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A phase II trial of continuous-infusion 6-mercaptopurine for childhood leukemia
P C Adamson1, S Zimm, A H Ragab
1Pediatric Branch, National Cancer Institute, Bethesda, MD 20892.
Insights
Continuous intravenous 6-mercaptopurine (6MP) showed limited effectiveness in pediatric leukemia patients with recurrent acute lymphoblastic leukemia (ALL). While overcoming oral 6MP bioavailability issues, significant hepatotoxicity was observed.
Area of Science:
- Pediatric Oncology
- Pharmacology
- Hematology
Background:
- Oral 6-mercaptopurine (6MP) has variable bioavailability, limiting its efficacy in treating refractory leukemia.
- Continuous intravenous infusion of 6MP was explored to improve drug delivery and therapeutic outcomes.
- Previous Phase I trials informed the dosing strategy for this Phase II study.
Purpose of the Study:
- To evaluate the efficacy and safety of continuous intravenous 6-mercaptopurine (6MP) in pediatric patients with refractory leukemia.
- To assess response rates in children with acute lymphoblastic leukemia (ALL) and acute nonlymphocytic leukemia (ANLL).
- To identify dose-limiting toxicities associated with this administration route.
Main Methods:
- A Phase II pediatric trial administered 6MP at 50 mg m-2 h-1 for 48 hours via continuous intravenous infusion.
- Forty children with relapsed/refractory acute lymphoblastic leukemia (ALL) and 17 with acute nonlymphocytic leukemia (ANLL) were enrolled.
- Treatment response and adverse events, particularly hepatotoxicity and mucositis, were monitored.
Main Results:
- One complete and one partial response were observed in 40 pediatric ALL patients previously treated with oral 6MP.
- No responses were seen in 17 patients with refractory acute nonlymphocytic leukemia (ANLL).
- Reversible hepatotoxicity occurred in approximately 50% of patients, identified as the primary dose-limiting toxicity; mucositis was infrequent.
Conclusions:
- Continuous intravenous 6MP administration improves bioavailability over oral intake but demonstrates limited activity as an induction agent in pediatric ALL.
- The observed hepatotoxicity necessitates careful monitoring in this patient population.
- Further research may be needed to optimize 6MP infusion strategies or explore combination therapies for refractory pediatric leukemia.
Abstract:
A phase II pediatric trial of a continuous intravenous infusion of 6-mercaptopurine (6MP) in patients with refractory leukemia was performed. The dosing schedule, 50 mg m-2 h-1 for 48 h, was based on the results of a previous phase I trial of this approach. Among the 40 children treated for acute lymphoblastic leukemia (ALL), all of whom had received prior therapy with oral 6MP, 1 complete and 1 partial response were achieved. No response was observed in 17 patients with refractory acute nonlymphocytic leukemia (ANLL). Reversible hepatotoxicity, the primary dose-limiting toxicity, was observed in approximately 50% of cases. Mucositis was encountered infrequently and was usually not severe. 6MP given on the present continuous intravenous infusion schedule overcomes the limited and variable bioavailability of oral 6MP but shows limited activity as induction agent in children with recurrent ALL.