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.
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.