Polymorphisms in folate-related genes: association with side effects of high-dose methotrexate in childhood acute lymphoblastic leukemia

Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: effects on methotrexate-related toxicity and survival

“…In line with our findings, decreased hematologic toxicity associated with the 1298 AC/CC genotypes was previously described in children with ALL treated with high-dose methotrexate; nevertheless these studies did not find greater toxicity associated with the 677T allele. 12,27 In contrast to what has been observed in childhood ALL, in adult ALL patients treated with methotrexate previous studies have shown a correlation between the MTHFR 677C>T and increases of mucositis and, hepatic and hematologic toxicity, 18,19 in line with our results. It should be noted that the doses of methotrexate administered to our patients during ALL maintenance therapy were lower than the doses used in childhood ALL.…”

“…2,11,12,14,15,26,27 Most of these studies did not find significant associations between the 677T allele and toxicity, 2,12,14,26,27 although one study reported a lower rate of episodes of toxicity among patients carrying the 677T allele 15 and another study showed that individuals with the 677T allele more frequently had to interrupt methotrexate treatment, suggesting that the MTHFR 677C>T serves as a predictor of toxicity during maintenance chemotherapy. 11 These different results are probably attributable to several factors including the methotrexate-dose, treatment protocol, ethnic background, and number of patients analyzed.…”

“…13 A further considerable result of our study concerns the TS enhancer repeat polymorphism and a higher risk of developing anemia in patients with the 3R3R genotype. Recently, this polymorphism was studied in childhood ALL; no association with toxicity was found, 2,12,27 although the 3R3R genotype was associated with a higher risk of hematologic relapse, 28 poorer outcome 13 and shorter event-free survival. 29,30 Finally, no association was identified between the RFC 80G>A polymorphism and the toxicities investigated.…”

“…MTHFR 677 C>T 9 and 1298 A>C) 10 can influence the effectiveness and the toxic effects of methotrexate. The relationship between polymorphisms affecting folate metabolism and methotrexate-related toxicity has been studied mainly in childhood ALL, 2,[11][12][13][14][15] while only a few studies have investigated this relationship in adult patients with hematologic diseases. 16,17 In particular, in adult ALL only MTHFR polymorphisms have been investigated and associated with increased methotrexaterelated toxicity.…”

Methotrexate-induced side effects are not due to differences in pharmacokinetics in children with Down syndrome and acute lymphoblastic leukemia

“…32 Furthermore, polymorphisms in genes linked to the pharmacodynamics of methotrexate, such as folate-metabolism related genes, could give rise to enhanced toxicity, as has been shown in previous studies by us and others. [35][36][37][38] Children harboring polymorphisms exhibited significantly more gastrointestinal toxicity. More knowledge on folaterelated polymorphisms may contribute to further individualization of methotrexate treatment in ALL and specifically for DS-ALL patients.…”