Targeting the leukemia microenvironment by CXCR4 inhibition in stem cell transpla

通过抑制干细胞移植中的 CXCR4 来靶向白血病微环境

• 批准号: 7656457
• 负责人: Marina Y Konopleva
• 金额: $ 33.88万
• 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: 2009-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7656457
• 关键词: AMD3100; Acute Myelocytic Leukemia; Address; Allogenic; Animal Model; Apoptosis; Ara-C; Biological; Blast Cell; Blood Circulation; Blood Component Removal; Bone Marrow; Busulfan; CSF3 gene; CXCR4 Receptors; CXCR4 gene; Cell Adhesion Molecules; Cell Cycle; Cell Death; Cell Survival; Cells; Clinical; Clinical Trials; Correlative Study; Coupled; Data; Development; Disease; Disease remission; Dose; Enrollment; Goals; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Homing; In complete remission; Induction of Apoptosis; Integrins; Leukemic Cell; Leukostasis; Life; Ligands; MAP Kinase Gene; Maintenance; Malignant - descriptor; Malignant Neoplasms; Marrow; Mediating; Molecular; Myeloid Leukemia; Normal Cell; Outcome; PI3K/AKT; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Play; Progression-Free Survivals; Recovery; Relapse; Relative (related person); Residual Neoplasm; Role; Safety; Signal Pathway; Signal Transduction; Staging; Stem cell transplant; Stem cells; Stromal Cells; Subgroup; Testing; Time; Toxic effect; Transplant Recipients; Treatment Efficacy; Treatment Failure; Treatment Protocols; analog; base; chemotherapy; cohort; conditioning; cytopenia; design; effective therapy; fludarabine; improved; in vivo; inhibitor/antagonist; innovation; leukemia; outcome forecast; peripheral blood; prospective; public health relevance; receptor; response; stem; tumor

DESCRIPTION (provided by applicant): The prognosis of patients with relapsed acute myeloid leukemia (AML) is extremely poor. Allogeneic stem cell transplantation is an effective treatment for AML in first remission, with approximately 60% achieving long-term progression-free survival. However, only 10-20% of patients with relapsed leukemia achieve durable remission. Likewise, patients with advanced remissions continue to have a relatively poor prognosis with stem cell transplantation and improved treatments are required. Our studies have demonstrated that microenvironment/leukemia interactions play a major role in chemoresistance of leukemic stem cells residing in the bone marrow niches. Our preliminary data indicate a key role for SDF-11/CXCR4 interactions in microenvironment-mediated chemoresistance. Inhibition of CXCR4 with the analogue of the only clinically available CXCR4 inhibitor AMD3100 results in mobilization of leukemic cells into the circulation and sensitization to chemotherapy, in part via blockade of the pro-survival signaling pathways. AMD3100 has been extensively used, alone or in combination with G-CSF, for the mobilization of normal hematopoietic stem cells into the circulation. Analysis of apheresis material from AML patients in remission mobilized with AMD3100/G- CSF demonstrated massive egress of AML cells into the peripheral blood, suggesting preferential mobilization of AML blasts. Based on these findings, we propose to test the hypothesis that mobilization of leukemic stem cells by CXCR4 inhibition and G-CSF will result in improved anti-leukemia activity of a standard preparative regimen followed by allogeneic stem cell transplantation. CXCR4 inhibitor AMD3100, G-CSF and busulfan/fludarabine chemotherapy will be administered sequentially to patients with advanced myeloid leukemias in the setting of allogeneic stem cell transplantation. This approach will also avoid potential concerns regarding the mobilization of normal stem cells and associated prolonged life-threatening cytopenias. To test this hypothesis, we propose the following Specific Aims: #1) To conduct a prospective phase I/II clinical trial to determine if addition of AMD3100 (plerixafor), a CXCR4 inhibitor, and G-CSF will improve the antileukemia effect of high dose busulfan-fludarabine conditioning regimen with allogeneic stem cell transplantation for the treatment of AML/MDS. G-CSF will be administered at a standard dose beginning on day -9 daily for 6 days; and AMD3100 will be given 8 h prior to Fludarabine and Busulfan starting on Day -7 for 4 doses. In Phase 1, a maximum of 24 patients will be treated in cohorts of three to determine the safe dose among the three doses 80, 160, 240 mcg/kg of AMD3100. Although the proposed treatment is likely to be safer in patients with low bulk disease because of a lower potential for leukostasis, we will start enrollment in Phase I with patients not in CR, to assure the safety of this approach. In Phase 2, a maximum of 32 additional patients, up to 16 per subgroup (in complete remission (CR) or not in remission (NCR)), will be treated at the AMD3100 dose chosen in Phase 1. The objective of Phase 2 is to determine if the combination of AMD3100 and G-CSF with busulfan, fludarabine will improve progression-free survival post allogeneic stem cell transplantation from an HLA-compatible donor compared to historical controls receiving busulfan-fludarabine alone. #2) to study the in vivo biological effects of disruption of the SDF-11/CXCR4 interactions by AMD3100. These correlative studies will evaluate the relative proportions of mobilized AML and/or normal progenitor cells, analyze expression of the target receptor and adhesion molecules, determine changes in cell cycle distribution of mobilized cells, and assess induction of apoptosis in AML vs normal cells. We anticipate that focus on stroma leukemia crosstalk may result in the development of strategies that alleviate the acquisition of a chemoresistant phenotype and enhance the efficacy of therapies in hematological malignancies and other tumor types. Further, differential analysis of mobilized leukemic and normal cells will provide crucial information for the incorporation of this approach in the up-front therapy for patients with untreated AML or in other hematologic malignancies. PUBLIC HEALTH RELEVANCE: The prognosis of AML patients upon relapse remains poor. AMD3100 and G-CSF are used for stem cell mobilization. In this study we will utilize AMD3100 / G-CSF combination to mobilize leukemic cells from bone marrow niches with the goal to enhance efficacy of busulfan/fludarabine conditioning regimen. This will be done in a setting of allogeneic hematopoietic stem cell transplantation in which hematologic recovery is derived from donor cells.

描述（由申请人提供）：复发性急性髓样白血病（AML）患者的预后非常差。同种异体干细胞移植是第一次缓解时AML的有效治疗方法，大约60％可实现长期无进展的生存。但是，只有10-20％的复发性白血病患者可实现持久的缓解。同样，随着干细胞移植的治疗，晚期缓解的患者的预后较差，并且需要改善治疗。我们的研究表明，微环境/白血病相互作用在居住在骨髓壁ni的白血病干细胞的化学上起着重要作用。我们的初步数据表明，在微环境介导的化学上，SDF-11/CXCR4相互作用的关键作用。用唯一临床上可用的CXCR4抑制剂AMD3100的类似物对CXCR4的抑制作用导致白血病细胞动员到循环中，并通过促进疗法的促进和化学疗法敏化，部分通过了促卵巢信号传导途径的阻断。 AMD3100已被广泛使用，单独或与G-CSF结合使用，以动员正常的造血干细胞进入循环系统。用AMD3100/g-CSF动员的缓解中AML患者的分离材料的分析表明，AML细胞大量出口到外周血中，表明优先动员了AML BLAST。基于这些发现，我们建议检验以下假设：通过CXCR4抑制和G-CSF动员白血病干细胞将导致标准制备方案的抗白血病活性改善，然后再进行同种异体干细胞移植。在同种异体干细胞移植的情况下，CXCR4抑制剂AMD3100，G-CSF和BUSULFAN/FLUDARABINE化学疗法将依次针对晚期髓样白血病患者。这种方法还将避免对正常干细胞的动员以及延长生命的胞质减少症的潜在问题。为了检验该假设，我们提出以下具体目的：＃1）进行I/II期临床试验，以确定是否添加AMD3100（PLERIXAFOR），CXCR4抑制剂和G-CSF是否会改善高剂量的堆积量链球菌 - 氟拉替氨甲列甲替型细胞的抗血清血症的效果，用于同种细胞的替代疗法。 G -CSF将从每天-9天开始以标准剂量进行6天；在Fludarabine和Busulfan在-7天开始进行4剂，将在8小时内给予AMD3100。在第1阶段中，最多将在三个同类中治疗24例患者，以确定三种剂量的80、160、240 mcg/kg AMD3100的安全剂量。尽管由于较低的白细胞症的潜力，我们提出的治疗可能会更安全，但我们将开始参加I期患者，以确保这种方法的安全性。 In Phase 2, a maximum of 32 additional patients, up to 16 per subgroup (in complete remission (CR) or not in remission (NCR)), will be treated at the AMD3100 dose chosen in Phase 1. The objective of Phase 2 is to determine if the combination of AMD3100 and G-CSF with busulfan, fludarabine will improve progression-free survival post allogeneic stem cell tr​​ansplantation from an与仅接受Busulfan-Fludarabine的历史对照组相比，与HLA兼容的供体相比。 ＃2）研究AMD3100对SDF-11/CXCR4相互作用破坏的体内生物学效应。这些相关研究将评估动员AML和/或正常祖细胞的相对比例，分析靶受体和粘附分子的表达，确定动员细胞的细胞周期分布的变化，并评估AML与正常细胞中凋亡的诱导。我们预计将重点放在基质上 白血病串扰可能会导致制定减轻化学抗性表型的策略，并增强疗法在血液学恶性肿瘤和其他肿瘤类型中的疗效。此外，对动员性白血病和正常细胞的差异分析将为未治疗AML或其他血液学恶性肿瘤患者的前期治疗中纳入这种方法至关重要的信息。公共卫生相关性：复发后AML患者的预后仍然很差。 AMD3100和G-CSF用于干细胞动员。在这项研究中，我们将利用AMD3100 / G-CSF组合来动员骨髓壁ni的白血病细胞，以增强Busulfan / Fludarabine调节方案的疗效。这将在同种异性造血干细胞移植的情况下完成，其中血液学恢复源自供体细胞。