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, & PTPN11, are frequently detected at diagnosis in patients with acute myeloid leukemia (AML) and may influence treatment response and survival. We aim to evaluate the prognostic significance of these mutations in newly diagnosed (ND) AML patients treated at the Cleveland Clinic Foundation. Methods We conducted a retrospective cohort study of adult patients diagnosed with ND AML between 1/2015-9/2023. Collected data included baseline demographics, treatment regimens, and molecular profiles. NGS was used to determine mutations in NRAS, KRAS, BRAF, NF1, & PTPN11. Primary endpoints were complete composite remission (CCR, defined as CR + CRi), overall survival (OS), and event-free survival (EFS). To determine associations between baseline variables and outcomes, we used multivariable logistic regression (MV-LR) and Cox proportional hazards regression (MV-CPH). MV models included age, gender, cytogenetics, TP53 status, and comorbidities (DM, hypertension, heart failure, and coronary artery disease). Results A total of 971 newly diagnosed AML patients were treated between 1/2015-9/2023. The median age was 66 years, 55% were male, and 89% were White. The median follow-up was 41 months (mo) (range 0.5-193). The frequency of tested mutations in the RAS-MAPK pathway were: 15% NRAS (n= 97/635), 7.5% KRAS (47/627), 7.6% NF1 (30/395), 7% PTPN11 (44/626), and 0.8% BRAF (5/614). NRAS-mutated (mt) AML patients were younger (61 vs. 66 years), had less high-risk cytogenetic (22% vs. 32%), more wildtype (wt) TP53 (95% vs. 80%), and higher average WBC (18 vs. 6 K/μL) at presentation than NRAS-wt AML (All P<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 P>0.05). 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 P<0.05). 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, P>0.05] but lower median OS (8.2 vs 12 mo) [MV CPH: HR 2.4, 95CI 1.6-3.4, P<0.01] and lower median EFS (3.9 vs 7.5 mo) [MV CPH: HR 2.1, 95CI 1.4-3, P<0.01]. 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 P>0.05) 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%, P<0.05). 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 P>0.05] 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 P>0.05] 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.