Anthracyclines have contributed significantly to the increased cure rate in pediatric oncology. Cardiac toxicity is an important late effect after anthracycline treatment and is thought to occur by reactive oxygen species mediated cardiac damage. We hypothesized that deactivating variants of superoxide dismutase II (SOD2) [rs4880 (-9Val > Ala)], catalase (CAT) [rs1001179 (-262C > T) and rs10836235 (c.66 + 78C > T)], GSTT1, and GSTM1 may increase the risk of developing cardiac toxicity, in patients exposed to anthracyclines. The hypothesis was tested in a cohort of 76 long-term survivals of acute lymphoblastic leukemia in childhood. Cardiac damage was evaluated as an attributive variable and compared to gene polymorphisms. In our study group, we show statistically significant correlation between CC homozygosity for CAT (rs10836235 (c.66 + 78C > T)) and cardiac damage after anthracycline exposure (p = 0.020). We found no statistically significant correlation between cardiac damage after anthracycline exposure and deactivating variants of SOD2 [rs4880 (-9Val > Ala)], CAT [rs1001179 (-262C > T), GSTT1, and GSTM1.

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The metabolism of a given drug depends, not solely on a particular enzyme, but rather on a complex metabolic network. Thiopurine S-methyltransferase (TPMT) catalyzes the methylation, and thus deactivation, of 6-mercaptopurine, a thiopurine used in the treatment of acute lymphoblastic leukemia. Low TPMT activity has been associated with severe toxicity of 6-mercaptopurine. Determination of mutations in the TPMT gene before starting 6-mercaptopurine therapy constitutes a quick, simple and cost-effective strategy to individualize thiopurine dosing. However, TPMT phenotype-to-genotype correlation is not complete, indicating a need for identification of novel biomarkers. Based on our recent findings and reviewing seemingly unrelated literature reports we present a synthesis of the current understanding of factors that influence TPMT activity and consequently modulate responsiveness to thiopurine treatment. Identification and understanding of these factors is crucial for improving the efficacy and safety of acute lymphoblastic leukemia treatment.

Adequate maintenance therapy for childhood acute lymphoblastic leukemia (ALL), with 6-mercaptopurine as an essential component, is necessary for retaining durable remission. Interruptions or discontinuations of the therapy due to drug-related toxicities, which can be life threatening, may result in an increased risk of relapse. In this retrospective study including 305 paediatric ALL patients undergoing maintenance therapy, we systematically investigated the individual and combined effects of genetic variants of folate pathway enzymes, as well as of polymorphisms in PACSIN2 and ITPA, on drug-induced toxicities by applying a multi-analytical approach including logistic regression (LR), classification and regression tree (CART) and generalized multifactor dimensionality reduction (GMDR). In addition to the TPMT genotype, confirmed to be a major determinant of drug related toxicities, we identified the PACSIN2 rs2413739TT genotype as being a significant risk factor for 6-MP-induced toxicity in wild-type TPMT patients. A gene-gene interaction between MTRR (rs1801394) and MTHFR (rs1801133) was detected by GMDR and proved to have an independent effect on the risk of stomatitis, as shown by LR analysis. To our knowledge, this is the first study showing PACSIN2 genotype association with hematological toxicity in ALL patients undergoing maintenance therapy.

SAM represents a potential pharmacometabolomic marker and therapeutic agent in TPMT-heterozygous subjects.

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.

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