The Impact of Frailty on Disease Relapse and Therapy Intensity in Older Adults with Acute Myeloid Leukemia: Biomarkers and Treatment Selection

About This Grant

Project Summary/Abstract: Acute myeloid leukemia (AML) is a cancer of the blood and bone marrow that primarily occurs in older adults (60 years and older). The incidence of myeloid neoplasms increases with age, peaking beyond 75 years. In the U.S., there are approximately 20,000 new patients diagnosed and 10,000 deaths due to AML every year, and only 10% of older adults will survive 5 years after diagnosis. The overall incidence in the U.S. has been rising about 1.5% each year, reflective of an aging population. Patients with AML over 60 years old have significantly worse survival compared to younger patients with AML. Since the 1970's, the standard initial therapy involves high-intensity induction chemotherapy with cytarabine, given over 7 days, and daunorubicin, over 3 days, (i.e, 7+3) to achieve remission. For most older adults with AML, chemotherapy is not curative and must be followed by consolidative allogeneic hematopoietic stem cell transplantation (HCT) with the goal of cure. However, many older patients are considered ineligible for high-intensity induction and HCT due to excess treatment-related mortality (TRM). This results in a great disparity: those most affected by AML are often considered ineligible for its treatments due to their age. A novel intermediate-intensity treatment approach, the combination of azacitidine and venetoclax (aza/ven), has transformed the treatment of older adults with AML. FDA-approved in 2020, aza/ven results in a 68% complete remission (CR) rate for patients over the age of 70 with newly diagnosed AML and has been given up to the 9th decade of life. Aza/ven has allowed a greater number of older adults to achieve CR and thus be eligible for consolidative HCT. However, the optimal treatment for older and/or frail adults with AML has yet to be established, including the choice of high-intensity (7+3) vs. intermediate-intensity (aza/ven) initial chemotherapy and the personalization of HCT to individual older patients. Despite the growing interest in incorporating geriatric assessments into decision- making, no standard geriatric assessments have been broadly tested or adopted in adults with AML. In prior analyses that form the background for this proposal, I established that Fried's frailty phenotype (FFP) was associated with overall survival in both patients 60 years and older with newly diagnosed AML and in patients undergoing consolidative HCT. Fit older adults had excellent survival, but pre-frail and frail patients died more frequently from disease-related deaths. This raises several key follow-up questions: 1) Why are disease- related deaths rather than treatment-related deaths associated with frailty? 2) Do pre-frail and frail patients fare better with less intensive induction chemotherapy? and 3) Are there biomarkers that correlate with both frailty and disease biology to explain this association? In this proposed project, I will answer these questions.