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.
|Hope, William W; Walsh, Thomas J; Goodwin, Joanne et al. (2016) Voriconazole pharmacokinetics following HSCT: results from the BMT CTN 0101 trial. J Antimicrob Chemother 71:2234-40|
|Wood, William A; Le-Rademacher, Jennifer; Syrjala, Karen L et al. (2016) Patient-reported physical functioning predicts the success of hematopoietic cell transplantation (BMT CTN 0902). Cancer 122:91-8|
|Burns, Linda J; Logan, Brent R; Chitphakdithai, Pintip et al. (2016) Recovery of Unrelated Donors of Peripheral Blood Stem Cells versus Recovery of Unrelated Donors of Bone Marrow: A Prespecified Analysis from the Phase III Blood and Marrow Transplant Clinical Trials Network Protocol 0201. Biol Blood Marrow Transplant 22:1108-1116|
|Steering Committee Of The Blood And Marrow Transplant Clinical Trials Network (2016) The Blood and Marrow Transplant Clinical Trials Network: An Effective Infrastructure for Addressing Important Issues in Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 22:1747-1757|
|Holtan, Shernan G; Verneris, Michael R; Schultz, Kirk R et al. (2015) Circulating angiogenic factors associated with response and survival in patients with acute graft-versus-host disease: results from Blood and Marrow Transplant Clinical Trials Network 0302 and 0802. Biol Blood Marrow Transplant 21:1029-36|
|Devine, Steven M; Owzar, Kouros; Blum, William et al. (2015) Phase II Study of Allogeneic Transplantation for Older Patients With Acute Myeloid Leukemia in First Complete Remission Using a Reduced-Intensity Conditioning Regimen: Results From Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncolo J Clin Oncol 33:4167-75|
|MacMillan, Margaret L; Robin, Marie; Harris, Andrew C et al. (2015) A refined risk score for acute graft-versus-host disease that predicts response to initial therapy, survival, and transplant-related mortality. Biol Blood Marrow Transplant 21:761-7|
|Khera, Nandita; Majhail, Navneet S; Brazauskas, Ruta et al. (2015) Comparison of Characteristics and Outcomes of Trial Participants and Nonparticipants: Example of Blood and Marrow Transplant Clinical Trials Network 0201 Trial. Biol Blood Marrow Transplant 21:1815-22|
|Levine, John E; Braun, Thomas M; Harris, Andrew C et al. (2015) A prognostic score for acute graft-versus-host disease based on biomarkers: a multicentre study. Lancet Haematol 2:e21-9|
|Jacobsen, Paul B; Le-Rademacher, Jennifer; Jim, Heather et al. (2014) Exercise and stress management training prior to hematopoietic cell transplantation: Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0902. Biol Blood Marrow Transplant 20:1530-6|
Showing the most recent 10 out of 14 publications