Correlation between number of molecular mutations and outcomes in de novo acute myeloid leukemia.
Authors: Chahine Zena , Johnson Anna , Taj Hiffsa , Morris Trevor , McAvoy Claire , Soule Ashley , Iragavarapu Chaitanya , Munker Reinhold , Yalniz Fevzi Firat , Qasrawi Ayman H. , Ramlal Reshma 
Published: June 2024

e18513

Background: Genomic sequencing of cancer has led to a deeper genetic understanding of the pathogenesis of acute myeloid leukemia (AML). Studies in myelodysplastic syndrome have shown that as the number of oncogenic mutations increases, patient outcomes progressively worsen. We hypothesized that patients with AML may also have a worse prognosis if they have a higher number of somatic mutations. To test this hypothesis, we examined the somatic mutational profile of 225 patients with previously untreated AML. Methods: A single-center retrospective analysis was done utilizing the cancer registry and evaluated patients with de novo AML diagnosed between January 2015 to January 2021. Patient characteristics, cytogenetics, and molecular data were collected by chart review. Patients with available cytogenetic and somatic mutations profile from next-generation sequencing (NGS) were included. Clinically significant (CS) mutations for AML were detected by NGS performed on the diagnostic bone marrow specimen. Statistical analysis was done using the Mann-Whitney U test for continuous variables and proportions were compared using Chi-square test. Results: A total of 225 De Novo AML patients met inclusion criteria. The median age at diagnosis was 61 (range, 21-86). The population was fairly distributed among males (52%) and females (48%). Approximately 51% (n=115) of patients had 0-2 mutations, 43% (n=97) had 3-5 mutations, and 6 % (n=13) had >5 CS mutations. The median number of CS mutations for the entire cohort was 2 (range: 0-9). Survival was worse in the group with >5 mutations when compared to those with 5 or less mutations (23 vs 7 months, p= 0.012). Patients with intermediate risk cytogenetics had a higher median number of CS mutations compared to the favorable and adverse risk group combined (3 versus 1, p < 0.001). To determine whether overall survival was impacted by the presence of an adverse mutation, a subgroup analysis was done using 43 patients with a normal karyotype and at least 1 adverse mutation. The cohort with >5 CS mutations had a significantly shorter OS compared to patients with ≤5 CS mutations (43 vs 9 months, p= 0.001). Conclusions: We found that patients with intermediate-risk cytogenetics have a high number of CS mutations. We found that a higher number of mutations (>5) led to statistically significant difference in survival. To determine whether this difference in survival was a result of the presence of adverse risk mutations vs. number of mutations alone, we analyzed our patients who had normal karyotype with at least one adverse genetic mutation and stratified them based on number of mutations. The presence of more than 5 CS mutations was associated with a worse OS. The number of clinically significant mutations may be an independent predictor of overall survival in AML. This can serve as another tool in stratifying AML risk with normal karyotype. A large prospective clinical trial is necessary to validate.