Sargrastim and Plerixafor vs. Filgrastim for Allogeneic Stem Cell Mobilization

描述（由申请人提供）：华盛顿大学的骨髓移植(BMT)/白血病项目是美国最大的项目之一，每年进行近400例移植，其中包括150多例同种异体移植。该项目自成立以来一直隶属于BMT临床试验网络，作为Case Western Consortium的一部分，并通过临床试验累积和试验设计输入为CTN做出了重大贡献。作为申请成为核心临床中心的一部分，我们建议利用在造血干细胞（HSC）动员方面的广泛机构经验和专业知识，领导一项随机II期临床试验，比较沙格拉替姆（GM-CSF）加普利沙福（plerixafor）与非格拉替姆（G-CSF）单独用于同种异体同胞供体HSC动员。该建议的基础是先前观察到与G-CSF动员的造血干细胞相比，GM-CSF动员的造血干细胞移植的同种异体受体急性GVHD的发生率显着降低，以及临床前数据显示GM-CSF和plerixafor之间的协同作用。在临床前和临床研究中，我们已经表明GM-CSF（小鼠）和plerixafor（人类）动员独特的辅助细胞和造血干细胞亚群，当注入移植受者体内时，会导致快速的多系植入和降低GvHD。减少GvHD的好处与以下事实相平衡：GM- CSF和plerixafor在人体中都是相对较弱的动员剂，并且在25- 40%的时间内，单次20升分离后，无法达到移植所需的最小CD34*细胞/kg （bbb20 × 10(R)）。因此，联合使用这些药物可以克服每种药物单独使用时明显减少的动员，同时在体内表现出降低GvHD的独特效果。为了验证这一假设，我们已经在我们的机构启动了第11阶段的试点研究，以评估GM-CSF/plerixa用于动员的可行性。我们预计在未来8-12个月内完成收益。假设满足HSC动员效率和急性GVHD发生率的最低标准，我们将建议通过CTN进行一项更大的多中心随机II期研究，将该方法与当前的护理标准（G-CSF）进行比较，主要终点是比较两组间急性GVHD的发生率。我们的假设是，实验臂将导致急性GVHD发生率显著降低（40%），而不影响收集的造血干细胞数量或增加供体毒性。完成这项研究将需要在1-2年的预期时间内累计108例患者。如果成功，这项研究将通过减少与移植相关的发病率和死亡率的主要原因，在该领域向前迈出重要的一步。相关性（见说明书）：急性GVHD仍然是同种异体干细胞移植成功的重要障碍，也是大量移植相关发病率和死亡率的来源。用皮质类固醇治疗急性GVHD同样具有相当大的长期毒性。因此，在不降低疾病复发风险的情况下，降低急性GVHD的发病率将是一项重大进展。

DESCRIPTION (provided by applicant): The Bone Marrow Transplant (BMT)/Leukemia Progrann at Washington University ranks among the largest in the United States, performing nearly 400 transplants annually, including over 150 allogeneic transplants. The program has been affiliated with the BMT Clinical Trials Network since its inception, as part of the Case Western Consortium, and has made significant contributions to CTN through clinical trials accrual and trial design input. As part of this application to become a Core Clinical Center, we propose to leverage extensive institutional experience and expertise in hematopoietic stem cell (HSC) mobilization by leading a randomized phase II clinical trial comparing sargrastim (GM-CSF) plus plerixafor with filgrastim (G-CSF) alone for allogeneic sibling donor HSC mobilization. The basis for this proposal is prior observation of a significantly lower incidence of acute GVHD in allogeneic recipients transplanted with GM-CSF mobilized HSCs compared with G-CSF mobilized HSCs, as well as pre-clinical data demonstrating synergy between GM-CSF and plerixafor. In preclinical and clinical studies we have shown that GM-CSF (in mice) and plerixafor (in humans) mobilize unique subsets of both accessory cells and hematopoietic stem cells that when infused into transplant recipients results in both rapid multilineage engraftment and reduced GvHD. The benefit of reduced GvHD is balanced by the fact that both GM- CSF and plerixafor are relatively weak mobilizing agents in humans and result in failure to reach the minimum number of CD34* cells/kg necessary for transplantation (>2 x 10(R)) after a single 20 liter apheresis between 25- 40% of the time. Therefore combining these agents may overcome this apparent reduced mobilization seen with each agent individually while presen/ing the unique effects of reducing GvHD in vivo. In order to test this hypothesis we have initiated a pilot phase 11 study at our institution to assess the feasibility of GM-CSF/plerixafor mobilization. We expect to complete accrual within the next 8-12 months. Assuming minimum criteria for HSC mobilization efficiency and acute GVHD incidence are met, we will propose to proceed with a larger multicenter randomized Phase II study through CTN to compare this approach with the current standard of care (G-CSF), with a primary endpoint of comparing the incidence of acute GVHD between the two arms. Our hypothesis is that the experimental arm will result in a significant reduction (40%) in the incidence of acute GVHD, without compromise in the number of HSCs collected or increased donor toxicity. Completion of this study would require accrual a total of 108 patients over an anticipated period of 1-2 years. If successful, this study would provide a significant step forward in the field, by reducing a major cause of transplant-related morbidity and mortality. RELEVANCE (See instructions): Acute GVHD remains a significant obstacle to successful outcomes in allogeneic stem cell transplantation, and a source of substantial transplant-related morbidity and mortality. Treatment of acute GVHD with corticosteroids is likewise associated with considerable long-term toxicity. Hence, reduction in the incidence of acute GVHD, without compromising the risk of disease relapse, would represent a significant advance.