Abstract
Osteonecrosis is one of the most common, serious, toxicities resulting from the treatment of acute lymphoblastic leukemia. In recent years, pediatric acute lymphoblastic leukemia clinical trials have used discontinuous rather than continuous dosing of dexamethasone in an effort to reduce the incidence of osteonecrosis. However, it is not known whether discontinuous dosing would compromise antileukemic efficacy of glucocorticoids. Therefore, we tested the efficacy of discontinuous dexamethasone against continuous dexamethasone in murine models bearing human acute lymphoblastic leukemia xenografts (n = 8 patient samples) or murine BCR-ABL+ acute lymphoblastic leukemia. Plasma dexamethasone concentrations (7.9 to 212 nM) were similar to those achieved in children with acute lymphoblastic leukemia using conventional dosages. The median leukemia-free survival ranged from 16 to 59 days; dexamethasone prolonged survival from a median of 4 to 129 days in all seven dexamethasone-sensitive acute lymphoblastic leukemias. In the majority of cases (7 of 8 xenografts and the murine BCR-ABL model) we demonstrated equal efficacy of the two dexamethasone dosing regimens; whereas for one acute lymphoblastic leukemia sample, the discontinuous regimen yielded inferior antileukemic efficacy (log-rank p = 0.002). Our results support the clinical practice of using discontinuous rather than continuous dexamethasone dosing in patients with acute lymphoblastic leukemia.
Highlights
With increasing intensity of treatment to improve the cure rates for acute lymphoblastic leukemia (ALL), toxic complications of chemotherapy have increased
For all dexamethasone-sensitive xenograft samples, there was improved leukemia-free survival (LFS) with at least one of the dexamethasone treatment regimens compared to no dexamethasone treatment
Because the cumulative incidence of symptomatic osteonecrosis in ALL patients can be as high as 10–20%,[1,2,3,4,5,6,7] efforts should be made to minimize treatment-related risk factors that may induce osteonecrosis without compromising antileukemic efficacy
Summary
With increasing intensity of treatment to improve the cure rates for acute lymphoblastic leukemia (ALL), toxic complications of chemotherapy have increased. The efficacy assessment was complicated by the additional vincristine, anthracycline, and asparaginase given during an additional course of reinduction.[15, 16] Many ALL clinical trials include a discontinuous glucocorticoid schedule, in which patients receive dexamethasone daily for 5–8 days, none for a period of some days, and daily again, in an attempt to reduce the incidence of osteonecrosis, without evidence on whether discontinuous and continuous dexamethasone dosing have equivalent antileukemic effect. We compared the antileukemic efficacy of these same dexamethasone regimens in a murine BCR-ABL Arf-/- preB cell ALL model in two different strains of mice [19] and in xenograft models of eight different primary ALL samples
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