Inosine Triphosphate Pyrophosphohydrolase (Itpa) Polymorphic Sequence Variants In Chinese All Children And Possible Association With Mercaptopurine Related Toxicity

Genetic polymorphisms are important factors in effects and toxicity of chemotherapeutics. This study aimed to investigate whether there was a correlation between genotype or haplotype of inosine triphosphate pyrophosphohydrolase (ITPA) and toxicities during maintenance therapy with mercaptopurine (6-MP) in Chinese patients with acute lymphoblastic leukemia (ALL). 95 ALL children who hospitalized between October 2004 and September 2007, were retrospectively analyzed. 6-MP toxicity was documented according to Common Toxicity Criteria, Version 2.0. ITPA sequencing was undertaken. Correlation between genotype/ haplotype and 6-MP toxicity was analyzed. The results indicated that 50 cases (52.6%) had grade III-IV of bone marrow inhibition. These children had long-term disease-free survival (DFS), without hepatic and other organs' dysfunction and secondary tumors. Three variations were observed in ITPA exon 2 (94 C -> A), exon 3 (138 G -> A), and exon 8 (561 G -> A), the 94A carriers (CA and AA) had a lower risk of developing 6-MP toxicity when compared with carriers of the CC genotype (odds ratio [OR] 0.34, 95% confidence interval [CI] 0.12-0.98, P = 0.039). The risk of 6-MP intolerance was decreased in patients with 138 allele and 561 allele polymorphism, but with no significant difference. Patients carrying the haplotype 94A-138A-561A was tolerance compared to those with wild-type haplotype 94C-138G-561G (OR: 0.26, 95% CI 0.07-0.94 P = 0.043). In conclusion, the risk of 6-MP intolerance was decreased in patients with 138 allele and 561 allele polymorphism, but without significant difference. Patients carrying the haplotype 94A-138A-561A was tolerance compared to those with the wild-type haplotype 94C-138G-561G.