P02?Allopurinol counteracts inadequate mercaptopurine metabolism in paediatric acute lymphoblastic leukemia

摘要

Background Mercaptopurine (6-MP), a cornerstone of childhood acute lymphoblastic leukemia (ALL) therapy, is metabolized to active 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine nucleotides (6-MMPN) potentially hepatotoxic (threshold of 5000 pmol/8x10sup8/sup RBC). In few cases, the equilibrium between 6-TGN and 6-MMPN is unbalanced and in favor to 6-MMPN with high risk of inefficacy and toxicities. Here, we treated patients with allopurinol which inhibits Xanthine Oxidase and Thiopurine S-methyl Transferase ( TPMT ) implicated in methylation of thiopurines. Methods Therapeutic drug monitoring of ALL patients was based on the determination of metabolites concentrations in red blood cells, measured by HPLC-UV after 3 weeks of stable 6-MP dose. After parental consent, individual genotypes are determined for TPMT (*2, *3B, *3C), ITPA (c.94CA) and HLA*B5801 (prior to allopurinol) by TaqMan allelic discrimination. Results In 8 patients, 6-MMPN/6-TGN ratio was too high, superior to 50 (range: 58–248) with 6-TGN under therapeutic threshold ( 250 pmol/8x10sup8/sup RBC). All patients have a wild-type TPMT genotype and for 3 patients, ITPA polymorphism could be involved to this disequilibrium. The co-administration of Allopurinol (50 mg n=5, 100 mg n=2), with a reduced 6-MP dose (around -50%) dose had a positive impact on metabolic ratio, inferior to 15 (range: 1- 13) with metabolites levels inside therapeutic window and on resolving some toxicities (hypoglycemia (n=4), hepatotoxicity (n=3)). For one patient, 200 mg of Allopurinol was administered without reducing 6-MP dose, the metabolic ratio decreased from 115 to 63 but metabolites levels were both at supratherapeutic levels. Conclusion Allopurinol was effective in redirecting 6-MP metabolism to 6-TGN. A standardized protocol for this co-administration needs to be established and DNA-TGN incorporation dosage could be helpful for this recommendation. Long-term follow-up is required to evaluate impact on safety and efficacy of ALL maintenance therapy.