Mycophenylate Mofetil for Treatment of Chronic GVHD

描述（由申请方提供）：慢性移植物抗宿主病（GVHD）发生在约60%的患者中，这些患者在接受异基因供体造血干细胞移植治疗血液恶性肿瘤后存活超过3个月。 除复发性恶性肿瘤外，慢性GVHD是该患者人群死亡和发病的主要原因。 长期以来，高剂量糖皮质激素一直是治疗慢性GVHD的主要手段，但其代价是相当高的发病率。 该项目的四个具体目标是寻求开发治疗慢性GVHD的新方法。 具体目标1拟完成一项多中心、III期双盲临床试验，以评价霉酚酸酯（MMF）治疗新诊断的慢性GVHD的疗效。 在特定目标2中，将当前研究的数据与欧洲联盟申办的类似研究的数据合并，以获得联合分析结果。 除了测试MMF用于慢性GVHD初始全身治疗的有效性和安全性外，该分析还将寻求验证NIH共识发展项目关于慢性GVHD严重程度分期标准的建议，并验证慢性GVHD“重叠”变体中发生的急性GVHD的特定表现作为慢性GVHD诊断后生存的预后指标。 在特定目标3中，本研究的数据将用于验证既往回顾性研究中确定的预后因素，检测慢性GVHD诊断时存在的其他预后特征，并制定可用于未来临床试验的缓解标准。 在具体目标4中，本研究的数据将用于检验以下假设：开始全身免疫抑制治疗后6个月慢性GVHD表现的重大改善与糖皮质激素剂量的重大减少与随后慢性GVHD的早期消退和所有免疫抑制治疗的撤销相关。 公共卫生相关性：拟定研究的结果将1）确定在标准初始全身免疫抑制方案中添加吗替麦考酚酯治疗慢性移植物抗宿主病（GVHD）的疗效和安全性，2）提供丰富的信息来源，对未来临床试验的设计非常有用。 需要解决的一个重要问题是慢性GVHD患者的结局是否可以通过在疾病发作时进行更强化的免疫抑制治疗来改善。

DESCRIPTION (provided by applicant): Chronic graft-versus-host disease (GVHD) occurs in approximately 60% of patients who survive for more than 3 months after hematopoietic stem cell transplantation from an allogeneic donor for treatment of hematological malignancy. Apart from recurrent malignancy, chronic GVHD is the leading cause of death and morbidity in this patient population. High-dose glucocorticoids have long served as the mainstay of treatment for chronic GVHD, at the cost of considerable morbidity. The four specific aims of this project seek to develop new approaches for treatment of chronic GVHD. Specific Aim 1 proposes to complete a multicenter, phase III double-blind clinical trial to evaluate the efficacy of mycophenolate mofetil (MMF) for treatment of newly diagnosed chronic GVHD. In Specific Aim 2, data from the current study will be combined with data from a similar study sponsored by a European consortium for a joint analysis results. In addition to testing the efficacy and safety of MMF for initial systemic treatment of chronic GVHD, the analysis will seek to validate recommendations of the NIH Consensus Development project with respect to criteria for staging the severity the chronic GVHD, and to validate specific manifestations of acute GVHD that occur in the "overlap" variant of chronic GVHD as prognostic indicators of survival after the diagnosis of chronic GVHD. In Specific Aim 3, data from the current study will be used to validate prognostic factors identified in previous retrospective studies, to test other prognostic characteristics present at the diagnosis of chronic GVHD, and to develop response criteria that could be used in future clinical trials. In Specific Aim 4, data from the current study will be used to test the hypothesis that major improvement in manifestations of chronic GVHD combined with a major reduction of glucocorticoid dose at 6 months after starting systemic immunosuppressive treatment is associated with subsequent early resolution of chronic GVHD and withdrawal of all immunosuppressive treatment. PUBLIC HEALTH RELEVANCE: Results of the proposed studies will 1) define the efficacy and safety of adding mycophenolate mofetil to standard initial systemic immunosuppressive regimens for treatment of chronic graft-versus-host disease (GVHD), and 2) provide a rich source of information that will be highly useful for the design of future clinical trials. An important question to be addressed is whether the outcomes for patients with chronic GVHD can be improved by more intensive immunosuppressive treatment at the onset of the disease.