Clinical significance of RAS-MAPK pathway mutations in Acute Myeloid Leukemia: Insights from a retrospective cohort

Abstract Background Dysregulation of the RAS-MAPK signaling pathway is among the most common molecular abnormalities observed in neoplastic processes and leads to uncontrolled cell proliferation and resistance to apoptosis. Somatic mutations in key components of this pathway, such as NRAS, KRAS, BRAF, NF1, 0.05). When comparing NRAS-mt to NRAS-wt AML, NRAS-mt AML had a similar CCR rate (61% vs 52%)MV LR: odds ratio (OR): 0.62, 95CI 0.3-1.4, median OS (13 vs 12 mo) MV CPH: hazard ratio (HR) 1.2, 95CI 0.9-1.6 and median EFS (9.6 vs 7 mo) MV CPH: HR 1.18, 95CI 0.9-1.6 (All P0.05). Patients with KRAS-mt AML had lower hemoglobin (7.8 vs. 8.4 g/dL), higher WBC (18 vs 6 K/μL), lower platelets (40 vs 54 μL), and more wt TP53 (95% vs. 81%) (All P0.05). When comparing KRAS-mt to KRAS-wt AML, KRAS-mt AML had similar CCR rate (54% vs 53%)MV LR: OR: 0.62, 95CI 0.3-1.4, P0.05 but lower median OS (8.2 vs 12 mo) MV CPH: HR 2.4, 95CI 1.6-3.4, P0.01 and lower median EFS (3.9 vs 7.5 mo) MV CPH: HR 2.1, 95CI 1.4-3, P0.01. Patients with BRAF-mt AML had a similar presentation to BRAF-wt AML. There was no difference in CCR rates (60% vs 52%), median OS (3.9 vs 12 mo), or median EFS (3.9 vs 7.1 mo) (all univariable, MV LR and MV CPH P0.05) between BRAF mt and wt AML. Patients with NF1-mt AML had a similar presentation to NF1-wt AML, except for a higher prevalence of hypertension (73% vs. 51%, P0.05). Mutation in NF1 was not associated with different CCR rates (54% vs 52%), median OS (13 vs 11 mo) or median EFS (8.1 vs 6.9 mo) all univariable, MV LR and MV CPH P0.05 than wt NF1 AML. Lastly, patients with PTPN11 mt AML had a higher prevalence of diabetes (36% vs 17%), hypertension (64% vs 48%), ECOG 3/4 (18% vs 7.4%) high-risk cytogenetics (49% vs. 30%) and higher absolute neutrophils (1.9 vs. 1 K/μL) at presentation. AML with mt-PTPN11 had similar CCR rates (59% vs 52%), median OS (12 vs 12 mo), and median EFS (8.4 vs 7.2 mo) all univariable, MV LR and MV CPH P0.05 compared to wildtype-PTPN11. Conclusion Although mutations in the RAS-MAPK pathway are common in AML, they exhibit distinct clinicopathological presentations. Notably, KRAS mutations, but not NRAS mutations, were significantly associated with a twofold increase in mortality, highlighting the need for focused attention on this subgroup. Mutations in PTPN11 and NF1 did not independently predict prognosis. While BRAF mutations were linked to particularly poor survival, their rarity limited the statistical significance of this finding. These results underscore the importance of integrating molecular profiling into frontline risk stratification and treatment planning for AML patients. However, targeting the MAPK pathway in AML remains a challenge.