Optimizing Allogeneic Hematopoietic Cell Transplantation for Older Patients with Hematologic Malignancies

优化老年血液恶性肿瘤患者的同种异体造血细胞移植

• 批准号: 10708049
• 负责人: Shannon Rose McCurdy
• 金额: $ 16.25万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10708049
• 关键词: Acceleration; Acute Myelocytic Leukemia; Affect; Age; Aging; Allogenic; Azacitidine; Biological Markers; Blood; Blood specimen; CD28 gene; Clinical; Cyclophosphamide; Data; Development; Disease; Disease remission; Disparity; Dose; Dysmyelopoietic Syndromes; Elderly; Enrollment; Exclusion; FDA approved; Future; Gait speed; Geriatric Assessment; Grant; Hand Strength; Hematologic Neoplasms; Hematopoietic Neoplasms; Immune; Incidence; Institution; Laboratory Scientists; Lead; Length; Lymphocyte; Malignant Bone Marrow Neoplasm; Measures; Mentors; Methotrexate; Morbidity - disease rate; Myeloproliferative disease; National Cancer Institute; Natural Killer Cells; Newly Diagnosed; Observational Study; Outcome; Patients; Pennsylvania; Phase I Clinical Trials; Phenotype; Physiological; Population; Prediction of Response to Therapy; Prevention strategy; Prophylactic treatment; Relapse; Sampling; Scientist; Site; T-Lymphocyte; Tacrolimus; Time; Toxic effect; Transplant Recipients; Transplantation; Universities; Work; age group; aging population; comorbidity; conditioning; curative treatments; frailty; graft vs host disease; hematopoietic cell transplantation; improved; innovation; mortality; novel; older patient; phase I trial; post-transplant; prevent; programmed cell death protein 1; senescence; specific biomarkers; standard of care; telomere; translational study; trend

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are cancers of the blood and bone marrow that primarily occur in older adults (those 60 years and older).1 The incidence of these myeloid neoplasms increases with age, peaking beyond 75 years old.2 The overall incidence in the U.S. has been rising about 1.5% each year, reflective of an aging population. The only potentially curative treatment is allogeneic hematopoietic cell transplantation (HCT). HCT is physiologically stressful and associated with treatment-related mortality (TRM), which occurs in 10-20% of young and healthy patients and in up to 40-50% of older patients with comorbidities. 3•4 We have seen a remarkable expansion in the number of older patients receiving HCT due to the development of reduced intensity conditioning (RIC) approaches. In 2000, patients over 60 represented <5% of transplant recipients, whereas in 2018 they represented 39% of HCT recipients.5 Patients over 70 were almost never transplanted before 2007; in 2018 they made up 9% of HCT recipients. 5 Despite these trends, older patients, particularly those over 70, are often not offered HCT. 6 This creates a weighty disparity: those most affected by these devastating disease are least likely to be offered the cure. The recently FDA approved combination of azacitidine and venetoclax results in a 68% complete remission (CR) rate for patients over the age of 70 with newly diagnosed AML, 7 whereas the prior standard-of-care (SOC) therapy in this age group seldom did. The availability of a highly effective induction for this age group necessitates innovation in HCT since (1) induction is not curative, with relapse occurring at a median of 12 months, (2) SOC HCT has a 5-year overall survival (OS) of only 29% in older patients,8 and (3) patients over 75 years old are excluded from SOC HCT. To understand the impact of SOC HCT recipients~ 60 years old, we measured geriatric parameters as part of the Frailty Study, which forms the preliminary data for this grant. Patients who were deemed fit according to Fried's frailty phenotype (FP) enjoyed a 2- year TRM of 12%, compared with 30% and 47% in pre-frail and frail recipients, respectively. 24 In addition, 66% of patients had a decline in their frailty phenotype at Day 30 post-HCT and 90% of patients were pre-frail or frail at this time point. This highlights that there is an unmet need for less toxic HCT strategies for older recipients. Graft-vs-host disease (GVHD) is one of the most significant complications after HCT and a leading cause of morbidity and mortality. Post-transplantation cyclophosphamide (PTCy) is a revolutionary GVHD prevention strategy that was pioneered by one of my mentors, Dr. Luznik, and has replaced SOC GVHD prophylaxis strategies for HLA-mismatched transplantation, in part due to my work9-17 and that of my collaborator on this project (Dr. Kanakry). 18-23 This project aims to expand the use of PTCy beyond HLA-mismatched transplantation, reducing the dose to allow safe HCT of older or prefrail/ frail recipients. Analyses will also be performed to explore the effects of HCT on biomarkers of aging. Dr. Kanakry is the laboratory scientist lead and I am the clinical scientist lead on this phase 1 clinical trial (OPTCy, NCT04959175) that is now open at its two sites: The National Cancer Institute and The University of Pennsylvania.

急性髓系白血病(AML)和骨髓增生异常综合征(MDS)是血液和骨髓的癌症， 主要发生在老年人(60岁及以上)。1这些髓系肿瘤的发病率随着年龄的增长而增加， 美国的总发病率一直在以每年约1.5%的速度增长，反映出 人口老龄化。唯一可能治愈的方法是异基因造血细胞移植(HCT)。血细胞比容是 生理压力和与治疗相关的死亡(TRM)，发生在10%-20%的年轻和 在健康的患者中，高达40%-50%的老年患者患有合并症。3·4我们已经看到了在 由于减少强度条件反射(RIC)方法的发展而接受HCT的老年患者的数量。 2000年，60岁以上的患者占移植受者的5%，而在2018年，他们占HCT的39% 受者。2007年前，5名70岁以上的患者几乎从未接受过移植；2018年，他们占HCT接受者的9%。5. 尽管有这些趋势，但老年患者，特别是70岁以上的患者，往往得不到HCT。这就产生了一个沉重的 差异：那些受这些毁灭性疾病影响最大的人最不可能得到治愈。 最近FDA批准的阿扎替丁和万乃馨的组合导致68%的完全缓解(CR)率 70岁以上新诊断的AML患者，7例，而这个年龄段以前的护理标准(SOC)治疗 小组很少这样做。为这一年龄段提供高效的诱导剂需要在HCT中进行创新，因为 (1)诱导不能治愈，复发的中位数为12个月。(2)SOC HCT的总生存期为5年。 (2)仅29%的老年患者中，8和(3)75岁以上的患者被排除在SOC HCT之外。要了解 SOC HCT接受者~60岁的影响，我们测量了老年参数作为脆弱研究的一部分，这项研究形成 这笔赠款的初步数据。根据Fry的脆弱表型(FP)被认为适合的患者享受2- 年TRM为12%，而虚弱前和虚弱受者分别为30%和47%。24此外，66%的 患者在HCT后30天其脆弱表型有所下降，90%的患者在这一天之前或虚弱 时间点。这突出表明，对老年接受者的毒性较低的HCT策略的需求尚未得到满足。 移植物抗宿主病(GVHD)是HCT后最重要的并发症之一，也是导致移植物抗宿主病的主要原因之一。 死亡率。移植后环磷酰胺(PTCy)是一种革命性的GVHD预防策略， 由我的一位导师Luznik博士首创，并取代了针对人类白细胞抗原不匹配的SOC GVHD预防策略 移植，部分归功于我的工作9-17和我在这个项目上的合作者(Kanakry博士)。18-23这个项目旨在 将PTCy的使用扩大到人类白细胞抗原不相合的移植，减少剂量以允许安全的老年或早产儿的Hct。 虚弱的接受者。还将进行分析，以探索红细胞压积对衰老生物标志物的影响。卡纳克里博士是 实验室科学家Lead和我是这一阶段临床试验的临床科学家Lead(OPTCy，NCT04959175)，即 现在它的两个网站：国家癌症研究所和宾夕法尼亚大学开放。