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.

项目摘要 缺乏HLA匹配的供体历史上是获得同种异体造血的主要障碍 许多患者，尤其是少数民族和混合种族的细胞移植（Allo-HCT） 背景。包括我们包括我们的几个中心的最新工作表明，使用t- 来自HLA - 荷兰供体和移植后环磷酰胺的移植移植物，以控制同种异体反应性 （HIDTPTCY）安全，治疗率较低，相关死亡率和慢性GVHD是安全的。这次进步预示了 对于需要Allo-HCT的患者来说，几乎普遍及时的供体可用性的可能性。此外， 相对较低的植物疗法成本将改善获得同种异体移植的机会 服务不足的社区和发展中国家。当对肿瘤疾病进行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。尤其是 因此，当使用非毛囊或降低强度制备​​方案（RIC）时。管理 蛋白酶体抑制剂在Allo-HCT后也可以通过直接抗癌活性减少复发 潜在的刺激自然杀手（NK）细胞同质性。此外，蛋白酶体抑制剂已经 证明可以抑制移植物抗宿主疾病。在一项机构试验审判中，我们评估了 hidtptcy后，口服可生物可利用的蛋白酶体抑制剂ixazomib 12个月 使用RIC。该试验的初步分析表明，尽管复发率相对较低，但毒性很小 随访短。另一个有潜力降低HIDTPTCY复发率的代理商是抗Slamf7 单克隆抗体elotuzumab。该抗体已被证明通过这种结合来激活NK细胞 鉴于现有的证据表明NK细胞同质反应性，受体，并且可能是特别有效的。 在这种情况下防止复发很重要。 Elotuzumab的活性也可以通过共同 暴露于蛋白酶体抑制剂。拟议的试验将是一项随机II期研究，比较后期 第一年 使用RIC进行急性髓样白血病后的归档。它将特别检验这些试剂的假设 单独或组合将降低复发率，以前已记录为43％ 在这种环境中，几个月而无需使用这些新颖的代理。此外，它将检验以下假设 代理不会提高非释放死亡率的速度，并且会得到很好的耐受性。对三臂的应计 将对使用AML的RIC进行HIDTPTCY后显示为重大复发的因素进行分层 在多变量分析中。该试验还将确定三臂中的哪个是最有前途的 结果，因此值得与标准护理的正式比较（使用RIC进行AML的HIDTPTCY没有 移植后的新型药物使用）在未来的随机III期试验中。