Genetic Profiling and Risk Stratification of Acute Myeloid Leukemia (AML): Comparative Analysis of the Jordanian AML Cohort (JAMLC) to the German-Austrian AML Study Group (AMLSG)

Background: AML is a heterogeneous and genetically diverse disease. Molecular risk stratification of AML is essential for prognostic and therapeutic decisions. The genetic landscape of AML differs between geographical regions and different populations with different environmental exposures and variable hereditary predisposition syndromes. Our study aims to describe the genetic landscape and the gene-gene interactions in the Jordanian AML Cohort (JAMLC) in comparison to cohort of patients enrolled on German-Austrian AML Study Group (AMLSG) trials as described by Papaemmanuil et al (NEJM, 2016) and their impact on outcomes. Methods: The study included patients diagnosed with AML and treated with intensive chemotherapy at King Hussein Cancer Center in Jordan between 2015 and 2023. Data were collected on demographics, clinical characteristics, allogeneic transplantation, and outcomes. Patients with available cytogenetic and molecular data were included. Molecular testing in the JAMLC was conducted using a 54-gene myeloid panel. Fisher's exact test was used to compare frequencies of different mutations between JAMLC and AMLSG, p-values were corrected after adjusting for multiple comparisons to account for false discovery rate. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Predictors of OS were evaluated in univariate and multivariate analyses using Cox proportional hazards regression. Statistical analysis was performed using SPSS v.28. Results: We identified 204 patients who were treated during the study period, of which 124 (61%) were males. In comparison to AMLSG, patients in JAMLC, were younger (median age at diagnosis was 44 vs 54 years). When evaluating specific mutations, patients in the JAMLC were more likely to have DNMT3A mutations (32.7% vs 22.7%, p=0.01), FLT3 (32.4% vs 16.5%, p<0.001), IDH2 (30.2% vs 8.7%, p<0.001), ASXL1 (7.3% vs 2.9%, p=0.01), GATA2 (6.8% vs 1.6%, p<0.001), BCOR (4.8% vs 1.6%, p=0.02). There was no statistically significant difference in the frequency of TP53 (6.8% vs. 5.8%), U2AF1 (1.9% vs 1.7%), SRSF2 (7.8% vs 5.1%), EZH2 (1.9% vs. 1.9%), RUNX1 (8.2% vs 8.7%), TET2 (8% vs 9.7%), NPM1 (29.4% vs 29.2%), PTPN11 (4.8% vs 7.7%), WT1 (5.8% vs 3.8%). Similarly, when comparing groups as per ELN 2022 classification, patients in the JAMLC were more likely to be classified as high risk (37.2% vs. 16.4%), and less likely to have intermediate (37.6% vs 44.4%) and favorable risk (25% vs. 30.7%) (p<0.00001). With a median follow-up of 13.7 (0.1-110.3 months), median OS was 24.7 months for the entire cohort (16.7-32.9 months). When looking at specific subgroups, median OS for favorable ELN was 32.9 months (23.7-NR), for ELN intermediate was 26.8 months (25.2 - NR) and for ELN high was 11 months (7.7 - 17.1). Patients in the ELN high-risk group had lower OS (HR for death: 1.95 95% CI 1.35-2.82, p<0.001) in comparison to patients with favorable and intermediate risk. Conclusion: Despite being a decade younger, patients in the Jordanian AML Cohort were as likely to have certain high-risk mutations (TP53, U2AF1, RUNX1, PTPN11, SRSF2, WT1) and more likely to have other high risk mutations (ASXL1, BCOR) and more likely to have ELN 2022 high-risk classification reflecting possible different biologic, environmental and genetic predisposition factors. Further work is needed to explore such underlying factors leading to differences in prevalence.