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Pharmacogenetics of thiopurines.

ABSTRACT: Polychemotherapeutic protocols for the treatment of pediatric acute lymphoblastic leukemia (ALL) always include thiopurines. Specific approaches vary in terms of drugs, dosages and combinations. Such therapeutic schemes, including risk-adapted intensity, have been extremely successful for children with ALL who have reached an outstanding 5-year survival of greater than 90% in developed countries. Innovative drugs such as the proteasome inhibitor bortezomib and the bi-specific T cell engager blinatumomab are available to further improve therapeutic outcomes. Nevertheless, daily oral thiopurines remain the backbone maintenance or continuation therapy. Pharmacogenetics allows the personalization of thiopurine therapy in pediatric ALL and clinical guidelines to tailor therapy on the basis of genetic variants in TPMT and NUDT15 genes are already available. Other genes of interest, such as ITPA and PACSIN2, have been implicated in interindividual variability in thiopurines efficacy and adverse effects and need additional research to be implemented in clinical protocols. In this review we will discuss current literature and clinical guidelines available to implement pharmacogenetics for tailoring therapy with thiopurines in pediatric ALL.

SUBMITTER: Franca R

PROVIDER: S-EPMC8992634 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Pharmacogenetics of thiopurines.

Franca Raffaella R Zudeh Giulia G Pagarin Sofia S Rabusin Marco M Lucafò Marianna M Stocco Gabriele G Decorti Giuliana G

Cancer drug resistance (Alhambra, Calif.) 20190619 2

Polychemotherapeutic protocols for the treatment of pediatric acute lymphoblastic leukemia (ALL) always include thiopurines. Specific approaches vary in terms of drugs, dosages and combinations. Such therapeutic schemes, including risk-adapted intensity, have been extremely successful for children with ALL who have reached an outstanding 5-year survival of greater than 90% in developed countries. Innovative drugs such as the proteasome inhibitor bortezomib and the bi-specific T cell engager blin ...[more]

PMID: 35582727

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Project description:Thiopurines have been a cornerstone in the treatment of inflammatory bowel disease (IBD). Although they have been used for more than 50 years, there are still some unsolved issues about their efficacy and, also, some safety concerns, mainly the risk of myelosuppression and life-threatening lymphoproliferative disorders. Furthermore, the development of biological therapy raises the question whether there is still a role for thiopurines in the IBD treatment algorithm. On the other hand, limited cost and wide availability make thiopurines a reasonable option in settings of limited resources and increasing prevalence of IBD. In fact, there is a growing interest in optimizing thiopurine therapy, since pharmacogenomic findings suggest that a personalized approach based on the genotyping of some molecules involved in its metabolism could be useful to prevent side effects. Polymorphisms of thiopurine methyltransferase enzyme (TPMT) that result in low enzymatic activity have been associated with an increased risk of myelotoxicity, especially in Caucasians; however, in Asians it is assumed that the variants of nudix hydrolase 15 (NUDT15) are more relevant in the development of toxicity. Age is also important, since in elderly patients the risk of complications seems to be increased. Moreover, the primo-infection of Epstein Barr virus and cytomegalovirus under thiopurine treatment has been associated with severe lymphoproliferative disorders. In addition to assessing individual characteristics that may influence thiopurines treatment outcomes, this review also discusses other strategies to optimize the therapy. Low-dose thiopurines combined with allopurinol can be used in hypermethylators and in thiopurine-related hepatotoxicity. The measurement of metabolites could be useful to assess compliance, identify patients at risk of adverse events and also facilitating the management of refractory patients. Thioguanine is also a rescue therapy in patients with toxicity related to conventional thiopurine therapy. Finally, the current indications for thiopurines in monotherapy or in combination with biologics, as well as the optimal duration of treatment, are also reviewed.

Dataset Information

Pharmacogenetics of thiopurines.

Publications

Pharmacogenetics of thiopurines.

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