Association of ITPA Genotype with Event-Free Survival and Relapse Rates in Children with Acute Lymphoblastic Leukemia Undergoing Maintenance Therapy

Abstract

Although the treatment of acute lymphoblastic leukemia (ALL) has improved significantly over recent decades, failure due to treatment-related toxicities and relapse of the disease still occur in about 20% of patients. This retrospective study included 308 pediatric ALL patients undergoing maintenance therapy and investigated the effects of genetic variants of enzymes involved in the 6-mercaptopurine (6-MP) metabolism and folate pathway on survival and relapse rates. The presence of at least one of the non-functional ITPA alleles (94C>A and/or IVS2+21A>C variant) was associated with longer event-free survival compared to patients with the wild-type ITPA genotype (p = 0.033). Furthermore, patients carrying at least one non-functional ITPA allele were shown to be at a lower risk of suffering early (p = 0.003) and/or bone marrow relapse (p = 0.017). In conclusion, the ITPA genotype may serve as a genetic marker for the improvement of risk stratification and therapy individualization for patients with ALL.

A Simple Method for TPMT and ITPA Genotyping Using Multiplex HRMA for Patients Treated with Thiopurine Drugs

“…Finally, in the last five years several independent studies on the large groups of ALL patients, the influence on 6MP metabolism and the toxic effect of multiple loci in the TPMT gene and the variation c.94C>A in the ITPA gene has been confirmed [ 9 , 22 ]. Moreover, in research by Smid et al [ 10 ], performed on a group of 408 ALL pediatric patients undergoing maintenance therapy with 6MP, the association between one non-functional ITPA allele and the lower risk of suffering early ( p = 0.003) and/or bone marrow relapse ( p = 0.017) was observed [ 10 ]. The authors concluded that the ITPA genotype can be used as a genetic marker for the improvement of survival rate and therapy individualization for patients with ALL [ 10 ].…”

“…Moreover, in research by Smid et al [ 10 ], performed on a group of 408 ALL pediatric patients undergoing maintenance therapy with 6MP, the association between one non-functional ITPA allele and the lower risk of suffering early ( p = 0.003) and/or bone marrow relapse ( p = 0.017) was observed [ 10 ]. The authors concluded that the ITPA genotype can be used as a genetic marker for the improvement of survival rate and therapy individualization for patients with ALL [ 10 ].…”

“…This allele is more common in Asian populations, with a frequency of 14–19 % [ 8 ]. Furthermore, it was observed that the ITPA c.94C/A genotype makes a contribution to the concentration of 6-methylmercaptopurine (6MMP) in red blood cells and the occurrence of hepatotoxicity [ 9 ] as well as the survival rate in pediatric patients with acute lymphoblastic leukemia (ALL) [ 9 , 10 ].…”

Tests that now deserve to be more widely adopted in IBD clinical practice

“…75 Furthermore, it was observed that the ITPA c.94C/A genotype makes a contribution to the concentration of 6-methylmercaptopurine in red blood cells and the occurrence of hepatotoxicity and acute lymphoblastic leukaemia in paediatric patients. 76 Predicting response to treatment with anti-TNF antibodies: TREM1, OSM, gene expression profiling of CD8+ T lymphocytes. Arijs et al demonstrated that various genes involved in the inflammatory cascade account for resistance to anti-TNFa therapy and predicted the response to infliximab therapy with 89% accuracy.…”

“…66,99 However, additional large international consortia are needed to facilitate the collection of rigorous cohorts of patients who develop (rare) adverse events and future studies should focus on the cost-effectiveness of these tests in the different ethnic populations. 75 ; Smid et al 76 ○ TREM1 ○ OSM ○ CD8+T gene profile…”