Susceptibility to thiopurine toxicity by TPMT and NUDT15 variants in Colombian children with acute lymphoblastic leukemia

Abstract


 Objective:
 This study aimed to correlate the genetic profile of the NUDT15 and TPMT genes with the side effects of the treatment of pediatric patients with acute lymphoid leukemia who were undergoing maintenance therapy at a tertiary care hospital in 2017.
 
 
 Methods:
 This was an analytical, longitudinal, observational study in which the genotypes of the genes of interest were determined by PCR allelic discrimination with TaqMan® probes in patients receiving chemotherapy during the maintenance phase in the Pediatric Hematology and Oncology Unit in 2017. Sociodemographic and clinical data corresponding to the first six months of their maintenance chemotherapy were collected, and the correlation between the genotypes obtained and the development of side effects during the maintenance phase of chemotherapy in these patients was evaluated.
 
 
 Results:
 Seventy pediatric patients were included in the study. Genetic analyses were carried out of these for NUDT15 and TPMT (rs1800462 and rs1800460) on 68 patients, while for the rs1142345 polymorphism, typing was achieved in 42 patients. 4/68 patients were heterozygous for NUDT15, and the same number of patients were heterozygous for rs1800462 and rs1142345, while for rs1800460, 6 heterozygous patients were identified. No statistically significant association was identified between the genetic variants and the outcomes of interest.
 
 
 Conclusion:
 Studies with a larger population size are needed and the evaluation of other genetic variants that may influence the development of side effects during maintenance chemotherapy.

Association of <i>NUDT15</i> gene polymorphism with adverse reaction, treatment efficacy, and dose of 6-mercaptopurine in patients with acute lymphoblastic leukemia: a systematic review and meta-analysis

“…In order to fill this gap, in our research, 603 patients in five studies were involved to compare the events of relapse in NUDT15 c.415C>T variant carriers with wild-type patients. 24,36,42,43,49 No significant difference was found in the relapse incidence between two groups (OR=1.20, 95% CI: 0.63-2.27; P=0.58) (Figure 6A), and the sensitivity analysis supported this finding. In addition, two studies with 402 patients has been no meta-analysis concerning the influence of gene polymorphism on the dosing of 6-MP in ALL.…”

“…They were published between 2015 and 2022. Ten of them came from China (including Hongkong and Taiwan), 25,26,[34][35][36][37][38][39][40][41] three from Japan, [42][43][44] three from Korea, [45][46][47] three from Thailand, [48][49][50] two from India, 27,51 one from Colombia, 24 Lebanon, 52 and Kurdistan 52 respectively, as well as one multiracial study. 21 Their sample size ranged from 51 to 404.…”

“…We compared the events of neutropenia in NUDT15 c.415C>T variant group and wild-type group based on ten studies comprising 1,082 patients with ALL. 24,27,35,38,45,46,[48][49][50][51] Correa-Jimenez et al 24 did not describe the definition of neutropenia, while three studies defined neutropenia as absolute neutrophil count (ANC) <1,500/µL, ANC <1,000/µL, and ANC <750/µL, 27,35,51 respectively, and the remaining six studies shared the same standard of neutropenia as ANC <500/µL (Online Supplementary Table S1). 38,45,46,[48][49][50] The variant group (CT+TT) was proven to be significantly associated with a 2.5-fold higher risk of neutropenia in comparison to the wild-type group (OR=2.52, 95% CI: 1.72-3.69; P<0.00001) (Figure 3A).…”

“…25,41,44 Association between NUDT15 c.415C>T polymorphism and 6-MP treatment interruption Five studies with 537 ALL patients were included to compare the events of treatment interruption in the NUDT15 c.415C>T variant group (CT+TT) and the wild-type group (CC). 24,27,40,43,45 The definition of treatment interruption of these included studies is listed in Online Supplementary Table S1. Specifically, treatment interruption was defined as the cessation of medicine administration caused by adverse events such as cytopenia, infections or hepatotoxicity.…”

“…Although the association between NUDT15 c.415C>T variants and 6-MP-induced myelotoxicity is widely recognized, the pooled increased risk, by involving more newly published research, of myelosuppression in ALL patients with NUDT15 c.415C>T variants has not been reported. [24][25][26][27] Moreover, the correlation between NUDT15 polymorphism and risk for hepatotoxicity, treatment interruption, dose intensity of 6-MP or relapse of ALL were not evaluated in previous meta-analysis. [28][29][30][31] In order to fill this gap, we conducted a systematic review and meta-analysis aiming to assess the association between NUDT15 gene polymorphism and adverse reaction, treatment efficacy and dose of 6-MP particularly in patients with ALL.…”