Sargrastim and Plerixafor vs. Filgrastim for Allogeneic Stem Cell Mobilization

描述(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骨髓移植项目之一，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投入为CTN做出了重大贡献。作为成为核心临床中心的应用的一部分，我们建议利用在造血干细胞动员方面的广泛机构经验和专业知识，领导一项随机的II期临床试验，比较沙拉替姆(GM-CSF)加普莱沙福和单独使用非格列格辛(G-CSF)动员异基因同胞捐赠者的HSC。这一建议的基础是事先观察到，与G-CSF动员的HSCs相比，使用GM-CSF动员的HSCs移植的异基因受者的急性GVHD发生率显著降低，以及临床前数据显示GM-CSF和普利沙福具有协同作用。在临床前和临床研究中，我们已经证明GM-CSF(在小鼠中)和plerixafor(在人类中)动员辅助细胞和造血干细胞的独特亚群，当将其注入移植受者时，可导致快速多系植入和减少GvHD。减少GvHD的好处与GM-CSF和plerixafor在人类中都是相对较弱的动员剂的事实相平衡，并导致在25%-40%的时间内无法达到移植所需的CD34*细胞/公斤的最低数量(&gt；2x10(R))。因此，结合这些药物可以克服单独使用每种药物时的这种明显的动员减少，同时呈现出在体内减少GvHD的独特效果。为了验证这一假设，我们在我们的机构启动了一项第11阶段的试验性研究，以评估GM-CSF/Plerixa动员的可行性。我们预计在未来8-12个月内完成应计。假设HSC动员效率和急性GVHD发生率的最低标准得到满足，我们将建议通过CTN进行一项更大规模的多中心随机第二阶段研究，将这种方法与目前的护理标准(G-CSF)进行比较，主要终点是比较两组急性GVHD的发生率。我们的假设是，实验ARM将显著降低(40%)急性GVHD的发生率，而不会损害收集的HSCs数量或增加供者的毒性。完成这项研究将需要在预期的1-2年期间累计108名患者。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一个主要原因，在该领域向前迈进一大步。相关性(见说明)：急性移植物抗宿主病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移植物抗宿主病也同样伴随着相当大的长期毒性。因此，在不降低疾病复发风险的情况下，降低急性移植物抗宿主病的发病率将是一个重大的进步。

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.