Glucocorticoids in Lymphoblastic Leukemia

描述(申请人提供)：儿童急性淋巴细胞白血病(ALL)的治愈率已提高到80%以上。目前的治疗在很大程度上依赖于糖皮质激素的密集使用，特别是地塞米松，以及多种其他抗白血病药物。在现代所有临床试验中，糖皮质激素的主要剂量限制不良反应是糖皮质激素引起的骨坏死或缺血性坏死。长期以来，糖皮质激素引起的骨坏死一直被认为与成人和儿童因固体器官移植、肾病、哮喘、关节炎和其他自身免疫性疾病而接受治疗的糖皮质激素暴露有关。我们小组和其他人已经确定了影响糖皮质激素诱导的骨坏死的可能的治疗相关和宿主相关的危险因素。然而，任何试图降低这种不良反应风险的治疗改变都必须与预期的抗白血病效果的可能减弱相权衡。因此，需要临床前模型来描述治疗相关和宿主相关的骨坏死风险因素，但这些模型必须结合对这些相同因素如何影响疗效(即复发风险)的研究。我们团队在过去的两年里一直在开发第一个糖皮质激素诱导的骨坏死的小鼠模型，作为扩大我们先前对急性淋巴细胞白血病儿童风险因素研究的必要平台。利用我们的临床数据作为我们在小鼠模型上进行实验室研究的动力，我们的目标是全面阐明糖皮质激素诱导的骨坏死的治疗相关和宿主相关的危险因素，并评估这些危险因素对抗白血病效果的影响。这些转化性研究问题不能在患者身上解决。我们提出了三个目标：在多药方案中比较间断和连续地塞米松治疗后骨坏死的发生率；比较间断和连续地塞米松在两种急性淋巴细胞白血病小鼠模型中的抗白血病作用；以及比较地塞米松在野生型、半合子和纯合子缺乏胚系基因缺陷的小鼠中的抗白血病作用，这些缺陷被确定为与临床骨坏死的易感性有关。我们的长期目标是为所有不影响预期抗白血病效果的人设计毒性较小的含糖皮质激素的方案。

DESCRIPTION (provided by applicant): Cure rates in childhood acute lymphoblastic leukemia (ALL) have increased to over 80%. Current therapies depend heavily upon the intense use of glucocorticoids, particularly dexamethasone, in addition to multiple other antileukemic agents. The major dose-limiting adverse effect of glucocorticoids in modern ALL clinical trials is glucocorticoid-induced osteonecrosis or avascular necrosis. Glucocorticoid-induced osteonecrosis has long been known to be related to glucocorticoid exposure in adults and children treated for solid organ transplant, nephropathies, asthma, arthritis, and other autoimmune diseases. Our group and others have identified putative treatment-related and host-related risk factors influencing glucocorticoid-induced osteonecrosis. However, any changes to therapy to attempt to decrease the risk of this adverse effect must be weighed against the possible attenuation of desired antileukemic effects. Thus, preclinical models that allow for the characterization of treatment-related and host-related risk factors for osteonecrosis are needed, but they must be coupled with studies on how those same factors affect effectiveness (i.e., relapse risk). Our group has spent the last two years developing the first murine model for glucocorticoid-induced osteonecrosis, as the necessary platform for extending our prior studies of risk factors in children with ALL. Using our clinical data as the impetus for our laboratory studies in murine models, our goal is to fully elucidate treatment-related and host-related risk factors for glucocorticoid-induced osteonecrosis, and to evaluate the influence of these risk factors on antileukemic effectiveness. These translational research questions cannot be addressed in patients. Three aims are proposed: to compare the frequency of osteonecrosis following discontinuous vs continuous dexamethasone in a multiagent regimen; to compare the antileukemic effects of discontinuous vs continuous dexamethasone in two murine models of ALL; and to compare the osteonecrotic vs antileukemic effects of dexamethasone in mice that are wild-type, hemizygous, and homozygous deficient for germline genetic defects identified as related to clinical susceptibility to osteonecrosis. Our long term objective is to design less toxic glucocorticoid-containing regimens for ALL that do not compromise desired antileukemic effectiveness.