Thiopurines (e.g., mercaptopurine [MP]) are highly effective against hematologic malignancies (leukemia and lymphoma) and autoimmune diseases (inflammatory bowel diseases [IBD]). In acute lymphoblastic leukemia (ALL) in particular, prolonged daily exposure to MP is indispensable for the cure of this cancer. However, thiopurines have narrow therapeutic indexes with dose-limiting hematopoietic toxicity that causes extensive morbidity, disruption of treatment, and possible mortality. Therefore, there is enormous clinical benefit from preemptively identifying patients at risk of thiopurine toxicity and individualizing therapy to mitigate it. Thiopurine toxicity is also highly influenced by inherited genetic variations, particularly polymorphisms in the TPMT gene as discovered by our group and others. Recently, we reported a novel variant in the NUDT15 gene that lead to its loss of nucleotide diphosphatase activity, excessive levels of active thiopurine metabolite, dramatic increase in MP-induced apoptosis and severe toxicity in patients (J Clin Oncol 2015 and unpublished preliminary results). Because the low activity NUDT15 allele alters the metabolism of thiopurines, we hypothesize that we can rationally reduce thiopurine dose in patients who inherit the NUDT15 variants and tailor their exposure to thiopurine active metabolite TGTP to the level comparable to wildtype patients receiving conventional doses, similar to the principle of TPMT-guided thiopurine dose reduction. To test this hypothesis, we propose three specific aims to 1) comprehensively identify MP toxicity-related NUDT15 and TPMT ALL (N=1,028), 2) characterize the effects of NUDT15 and characterize how NUDT15 and variants influence thiopurine disposition in children with ALL (N=1,550), TPMT variants variants in children with on its function, and finally 3) TPMT from which to develop a NUDT15-/TPMT-based pharmacogenetic algorithm for MP dose adjustments. Successful completion of these studies is likely to establish a novel precision medicine paradigm for thiopurine therapy to proactively individualize dose before toxicity occurs. We are confident that this highly translational project will likely have immediate impact on the treatment of ALL, and our findings can be readily extrapolated to thiopurine therapy for non-malignant conditions (e.g., IBD) thus impact a large number of patients.

Public Health Relevance

Thiopurines are widely used as anti-cancer drugs in patients with hematologic malignancies and as immunosuppressive drugs in inflammatory bowel diseases. However, thiopurines have a very narrow therapeutic index with dose-limiting hematopoietic toxicity that cases extensive morbidity and possible mortality. Building upon compelling data from our preliminary studies, we propose to develop a novel pharmacogenetics- based thiopurine dosing algorithm to preemptively identify patients at risk of toxicity and individualize therapy to mitigate it.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
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Garcia, Martha
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St. Jude Children's Research Hospital
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Nishii, Rina; Moriyama, Takaya; Janke, Laura J et al. (2018) Preclinical evaluation of NUDT15-guided thiopurine therapy and its effects on toxicity and antileukemic efficacy. Blood 131:2466-2474
Zhu, Yiping; Yin, Dandan; Su, Yali et al. (2018) Combination of common and novel rare NUDT15 variants improves predictive sensitivity of thiopurine-induced leukopenia in children with acute lymphoblastic leukemia. Haematologica 103:e293-e295
Tsujimoto, Shinichi; Osumi, Tomoo; Uchiyama, Meri et al. (2018) Diplotype analysis of NUDT15 variants and 6-mercaptopurine sensitivity in pediatric lymphoid neoplasms. Leukemia 32:2710-2714
Moriyama, Takaya; Nishii, Rina; Lin, Ting-Nien et al. (2017) The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia. Pharmacogenet Genomics 27:236-239
Liu, C; Yang, W; Pei, D et al. (2017) Genomewide Approach Validates Thiopurine Methyltransferase Activity Is a Monogenic Pharmacogenomic Trait. Clin Pharmacol Ther 101:373-381
Liu, Chengcheng; Janke, Laura J; Yang, Jun J et al. (2017) Differential effects of thiopurine methyltransferase (TPMT) and multidrug resistance-associated protein gene 4 (MRP4) on mercaptopurine toxicity. Cancer Chemother Pharmacol 80:287-293
Moriyama, Takaya; Yang, Yung-Li; Nishii, Rina et al. (2017) Novel variants in NUDT15 and thiopurine intolerance in children with acute lymphoblastic leukemia from diverse ancestry. Blood 130:1209-1212