Understanding thiopurine methyltransferase polymorphisms for the targeted treatment of hematologic malignancies

ABSTRACT

Introduction

Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurines (mercaptopurine (MP) and tioguanine (TG)), chemotherapeutic agents used in the treatment of acute lymphoblastic leukemia (ALL). Polymorphisms in TPMT gene encode diminished activity enzyme, enhancing accumulation of active metabolites, and partially explaining the inter-individual differences in patients’ clinical response.

Areas covered

This review gives an overview on TPMT gene and function, and discusses the 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 since1990, and on PharmGKB.

Expert opinion

To titrate thiopurines safely and effectively, achieve the right degree of lymphotoxic effect and avoid excessive myelosuppression, the optimal management will combine a preemptive TPMT genotyping to establish a safe initial dose with a close phenotypic monitoring of TPMT activity and/or of active metabolites during long-term treatment. Compared to current ALL protocols, replacement of TG by MP during reinduction phase in TPMT heterozygotes and novel individualized TG regimens in maintenance for TPMT wild-type subjects could be investigated to improve outcomes while avoiding risk of severe hepatotoxicity.

KEYWORDS:

• Acute lymphoblastic leukemia
• genetic polymorphisms
• myelosuppression
• sinusoidal obstruction syndrome
• thiopurines
• TPMT

Article highlights box

• Thiopurine S-methyltransferase (TPMT) is an important phase II enzyme, known for its role in the metabolic transformation of thiopurine drugs (mercaptopurine (MP) and tioguanine (TG)); TPMT activity is inversely related to the cytoplasmic accumulation of active thiopurine metabolites.

• TPMT is a polymorphic gene; the majority of identified single nucleotide polymorphism encode for a diminished activity enzyme.

• TPMT pharmacogenetic guidelines to prevent severe thiopurine-induced myelosuppression are currently available; prescribing recommendations apply primarily to starting doses.

• Measurement of thiopurine metabolites in patients’ red blood cells is generally considered a surrogate marker for thiopurine efficacy and toxicity during a long-term therapy; however, in hematological diseases, clinical applicability of this therapeutic drug monitoring is still limited.

• TG, but not MP, is associated with an enhanced incidence of sinusoidal obstruction syndrome (SOS) in patients affected by acute lymphoblastic leukemia (ALL). The role of TPMT polymorphisms or thiopurine metabolites’ levels in the prediction of TG-induced SOS in ALL patients needs to be better characterized.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

We confirmed that the above declaration of interest is correct

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Author contributions

Writing – original draft, Stefania Braidotti, and Raffaella Franca; Writing – review and editing, Giuliana Decorti and Gabriele Stocco.

Additional information

Funding

This paper was not funded.