Phase II study of topotecan in combination with dexamethasone, asparaginase, and vincristine in pediatric patients with acute lymphoblastic leukemia in first relapse

BACKGROUND. The authors evaluated the response rate, toxicity, and pharmacokinetics of topotecan given before standard induction therapy for childhood acute lymphoblastic leukemia (ALL) in first relapse. METHODS. Patients received topotecan (2.4 mg/m² daily as a 30-minute infusion) for 5 days before induction therapy with dexamethasone, vincristine, and asparaginase (native or pegylated Escherichia coli). The pharmacokinetics of topotecan were measured with the first dose of treatment in 23 patients. RESULTS. Twenty-eight of 31 patients with circulating blast cells were evaluable for response to topotecan. Twenty-five patients (89.3%) had a response (>25% decrease in circulating blast cells). The leukocyte count (P = .0001) and blast cell count (P = .0009) declined significantly during topotecan therapy. The median (range) topotecan lactone area under the concentration-time curve after the first dose was 85.4 L/hour/m² (range, 38.7-229.3 L/hour/m²). At die end of induction, 23 patients (74.2%) had a complete response, 1 patient (3.2%) had a partial response, 5 patients (16.1%) had no response, and 2 patients had died of infection. Six of the 17 patients who were studied for minimal residual disease (MRD) achieved MRD-negative status at the end of induction. The main toxicities were hematologic, gastrointestinal, and hepatic. The estimated 5-year survival rate, event-free survival rate, and cumulative incidence of second relapse were 24.1% ± 7.9%, 18.2% ± 7.4%, and 22.8% ± 8.7%, respectively, in the 29 patients who had a hematologic first relapse. CONCLUSIONS. A regimen comprising single-agent topotecan given with a standard 3-drug combination was effective in inducing remission in pediatric patients with relapsed ALL and was tolerated well.