Our results suggest that pharmacokinetic monitoring during treatment with [E coli asparaginase] to identify patients with silent inactivation may be an effective strategy to improve the outcome of children and adolescents with ALL.
—Lynda M. Vrooman, MD, and colleagues
Findings from the Dana-Farber Cancer Institute ALL Consortium Protocol 00-01, recently reported by Lynda M. Vrooman, MD, Dana-Farber Cancer Institute, and colleagues in Journal of Clinical Oncology, indicate that postinduction dexamethasone and individualized dosing of Escherichia coli–derived L-asparaginase (Elspar) improved outcomes in children and adolescents with newly diagnosed acute lymphoblastic leukemia (ALL) compared with prednisone and fixed-dose E coli asparaginase.1 Prior studies had suggested that dexamethasone might have greater antileukemic activity than prednisone, and optimal dosing of asparaginase has remained undefined.
In the study, patients who achieved complete remission during induction treatment were eligible for two randomizations: (1) dexamethasone or prednisone given as 5-day pulses every 3 weeks; and (2) weekly E coli asparaginase given as a 25,000 IU/m2 fixed dose or as an individualized dose starting at 12,500 IU/m2 and adjusted every 3 weeks according to an algorithm to maintain nadir serum asparaginase activity between 0.10 and 0.14 IU/mL.
The study enrolled 492 evaluable patients aged 1 to 18 years between 2000 and 2004, of whom 473 had achieved complete remission. Of these, 408 patients (86%) were randomly assigned to prednisone (n = 207) or dexamethasone (n = 201) and 384 (81%) were randomly assigned to fixed-dose E coli asparaginase (n = 195) or individualized-dose E coli asparaginase (n = 189).
Overall, patients had a median age of 4.75 years (range, 1–18 years; 77% aged 1–9 years), 54% were male, 43% were high-risk, 79% had white blood cell (WBC) counts less than 50,000 × 109/L, 90% had B lineage immunophenotype, and 83% had CNS1 status. Over a median follow-up of 4.9 years, 5-year event-free survival among all patients was 80% and 5-year overall survival was 91%.
Estimates of event-free and overall survival included only patients who were alive and in complete remission at the start of intensification therapy. Five-year event-free survival was significantly greater in patients randomized to dexamethasone compared with those randomized to prednisone (90% vs 81%, P = .01). The trend toward superior event-free survival with dexamethasone was observed in patient subsets defined by age, risk group, phenotype, and other characteristics. There was no significant difference between groups in 5-year overall survival (95% vs 94%).
The overall incidence of osteonecrosis did not differ by steroid group. However, dexamethasone was associated with a significantly greater incidence in patients aged 10 to 18 years (23% vs 5%, P = .02). Among high-risk patients receiving dexamethasone, osteonecrosis occurred significantly more frequently in those aged 10 to 18 years than in younger patients 23% vs 3%, P < .01). Among high-risk patients receiving prednisone, there was no difference in incidence of osteonecrosis by age. There was no difference in overall incidence of bone fracture between steroid groups; however, among patients aged 10 to 18 years, there was a borderline significantly greater incidence in those receiving dexamethasone (29% vs 10%, P = .06).
Infections occurred significantly more frequently in dexamethasone patients overall (19% vs 11%, P = .03) and among dexamethasone patients aged 10 to 18 years (23% vs 2%, P = .004). One infection-related death occurred in a patient in the prednisone group.
Asparaginase Dose Comparison
There was no difference between groups with regard to E coli asparaginase toxicity; for the individualized-dose group vs the fixed-dose group, any toxicity occurred in 31% vs 32%, with asparaginase clinical allergy occurring in 21% vs 20%, pancreatitis in 6% vs 5%, and thrombosis in 7% and 8%. Moreover, there was no difference between individualized-dose and fixed-dose groups with regard to proportion of patients completing at least 25 weeks of asparaginase treatment (86% and 88%).
Five-year event-free survival was significantly greater in the individualized-dose group compared with the fixed-dose group (90% vs 82%, P = .04), with trends toward improved event-free survival with individualized dosing being observed in subgroups defined by age, risk group, phenotype, and other characteristics. There was no significant difference in 5-year overall survival between groups (96% vs 93%).
On the individualized-dose arm, patients with silent inactivation of asparaginase were prospectively identified based on persistently low nadir asparaginase enzyme levels and/or a low level in the presence of an anti-asparaginase antibody occurring in the absence of clinical allergy. Patients with silent inactivation on the individualized-dose arm were switched to an alternative asparaginase preparation (either Erwinia chrysanthemi [Erwinaze] or pegaspargase [Oncaspar]), similar to patients with clinical allergy. On the fixed-dose arm, patients with silent inactivation were not prospectively identified. Only those with clinical allergy to E coli asparaginase changed asparaginase preparations.
Significantly more patients in the individualized-dose group were switched from E coli asparaginase to another asparaginase preparation (34% vs 22%, P = .01); similar proportions on both arms switched due to clinical allergy (21% and 20%), but an additional 10% of individualized-dose patients switched due to silent inactivation. Most (90%) of these latter patients subsequently had at least one nadir serum asparaginase activity of 0.1 IU/mL or greater, while 9% of the fixed-dose group never had nadir serum asparaginase activity of at least 0.1 IU/mL, never developed clinical allergies, and never switched formulations.
The 5-year event-free survival rate among patients with persistently low nadir serum asparaginase activity who never switched preparations was similar in the individualized-dose group (78%, n = 12) and the fixed-dose group (76%, n = 18); in contrast, 5-year event-free survival was high in individualized-dose patients who switched to a different preparation due to silent inactivation (95%, n = 19). As noted by the investigators, these results “suggest that prospectively monitoring for the development of silent inactivation (and not just clinical allergy) and changing asparaginase preparations may improve outcome.”
A total of 361 patients participated in both randomization schemes. Proportional hazards analysis including only these patients showed that both dexamethasone (hazard ratio [HR] = 0.49, P = .02) and individualized-dose asparaginase (HR = 0.52, P = .04) were independent predictors of better event-free survival.
The investigators concluded:
Our study demonstrates that postinduction dexamethasone and [individualized dosing] of L-asparaginase improves [event-free survival] in pediatric patients with newly diagnosed ALL…. Dexamethasone was associated with a higher infection rate and, in older children, increased incidence of osteonecrosis and fracture … [and] we found no difference in asparaginase-related toxicity by [E coli asparaginase] dosing method…. Importantly, dexamethasone was associated with a better outcome in younger patients (1 to 10 years old) without any increased risk of skeletal toxicity. Considering its beneficial impact in reducing relapse risk, we continue to use dexamethasone in postinduction therapy for all age groups. Future studies should focus on minimizing the toxicity of dexamethasone in older pediatric patients without compromising efficacy. Our results suggest that pharmacokinetic monitoring during treatment with [E coli asparaginase] to identify patients with silent inactivation may be an effective strategy to improve the outcome of children and adolescents with ALL. ■
Disclosure: Dr. Lewis B. Silverman has served as a consultant or advisor for Enzon Pharmaceuticals and EUSA Pharma, Dr. Jeffrey G. Supko has received research funding from EUSA Pharma, Dr. Mary V. Relling has received research funding from Sigma-Tau Pharmaceuticals and Enzon Pharmaceuticals, and Dr. Stephen E. Sallan has received research funding from Enzon Pharmaceuticals and EUSA Pharma. All other authors of the study reported no potential conflicts of interest.
1. Vrooman LM, Stevenson KE, Supko JG, et al: 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. J Clin Oncol 31:1202-1210, 2013.