The current guideline describes the gene-drug interactions for TPMT, NUDT15 and thiopurines (azathioprine, 6-mercaptopurine and thioguanine). For TPMT or NUDT15 IM treated for leukaemia, starting with the normal dose can be considered and then decrease the dose to the advised dose described above in case toxicities occur. For NUDT15 PM reduced starting dose is advised only if an alternative is not possible, due to a higher uncertainty in the calculated dose reduction for NUDT15 PM than for TPMT PM.DPWG classifies genotyping for TPMT and NUDT15 "essential" before thiopurine initiation.

The thiopurines 6-mercaptopurine and 6-thioguanine (TG) are analogs of guanine and are used in the treatment of hematological malignancies and immune-mediated inflammatory diseases. dMeTG could also be detected in patient samples, although in low amounts and primarily in samples with high DNA-TG levels. The developed method for the quantitation of dMeTG and dTG can be used in further studies to investigate the role of DNA-MeTG in the mechanism of action of thiopurines, including its antileukemic efficacy and effects on acquired mutations.

Excessive 6-thioguanine (6-TGN) levels worsen neutropenia, while elevated 6-methylmercaptopurine (6-MMP) levels contribute to hepatotoxicity. In contrast, two variants in the IMPDH1 gene, rs2228075 and rs2278294, are correlated with more frequent neutropenia. These findings highlight novel genetic variants influencing 6-MP metabolism and toxicity in paediatric ALL patients.

HOXA5 plays a dual role in solid versus hematologic malignancies and serves as a key spatial immune regulator. It is a robust prognostic biomarker and therapeutic target in AML, with mercaptopurine representing a promising repurposing candidate.

Mercaptopurine (MP)-based maintenance therapy is essential to cure acute lymphoblastic leukemia (ALL). Dose escalation is unlikely to improve myelosuppression but will increase the risk of hepatotoxicity. Low-dose mercaptopurine combined with allopurinol can improve efficacy and reduce the risk of hepatotoxicity.

Thiopurines such as 6-mercaptopurine (6MP) are essential in ALL maintenance therapy...This study identifies GNAQ as a novel gene associated with thiopurine tolerance in ALL patients lacking known risk alleles in TPMT and NUDT15. Moreover, this research highlighted the innovative use of TWAS, providing deeper insights into the molecular mechanisms that explain drug response variability.

Experimentally, knocking-down NUDT15 sensitizes the cancer cell lines to mercaptopurine treatment by inhibiting cell cycle progression and increasing apoptosis, but does not induce mercaptopurine-related leucopenia in xenograft model. Our study elucidates the molecular basis for precise mercaptopurine therapy in RB1-deficient tumors and demonstrates how leveraging collateral lethality alongside drug repurposing uncovers targetable vulnerabilities in stratified patient cohorts.

P=N/A, N=64, Suspended, Children's Oncology Group | Active, not recruiting --> Suspended

One mother underwent antileukemic treatment including thioguanine during early pregnancy; the other received 6-mercaptopurine for Crohn's disease throughout gestation. Each underwent allogeneic hematopoietic stem cell transplantation and is currently in remission. These findings suggest a possible link between prenatal thiopurine exposure and leukemogenesis.

The management of acute lymphoblastic leukemia (ALL), the most common pediatric malignancy, critically relies on thiopurine therapy, such as 6-mercaptopurine (6-MP), during the maintenance phase...In conclusion, NUDT15 pharmacogenetics is essential for improving patient safety and thiopurine dosage optimization in the treatment of ALL. For thiopurine tailored medicine to be widely and fairly implemented, future research should focus on increasing genetic data across different populations, improving the dose adjustment algorithm, and harmonizing therapeutic guidelines.

Thiopurines (azathioprine and mercaptopurine) are immunosuppressant drugs widely used for the treatment of acute lymphocytic leukemia, organ transplantation and autoimmune diseases, including inflammatory bowel diseases. Patients harboring any of these variants exhibited a significantly higher TIM risk (P = 0.032). These findings underscore the importance of considering rare genetic variants, particularly in xanthine dehydrogenase (XDH), in TIM susceptibility and open new opportunities for optimizing treatment efficacy and safety in clinical practice for IBD patients beyond the well-established TPMT and NUDT15 genetics.

This study showed that the commonly genotyped variants in TPMT are rare in pediatric acute lymphoblastic leukemia patients from Ethiopia.