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6-mercaptopurine plasma levels in children with acute lymphoblastic leukemia: relation to relapse risk and
Insights
Monitoring 6-mercaptopurine plasma levels in children with acute lymphoblastic leukemia is crucial. Consistent monitoring helps predict relapse risk and myelotoxicity, improving remission maintenance therapy outcomes.
Area of Science:
- Pediatric Oncology
- Pharmacokinetics
- Hematology
Background:
- Acute lymphoblastic leukemia (ALL) is the most common childhood cancer.
- Remission maintenance therapy with 6-mercaptopurine is standard for ALL.
- Individual variability in drug metabolism can affect treatment efficacy and toxicity.
Purpose of the Study:
- To investigate the relationship between plasma 6-mercaptopurine levels and treatment outcomes in children with ALL.
- To assess the impact of interpatient and intrapatient variability in drug concentrations on relapse and toxicity.
Main Methods:
- Plasma 6-mercaptopurine levels were measured using HPLC in 22 children receiving daily oral therapy.
- Repeated blood sampling (1-12 times per patient) was performed over 3 years.
- Correlations between drug levels (peak plasma concentration and AUC) and clinical events (relapse, myelotoxicity) were analyzed.
Main Results:
- Significant interpatient and intrapatient variations in 6-mercaptopurine plasma levels were observed.
- Lower mean peak plasma concentrations (<135 ng/ml) and AUC (<251 ng ml-1 h) were associated with a higher risk of relapse (p<0.05).
- Higher mean peak plasma concentrations (>166 ng/ml) and AUC (>363 ng/ml/h) were linked to severe myelotoxicity.
Conclusions:
- Repeatedly monitoring 6-mercaptopurine plasma levels is important for optimizing remission maintenance therapy in pediatric ALL.
- Therapeutic drug monitoring can help individualize treatment to minimize relapse risk and prevent toxicity.
- Understanding drug concentration variability is key to improving long-term outcomes for children with ALL.
Abstract:
Plasma levels of 6-mercaptopurine were determined in 22 consecutive children with acute lymphoblastic leukemia on oral remission maintenance therapy during the time period of August 1984 to January 1988. Each child received the drug once daily for up to 3 years and was studied repeatedly (1-12 times). An HPLC method was used for drug analysis. We found large interpatient variations in the mean peak plasma concentration (range of 50-424 ng/ml) and in the mean area under the concentration vs. time from 0-4 h curve (range of 82-637 ng ml-1 h). There were also pronounced variations between different sampling occasions in the same patient. Nine of the 22 patients had complications during the maintenance therapy. Five children with a mean peak plasma level below 135 ng/ml and a mean area under the curve (AUC) value below 251 ng ml-1 h relapsed (three in the central nervous system and two in the bone marrow). Both children with a bone marrow relapse died. Relapse risk was related to the AUC (p less than 0.05). Four children with a mean peak plasma level above 166 ng/ml and a mean AUC value above 363 ng/ml/h developed severe myelotoxicity, which necessitated a temporary cessation of the maintenance therapy. In addition, two patient relapsed 6 and 11 months after termination of maintenance therapy. Their mean peak and AUC values were not low but the concentrations decreased markedly towards the end of the maintenance period. The results indicate that the plasma levels of 6-mercaptopurine, when determined repeatedly, might be of significance for the outcome of the remission maintenance treatment.