Investigating Racially Induced Metabolic and Genomic Signatures Mediating Inferior Survival in African Americans with Acute Myelogenous Leukemia

Background: African American (AA) patients experience worse survival outcomes compared to other patients with acute myelogenous leukemia (AML), independent of socioeconomic and molecular factors. 1 Indeed, our group previously demonstrated inferior survival in AA associated with the proxy for (1) genomic instability and (2) suggestion for inability to achieve protein damaging threshold among concurrent mutations. 2 In study expansion, we have confirmed worse overall survival (OS) for AA patients, and detected rapid attrition of AA patients, soon after diagnosis and therapy initiation. Given high incidence of cardiometabolic complications in AA patients, this prompted us to investigate the link between deranged metabolism and clinical outcomes. Additionally we explored nucleotide modifications that influence leukemogenesis in AA patients. In previous data, obesity correlated with poor outcomes for patients with acute promyelocytic leukemia (APL), but not in other AML, including in the CALGB cohort. 3-5 Interestingly, obesity is linked to 1) FTO/IRX3 pathways that block hematopoietic stem cell differentiation, and 2) oxidative stress, which may induce DNA damage favoring C>A and G>T nucleotide changes 6,7 and aberrant bone marrow microenvironment 8. Methods: We conducted retrospective analysis of 272 AML patients from Baylor TX, Georgetown DC, and Washington Hospital Center DC, including demographic and clinical variables (age, sex, race, BMI, comorbidities, smoking, treatments, and outcomes). APL patients were excluded. For patients with NGS data, mutation frequencies were annotated by ethnicity and prioritized by ELN 2022 classification. Chi-square and t-test evaluated differences in categorical and continuous variables respectively. Logistic binary regression was used to detect predictors for racial induced survival. SAS software was used. Results: Our expanded cohort has 272 AML patients, with 43 AA and 229 non-AA. AA patients showed worse OS than non-AA patients (Fig 1; 149 days vs 605 days, p=0.01). There were not any AA patients with favorable risk ELN 2022 disease status. Neither ELN 2022 risk groups nor presence of MDS-like mutations differentiated worse outcomes for AA patients, so we opted to examine the effect of obesity among AA and non-AA patients with intermediate and high risk AML (given no favorable risk AA patients in our cohort). Mean BMI for our AA patients was 28, with AA patients with BMI>28 showing significantly worse OS (Fig 1; 67 day