Improved Response With Higher Corticosteroid Dose in Children With Acute Lymphoblastic Leukemia

Abstract

PURPOSE: We investigated whether there was a dose-response relationship for the use of corticosteroids in childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Three hundred sixty-nine patients, ages 1 to 18 years with ALL, were randomly assigned to receive one of four different doses of corticosteroid (prednisolone 40 mg/m2/d or dexamethasone 6, 18, or 150 mg/m2/d) administered as a 3-day, single-drug window before initiation of standard, multidrug induction chemotherapy. Corticosteroid drug response was measured by reduction in bone marrow blast counts and absolute peripheral blast counts after 3 days. Glucocorticoid receptor (GCR) number and the effective concentration of dexamethasone resulting in a 50% reduction of leukemic cell viability in vitro (EC-50) were evaluated at days 0 and 3. RESULTS: Increasing dexamethasone doses resulted in greater marrow blast response (P = .007), with a similar trend in peripheral-blood blast response. High-dose corticosteroid regimens (dexamethasone 18 or 150 mg/m2/d) elicited better responses than standard doses of dexamethasone or prednisone (bone marrow, P = .002; peripheral blasts, P = .05). Among patients treated with standard-dose corticosteroids, 38% with resistant (EC-50 > 10-7) peripheral blasts had a good response compared with 92% with sensitive (EC-50 < 10-7) peripheral blasts (P = .01). In contrast, there was no differential response according to EC-50 group after high-dose corticosteroids. Similarly, an association between response and GCR on peripheral-blood blasts was noted after standard-dose corticosteroid regimens but not after high-dose corticosteroid regimens. CONCLUSION: Response of ALL to glucocorticoid therapy increased with dose. Higher-dose corticosteroid treatment abrogated the effect of relative drug insensitivity and of low GCR on peripheral blasts.