Effect and mechanism of allopurinol in acute lymphoblastic leukemia maintenance therapy: Reducing hepatotoxicity and improving myelosuppression effect via thiopurine methyltransferase inhibition and increased DNA-thioguanine levels.
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Mercaptopurine (MP)-based maintenance therapy is essential to cure acute lymphoblastic leukemia (ALL). However, insufficient myelosuppression and MP-related hepatotoxicity occasionally occur. The investigation of the strategies to improve the efficacy and toxicities is warranted. The role of allopurinol combination therapy has been reported, but its effects need further verification, and the underlying mechanism remains unclear. Two hundred and eight pediatric patients requiring maintenance therapy were enrolled to investigate the effect of allopurinol combination and the potential mechanisms underlined. Blood samples were collected to determine drug metabolite levels [6-thioguanine nucleotides (6-TGN), 6-methyl mercaptopurine (6-MMP), DNA-thioguanine (DNA-TG)], thiopurine methyltransferase (TPMT) activity, and NUDT15/TPMT genotypes. Hematological values and hepatic function were measured as well. The results indicated that TPMT∗1/∗1/NUDT15∗1/∗1 patients with inadequate myelosuppression exhibited significantly higher doses of MP, increased 6-MMP concentrations, and elevated 6-MMP:6-TGN/6-MMP: DNA-TG ratios (P < .001), indicating that MP-methylated pathway was overactivated and intensifying MP dosing could not lead to adequate myelosuppression effect, but instead primarily lead to higher risk of hepatotoxicity. In contrast, after allopurinol combination with dose reduction in MP, TPMT activity decreased significantly leading to a significant reduction in the 6-MMP:6-TGN and 6-MMP: DNA-TG ratios and improvement in alanine aminotransferase and aspartate aminotransferase levels. Meanwhile, DNA-TG levels increased by an average of 257.5 fmol/μg DNA, resulting in better control of white blood cell and absolute neutrophil count. In conclusion, low-dose MP combined with allopurinol, rather than intensifying MP dose, could be an alternative strategy for better efficacy and lower risk of hepatotoxicity. SIGNIFICANCE STATEMENT: Patients requiring higher mercaptopurine doses may indicate the overactivation of methylation metabolism. 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.