Racial disparities in genomic alterations and survival outcomes in Acute Myeloid Leukemia (AML)

Abstract

Abstract Background: Survival outcomes in AML are influenced by multiple patient- and disease-related factors, including age, performance status, prior malignancies or treatments, cytogenetics, and molecular features. Several studies have shown that race is linked to differences in driver mutations, which impact patient outcomes. Black and Hispanic population represent two major minorities in the US and are mostly underrepresented in clinical trials compared to the White population. Hence, the underlying genomic differences and their impact on prognosis remain poorly understood. Methods: This was a retrospective study at Moffitt Cancer Center on patients diagnosed with AML between 1/2014 and 12/2024. Patients were divided into 3 groups based on their reported race as Black, Hispanic, or White. Kaplan-Meier analysis with log-rank test was used to estimate overall survival (OS). Multivariate analysis used Cox proportional hazards regression and backward stepwise selection retaining variables with p<0.05. Results: A total of 620 patients including 15.2% Black, 16.8% Hispanic, and 68.1% White were identified. Median age at diagnosis were 58 (range: 18-89), 53 (16-90), and 68 (20-93) years for Black, Hispanic, and White, respectively (p<0.001). Hispanic had higher percentages of marrow blasts compared to White (63 vs. 50%, p=0.02) but comparable to Black (63 vs 55%, p=0.25). Myeloid molecular panel was available in most patients (Black 88.2%, Hispanic 79.8%, White 96.4%, p<0.001). ELN 2022 risk distribution was similar across races (p=0.16): favorable 21.5% (White 22.3 vs Black 14.9 vs Hispanic 24.3%), intermediate 24.1% (23.5 vs 21.3 vs 29.1%), and adverse 54.4% (54.2 vs 63.8 vs 46.6%). Notably, rates of hematopoietic cell transplant (HCT) were not different by races (p=0.847). Compared to the White cohort, use of frontline intensity chemotherapy regimen was significantly higher in Black (77.4 vs 57%, p=0.001) and Hispanic (78.6 vs 57%, p<0.001). The most prevalent mutations (>15%) occurred at similar rates across cohorts: DNMT3A in 23.9% (White 24.3 vs Black 24.7 vs Hispanic 21.1%; p=0.81), NPM1 in 23.2% (24 vs 15.7 vs 26.7%; p=0.18), FLT3-ITD in 18.1% (16.7 vs 16.7 vs 25.8%; p=0.11), TET2 in 17.5% (16.7 vs 18.4 vs 20.8%; p=0.67), and TP53 in 15.5% (16.9 vs 14.3 vs 9.2%; p=0.22). Black showed greater frequency of mutations in KRAS (12.5%) (White 5.4%, p=0.05; Hispanic 1.3%, p=0.02) and NOTCH1 (11%) (White 0.5%, p<0.001; Hispanic 1.3%, p=0.02), whereas mutations in ETV6 was more frequently detected in Hispanic compared to White (5.3 vs 0.7%, p=0.04). With a median follow up of 3.41 years, median OS of the entire cohort was 2.2 years (95% CI, 1.8-3.1). Median OS were 2.2 (95% CI, 1.7–4.0), 1.5 (95% CI, 1.3–2.4), and 3.1 (95% CI, 1.8–NR) years for White, Black and Hispanics, respectively (p=0.04). Pairwise comparisons showed a significant difference only between Hispanic and Black (p=0.01). Among patients with intermediate-risk AML, Black had significantly shorter median OS compared to White (1.5 vs 3.4 years, p=0.01) and compared with Hispanic (1.5 vs 4.5 years, p=0.002). There was no difference in OS between cohorts for patients with favorable and adverse risk AML. In univariate analyses, shorter OS in Whites were observed for those with TP53 (HR 4.48, p=0.003), ASXL1 (HR 1.83, p=0.04), and U2AF1 (HR 2.38, p=0.005), while those with NPM1 longer (HR 0.46, p=0.003). In Blacks, TP53 was associated with worse OS (HR 3.54, p=0.017). None were significant in Hispanics. Based on clinical significance and univariate model, a multivariate model was created using the following variable: race, gender, age, prior myeloid malignancy, ELN 2022, HCT, TP53, and IDH2. After adjustment, Black patients had significantly worse OS compared to Whites (HR 1.45, 95% CI 1.02–2.07, p=0.04), whereas Hispanic patients had similar OS to Whites (HR 1.25, 95% CI 0.88–1.77, p=0.20). Conclusion: In this large AML cohort, Black and Hispanic patients were diagnosed younger than Whites. Black patients had shorter OS, particularly in the intermediate-risk group, while Hispanic patients had OS comparable to Whites and superior to Blacks. Mutation profiles were broadly similar, with notable differences in KRAS, NOTCH1, and ETV6. Black race remained an independent predictor of worse OS after adjustment, underscoring the need for greater minority representation in clinical trials. Further subgroup analyses within each racial group will be presented at the meeting.