Preclinical evaluation of NUDT15-guided thiopurine therapy and its effects on toxicity and antileukemic efficacy

• Published in: Blood Vol. 131; no. 22; pp. 2466 - 2474
• Main Authors: Nishii, Rina, Moriyama, Takaya, Janke, Laura J., Yang, Wenjian, Suiter, Chase C., Lin, Ting-Nien, Li, Lie, Kihira, Kentaro, Toyoda, Hidemi, Hofmann, Ute, Schwab, Matthias, Takagi, Masatoshi, Morio, Tomohiro, Manabe, Atsushi, Kham, Shirley, Jiang, Nan, Rabin, Karen R., Kato, Motohiro, Koh, Katsuyoshi, Yeoh, Allen Eng-Juh, Hori, Hiroki, Yang, Jun J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 31-05-2018; American Society of Hematology
• Subjects: Animals; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - therapeutic use; Antimetabolites, Antineoplastic - toxicity; Child; CRISPR-Cas Systems; Drug Dosage Calculations; Drug Evaluation, Preclinical; Gene Deletion; Gene Editing; Genotype; Humans; Leukemia - drug therapy; Leukemia - genetics; Leukemia - pathology; Lymphoid Neoplasia; Mercaptopurine - administration & dosage; Mercaptopurine - therapeutic use; Mercaptopurine - toxicity; Mice; Mice, Knockout; Phosphoric Diester Hydrolases - genetics; Pyrophosphatases - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2017-11-815506

Thiopurines (eg, 6-mercaptopurine [MP]) are highly efficacious antileukemic agents, but they are also associated with dose-limiting toxicities. Recent studies by us and others have identified inherited NUDT15 deficiency as a novel genetic cause of thiopurine toxicity, and there is a strong rationale for NUDT15-guided dose individualization to preemptively mitigate adverse effects of these drugs. Using CRISPR-Cas9 genome editing, we established a Nudt15−/− mouse model to evaluate the effectiveness of this strategy in vivo. Across MP dosages, Nudt15−/− mice experienced severe leukopenia, rapid weight loss, earlier death resulting from toxicity, and more bone marrow hypocellularity compared with wild-type mice. Nudt15−/− mice also showed excessive accumulation of a thiopurine active metabolite (ie, DNA-incorporated thioguanine nucleotides [DNA-TG]) in an MP dose–dependent fashion, as a plausible cause of increased toxicity. MP dose reduction effectively normalized systemic exposure to DNA-TG in Nudt15−/− mice and largely eliminated Nudt15 deficiency–mediated toxicity. In 95 children with acute lymphoblastic leukemia, MP dose adjustment also directly led to alteration in DNA-TG levels, the effects of which were proportional to the degree of NUDT15 deficiency. Using leukemia-bearing mice with concordant Nudt15 genotype in leukemia and host, we also confirmed that therapeutic efficacy was preserved in Nudt15−/− mice receiving a reduced MP dose compared with Nudt15+/+ counterparts exposed to a standard dose. In conclusion, we demonstrated that NUDT15 genotype–guided MP dose individualization can preemptively mitigate toxicity without compromising therapeutic efficacy.
•We established a Nudt15 knockout mouse model with which to evaluate individualized thiopurine therapy.•Preemptive NUDT15 genotype–guided thiopurine dosing can effectively prevent drug toxicity without compromising antileukemic efficacy.
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