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

Schwartz, Cindy L.
Thompson, E. Brad
Gelber, Richard D.
Young, Mary L.
Chilton, David
Cohen, Harvey J.
Sallan, Stephen E.

From the Departments of Pediatric Oncology and Biostatistical Science, Dana-Farber Cancer Institute, and Division of Hematology/Oncology Children’s Hospital, Boston, MA; University of Texas Medical Branch, Galveston, TX; Johns Hopkins Oncology Center, Baltimore, MD; and Stanford University Medical Center, Palo Alto, CA.

Submitted January 6, 2000; accepted October 26, 2000.

Supported in part by grants no. CA68484 and CA06516 from the National Institutes of Health and National Cancer Institute and the Walls Medical Research Foundation (to E.B.T.).

Address reprint requests to Cindy L. Schwartz, MD, Division of Pediatric Oncology CMC-800, Johns Hopkins Oncology Center, 600 N. Wolfe St, Baltimore, MD 21287.

Journal of Clinical Oncology 19(4):p 1040-1046, February 15, 2001.

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.