Introduction: Previous reports have identified an increased incidence of B-ALL and APL in Hispanic populations, which we confirmed in an analysis of the Florida Cancer Data System (Swords et. al. BCJ October 2016). In this analysis, we also demonstrated an increased incidence of AML in Hispanic patients in Florida, and that these patients may have worse outcomes. Given these findings, we hypothesize that the adverse prognosis of Hispanic AML patients may be due to distinct mutational profiles. Therefore, we present here the analysis of a cohort of Hispanic vs. Non-Hispanic AML patients (n=227) in South and Central Florida.
Methods: We obtained clinically relevant mutational data (11-gene AML Molecular Profile and 40-gene Myeloid Molecular Profile performed by Genoptix Laboratories) on AML patients treated from 2012-present, at Sylvester Comprehensive Cancer Center (SCCC) and Moffitt Cancer Center (MCC). Mutational profiling utilizing an amplicon-based targeted next generation sequencing platform was done on an Illumina MiSeq instrument. At both centers, we obtained IRB approval to perform a retrospective chart review in order to collect and analyze clinical data, including laboratory, cytogenetic, molecular genetic, demographic and outcome data. Categorical data were analyzed by Fisher exact test or Chi-square test as appropriate. Continuous data were analyzed by independent t-test and Wilcoxon-Mann Whitney test for parametric and non-parametric data, respectively. Statistical analysis was performed using Stata and Circos plots using Circos, both as previously described.
Results: We examined the mutational profiles of 227 AML patients treated at SCCC and MCC. Results from the 11-gene profile were available for 160 patients between both centers, and an extended 40-gene myeloid molecular panel on an additional 67 SCCC patients. Median age was 65 years (range 19-91). 57% of patients were male; 86.8% were white, 7.9% black, and 5.3% other; and 25.6% self-identified as Hispanic versus 74.5% Non-Hispanic (Table 1). Of the 58 Hispanic patients, 28 identified as white, 1 as black, and 9 as other. Hispanic patients were younger than Non-Hispanic patients (median age 60 vs. 67, p=0.001). At sample collection, median WBC was 3.97 (1.4-67.9) K/µl, median bone marrow blast percentage 39.5 (15-90), and 30.2% of patients had antecedent MDS. Favorable-risk, intermediate-risk, and poor-risk cytogenetics occurred in 7.73%, 65.91%, and 26.36% of patients, respectively. No significant differences in WBC, antecedent MDS, or cytogenetics were observed across ethnicity. In the 227 patient cohort, the most frequent mutations included RUNX1 (23.9%), DNMT3A (18.1%), and TET2 (18.1%), as demonstrated in Table 1 and Figure 1. 51 patients (22.5%) has an IDH mutation (21 IDH1, 30 IDH2), and IDH1 was 20 times more common in Non-Hispanics vs. Hispanics (p=0.019), Figure 2. IDH2 was also more common in the Non-Hispanic population (21:9), but this was not statistically significant. Mutations in ETV6 and WT1 were more common in the Hispanic population and statistically significant (p=0.024 and p=0.046, respectively). There was also a trend toward ASXL1 mutations being more common in non-Hispanic patients (p=0.1) and KRAS mutations being more common in Hispanics (p=0.06) (Table 1). We also note that, compared to TCGA data, our cohort had fewer FLT3, NPM1, and DNMT3A mutations than would be expected, while RUNX1 mutations appeared to be enriched.
Conclusion: We examined mutational frequency and outcomes in 227 Hispanic and Non-Hispanic AML patients in Florida. We showed that IDH1 mutations were significantly more common in Non-Hispanic patients (20:1, p=0.019), with a trend towards increased IDH2 and ASXL1 mutations in this population as well. We also demonstrated a significant increase in ETV6 and WT1 mutations in Hispanic patients. Given that IDH and WT1 mutations tend to be mutually exclusive, as both alter TET function, it is interesting to consider that distinct driver mutations converging on a common AML pathway could differ by ethnicity. Survival analysis by ethnicity is ongoing, and we will present updated data at the ASH meeting. We will also report on the prognostic significance of these mutations in Hispanic vs. Non-Hispanic patients (most existing data underrepresents Hispanic patients). We are currently expanding our study with additional centers.
Disclosures: Vaupel: Genoptix Laboratory: Employment. Hall: Genoptix Laboratory: Employment. Lancet: Bio-Path Holdings: Consultancy; Celgene: Consultancy; BioSight: Consultancy; Erytech: Consultancy; Janssen: Consultancy; Jazz Pharmaceuticals: Consultancy; Boehringer Ingelheim: Consultancy; Novartis: Consultancy; Pfizer: Other: Institutional research funding, Research Funding. Padron: Incyte: Honoraria, Research Funding. Swords: TBD: Other: TBD. Watts: Jazz Pharmaceuticals: Consultancy, Speakers Bureau.