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异基因干细胞移植治疗恶性血液病的主要障碍。正在制定新的策略，需要招募大量患者。一种这样的策略是利用蛋白体抑制剂硼替佐米的特定特性。通过抑制蛋白酶体和改变核因子KB（NF-κ B）代谢，硼替佐米影响多种信号传导途径，包括减弱白细胞介素-6（IL-6）介导的细胞生长、直接凋亡效应和抑制Th 1细胞因子。与IL-6介导的作用的关系是特别相关的，因为CD 4 + T细胞，特别是CD 4 + FOXP 3+调节性T细胞（Treg）在GVHD患者中是低的。IL-6和TGF-β在调节Th 17细胞和Treg之间的平衡中起着非常重要的作用。这两种T细胞亚群在GVHD的发展中具有显著和拮抗作用。IL-6与TGF-β一起诱导Th 17细胞从初始T细胞发育。相反，IL-6抑制TGF-β诱导的Treg分化。因此，在IL-6不存在的情况下，TdR是有利的。鉴于IL-6在改变Treg和Thl 7细胞之间的平衡中的关键作用，控制IL-6产生可用于控制GVHD。因此，硼替佐米减弱IL- 6介导的作用的能力表明其在预防GVHD中的效用。它还对可能介导GVHD的同种异体抗原呈递DC和同种异体反应性效应T细胞具有抑制作用。硼替佐米与他克莫司和甲氨蝶呤（tac/mtx/bort）的组合已在I/II期试验中显示可用于预防GVHD。本申请的具体目的是使用一项III期、随机、双盲、多中心试验，比较tac/mtx/bort与tac/mtx/安慰剂，以确定硼替佐米是否实质性有助于预防GVHD。将研究接受低强度无关供体移植的骨髓恶性肿瘤患者。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（请参阅说明）; GVHD仍然是异基因干细胞移植的关键障碍。BMT-CTN和DFCI/BWH移植计划的主要目标是控制或利用GVHD。这将有助于降低干细胞移植的发病率，提高恶性血液病患者的生存率。它也将揭示重要的GVHD的病理生理学，可应用于未来的研究。

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.