Glucocorticoids in Lymphoblastic Leukemia

描述（申请人提供）：儿童急性淋巴细胞白血病（ALL）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大量使用，特别是地塞米松，此外还有多种其他抗白血病药物。在现代ALL临床试验中，糖皮质激素的主要剂量限制性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，糖皮质激素诱发的骨坏死一直被认为与成人和儿童在接受实体器官移植、肾病、哮喘、关节炎和其他自身免疫性疾病治疗时的糖皮质激素暴露有关。我们的研究小组和其他研究人员已经确定了影响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。然而，任何试图降低这种不良反应风险的治疗变化都必须与预期的抗白血病效果的可能衰减进行权衡。因此，需要建立临床前模型，以确定骨坏死的治疗相关和宿主相关危险因素的特征，但它们必须与研究这些相同因素如何影响疗效（即复发风险）相结合。我们的团队在过去的两年里开发了第一个糖皮质激素诱导的骨坏死小鼠模型，作为扩展我们之前对ALL儿童危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中进行实验室研究的动力，我们的目标是充分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。这些转化研究的问题不能在患者身上解决。提出了三个目的：比较多药方案中间断地塞米松治疗与连续地塞米松治疗后骨坏死的发生率；比较间断地塞米松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；并比较地塞米松对野生型、半合子和纯合子小鼠的骨坏死和抗白血病效果，这些小鼠的种系遗传缺陷被确定为与骨坏死的临床易感性相关。我们的长期目标是设计毒性较低的含糖皮质激素的ALL治疗方案，同时不影响预期的抗白血病效果。

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.