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

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 deficiency as a novel genetic cause of thiopurine toxicity, and there is a strong rationale for guided dose individualization to preemptively mitigate adverse effects of these drugs. Using CRISPR-Cas9 genome editing, we established a mouse model to evaluate the effectiveness of this strategy in vivo. Across MP dosages, mice experienced severe leukopenia, rapid weight loss, earlier death resulting from toxicity, and more bone marrow hypocellularity compared with wild-type mice. 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 mice and largely eliminated 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 deficiency. Using leukemia-bearing mice with concordant genotype in leukemia and host, we also confirmed that therapeutic efficacy was preserved in mice receiving a reduced MP dose compared with counterparts exposed to a standard dose. In conclusion, we demonstrated that genotype-guided MP dose individualization can preemptively mitigate toxicity without compromising therapeutic efficacy.