Molecular Landscape in Acute Myeloid Leukemia (AML) Patients (pts) from Mexico As an Initial Study to Identify Healthcare Disparities in Hispanic Populations: Alliance for Clinical Trials in Oncology [Alliance]

Health care disparities are associated with social, economic and environmental disadvantages and may adversely affect minority groups. "Hispanic or Latino” refers to a person of Cuban, Mexican, Puerto Rican, South or Central American, or other Spanish origin or culture regardless of race. To begin to understand disparities in Hispanic pts with AML, we thought to characterize and compare clinical features, mutationallandscape and disease outcomes of AML pts from Mexico and Hispanic (Hisp) AML pts living in the US and compare them with those of non-Hispanic White (NHW) pts.

Methods: We assessed molecular features and outcomes of 48 adult AML pts diagnosed and treated with anthracycline and cytarabine combination (90%) at the Hospital General De Mexico (HGM, a urban public tertiary hospital and a referral institution for AML pts in Mexico City) (cohort 1: Mex), as well as 48 adult AML pts who self-identified as Hispanic and 1496 non-Hispanic White pts similarly treated on frontline Alliance protocols (cohort 2: A-Hisp, A-NHW). No pt received an allogeneic transplant in 1st complete remission. Mutational status of 55 protein-coding genes in addition to the main fusion gene rearrangements at time of diagnosis were determined by both study groups centrally using targeted NGS platforms. Last, we used 2 additional reported Hispanic cohorts in the US and large international cohorts for validation of the identified molecular and clinical features (cohort 3 [] and 4).

Results: Median age at diagnosis for cohorts 1 and 2 was younger than reported for AML, 38yo (15-86) for cohort 1 vs 45yo (17-83) for cohort 2. Somatic mutations in the cohort 1 were detected in 96% of pts, similar to the A-Hisp subset of cohort 2 (94%). The most prevalent mutations in the cohorts were FLT3 (Mex 29%, A-Hisp 33%, A-NHW 42%, p= 0.654), followed by CEBPA (Mex 21%, A-Hisp 15%, A-NHW 13%, p=0.214), TET2(Mex 19%, A-Hisp 8%, A-NHW 16%, p=0.322), DNMT3A (Mex 19%, A-Hisp 18%, A-NHW 24%, p=0.5498), RUNX1 (Mex 15%, A-Hisp 0%, A-NHW 12%, p<0.001) and NPM1 (Mex 12%, A-Hisp 29%, A-NHW 35%, p=0.002). Fusion genes were detected in 21% of pts, with t(8;21)(RUNX1-RUNX1T1) being the most commonly found (Mex 13%, A-Hisp 6%, A-NHW 3%, p=0.005), followed by MLL rearrangements (Mex 4%, A-Hisp 16%, A-NHW 5%, p=0.015) and inv(16)(CBFB-MYH11) (Mex 2%, A-Hisp 10%, A-NHW 2%, p=0.003). We found some commonalities in the genetic alterations between these two Hispanic cohorts (i.e., CEBPA, FLT3, DNMT3A), however median overall survival (OS) for the Mexican cohort was 9mo, worse than OS for cohort 2 (A-Hisp 15mo, A-NHW 14mo).

Those molecular differences were validated in 2 additional international cohorts (TCGA and Pappaemmanuil et al., NEJM, 2016). Notably, there was an overrepresentation of CEBPA mutated AML in both cohort 1 and A-Hisp (cohort 2). The most notable difference between the two Hispanic cohorts (Mex vs A-Hisp) was the prevalence of mutated NPM1, which was higher in the US A-Hisp dataset, similar to what is described in other international cohorts for de novo AML.

Conclusion: Mexican AML pts have a distinct genetic makeup and overall poorer outcomes compared to other international cohorts. These differences in genetic alterations point to differences in host genetic susceptibility and environmental factors. Because the term Hispanic reflects a culture rather than a genetically defined ethnicity we will perform ancestry-specific analysis to better characterize the genetic differences and determine who is represented within this heterogeneous population, particularly in the self-reported population living in the US. Some of the detected variants are targetable mutations that could influence disease management decisions. It is important to use ancestry-specific analysis, as compared with self-reported race and ethnicity, to better understand the impact on disparities and highlighting the importance of increasing enrollment of Hispanic pts in clinical trials. Knowing who is accessing healthcare in the US as self-reported Hispanic will help understand whether the differences in outcome are related to healthcare access or there is a genetic component that could explain some of the differences in age of onset and molecular findings observed in cohorts of similar ethnic background.

Byrd:Novartis: Consultancy; Pharmacyclics: Research Funding; Syndax: Consultancy; Zencor: Research Funding; Ohio State University: Patents & Royalties; Newave: Consultancy; AstraZeneca: Consultancy; Kura: Consultancy; Vincerx: Consultancy, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company; Trillium: Consultancy; Janssen: Consultancy; AbbVie: Consultancy. Stock:Syndax: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Servier: Honoraria; Newave Pharmaceuticals: Consultancy; Pluristem: Consultancy, Honoraria; MorphoSys: Honoraria; Kura Oncology: Honoraria; Kite: Honoraria; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria; Agios: Honoraria. Stone:Epizyme: Consultancy; GSK: Consultancy; Jazz: Consultancy; OncoNova: Consultancy; Syros: Consultancy; Gemoab: Consultancy; Takeda: Consultancy; Syntrix: Consultancy; Janssen: Consultancy; Elevate Bio: Consultancy; BMS: Consultancy; BerGenBio: Consultancy; Kura Oncology: Consultancy; Novartis: Consultancy; Syndax: Consultancy; Innate: Consultancy; Foghorn Therapeutics: Consultancy; Boston Pharmaceuticals: Consultancy; Astellas: Consultancy; Arog: Consultancy, Research Funding; Apteva: Consultancy; Aprea: Consultancy; Actinium: Consultancy; Abbvie: Consultancy, Research Funding. Hassane:Tempus: Current Employment. Eisfeld:Karyopharm Therapeutics: Other: Spouse is current company employee. Guzman:Samus Therapeutics: Other: Inventor on licensed IP; BridgeMedicines: Research Funding; Seq RX: Current holder of stock options in a privately-held company.