Pharmacogenetic studies in children with acute lymphoblastic leukemia in Argentina

Abstract

The aim of this study was to evaluate the influence of the most common genetic variants in methylenetetrahydrofolate reductase (MTHFR), thiopurine methyltransferase (TPMT) and glutathione-S-transferases (GSTs) on the outcome of acute lymphoblastic leukemia (ALL) treatment in Argentinean children. Two hundred and eighty-six patients with ALL treated with two Berlin-Frankfurt-Münster (BFM)-based protocols were analyzed. Ten genetic variants were studied. Toxicity was evaluated during the consolidation phase. Children who received 2 g/m(2)/day of methotrexate and carried at least one 677T allele in MTHFR showed an increased risk of developing severe leukopenia (p = 0.004) and neutropenia (p = 0.003). Intermediate-risk (IR) patients with a heterozygous TPMT genotype had a higher probability of event-free survival than those with a wild-type genotype. Genotyping of MTHFR polymorphisms might be useful to optimize consolidation therapy, reducing the associated severe hematologic toxicity. Further studies are necessary to establish the usefulness of MTHFR and TPMT variants as additional markers to predict outcome in the IR group.

TPMT and NUDT15 genes are both related to mercaptopurine intolerance in acute lymphoblastic leukaemia patients from Uruguay

“…The spectrum and frequency of heterozygotes (10·5%) is similar to that observed for other Latin‐American and European populations. However, the ITPA 94A variant frequency (5·3%) was higher than that reported for a Chilean population (Silva et al , ; Farfan et al , ; Aráoz et al , ). Interestingly, 11 of the 115 individuals analysed were heterozygous for NUDT15 variants: five for NUDT15*2 , two for *3 , one for *4 and three for *6 .…”

MTHFR polymorphisms in childhood acute lymphoblastic leukemia: influence on methotrexate therapy

“…Neutropenia was analyzed in 4 studies. Only the study of Aráoz et al26 found risk 677T allele associated to neutropenia in patients who received low doses of MTX (2 g/m 2 ). None of the other 3 studies found association.…”

“…From them, only 5 found significant associations with toxicity, but with contradictory results: 2 studies related the T variant allele to a decrease in toxicity risk,24,25 whereas the other 3 associated it to increased risk (Table 1). 26–28…”

“…Contradictory results were also seen for leukopenia, for which Haase et al25 showed that the C677T T variant allele was associated with a decreased toxicity, whereas Aráoz et al26 found that this allele increased the risk of severe leukopenia, but only in carriers who received 2 g/m 2 of MTX. However, Aráoz et al26 also observed that the 677T allele did not seem to modulate the presence of severe adverse events in patients who received 5 g/m 2 of MTX. The analysis of leukopenia in the other 3 studies showed no association with toxicity (Table 2).…”

“…These studies included a low number of patients (n=21 and n=35, respectively), whereas the studies that did not result in significance were performed in cohorts of 106,32 161,26 and 12727 patients. Since our previous review found no association in 5 of the 6 studies that analyzed anemia and the one that showed association was performed in a population of 37 patients,33 we can conclude that A1298C variant is not a good marker for anemia.…”