6-mercaptopurine Metabolites as Predictors of Neutropenia and Hepatotoxicity in Pediatric Acute Lymphoblastic Leukemia

Background: 6-Mercaptopurine (6-MP) is used to treat childhood acute lymphoblastic leukemia (ALL). The concentrations of 6-MP metabolites in red blood cells (RBCs), specifically 6-thioguanine (6-TG) and 6-methyl mercaptopurine nucleotides (6-MMP), are associated with the drug’s therapeutic responses and adverse effects.  Objectives: This study aimed to assess the metabolites of 6-MP and their relationships with hepatotoxicity and neutropenia in the erythrocytes of children with ALL. Methods: A total of 32 children with ALL treated with 6-MP were included in this study. The patients were assigned to the case group (13 patients with neutropenia and hepatotoxicity) and the control group (19 patients without neutropenia and hepatotoxicity). Each child’s biochemical parameters (leukocyte count, alanine transaminase, aspartate transferase, lactate dehydrogenase, bilirubin levels, urea levels, creatinine, and creatinine clearance) were also measured. The concentrations of 6-MP metabolites were measured using high-performance liquid chromatography (HPLC) and analyzed by mixed model analysis. Results: No significant differences were found between the case and control groups regarding gender, age, body mass index, drug dose, and the number of dose reductions. However, there is a significant relationship between the case and control groups regarding white blood cells (WBC) (P=0.01), neutrophil count (P=0.001), and absolute neutrophil count (ANC) (P=0.0002). Our results indicated a strong inverse correlation between high concentrations of 6-TG and WBC counts, neutrophil counts, and ANC. Furthermore, a direct correlation was observed between the levels of metabolites (6-TG and 6-MMP) and hepatotoxicity. Conclusions: Our findings support the association between the levels of 6-MP metabolites and adverse effects, including neutropenia and hepatotoxicity. These findings also emphasize the importance of personalized treatment approaches, especially therapeutic drug monitoring in cases with severe unexplained adverse effects, to optimize therapeutic outcomes in pediatric ALL patients.

6-mercaptopurine Metabolites as Predictors of Neutropenia and Hepatotoxicity in Pediatric Acute Lymphoblastic Leukemia Keywords:

Acute lymphoblastic leukemia (ALL) , 6- Mercaptopurine (6-MP) , Neutropenia , Hepatotoxicity