Acute and chronic GVHD remain major barriers to the widespread and succesful application of allgoeneic stem cell transplantation in the management of hematologic malignancies. New strategies are under development that require large numbers of patients to be enrolled. One such strategy is to take advantage of specific characteristics of the proteosome inhibitor bortezomib. By inhibiting the proteasome and altering nuclear factor KB (NF-KB) metabolism, bortezomib affects multiple signaling pathways, including attenuation of interleukin-6 (IL-6)-mediated cell growth, a direct apoptotic effect, and suppression of Th1 cytokines. A relationship to IL-6 mediated effects is particularly pertinent, since CD4+ T cells and particularly the CD4+FOXP3+ regulatory T cells (Treg) are low in patients with GVHD. IL-6 and TGF-P have very important roles in regulating the balance between Th17 cells and Treg. These two T cell subsets have prominent and antagonistic roles in the development of GVHD. lL-6 together with TGF-P induces the development of Th17 cells from naive T cells. In contrast, lL-6 inhibits TGF-P -induced Treg differentiation. Thus, in the absence of lL-6, Tregs are favored. Given the critical role of IL-6 in altering the balance between Treg and Th17 cells, controlling lL-6 production may be useful in the control of GVHD. Thus, bortezomib's ability to attenuate IL- 6 mediated effects suggests its utility in the prevention of GVHD. It also has inhibitory effects on alloantigen presenting DC and alloreactive effector T cells that likely mediate GVHD. Bortezomib in combination with tacrolimus and methotrexate (tac/mtx/bort) has been shown to be useful in preventing GVHD in a phase l/ll trial.
The specific aim of this application is to use a phase III, randomized, double-blind, multicenter trial comparing tac/mtx/bort with tac/mtx/placebo to determine whether bortezomib will contribute substantively to the prevention of GVHD. Patients with myeloid malignancies undergoing reduced intensity, unrelated donor transplantation will be studied. Data on toxicity, engraftment, immunologic recovery, event-free, and overall survival will be obtained.
;GVHD remains a critical barrier to allogeneic stem cell transplantation. A principal goal of the BMT-CTN and of the DFCI/BWH transplantation program is to control or harness GVHD. This will function to reduce the morbidity of stem cell transplantation and improve the survival of patients with hematologic malignancies. It will also shed important light on the pathophysiology of GVHD that can be applied to future studies.
|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 22:1747-57|
|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|
|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 MULTICENTER STUDY. Lancet Haematol 2:e21-e29|
|BolaÃ±os-Meade, Javier; Logan, Brent R; Alousi, Amin M et al. (2014) Phase 3 clinical trial of steroids/mycophenolate mofetil vs steroids/placebo as therapy for acute GVHD: BMT CTN 0802. Blood 124:3221-7; quiz 3335|
|Yanik, Gregory A; Horowitz, Mary M; Weisdorf, Daniel J et al. (2014) Randomized, double-blind, placebo-controlled trial of soluble tumor necrosis factor receptor: enbrel (etanercept) for the treatment of idiopathic pneumonia syndrome after allogeneic stem cell transplantation: blood and marrow transplant clinical trials ne Biol Blood Marrow Transplant 20:858-64|
|Wagner Jr, John E; Eapen, Mary; Carter, Shelly et al. (2014) One-unit versus two-unit cord-blood transplantation for hematologic cancers. N Engl J Med 371:1685-94|
|BolaÃ±os-Meade, Javier; Wu, Juan; Logan, Brent R et al. (2013) Lymphocyte phenotype during therapy for acute graft-versus-host disease: a brief report from BMT-CTN 0302. Biol Blood Marrow Transplant 19:481-5|
|Vose, Julie M; Carter, Shelly; Burns, Linda J et al. (2013) Phase III randomized study of rituximab/carmustine, etoposide, cytarabine, and melphalan (BEAM) compared with iodine-131 tositumomab/BEAM with autologous hematopoietic cell transplantation for relapsed diffuse large B-cell lymphoma: results from the BMT C J Clin Oncol 31:1662-8|
|Pasquini, Marcelo C; Devine, Steven; Mendizabal, Adam et al. (2012) Comparative outcomes of donor graft CD34+ selection and immune suppressive therapy as graft-versus-host disease prophylaxis for patients with acute myeloid leukemia in complete remission undergoing HLA-matched sibling allogeneic hematopoietic cell transpl J Clin Oncol 30:3194-201|
|Levine, John E; Logan, Brent R; Wu, Juan et al. (2012) Acute graft-versus-host disease biomarkers measured during therapy can predict treatment outcomes: a Blood and Marrow Transplant Clinical Trials Network study. Blood 119:3854-60|
Showing the most recent 10 out of 20 publications