Influence of variants in folate metabolism genes on 6-mercaptopurine induced toxicity during treatment for childhood acute lymphocytic leukemia.

Purpose: To analyze influence of variants in TYMS, MTHFR, SLC19A1 and DHFR genes on 6-mercaptopurine (MP) induced toxicity during maintenance phase of treatment for childhood acute lymphocytic leukemia (ALL).

Methods: One-hundred twenty-seven children with ALL that received maintenance therapy were involved in this study. All patients were treated according to Berlin-Frankfurt-Muenster (BFM) based protocols. Myelotoxicity and hepatotoxicity were evaluated using surrogate markers (median 6-MP dose, number of leukopenic episodes and levels of bilirubin and transaminases on each visit).

Results: Higher number of leukopenic episodes, as a surrogate marker of 6-MP myelotoxicity, was found in carriers of TYMS 3R3R and 3R4R genotypes (p=0.067) as well as in TYMS 3R6bp+ (28bp VNTR, 6bp indel) haplotype carriers (p=0.015). Carriers of DHFR CATAG (-680, -675, -556, -464, -317) haplotype were also found to have higher number of leukopenic episodes (p=0.070). SLC19A1 c.80A allele (p=0.079) and TYMS 2R6bp+ (5'UTR VNTR, 6bp indel) haplotype carriers (p=0.078) had fewer leukopenic episodes. No difference in genotype frequencies between the control group of volunteered blood donors and childhood ALL patients was found.

Conclusions: Variants in TYMS, SLC19A1 and DHFR genes are potential biomarkers of myelotoxicity and could be used for 6-MP therapy individualization in maintenance phase of childhood ALL treatment, alongside with well-established TPMT variants.