Plerixafor/G-CSF with Sorafenib for Acute Myelogenous Leukemia with FLT3-ITD Muta

Plerixafor/G-CSF 联合索拉非尼治疗带有 FLT3-ITD Muta 的急性髓性白血病

• 批准号: 7936811
• 负责人: MICHAEL ANDREEFF
• 金额: $ 20万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-21 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936811
• 关键词: Plerixafor; CSF; Sorafenib; Acute; Myelogenous

DESCRIPTION (provided by applicant): The prognosis of patients with relapsed AML harboring Fms-like tyrosine kinase 3 gene (FLT3) mutations is extremely poor. Studies have demonstrated that microenvironment/leukemia interactions play a major role in the chemoresistance of leukemic stem cells residing in bone marrow niches and that the SDF-1a/CXCR4 axis is a key regulator of this interaction. The applicant states they have recently discovered that Sorafenib, an agent approved by the FDA for the treatment of renal cell and hepatocellular carcinoma, is a superb inhibitor of FLT3-ITD (internal tandem duplication) signaling in AML (IC502nM) with high clinical activity in Phase 1 studies as a single agent, and in combination with Idarubicin and Ara-C3. Sorafenib has shown greater clinical activity in early studies than PKC-412 or CEP-701, probably because of lower protein binding. A study by Dr. Small from Johns Hopkins has shown complete inhibition of FLT3-ITD phosphorylation by serum from patients treated with Sorafenib at MD Anderson Cancer Center. This effect was not consistent with other inhibitors. In the applicant's Phase 1 study, Sorafenib alone eradicated leukemic cells from circulation and showed a 55% reduction of bone marrow blasts. High CXCR4 levels have been associated with poor prognosis, and FLT3 mutations have been reported to highly upregulate CXCR4, thus anchoring leukemic cells/stem cells firmly in the bone marrow microenvironment. These findings provide the rationale for the currently proposed studies. The applicant has recently reported that in preclinical leukemia studies, inhibition of CXCR4 with an analogue of the first clinically available and recently FDA approved CXCR4 inhibitor (AMD3100, Plerixafar) resulted in mobilization of leukemic cells into the circulation and sensitization to the pro-apoptotic effects of the FLT3 inhibitor Sorafenib. G-CSF is now known to cleave SDF-1 and has been shown to enhance the effect of CXCR4 blockade. The applicant and others have used G-CSF for "priming" AML to chemotherapy, and it has been widely used for the treatment of relapsed AML in the FLAG protocol. In recent studies of stem cell mobilization, G-CSF was found to greatly enhance the ability of CXCR4 inhibitor AMD3100 to mobilize hematopoietic stem cells. AMD3100 has been extensively used, in combination with G-CSF, for the mobilization of normal hematopoietic stem cells into the circulation and was recently approved by the FDA for this indication. AML patients in remission who were treated with AMD3100/G-CSF had massive egress of AML cells into the circulation, providing first proof of principle in leukemia patients. In addition, preferential mobilization of AML over normal cells has been found, further supporting the clinical development of this therapeutic concept. Of note, Sorafenib is not toxic to normal hematopoietic cells. Based on these findings, the investigator proposes to test the hypothesis that mobilization of leukemic stem cells by disrupting the SDF-1a/CXCR4 axis by AMD3100/G-CSF will result in improved anti-leukemia activity of Sorafenib in AML patients with mutated FLT3. CXCR4 inhibitor AMD3100, G-CSF and Sorafenib will be administered sequentially to patients with advanced myeloid leukemia.

描述（由申请人提供）： 携带 Fms 样酪氨酸激酶 3 基因 (FLT3) 突变的复发性 AML 患者的预后极差。研究表明，微环境/白血病相互作用在骨髓微环境中白血病干细胞的化疗耐药性中发挥着重要作用，并且 SDF-1a/CXCR4 轴是这种相互作用的关键调节因子。申请人表示，他们最近发现索拉非尼（Sorafenib）是 FDA 批准用于治疗肾细胞癌和肝细胞癌的药物，是 AML 中 FLT3-ITD（内部串联重复）信号传导的极好抑制剂（IC502nM），在 1 期研究中作为单一药物以及与 Idarubicin 和 Ara-C3 联合使用时具有很高的临床活性。索拉非尼在早期研究中显示出比 PKC-412 或 CEP-701 更大的临床活性，可能是因为蛋白质结合较低。约翰·霍普金斯大学的 Small 博士进行的一项研究表明，MD 安德森癌症中心接受索拉非尼治疗的患者的血清可完全抑制 FLT3-ITD 磷酸化。这种效果与其他抑制剂并不一致。 在申请人的第一阶段研究中，单独使用索拉非尼可以根除循环中的白血病细胞，并显示骨髓原始细胞减少 55%。高CXCR4水平与不良预后相关，据报道FLT3突变可高度上调CXCR4，从而将白血病细胞/干细胞牢固地锚定在骨髓微环境中。这些发现为当前提出的研究提供了理论依据。 申请人最近报道，在临床前白血病研究中，用第一个临床上可用且最近 FDA 批准的 CXCR4 抑制剂（AMD3100，Plerixafar）的类似物抑制 CXCR4 导致白血病细胞动员进入循环，并对 FLT3 抑制剂索拉非尼的促凋亡作用敏感。现在已知 G-CSF 可以裂解 SDF-1，并且已被证明可以增强 CXCR4 阻断的效果。申请人和其他人已使用G-CSF来“引发”AML化疗，并且在FLAG方案中已广泛用于治疗复发性AML。在最近的干细胞动员研究中，发现G-CSF可以大大增强CXCR4抑制剂AMD3100动员造血干细胞的能力。 AMD3100 已与 G-CSF 联合广泛用于将正常造血干细胞动员到循环系统中，并且最近获得 FDA 批准用于该适应症。 接受 AMD3100/G-CSF 治疗的缓解期 AML 患者有大量 AML 细胞进入循环系统，这为白血病患者提供了第一个原理证明。此外，还发现 AML 比正常细胞优先动员，进一步支持了这一治疗概念的临床发展。值得注意的是，索拉非尼对正常造血细胞没有毒性。 基于这些发现，研究人员提议检验以下假设：AMD3100/G-CSF 通过破坏 SDF-1a/CXCR4 轴来动员白血病干细胞，从而提高索拉非尼在 FLT3 突变的 AML 患者中的抗白血病活性。 CXCR4抑制剂AMD3100、G-CSF和索拉非尼将依次给予晚期粒细胞白血病患者。