Effect of genetic alterations of cytarabine-metabolizing enzymes in childhood acute lymphoblastic leukemia

ABSTRACT

Single nucleotide polymorphisms [SNPs] of deoxyctidine kinase [dCK] and cytidine deaminase [CDA] are known to alter their enzymatic activities, which affect the metabolism of cytarabine. Currently, treatment of childhood acute lymphoblastic leukemia [ALL] includes cytarabine, especially in high-risk patients. Therefore we hypothesized that a genetic variation of dCK and CDA genes may influence the risk of cytarabine-related toxicities and early response to treatment. We included children diagnosed with ALL and lymphoblastic lymphoma [LL] stage III and IV. The patients received a modified ST Jude Total Therapy Study XV protocol. Cytarabine was used during induction remission [low-dose cytarabine] and reinduction II [high-dose cytarabine] phases. Genotyping of dCK -360 > G and -201 > T and CDA 79A > C and 208G > A was performed. Minimal residual disease [MRD] at the end of the induction phase was measured using flow cytomery. Ninety-four children with ALL [n=90] and LL [n=4] were analyzed. The median age at diagnosis was 5.8 years [range, 0.4-15 years]. All four SNPs showed predominant wild type alleles. There was no CDA-208A allele in our population. Children with dCK-360G allele were at risk of mycositis after receiving low-dose cytarabine [OR=3.7; 95% CI, 1.2-11.3]. Neither dCK nor CDA polymorphisms affected the MRD status at the end of induction phase. The dCK-360G allele was found to found to increase the risk of mucositis after expose to low-dose cytarabine in childhood ALL therapy