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.

急性髓性白血病（AML）和骨髓增生异常综合征（MDS）是血液和骨髓的癌症