Understanding thiopurine methyltransferase polymorphisms for the targeted treatment of hematologic malignancies

Abstract

IntroductionThiopurine methyltransferase (TPMT) catalyses the S-methylation of thiopurines, such as mercaptopurine and tioguanine (TG), fundamental chemotherapeutic agents used in the treatment of acute lymphoblastic leukemia (ALL). Polymorphisms in TPMT gene encode diminished activity enzyme, thus enhancing accumulation of active metabolites, and partially explaining the inter-individual differences in patients' clinical response. Areas coveredThis review gives an overview on TPMT gene and function, and discusses the well-established pharmacogenomic implications of TPMT variants in the prevention of severe thiopurine-induced hematological toxicities and the less known implication on TG-induced sinusoidal obstruction syndrome. Additional genetic and non-genetic factors impairing TPMT activity are considered. Literature search was done in PubMed for English articles published between 1990 and June 2021, and on PharmGKB for thiopurine drugs. Expert opinionIn order to titrate thiopurines safely and effectively, achieve the right degree of lymphotoxic effect and avoid excessive myelosuppression, the optimal management will combine a pre-emptive TPMT genotyping to establish a safe initial dose to a close phenotypic monitoring of the TPMT activity and/or of the active metabolites during the long-term treatment. Compared to current ALL protocols, replacement of TG by MP during reinduction phase in TPMT heterozygotes as well as novel individualized TG regimens in maintenance for TPMT wild type subjects could be investigated to further improve outcomes while avoiding the risk of severe hepatotoxicity.

A bioinformatics approach to the identification of novel deleterious mutations of human TPMT through validated screening and molecular dynamics

“…One of the major reasons for the cytotoxic side effects of thiopurine drugs is TPMT deficiency in patients and most TPMT polymorphisms often reduce TPMT activity 8 . Furthermore, it has already been established that several alleles of TPMT are in fact, disease-associated with respect to leukemia 9 – 13 , IBD 14 – 19 , and more.…”

DNA‐Thioguanine Nucleotides as a Marker for Thiopurine Induced Late Leukopenia after Dose Optimizing by NUDT15 C415T in Chinese Patients with IBD

“…Second, we were not able to impute all single‐nucleotide polymorphisms, which probably affect DNA‐TG production and thiopurine toxicity. The conclusions on the variants, such as ITPA 32–34 and ABCC4 , 15,35 are controversial and the other omitted TPMT or NUDT15 variants are exceedingly rare 6,31,36,37 . A larger sample size is needed to prove DNA‐TG as an independent marker when considering these variants.…”

“…The conclusions on the variants, such as ITPA [32][33][34] and ABCC4, 15,35 are controversial and the other omitted TPMT or NUDT15 variants are exceedingly rare. 6,31,36,37 A larger sample size is needed to prove DNA-TG as an independent marker when considering these variants.…”

LC–MS/MS Method for Measurement of Thiopurine Nucleotides (TN) in Erythrocytes and Association of TN Concentrations With TPMT Enzyme Activity

“…Patients with intermediate TPMT activity could also be at risk of bone marrow toxicity and are recommended to reduce the dose and have frequent thiopurine metabolites monitoring. Patients with high TPMT activity are not considered to be at a risk of bone marrow toxicity and standard dosing, and periodic thiopurine metabolite monitoring is recommended ( Lee et al, 2021 ; Franca et al, 2021 ).…”