Postinduction dexamethasone and individualized dosing of Escherichia Coli L-asparaginase each improve outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia: results from a randomized study--Dana-Farber Cancer Institute ALL Consortium Protocol 00-01

Abstract

Purpose: We assessed the toxicity and efficacy of dexamethasone and a novel dosing method of Escherichia coli L-asparaginase (EC-Asnase) in children and adolescents with newly diagnosed acute lymphoblastic leukemia (ALL).

Patients and methods: Patients achieving complete remission (CR) on Dana-Farber Cancer Institute ALL Consortium Protocol 00-01 were eligible for random assignment to 1) dexamethasone or prednisone, administered as 5-day pulses, every 3 weeks, and 2) weekly EC-Asnase, administered as a 25,000 IU/m(2) fixed dose (FD) or individualized dose (ID) starting at 12,500-IU/m(2), adjusted every 3 weeks based on nadir serum asparaginase activity (NSAA) determinations.

Results: Between 2000 and 2004, 492 evaluable patients (ages 1 to 18 years) enrolled; 473 patients (96%) achieved CR. Four hundred eight patients (86%) participated in the corticosteroid randomization and 384 patients (81%) in the EC-Asnase randomization. With 4.9 years of median follow-up, dexamethasone was associated with superior 5-year event-free survival (EFS; 90% v 81% for prednisone; P = .01) but higher rates of infection (P = .03) and, in older children, higher cumulative incidence of osteonecrosis (P = .02) and fracture (P = .06). ID EC-Asnase had superior 5-year EFS (90% v 82% for FD; P = .04), but did not reduce the frequency of asparaginase-related toxicity. Multivariable analysis identified both dexamethasone and ID EC-Asnase as independent predictors of favorable EFS.

Conclusion: There was no overall difference in skeletal toxicity by corticosteroid type; dexamethasone was associated with more infections and, in older children, increased incidence of osteonecrosis and fracture. There was no difference in asparaginase-related toxicity by EC-Asnase dosing method. Dexamethasone and ID EC-Asnase were each associated with superior EFS. Monitoring NSAA during treatment with EC-Asnase may be an effective strategy to improve outcome in pediatric ALL.

Trial registration: ClinicalTrials.gov NCT00165178.

Fig 1.

Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia (ALL) Consortium Protocol 00-01 flow diagram. Patients with newly diagnosed ALL were enrolled (N = 498); 492 patients were considered evaluable. Of these 492 patients, 473 patients achieved complete remission (CR). Of the 473 patients who achieved CR, 408 patients (86%) participated in the corticosteroid random assignment and 384 (81%) in the asparaginase random assignment. Ph, Philadelphia chromosome. (*) Includes 13 patients with persistent leukemia at end of first month and three patients who did not recover blood counts by day 49.

Fig 2.

(A) Event-free survival (EFS) and overall survival (OS) for all patients. With a median follow-up of 4.9 years, the 5-year EFS for 492 evaluable patients was 80% (95% CI, 76% to 84%) and the 5-year OS was 91% (95% CI, 88% to 93%). (B) EFS results of corticosteroid randomization. The 5-year EFS for patients randomly assigned to prednisone was 81% (95% CI, 75% to 87%) compared with 90% (95% CI, 85% to 94%) for those randomly assigned to dexamethasone (P = .01). (C) EFS results of asparaginase randomization. The 5-year EFS for patients randomly assigned to fixed-dosing of asparaginase was 82% (95% CI, 75% to 87%) compared with 90% (95% CI, 84% to 94%) for those randomly assigned to individualized dosing (P = .04).