Thiopurine-S-methyl-transferase gene polymorphism and drug-related toxicity in children treated for acute leukemia and Non-Hodgkins lymphoma

INTRODUCTION: Thiopurine S-methyltransferase (TPMT) is an essential enzyme in thiopurine drugs' metabolism, and its activity may be change due to different polymorphisms in the TPMT gene. TPMT gene has different genetic polymorphisms in different ethnic groups. This study aimed to determine the frequency of TPMT polymorphisms in children with acute leukemia/ non-Hodgkin lymphoma (AL/ NHL ) and healthy children and to evaluate their association with severe toxicities in the study population.

METHODS: Sixty-seven pediatric AL/NHL patients and 84 healthy children evaluated. Genotyping for the TPMT*2, TPMT*3A, TPMT*3B, TPMT*3C, TPMT*4, TPMT*5, TPMT*6, and TPMT*7 alleles performed by real-time PCR technique. The number of grade ≥3 hematologic and hepatic toxicities recorded from the patient charts.

RESULTS: In AL/NHL patients, we found that the patients had generally wild-type TPMT*1 allele in 80.6%, whereas TPMT*2 (238G>C) in 1.5%, TPMT*3A (c.460G>A and c.719A>G) in 0%, TPMT*3B polymorphisms (460G>A) in 17.9 %. We found wild-type TPMT*1 allele in 98.8% and TPMT*3B polymorphisms (460G>A) in 1.2% in healthy volunteers. Grade grade ≥3 myelosuppression developed in 22/54 patients with wild type allele while in 5/12 patients with TPMT*3B allele. Six (8.9%) patients had grade ≥3 AST elevations while 17 (25%) patients had grade ≥3 ALT elevations (1-5 times), and 42 patients had (62.6%) grade ≥3 total bilirubin elevations.
DISCUSSION AND CONCLUSION: TPMT*3B polymorphism was the most common allele detected in our study group. This allele frequency is very high according to other studies from our country and overrepresented in comparison to healthy volunteers. We did not find any relationship between severe hematologic/hepatic toxicities and TPMT gene polymorphisms.