Dataset Information

TPMT*3C as a Predictor of 6-Mercaptopurine-Induced Myelotoxicity in Thai Children with Acute Lymphoblastic Leukemia.

ABSTRACT: The response to 6-mercaptopurine (6-MP) can be altered by genetic polymorphisms in genes encoding drug-metabolizing enzymes and drug transporters. The purpose of this study was to investigate the association between genetic polymorphisms of drug-metabolizing enzymes (TPMT 719A > G (*3C), ITPA 94C > A and ITPA 123G > A) and drug transporters (MRP4 912C > A and MRP4 2269G > A) with 6-MP-related myelotoxicity and hepatotoxicity in Thai children with acute lymphoblastic leukemia (ALL). The prescribed dosage of 6-MP and its adverse effects were assessed from medical records during the first 8 weeks and 9-24 weeks of maintenance therapy. Children with the TPMT*1/*3C genotype had a higher risk of leukopenia with an odds ratio (OR) of 4.10 (95% confidence interval (CI) of 1.06-15.94; p = 0.033) compared to wild type (TPMT*1/*1) patients. Heterozygous TPMT*3C was significantly associated with severe neutropenia with an increased risk (OR, 4.17; 95% CI, 1.25-13.90); p = 0.014) during the first 8 weeks. No association was found among ITPA94C > A, ITPA123G > A, MRP4 912C > A, and MRP4 2269G > A with myelotoxicity and hepatotoxicity. The evidence that TPMT heterozygotes confer risks of 6-MP-induced myelotoxicity also supports the convincing need to genotype this pharmacogenetic marker before the initiation of 6-MP therapy.

SUBMITTER: Jantararoungtong T

PROVIDER: S-EPMC8400562 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

TPMT*3C as a Predictor of 6-Mercaptopurine-Induced Myelotoxicity in Thai Children with Acute Lymphoblastic Leukemia.

Jantararoungtong Thawinee T Wiwattanakul Supaporn S Tiyasirichokchai Rawiporn R Prommas Santirhat S Sukprasong Rattanaporn R Koomdee Napatrupron N Jinda Pimonpan P Rachanakul Jiratha J Nuntharadthanaphong Nutthan N Pakakasama Samart S Anurathapan Usanarat U Hongeng Suradej S Sukasem Chonlaphat C

Journal of personalized medicine 20210811 8

The response to 6-mercaptopurine (6-MP) can be altered by genetic polymorphisms in genes encoding drug-metabolizing enzymes and drug transporters. The purpose of this study was to investigate the association between genetic polymorphisms of drug-metabolizing enzymes (TPMT 719A > G (*3C), ITPA 94C > A and ITPA 123G > A) and drug transporters (MRP4 912C > A and MRP4 2269G > A) with 6-MP-related myelotoxicity and hepatotox ...[more]

PMID: 34442427

Similar Datasets

Project description:Background: Acute lymphoblastic leukemia (ALL) is the most common cancer seen in children worldwide and in the Middle East. Although there have been major advances in treatment approaches for childhood ALL, serious toxicities do occur but with significant inter-individual variability. The aim of this study is to measure the frequency of polymorphisms in candidate genes involved in 6-Mercaptopurine (6-MP) disposition in a combined cohort of Middle Eastern Children with ALL, and evaluate whether these polymorphisms predict 6-MP intolerance and toxicity during ALL maintenance therapy. Methods: The study includes children treated for ALL on two treatment protocols from two cohorts; one from Lebanon (N = 136) and another from Kurdistan province of Iran (N = 74). Genotyping for the following six candidate genetic polymorphisms: ITPA 94C > A (rs1127354) and IVS2+21A > C (rs7270101), TPMT*2 238G > C (rs1800462), TPMT*3B 460G > A (rs1800460) and *3C 719A > G (rs1142345), and NUDT15 415C > T (rs116855232) was performed and analyzed in association with 6-MP dose intensity and toxicity. Results: As expected, TPMT and NUDT15 variants were uncommon. As for ITPA, both polymorphisms were more common in the Lebanese as compared to the Kurdish cohort with a minor allele frequency of 0.05 for 94C > A and 0.14 for IVS2+21A > C in the Lebanese only (N = 121), and of 0.01 for either ITPA polymorphism in Kurds. The most significant toxic effects were depicted with the NUDT15 polymorphism with a median 6-MP dose intensity of 33.33%, followed by 46.65% for TPMT*3A polymorphism, followed by 65.33% for two ITPA risk allele carriers and 74% for one ITPA risk allele carriers, in comparison to a median of 100% for the homozygous wild type in the combined cohort (P < 0.001). In addition, the onset of febrile neutropenia was significantly higher in variant allele carriers in the combined cohorts. Conclusions: These data confirm the predictive role of TPMT, NUDT15, and ITPA in 6-MP intolerance in Middle Eastern children with ALL. Given the relatively high frequency of ITPA variants in our study and their significant association with 6-MP dose intensity, we recommend that physicians consider genotyping for ITPA variants in conjunction with TPMT and NUDT15 prior to 6-MP therapy in these children.

Project description:Mercaptopurine (MP) is a commonly used maintenance regimen for childhood acute lymphoblastic leukemia (ALL). However, 6-MP has a narrow therapeutic index, which causes dose-limiting toxicities in hematopoietic tissues. Recent studies reported several candidate pharmacogenetic markers such as TPMT, NUDT15, ITPA, and APEX1, which predict the possibility of 6-MP related toxicities. The aim of this study is to evaluate the effect of major variants of these genes on 6-MP intolerances and toxicities in pediatric acute lymphoblastic leukemia (ALL) patients. A total of 83 pediatric ALL patients were included (56 males and 27 females). The NUDT15 c.415C>T (rs116855232), NUDT15 c.55_56insGAGTCG (rs746071566), ITPA c.94C>A (rs1127354), ITPA c.IVS2+21A>C (rs7270101), APEX c.190A>G (rs2307486), and TPMT variants were analyzed by sanger sequencing. Correlations between indexes of 6-MP-related toxicities or 6-MP intolerance (absolute neutrophil count [ANC] at several time point, days of ANC < 1 × 103/mm3, days of ANC < 0.5 × 103/mm3, frequency of febrile neutropenia, maximum AST and ALT, 6-MP dose and 6-MP dose intensity during maintenance therapy) and genetic variations were analyzed. The NUDT15 c.415C>T allele carrier showed significantly low 6-MP doses at the final maintenance therapy period than the wild type carrier (p = 0.007). The 6-MP dose intensities at the sixth and final maintenance period were also significantly low in NUDT15 c.415C>T carriers (p = 0.003 and 0.008, respectively). However, indexes for neutropenia, days of febrile neutropenia, maximum AST, and ALT levels were not associated with the presence of c.415C>T as well as other analyzed variants. When analyzing the effect of the coexistence of NUDT15 c.415C>T and ITPA c.94C>A, no significant differences were found between the NUDT15 c.415C>T carrier and carrier with both variations. The NUDT15 c.415C>T was the most useful marker to predict 6-MP intolerance among analyzed variants in our study population. Although we could not find association of those variants with 6-MP induced toxicities and the synergistic effects of those variants, a well-planed larger scale study would be helpful in clarifying new candidates and their clinical effects.

Project description:Objective: To investigate the effect of genetic polymorphisms of TPMT*2 rs1800462, TPMT*3B rs1800460, TPMT*3C rs1142345, and NUDT15 rs116855232 on the tolerance of 6-mercaptopurine (6-MP) therapy in adult acute lymphoblastic leukemia (ALL) . Methods: A total of 216 adult patients who were diagnosed with ALL and treated with cyclophosphamide, cytarabine, and 6-MP [complementary and alternative medicine (CAM) regimen] from September 2015 to December 2019 were included. Polymorphisms were detected by TaqMan SNP Genotyping Assay. Combined with clinical data, the influence of genetic polymorphism on the tolerance of 6-MP in the treatment of ALL was analyzed. Results: Among the 216 patients, 185 (85.65%) patients had B-ALL and 31 (14.35%) patients had T-ALL. 216 (100%) patients had CC genotype for both TPMT*2 rs1800462 and TPMT*3B rs1800460. The number of TT and TC genotypes for TPMT*3C rs1142345 was 209 (96.76%) and 7 (3.24%) , respectively. The allele frequency was 1.62% for TPMT*3C rs1142345. The number of CC, CT, and TT genotypes for NUDT15 rs116855232 was 166 (76.85%) , 48 (22.22%) , and 2 (0.93%) , respectively. The allele frequency was 12.04% for NUDT15 rs116855232. The TPMT*3C rs1142345 mutant group (TC+CC genotype) had less transfusion volume of packed red blood cell than the wild group (CC genotype) (P=0.036) , and the mutant group (TC+CC genotype) had a higher risk to develop hepatotoxicity (increased aspartate aminotransferase) than the wild group (CC genotype) (OR=9.559, 95% CI 1.135-80.475, P=0.038) . The durations of white blood cells (WBC) <1×10(9)/L and absolute neutrophil count (ANC) <0.5×10(9)/L in the NUDT15 rs116855232 mutation group (CT+TT genotype) were longer than that in the wild group (CC genotype) (P=0.005, P=0.007) , and the transfusion volume of apheresis-derived platelets in the mutant group (CT+TT type) was greater than that in the wild group (CC genotype) (P=0.014) . Conclusion: Genetic polymorphism of TMPT and NUDT15 has an effect on the tolerance of 6-MP in the treatment of adult ALL. Detecting genotypes of patients with ALL before treatment helps to optimize the dosage of 6-MP, which may help shorten the bone marrow suppression duration and reduce blood transfusion volume.

Dataset Information

TPMT*3C as a Predictor of 6-Mercaptopurine-Induced Myelotoxicity in Thai Children with Acute Lymphoblastic Leukemia.

Publications

<i>TPMT*3C</i> as a Predictor of 6-Mercaptopurine-Induced Myelotoxicity in Thai Children with Acute Lymphoblastic Leukemia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets