# Synergistic adverse prognosis of CEBPA and NRAS co-mutation in acute myeloid leukemia: a retrospective cohort study

## TL;DR

This study finds that patients with acute myeloid leukemia who have mutations in both CEBPA and NRAS genes have a significantly worse prognosis.

## Contribution

The study identifies a novel high-risk AML subgroup defined by co-mutation of CEBPA and NRAS genes.

## Key findings

- CEBPA and NRAS mutations are independent predictors of achieving complete remission in AML patients.
- Co-mutation of CEBPA and NRAS is an independent adverse prognostic factor, increasing the risk of death by 3.15-fold.
- Routine NRAS screening in CEBPA-mutated AML patients is recommended to improve risk stratification.

## Abstract

Current prognostic stratification for acute myeloid leukemia (AML) patients primarily relies on international guidelines such as ELN 2022. However, these guidelines provide limited explicit guidance on how to comprehensively assess prognosis when patients harbor concurrent multiple gene mutations, potentially leading to inaccurate risk stratification.

This retrospective cohort study enrolled 299 adult AML patients (median age: 53.5 years). Clinical features, mutation status of prognosis-related genes, complete remission (CR) rate after two induction courses, and overall survival (OS) were analyzed. Logistic regression and Cox proportional hazards models were employed.

In this study cohort, the incidence rates of NRAS and CEBPA single mutations were 15.38% (46/299) and 13.37% (40/299), respectively, while the NRAS and CEBPA co-mutation rate was 4.68% (14/299). Both univariate and multivariate logistic regression analyses demonstrated that CEBPA mutation (OR = 2.807, 95% CI: 1.244–6.333, P = 0.013) and NRAS mutation (OR = 4.028, 95% CI: 1.760–9.219, P = 0.001) were independent positive predictive factors for achieving complete remission after two treatment courses. Survival analysis indicated that neither NRAS single mutation (HR = 1.11, 95% CI: 0.60–2.04, P = 0.738) nor CEBPA single mutation (HR = 0.70, 95% CI: 0.36–1.34, P = 0.280) was significantly associated with overall survival. Notably, NRAS and CEBPA co-mutation was confirmed as an independent adverse prognostic factor, conferring a 3.15-fold increased risk of death (HR = 3.15, 95% CI: 1.08–9.21, P = 0.036) compared to patients without either mutation.

The NRAS and CEBPA co-mutation defines a distinct molecular subtype with independently poor prognosis in AML. Routine NRAS mutation screening in patients with CEBPA-mutated AML is warranted to refine risk stratification, particularly for identifying this high-risk subgroup, which may benefit from more intensive or novel therapeutic approaches.