Distinct Clinical and Genetic Features of Acute Myeloid Leukemia (AML) in Obese Vs. Non-Obese Patients: A Comparative Study
Authors: Johnson Anna , Chahine Zena , Morris Trevor , Soule Ashley , Taj Hiffsa , McAvoy Claire , Zhou Xitong , Iragavarapu Chaitanya , Munker Reinhold , Monohan Gregory , Ramlal Reshma , Qasrawi Ayman , Yalniz Fevzi 
Published: December 2023

Aims: Acute myeloid leukemia (AML) represents 80% of the cases of acute leukemia in adults, and obesity has been found to be associated with an increased risk of developing AML. However, there is no data regarding the presenting clinical, cytogenetic, and molecular features of AML in obese patients.
Methods: We retrospectively evaluated adult patients with newly diagnosed AML treated at our institution from January 2017 to January 2021. Patients with acute promyelocytic leukemia (APL), as well as those with secondary and therapy-related AML, were excluded. Patients with an available genetic profile obtained from next-generation sequencing (NGS) were included. Demographic, clinical, laboratory, and pathologic data were obtained from clinical records. Obesity was defined as a BMI &gt; 30. A 97-gene panel was used for NGS analysis. Cytogenetic and molecular data, along with responses to treatments, were classified according to the European LeukemiaNet2022 (ELN) guidelines. Statistical analysis included the Mann-Whitney test for continuous variables, Fisher's exact test for categorical variables, and Kaplan-Meier survival curves for overall survival and relapse-free survival.
Results: We identified 185 newly diagnosed de novo AML cases for analysis, of which 90 (49%) were classified as obese (Table). The median age at diagnosis was 60 (range, 20-91), and 84 (46%) were male. The most commonly mutated gene was DNMT3A (n=42, 23%), followed by IDH2 (n=36, 19%), and FLT3-ITD (n=33, 18%). Approximately 47% (n=79) of patients had adverse risk based on ELN2022 risk classification by genetics, and 40% (n=23) had adverse cytogenetic risk. The majority of patients were treated with intermediate or high-dose cytarabine-based regimens (n=128, 73%), and the rest with HMA plus venetoclax (n=29, 16%) and HMA alone (n=19, 11%). The median follow-up was 22 months (range, 1-71 months), and the estimated median overall survival (OS) was 21 months for the entire patient population. Within the follow-up, approximately half of the patients (n=90, 47%) died.
Compared to non-obese patients, obese patients were younger at presentation (55 vs. 63, p=0.04) and consisted of more females (n=48 (55%) vs. n=36 (38%), p=0.02). Obese patients had a significantly lower number of mutations (p=0.01), particularly in spliceosome (n=12 (13%) vs. n=29 (31%), p=0.007) and transcription factor genes (n=17 (19%) vs. n=31 (33%), p=0.04). Obese patients were noted to have more NPM1 mutations (n=21 (23) vs. n=11 (11%), p=0.05) (Figure). According to ELN2022, obese patients were classified more favorably than non-obese patients (p=0.002).
Patients were treated with similar regimens across the study populations, and obese patients' estimated OS was significantly longer than that of non-obese patients (44 vs. 13 months, p=0.02). The median follow-up was comparable in obese vs. non-obese patients, and within the follow-up, fewer obese patients died (n=36 (40%) vs. n=54 (57%), p=0.02).
Conclusions: AML in obese patients appears to have distinct clinical and genetic characteristics compared to non-obese patients. This suggests that different underlying mechanisms may contribute to leukemogenesis in these two patient groups. Future studies should focus on elucidating the specific molecular pathways and mechanisms through which obesity influences AML development, which could pave the way for novel treatment approaches tailored to obese patients.