHFR C677T or A1298C polymorphisms and toxicity. Conclusion: Our findings demonstrate that toxicity after HDMTX is influenced by coadministrated antimetabolites, and modifiable by alterations in 6MP dose. Prevention of toxicity related withdrawals through 6MP dose reduction could be a way of increasing total dose intensity.