AbstractBackgroundIn older patients with acute myeloid leukemia (AML), the definition of fitness, prognosis, and risk of death represents an open question.MethodsIn the present study, we tested the impact on survival of disease‐ and patient‐related parameters in a large cohort of elderly AML patients homogeneously assigned to treatment with hypomethylating agents (HMAs).ResultsIn 131 patients with a median age of 76 years, we confirmed that early response (<0.001) and biology‐based risk classification (p= 0.003) can select patients with better‐predicted survival. However, a full disease‐oriented model had limitations in stratifying our patients, prompting us to investigate the impact of baseline comorbidities on overall survival basing on a comorbidity score. The albumin level (p= 0.001) and the presence of lung disease (p= 0.013) had a single‐variable impact on prognosis. The baseline comorbidity burden was a powerful predictor of patients' frailty, correlating with increased incidence of adverse events, especially infections, and predicted overall survival (p< 0.001).ConclusionThe comorbidity burden may contribute to impact prognosis in addition to disease biology. While the therapeutic armamentarium of elderly AML is improving, a comprehensive approach that combines AML biology with tailored interventions to patients' frailty is likely to fully exploit the anti‐leukemia potential of novel drugs.