A Randomized Trial of Tac/MTX/bortezomib vs Tac/MTXplacebo in Allogeneic HSCT

描述（由申请人提供）：急性和慢性GVHD仍然是广泛和成功应用全基因干细胞移植治疗血液恶性肿瘤的主要障碍。新策略正在制定中，需要大量患者入组。一种这样的策略是利用蛋白质体抑制剂硼替佐米的特殊特性。硼替佐米通过抑制蛋白酶体和改变核因子KB （NF-KB）代谢，影响多种信号通路，包括抑制白细胞介素6 （IL-6）介导的细胞生长、直接凋亡效应和抑制Th1细胞因子。由于CD4+ T细胞，特别是CD4+FOXP3+调节性T细胞（Treg）在GVHD患者中较低，因此与IL-6介导的作用的关系尤为相关。IL-6和TGF-P在调节Th17细胞与Treg之间的平衡中具有非常重要的作用。这两个T细胞亚群在GVHD的发展中具有突出的拮抗作用。lL-6与TGF-P共同诱导幼稚T细胞中Th17细胞的发育。相反，lL-6抑制TGF-P诱导的Treg分化。因此，在缺乏il -6的情况下，treg更受青睐。考虑到IL-6在改变Treg和Th17细胞之间的平衡中的关键作用，控制IL-6的产生可能有助于控制GVHD。因此，硼替佐米减弱IL- 6介导作用的能力表明其在预防GVHD方面的效用。它对可能介导GVHD的同种异体抗原呈递DC和同种异体反应效应T细胞也有抑制作用。硼替佐米联合他克莫司和甲氨蝶呤（tac/mtx/博特）在1 / 11期试验中被证明对预防GVHD有用。本申请的具体目的是通过一项III期、随机、双盲、多中心试验，比较tac/mtx/博特与tac/mtx/安慰剂，以确定硼替佐米是否能实质性地预防GVHD。髓系恶性肿瘤患者接受低强度，无关供体移植将被研究。将获得有关毒性、植入、免疫恢复、无事件和总生存期的数据。相关性（见说明书）；GVHD仍然是同种异体干细胞移植的关键障碍。BMT-CTN和DFCI/BWH移植项目的主要目标是控制或控制GVHD。这将有助于降低干细胞移植的发病率，提高血液恶性肿瘤患者的生存率。它也将对GVHD的病理生理学有重要的启示，可以应用于未来的研究。

DESCRIPTION (provided by applicant): 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. RELEVANCE (See instructions); 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.