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，包括150多例同种异体移植。该计划自成立以来一直隶属于BMT临床试验网络，作为Case Western联盟的一部分，并通过临床试验应计和试验设计输入为CTN做出了重大贡献。作为申请成为核心临床中心的一部分，我们建议通过领导一项随机II期临床试验，比较沙格司亭（GM-CSF）联合普乐沙福与非格司亭（G-CSF）单药用于异基因同胞供体HSC动员，从而利用在造血干细胞（HSC）动员方面的广泛机构经验和专业知识。该建议的基础是先前观察到移植了GM-CSF动员的HSC的同种异体受者中急性GVHD的发生率显著低于移植了G-CSF动员的HSC的受者，以及临床前数据证明了GM-CSF和普乐沙福之间的协同作用。在临床前和临床研究中，我们已经表明，GM-CSF（小鼠）和plerixafor（人体）可动员辅助细胞和造血干细胞的独特亚群，当将其输注到移植受体中时，可导致快速多系移植并减少GvHD。减少GvHD的益处被以下事实所平衡：GM-CSF和plerixafor在人体中均为相对弱的动员剂，并且在25- 40%的时间内，在单次20升单采血液成分术后，不能达到移植所需的最低数量的CD 34 * 细胞/kg（>2 × 10（R））。因此，组合这些药剂可以克服单独使用每种药剂所见的这种明显减少的动员，同时呈现减少体内GvHD的独特作用。为了检验这一假设，我们在我们的机构启动了一项11期试点研究，以评估GM-CSF/plerixafor动员的可行性。我们预计将在未来8-12个月内完成计提。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进行一项更大规模的多中心随机II期研究，以比较该方法与当前标准治疗（G-CSF），主要终点是比较两组之间的急性GVHD发生率。我们的假设是，实验组将导致急性GVHD的发生率显著降低（40%），而不会影响收集的HSC数量或增加供体毒性。完成本研究需要在1-2年的预期时间内招募总计108例患者。如果成功，这项研究将通过减少移植相关发病率和死亡率的主要原因，在该领域向前迈出重要一步。相关性（参见说明）：急性GVHD仍然是异基因干细胞移植成功的重要障碍，也是移植相关发病率和死亡率的主要来源。用皮质类固醇治疗急性GVHD同样与相当大的长期毒性相关。因此，在不损害疾病复发风险的情况下降低急性GVHD的发生率将代表一个重大进展。

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.