Molecular characteristics and outcomes in Hispanic and non‐Hispanic patients with acute myeloid leukemia

Abstract Hispanic patients have been reported to have an increased incidence of AML and possibly inferior outcomes compared to non‐Hispanics. We conducted a retrospective study of 225 AML patients (58 Hispanic and 167 non‐Hispanic) at two academic medical centers in Florida. Disease characteristics, cytogenetics, mutation profiles, and clinical outcomes were assessed. Hispanic patients were younger at presentation than non‐Hispanics (p = 0.0013). We found associations between single gene mutations and ethnicity, with IDH1 mutations being more common in non‐Hispanics (95.2% vs. 4.8%, p = 0.0182) and WT1 mutations more common in Hispanics (62.5% vs. 37.5%, p = 0.0455). We also found an emerging trend towards adverse risk cytogenetics in Hispanic patients (p = 0.1796), as well as high risk fusions such as MLL‐r (70% vs. 30%, p = 0.004). There was no difference in overall survival (OS) between Hispanic and non‐Hispanics patients. When examining only newly diagnosed patients (n = 105), there was improved OS in Hispanics (median 44.7 months vs. 14 months, p = 0.026) by univariate analysis and equivalent OS by multivariate analysis (hazard ratio = 1.52 [95% CI = 0.74–3.15]). Hispanics with a driver mutation not class‐defining had improved survival compared to non‐Hispanics. Our study demonstrates significant genetic differences between Floridian Hispanics and non‐Hispanics, but no difference in OS in patients treated at an academic medical center.

such as karyotype and molecular mutations. The Hispanic population comprises the largest minority group in the United States, currently representing nearly 20% of the population (26% in Florida), and it is expected to approach 30% by 2060. Cancer is the leading cause of death among Hispanics in the US (Prevention, CDC Fast Facts 2021; Arias et al National Vital Statistics 2021), who appear to develop distinct subtypes of leukemia: previous publications have revealed an increased incidence rate of B-acute lymphoblastic leukemia (B-ALL) and of acute promyelocytic leukemia (APL) [1][2][3][4], which has been confirmed in an analysis of the Florida Cancer Data System.
Hispanics also may have an increased incidence rate of AML as a whole, possibly linked with inferior outcomes, compared to their non-Hispanic counterparts [4]. This finding is supported by data on non-APL AML from the Surveillance, Epidemiology, and End Results (SEER) database, which confirms a shorter median survival for Hispanic patients compared to non-Hispanic white patients [5]. Whether differences in survival could be associated with distinct molecular mutations is unknown. To address this question, we assessed the molecular profiles and outcomes of Hispanics and non-Hispanic patients with AML treated at two academic medical centers in Florida.

Patients
Newly no patients were excluded. Cytogenetic risk as defined per European LeukemiaNet criteria. Newly diagnosed patients were treated with less-intensive and intensive chemotherapy regimens, with lessintensive defined as hypomethylating agent-based therapy, and more intensive as cytarabine-and anthracycline-based regimens. Patients who had relapsed or refractory disease were also treated with lessintensive and intensive therapies. Ethnicity (Hispanic or non-Hispanic) was self-identified by patients, as was race.

Statistics
Patient demographics and disease characteristics were summarized using descriptive statistics. The association between ethnicity and study covariates was examined using chi-square test. For continuous variables, Wilcoxon signed-rank test was used to compare groups.

Patient outcomes by molecular subgroups
We also examined OS by the most common class-defining molecular subgroups: driver not class-defining, mutated chromatin/splicing, NPM1/CEBPA/t(8;21)/inv (16), and TP53/aneuploidy [6]. California [8,9]. There are data to suggest that while the incidence of AML, barring APL, is lower in Hispanics compared to non-Hispanics, they are often diagnosed at a younger age and may have a poorer age adjusted overall survival [5,[10][11][12][13]. The genetic and socioeconomic differences accounting for the possible discrepancies in prognosis and survival are not well accounted for at this time.
To better answer these questions, we examined NGS data on 225 AML patients and found that certain gene mutations clustered by ethnicity. IDH1 mutations were more common in non-Hispanic patients, while WT1 mutations were more common in Hispanic patients. Interestingly, both of these genes affect TET protein activity and DNA methylation. However, there was no association between TET2 or IDH2 mutations, or any other single gene mutation, and ethnicity. We also examined mutation risk groups/molecular subgroups and found that Hispanic patients were more likely to have an adverse risk AML fusion [11q23, inv (3)  Prior work as shown that regional location can play a role in AML outcomes in the Hispanic population [15]. Factors such as poverty, income, and education status have also been linked to inferior survival, which may explain the inferior risk reported in SEER Medicare analysis [5,12,[16][17][18]. Our data may suggest that, while there are some genetic differences, "modifiable" factors such as socioeconomic inequity, healthcare access, environmental factors, etc. are the primary drivers for the discrepancies in outcome reported in the past, and correction of these factors could improve AML outcomes in Hispanic patients. Secondly, the Hispanic diaspora is diverse and includes people of Mexican, South/Central American, Cuban, Puerto Rican, or other Spanish-speaking cultures. Ethnicity on this study was self-reported, so we do not know the exact descent, which is quite vast for Hispanics and may drive genetic differences. While Florida is one of three states where half the Hispanic population currently resides (the others being California and Texas), it likely over-represents certain subsets of the Hispanic population, such as Cuban or Puerto Rican Americans who are genetically disparate from other under-represented groups, such as those of Mexican origin [10,11]. Strengthening these data to further characterize the relationship between ethnicity and AML genotype and outcomes will require a multi-institutional effort moving forward.

AUTHOR CONTRIBUTIONS
TB, JM, and CT collected and analyzed the data, interpreted the data, and edited the manuscript. DK performed statistical analysis and edited the manuscript. AT, MS, NC, RS, EP, and JL analyzed and interpreted the data and edited the manuscript. JW conceived and coordinated the study, analyzed and interpreted the data, and wrote the manuscript. All authors discussed the results and commented on the manuscript.

ACKNOWLEDGMENT
This work was supported by a National Institutes of Health P30 CA008748-Cancer Center Support Grant.

FUNDING INFORMATION
National Institutes of Health, Grant Number: P30 CA008748

CONFLICT OF INTEREST
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.

ETHICS STATEMENT
This study was IRB-approved under protocol 20160255 on April 14, 2016. The IRB approved the study with a waiver of consent (retrospective chart review).