Reduction of Relapse Risk Through Incorporation of Novel Biologic Agents Following Reduced Intensity Haploidentical Donor Transplant for Acute Myeloid Leukemia.

通过在降低强度的单倍体相合供体移植治疗急性髓系白血病后加入新型生物制剂来降低复发风险。

• 批准号: 10187636
• 负责人: Asad Bashey
• 金额: $ 15.41万
• 依托单位: NORTHSIDE HOSPITAL ATLANTA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-22 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10187636
• 关键词: Acute Myelocytic Leukemia; Age; Allogenic; Antibodies; Bioavailable; Biological Products; Bone Marrow; Bone Marrow Transplantation; Cell physiology; Cyclophosphamide; Data; Developing Countries; Disease; Donor person; Exposure to; Failure; Family; Future; Hematopoietic; Homologous Transplantation; Immune system; Improve Access; Intervention; Lymphoid; Malignant Neoplasms; Minority; Monoclonal Antibodies; Morbidity - disease rate; Natural Killer Cells; Oral Administration; Outcome; Patients; Pharmaceutical Preparations; Phase; Preparation; Prior Therapy; Procedures; Progression-Free Survivals; Proteasome Inhibitor; Publishing; Race; Randomized; Regimen; Relapse; Reporting; Safety; Siblings; Testing; Time; Toxic effect; Transplantation; Treatment Failure; Work; anticancer activity; arm; base; chronic graft versus host disease; comorbidity; conditioning; cost; design; ethnic minority population; follow-up; graft vs host disease; hematopoietic cell transplantation; improved; leukemia relapse; mortality; neoplastic; novel; novel strategies; novel therapeutics; patient population; phase 2 study; phase II trial; phase III trial; pilot trial; post-transplant; prevent; racial minority; receptor binding; relapse prediction; relapse risk; standard of care; underserved community

Project Summary Lack of an HLA-matched donor has historically been a major obstacle to accessing allogeneic hematopoietic cell transplantation (allo-HCT) in many patients, particularly those from ethnic minorities and mixed race backgrounds. Recent work pioneered by a few centers including ours has demonstrated that the use of T- replete grafts from HLA-haploidenical donors and post-transplant cyclophosphamide to control alloreactivity (HIDTptCy) is safe with low rates of treatment related mortality and chronic GVHD. This advance has heralded the possibility of almost universal timely donor availability for patients that need allo-HCT. Furthermore, the relatively low graft-acquisition costs of HIDTptCy will improve access to allogeneic transplantation in underserved communities and developing nations. When HIDTptCy are performed for neoplastic diseases, relapse or progression of malignancy remains the most important cause of treatment failure. This is particularly so when non-myeloablative or reduced-intensity preparative regimens (RIC) are used. Administration of proteasome inhibitor drugs post allo-HCT may reduce relapse through direct anti-cancer activity as well potential stimulation natural killer (NK) cell alloreactivity. Furthermore, proteasome inhibitors have been demonstrated to inhibit graft-versus host disease. In an institutional pilot trial we have assessed the safety of the administration of the orally bioavailable proteasome inhibitor ixazomib for 12 months following HIDTptCy using RIC. Preliminary analysis of this trial has shown minimal toxicity with relatively low rates of relapse albeit with short follow-up. Another agent with potential to decrease relapse rates post HIDTptCy is the anti-SLAMF7 monoclonal antibody elotuzumab. This antibody has been shown to activate NK cells through binding of this receptor and may be particularly effective post HIDTptCy given the existing evidence that NK cell alloreactivity is important at preventing relapse in this setting. The activity of elotuzumab may also be augmented by co- exposure to a proteasome inhibitor. The proposed trial will be a randomized phase II study comparing the post- transplant administration of ixazomib versus elotuzumab versus ixazomib + elotuzumab during the first year post HIDTptCy using RIC for acute myeloid leukemia. It will specifically test the hypothesis that these agents alone or in combination will decrease the relapse rate which has been previously documented to be 43% at 12 months in this setting without use of these novel agents. Furthermore, it will test the hypothesis that these agents will not increase the rate of non-relapse mortality and will be well tolerated. Accrual to the three arms will be stratified for factors shown to be significant predictors of relapse following HIDTptCy using RIC for AML in multivariable analysis. This trial will also determine which of the three arms has the most promising outcomes and thus merits formal comparison to the standard-of care (HIDTptCy using RIC for AML without post-transplant novel agent use) in a future randomized phase III trial.

项目概要 缺乏 HLA 匹配的供体历来是获得同种异体造血的主要障碍 许多患者，特别是少数民族和混血患者接受细胞移植（allo-HCT） 背景。包括我们在内的一些中心最近开创的工作表明，使用 T- 补充来自 HLA 单倍体供体的移植物和移植后环磷酰胺以控制同种异体反应性 (HIDTptCy) 是安全的，治疗相关死亡率和慢性 GVHD 发生率较低。这一进展预示着 为需要同种异体 HCT 的患者提供几乎普遍的及时供体的可能性。此外， HIDTptCy 相对较低的移植获得成本将改善同种异体移植的机会 服务不足的社区和发展中国家。当针对肿瘤疾病进行 HIDTptCy 时， 恶性肿瘤的复发或进展仍然是治疗失败的最重要原因。这一点特别 因此，当使用非清髓性或降低强度的准备方案 (RIC) 时。管理 同种异体 HCT 后的蛋白酶体抑制剂药物也可以通过直接抗癌活性来减少复发 潜在刺激自然杀伤 (NK) 细胞同种异体反应性。此外，蛋白酶体抑制剂已被 被证明可以抑制移植物抗宿主病。在一项机构试点试验中，我们评估了 HIDTptCy 后口服生物可利用的蛋白酶体抑制剂伊沙佐米 12 个月 使用 RIC。该试验的初步分析表明，尽管毒性很小，但复发率相对较低 后续行动很短。另一种可能降低 HIDTptCy 后复发率的药物是抗 SLAMF7 单克隆抗体埃罗妥珠单抗。该抗体已被证明可以通过结合该抗体来激活 NK 细胞 鉴于 NK 细胞同种异体反应性的现有证据，HIDTptCy 后可能特别有效 在这种情况下对于预防复发很重要。 elotuzumab 的活性也可以通过共作用增强 接触蛋白酶体抑制剂。拟议的试验将是一项随机 II 期研究，比较术后 第一年期间伊沙佐米与埃罗妥珠单抗的移植给药对比伊沙佐米+埃罗妥珠单抗 HIDTptCy 后使用 RIC 治疗急性髓系白血病。它将专门检验这些代理的假设 单独或联合使用将降低复发率，此前记录为 12 岁时复发率为 43% 在这种情况下几个月不使用这些新型药物。此外，它将检验这些假设 药物不会增加非复发死亡率，并且耐受性良好。三臂应计 将使用针对 AML 的 RIC 对显示为 HIDTptCy 后复发的显着预测因子的因素进行分层 在多变量分析中。该试验还将确定三个臂中哪一个最有希望 的结果，因此值得与护理标准进行正式比较（HIDTptCy 使用 RIC 治疗 AML，无需 移植后新药的使用）在未来的随机 III 期试验中。