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: 10434084
• 负责人: Asad Bashey
• 金额: $ 15.31万
• 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/10434084
• 关键词: Acute Myelocytic Leukemia; Age; Allogenic; Antibodies; 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; 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; follow-up; graft vs host disease; hematopoietic cell transplantation; improved; inhibitor therapy; 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匹配的供体历来是获得同种异体造血干细胞移植的主要障碍。 在许多患者中，特别是来自少数民族和混合种族的患者， 背景包括我们在内的一些中心最近的工作表明，使用T- 从HLA-单倍性供体的完全移植物和移植后环磷酰胺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的发生率低。这一进展预示着 对于需要allo-HCT的患者，几乎普遍的及时供体可用性的可能性。而且 HIDTptCy相对较低的移植物获取成本将改善异基因移植的可及性， 贫困地区和发展中国家。当HIDTptCy用于肿瘤性疾病时， 恶性肿瘤的复发或进展仍然是治疗失败的最重要原因。这是特别 因此，当使用非清髓性或降低强度的准备方案（RIC）时。总局 allo-HCT后的蛋白酶体抑制剂药物也可通过直接抗癌活性减少复发 潜在刺激自然杀伤（NK）细胞同种异体反应性。此外，蛋白酶体抑制剂已经被用于治疗癌症。 证实能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后口服生物可利用蛋白酶体抑制剂ixazomib 12个月 使用RIC。这项试验的初步分析显示，尽管药物的毒性很小，但复发率相对较低， 短的后续行动。具有降低HIDTptCy后复发率潜力的另一种药剂是抗SLAMF7 单克隆抗体埃罗妥珠单抗这种抗体已被证明通过结合这种抗体激活NK细胞。 考虑到现有证据表明NK细胞同种异体反应性 对防止这种情况下的复发很重要埃罗妥珠单抗的活性也可以通过共- 暴露于蛋白酶体抑制剂。拟议的试验将是一项随机的II期研究， 第一年内ixazomib vs elotuzumab vs ixazomib + elotuzumab的移植给药 HIDTptCy后使用RIC治疗急性髓性白血病。它将专门测试这些代理人的假设， 单独或联合使用将降低复发率，先前记录的复发率为43%， 在这种情况下，没有使用这些新的代理人。此外，它将测试假设，这些 药物不会增加非复发死亡率，并且耐受性良好。应计到三个武器 将根据显示为使用RIC治疗AML的HIDTptCy后复发的显著预测因素的因素进行分层 在多变量分析中。这次试验也将决定这三种武器中哪一种最有希望 结果，因此值得与标准治疗（使用RIC治疗AML的HIDTptCy， 移植后新药物的使用）在未来的随机III期试验。