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）：