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.