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

描述（由申请人提供）： 携带FLT 3基因突变的复发性AML患者的预后极差。研究表明，微环境/白血病相互作用在驻留在骨髓龛中的白血病干细胞的化学抗性中起主要作用，并且SDF-1a/CXCR 4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（FDA批准用于治疗肾细胞癌和肝细胞癌的药物）是AML中FLT 3-ITD（内部串联重复）信号传导的极好抑制剂（IC 502 nM），在I期研究中作为单药以及与艾达鲁肽和Ara-C3联合给药具有高临床活性。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，可能是因为较低的蛋白结合。来自约翰霍普金斯的Small博士的一项研究显示，来自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FLT 3-ITD磷酸化。这种效果与其他抑制剂不一致。 在申请人的1期研究中，索拉非尼单独从循环中根除白血病细胞，并显示骨髓原始细胞减少55%。高CXCR 4水平与预后不良相关，据报道FLT 3突变可高度上调CXCR 4，从而将白血病细胞/干细胞牢固地锚定在骨髓微环境中。这些发现为目前拟议的研究提供了依据。 申请人最近报道，在临床前白血病研究中，用第一种临床可用且最近FDA批准的CXCR 4抑制剂（AMD 3100，普乐沙法）的类似物抑制CXCR 4导致白血病细胞动员进入循环并对FLT 3抑制剂索拉非尼的促凋亡作用敏感。目前已知G-CSF可切割SDF-1，并已显示可增强CXCR 4阻断的效果。申请人和其他人已经使用G-CSF用于“引发”AML化疗，并且其已经在FLAG方案中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极大地增强了CXCR 4抑制剂AMD 3100动员造血干细胞的能力。AMD 3100已广泛用于与G-CSF联合动员正常造血干细胞进入循环，最近FDA批准用于该适应症。 接受AMD 3100/G-CSF治疗的缓解期AML患者的AML细胞大量流出到循环中，这为白血病患者提供了第一个原理证明。此外，已经发现AML相对于正常细胞的优先动员，进一步支持这种治疗概念的临床开发。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，研究者建议检验以下假设：通过AMD 3100/G-CSF破坏SDF-1a/CXCR 4轴动员白血病干细胞将导致索拉非尼在FLT 3突变的AML患者中的抗白血病活性改善。CXCR 4抑制剂AMD 3100、G-CSF和索拉非尼将依次给予晚期髓性白血病患者。

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.