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.
Highlights
Treatment of pediatric acute lymphoblastic leukemia (ALL) has improved drastically over the last forty years, with the long termsurvival rate for children diagnosed with ALL such that approximately 85% survive for 5 years or more after diagnosis [1]
Since folate and methionine pathways are crucial for SAM synthesis, other polymorphisms in enzyme-coding genes (such as 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR), methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), betaine–homocysteine S-methyltransferase (BHMT), and glycine Nmethyltransferase (GNMT)) could influence TPMT activity and affect the safety and efficacy of 6-MP therapy
In the present retrospective study we aimed to investigate the association of selected polymorphisms in genes involved in the folate and methionine pathway (MTHFR 677C.A, methylenetetrahydrofolate reductase (MTHFR) 1298A.C, MTRR 66A.G, MTHFD1 1958G.A, BHMT 742G.A, glycine N-methyltransferase (GNMT) 1298C.T), as well as polymorphisms of PACSIN2 and Inosine triphosphate pyrophosphatase (ITPA) (94C.A and IVS2+21A.C), and long-term outcome and relapse rates in pediatric ALL patients undergoing maintenance therapy with 6-MP
Summary
Treatment of pediatric acute lymphoblastic leukemia (ALL) has improved drastically over the last forty years, with the long termsurvival rate for children diagnosed with ALL such that approximately 85% survive for 5 years or more after diagnosis [1] This great improvement can be attributed both to risk-adjusted treatment based on the identification of several biological and clinical prognostic factors which facilitated the definition of patient subgroups with different relapse risks, and the implementation of rationally designed phases in the treatment backbone of ALL [2]. A recent study in ALL patients conducted by Stocco et al [13] has shown that genetic variation in PACSIN2 influences TPMT activity and is significantly associated with the incidence of 6-MP-related gastrointestinal toxicity [13]
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