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Background: Osteonecrosis is a common toxicity associated with glucocorticoid (e.g., dexamethasone and prednisone) treatment of children with acute lymphoblastic leukemia (ALL), but risk factors are incompletely defined. Infections are also a common complication of ALL therapy. Lipopolysaccharide (LPS) is used experimentally to mimic infection-related systemic effects. To our knowledge, the contribution of systemic infections to the risk of glucocorticoid-induced osteonecrosis has not been investigated., Procedure: Patients with ALL on St. Jude Total Therapy XV (n = 365) were assessed for documented bacteremia prior to development of osteonecrosis, which was confirmed by MRI, and graded using the National Cancer Institute's Common Terminology for Adverse Events (version 3.0). In a preclinical model, Balb/cJ mice treated with dexamethasone plus or minus LPS were assessed for frequency and severity of osteonecrosis and arteriopathy., Results: We found that patients with ALL who experienced bacteremia had a higher frequency of symptomatic osteonecrosis (≥grade 2) than those who did not (OR: 1.88; 95% CI, 1.03-3.41, P = 0.038). LPS exacerbated experimental dexamethasone-induced osteonecrosis. Mice treated with dexamethasone plus LPS had a higher incidence of osteonecrosis (P = 0.00086) and arteriopathy (P = 0.0047) than did those treated with dexamethasone alone, and the severity of osteonecrosis (P = 0.00045) and arteriopathy (P = 0.0048) was also more pronounced with the addition of LPS treatment. The increase in osteonecrosis was not explained by any alteration of dexamethasone pharmacokinetics by LPS., Conclusions: These data identify systemic infection during ALL therapy as a novel risk factor in the development of glucocorticoid-induced osteonecrosis., (© 2019 Wiley Periodicals, Inc.)

Introduction: Combination therapy for acute lymphoblastic leukemia (ALL) is highly effective but results in significant toxicity including osteonecrosis. Asparaginase is known to potentiate both the antileukemic and osteonecrosis-inducing effects of dexamethasone. The schedule of dexamethasone alters osteonecrosis risk. However, the effects of the interaction with asparaginase are unknown when dexamethasone is given on a discontinuous schedule., Methods: Using the murine model of osteonecrosis, we compared the frequency of osteonecrosis in mice receiving discontinuous dexamethasone (3.5 days/ week) with mice receiving asparaginase and discontinuous dexamethasone. We then tested the effect on antileukemic efficacy using six pediatric ALL xenografts., Results: The addition of asparaginase to discontinuous dexamethasone did not alter the rate of osteonecrosis compared to dexamethasone alone (7/35 in dexamethasone with asparaginase combination vs. 10/36 in dexamethasone alone, p = 0.62) despite increasing steady-state plasma dexamethasone levels (103.9 nM vs. 33.4 nM, p = 9.2x10-7). Combination therapy with asparaginase and dexamethasone demonstrated synergistic antileukemic effects across all six xenografts studied., Conclusions: When discontinuous dexamethasone was given, its anti-leukemic activity synergized with asparaginase but the osteonecrosis-worsening effects of asparaginase (above dexamethasone alone) were not observed. Thus, there is a favorable drug interaction (unchanged toxicity, synergistic efficacy) between discontinuous dexamethasone and asparaginase., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: MVR has received research funding from Servier. No other authors have competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Osteonecrosis is a common dose-limiting toxicity of glucocorticoids. Data from clinical trials suggest that other medications can increase the risk of glucocorticoid-induced osteonecrosis. Here we utilized a mouse model to study the effect of asparaginase treatment on dexamethasone-induced osteonecrosis. Mice receiving asparaginase along with dexamethasone had a higher rate of osteonecrosis than those receiving only dexamethasone after 6 weeks of treatment (44% vs. 10%, P = 0.006). Similarly, epiphyseal arteriopathy, which we have shown to be an initiating event for osteonecrosis, was observed in 58% of mice receiving asparaginase and dexamethasone compared to 17% of mice receiving dexamethasone only (P = 0.007). As in the clinic, greater exposure to asparaginase was associated with greater plasma exposure to dexamethasone (P = 0.0001). This model also recapitulated other clinical risk factors for osteonecrosis, including age at start of treatment, and association with the systemic exposure to dexamethasone (P = 0.027) and asparaginase (P = 0.036). We conclude that asparaginase can potentiate the osteonecrotic effect of glucocorticoids.

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.

Patients undergoing glucocorticoid therapy for a variety of disorders, including autoimmune diseases and hematological malignancies, are at risk of developing osteonecrosis. Despite extensive research in both patients and animal models, the underlying pathogenesis remains unclear. Proposed inciting mechanisms include intravascular thrombotic occlusion, marrow fat hypertrophy, osteocyte and/or endothelial cell apoptosis, hypercoagulability, and vasoconstriction of specific arteries and arterioles supplying bone. Our laboratory has developed a model of steroid-induced osteonecrosis in BALBcJ mice which reflects clinically relevant exposures to glucocorticoids in which treated mice develop osteonecrosis of the distal femoral epiphysis when administered 4 to 8 mg/L dexamethasone in drinking water for 6 weeks. We identified lesions in arterioles supplying this area, with the mildest occurring in knees without any evidence of osteonecrosis. However, arteriopathy was more common among mice that did versus did not develop osteonecrosis (P < 0.0001); in mice with osteonecrosis, the associated vessels showed transmural necrosis and thickening of the vessel wall progressing to the point of luminal obstruction. In the most severe cases of osteonecrosis, end-stage lesions consisted of fully occluded vessels with marrow and bone necrosis involving the entire epiphysis. We propose that a primary arteriopathy is the initiating event in the genesis of steroid-induced osteonecrosis and provides a basis for future investigation of this disease process., (Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)