Clinical Utility of Frailty Scoring in Elderly Acute Myeloid Leukemia Patients Treated With Venetoclax and Hypomethylating Agents

: Acute myeloid leukemia (AML) in elderly patients presents a major therapeutic challenge, as many are deemed unfit for intensive chemotherapy due to age, comorbidities, or frailty. Venetoclax in combination with hypomethylating agents (HMA) has emerged as a standard-of-care for this population, yet outcomes remain heterogeneous and predictive tools are limited. In this retrospective single-center study, we analyzed 52 treatment-naïve AML patients receiving venetoclax combined with either azacitidine (n = 33) or decitabine (n = 19) at the Hematology Department of Cosenza Hospital between August 2021 and June 2025. Frailty was assessed using the Clinical Frailty Scale (CSHA CFS), with 19 patients classified as low frailty (score ≤ 3) and 33 as high frailty (score > 3). The median age was 75.3 years (range 58.2-89.2), and the cohort included 33 de novo and 19 secondary AML cases. After a median follow-up of 18 months, 34 patients (65.4%) had died: 14 due to disease progression, 12 due to treatment-related toxicity-predominantly severe infections-and 5 from unrelated causes. ROC curve analysis showed that a CFS score > 3 was associated with worse survival (AUC 0.75, 95% CI 0.61-0.89, p < 0.004), with median overall survival of 7.6 months for low-frailty patients versus 2.5 months for high-frailty patients (1-year OS 44.1% vs. 18.7%, p = 0.031). Multivariate analysis confirmed that lower frailty (p = 0.031) and azacitidine-based therapy (p = 0.025) were independently associated with improved survival. Overall response rate was 48%, including 21 complete responses (CR/CRi) and 4 partial responses. Frailty was the only significant predictor of response (p = 0.005), whereas age, sex, type of AML, ELN risk score, renal function, BMI, or type of HMA did not significantly influence outcomes. Grade 3-4 treatment-related adverse events occurred in all patients, predominantly hematological; non-hematological events included infections (61.9%), cardiotoxicity (11.9%), and liver toxicity (9.5%). High-frailty patients experienced a higher incidence of infections (72.7% vs. 36.8%, p = 0.02) and hospitalizations (57.6% vs. 21.1%, p = 0.011). These results suggest that the CSHA CFS is a simple and clinically meaningful tool to stratify elderly AML patients for venetoclax-HMA therapy, identifying those at higher risk of treatment-related complications and poor survival. Incorporating frailty assessment into routine practice may enhance patient selection, optimize supportive care, and guide individualized therapeutic decisions. Prospective, multicenter studies are warranted to validate these findings and refine the use of frailty-guided treatment strategies in this vulnerable population.