Systemic Exposure to Dexamethasone and Asparaginase Affects Risk of Relapse in Children with Acute Lymphoblastic Leukemia

Dexamethasone and asparaginase are key components of acute lymphoblastic leukemia (ALL) treatment. We previously observed that patients with a higher systemic exposure to asparaginase had a lower clearance and thus a higher systemic exposure to dexamethasone (Yang et al, J Clin Oncol; 26:1932–9, 2008). Whether interpatient dexamethasone pharmacokinetic variability contributes to relapse risk is not known. We determined the prognostic influence of dexamethasone plasma clearance and of anti-asparaginase antibody levels on risk of relapse via multivariate analyses after adjusting for standard clinical and biologic prognostic factors (treatment risk arm, age, race, initial leukocyte count, ALL immunophenotype, minimal residual disease and CNS status) in 410 children with ALL who were treated on a front-line clinical trial (St. Jude Total XV) and were evaluable for the pharmacologic measures through at least 22 weeks from diagnosis. Dexamethasone apparent clearance (average ± standard deviation) was significantly (p = 3 ×10⁻⁸) higher in patients with detectable serum levels of anti-asparaginase antibodies (17.7 ± 18.6 L/h/m²) compared to patients with no detectable antibodies (10.6 ± 5·99 L/h/m²), consistent with higher exposure to asparaginase being associated with higher exposure to dexamethasone. In multivariate analysis, higher dexamethasone clearance was associated with a higher risk of any relapse (hematologic, CNS, combined, and other; hazard ratio 1.56, 95% confidence interval, 1.1–2.19; p = 0.01) and of any CNS relapse (CNS and CNS + hematologic; hazard ratio 1.93, 95% confidence interval 1.1–3.37; p = 0.02). CNS relapse was also more frequent in patients with vs. those without anti-asparaginase antibodies (5-year cumulative risk of 4.9% vs. 1.8%; p = 0.02). Classification and regression tree analysis revealed that a dexamethasone clearance greater than 37.5 L/h/m² might distinguish patients at higher risk of relapse (Figure). In conclusion, the presence of anti-asparaginase antibodies is associated with increased systemic clearance of dexamethasone. Lower exposure to dexamethasone and asparaginase are associated with an increased risk of relapse in children with ALL treated with contemporary therapy.