Bortezomib and Idarubicin in the Treatment of AML

描述（由申请人提供）：急性髓性白血病（AML）是一种造血细胞的克隆性恶性疾病，以异常母细胞增殖和造血功能受损为特征。虽然具有良好细胞遗传学的年轻患者在剂量强化化疗中有越来越好的预后，但他们只占该疾病患者的少数。有不良细胞遗传学、高龄（>=60）和既往血液病的患者完全缓解的发生率降低；即使在那些获得初步缓解的患者中，大多数复发和生存率也很差。显然，这是一个需要新疗法的患者群体。我们实验室的研究表明，在体内容易达到的浓度下，蛋白酶体抑制剂硼替佐米与蒽环类药物依达柔比星联合使用，可以在体外快速诱导人原发性AML细胞凋亡。我们实验室的研究表明，以这种方式诱导的细胞凋亡与原发性AML细胞的几种特异性变化相关。在用硼替佐米和依达柔比星治疗后，可以迅速观察到NF-kappaB的强烈抑制，表明重要的生存信号受到抑制。此外，治疗后的AML细胞中p53蛋白水平显著升高，提示p53介导的基因表达变化可能参与了这种联合治疗诱导的细胞凋亡。根据我们的观察，我们建议将新型药物硼替佐米和依达柔比星用于新诊断、老年或复发的AML患者进行I期和II期临床试验。在体内监测细胞凋亡的诱导，以及重要的相关研究分析NF-kappaB的抑制和p53表达的增加。我们预计，通过这种新的治疗方案，我们将观察到有效的抗白血病活性和完全的临床缓解。

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is a clonal, malignant disease of hematopoietic cells, characterized by the proliferation of abnormal blast cells and impaired hematopoiesis. While younger patients with favorable cytogenetics have increasingly favorable outcomes with dose intensive chemotherapy, they represent a distinct minority of patients with this disease. Patients with unfavorable cytogenetics, advanced age (>=60), and antecedent hematologic disorders have a decreased incidence of complete remission; even in those who achieve an initial remission, the majority relapse and survival is poor. Clearly this is a patient population for whom novel therapies are needed. Studies from our laboratory have demonstrated that the combination of the proteasome inhibitor, bortezomib, with the anthracycline, idarubicin, at concentrations readily achievable in vivo can rapidly induce apoptosis in primary human AML cells in vitro. Studies from our laboratory have demonstrated that apoptosis induced in this fashion correlates with several specific changes in primary AML cells. Following treatment with bortezomib and idarubicin strong inhibition of NF-kappaB is rapidly observed, indicating inhibition of important survival signals. In addition, levels of p53 protein are strongly increased in treated AML cells, suggesting p53 mediated changes in gene expression might be involved in the apoptosis induced by this combination. Based on our observations we propose a phase I and II clinical trial with the novel agent, bortezomib, and idarubicin given to newly diagnosed, elderly or relapsed AML patients. Monitoring for in vivo induction of apoptosis, as well as, important correlative studies assaying for inhibition of NF-kappaB and increased p53 expression are proposed. We anticipate that with this novel treatment regimen we will observe potent anti-leukemic activity and complete clinical remissions.