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

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AML患者预后极差。研究表明，微环境/白血病的相互作用在白血病干细胞的化疗耐药中起主要作用，SDF-1a/CXCR4轴是这种相互作用的关键调节因子。申请人声明，他们最近发现，索拉非尼是FDA批准用于治疗肾细胞和肝细胞癌的药物，是急性髓细胞白血病(IC502 NM)中Flt3-ITD(内部串联复制)信号的极佳抑制剂，在1期研究中作为单一药物并与伊达比星和Ara-C3联合使用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斯莫尔博士的一项研究表明，MD Anderson癌症中心接受索拉非尼治疗的患者的血清完全抑制了Flt3-ITD的磷酸化。这种作用与其他抑制剂不一致。 在申请者的第一阶段研究中，索拉非尼单独根除了血液循环中的白血病细胞，并显示骨髓母细胞减少了55%。CXCR4水平高与预后不良有关，据报道，Flt3突变可高度上调CXCR4，从而使白血病细胞/干细胞牢固地锚定在骨髓微环境中。这些发现为目前提议的研究提供了理论基础。 申请人最近报告说，在临床前白血病研究中，用第一个临床可用的、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到循环中，并使其对Flt3抑制剂Sorafenib的促凋亡作用敏感。目前已知G-CSF可裂解SDF-1，并已被证明可增强CXCR4的阻断作用。申请人和其他人使用G-CSF进行化疗，并在FLAG方案中被广泛用于治疗复发的AML。在最近的干细胞动员研究中发现，G-CSF能显著增强CXCR4抑制剂AMD3100动员造血干细胞的能力。AMD3100已被广泛用于动员正常的造血干细胞进入循环，并与G-CSF联合使用，最近被FDA批准为这一适应症。 在接受AMD3100/G-CSF治疗的AML缓解期患者中，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则性证据。此外，AML细胞的优先动员也被发现，进一步支持了这一治疗概念的临床发展。值得注意的是，索拉非尼对正常的造血细胞没有毒性。 基于这些发现，研究人员建议验证这样一种假设，即通过AMD3100/G-CSF通过破坏SDF-1a/CXCR4轴来动员白血病干细胞将导致具有突变Flt3的AML患者索拉非尼抗白血病活性的改善。CXCR4抑制剂AMD3100、G-CSF和索拉非尼将依次用于晚期髓系白血病患者。

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.