Chronic myeloid leukemia (CML) patients who have experienced failure and/or intolerance to multiple lines of treatment have limited therapeutic possibilities. Asciminib is a first-in-class tyrosine kinase inhibitor (TKI) that inhibits the ABL Myristoyl Pocket (STAMP or Specifically Targeting the ABL Myristoyl Pocket) within the BCR::ABL1 oncoprotein. This retrospective Italian analysis reports the efficacy and safety outcomes of asciminib in treating 77 CML patients in chronic phase (CML-CP) within a compassionate use setting. Patients were heavily pretreated with a median of 3 TKIs (55.8% had prior ponatinib exposure). Overall, 57.1% and 42.9% patients switched to asciminib because of resistance and intolerance, respectively. Asciminib maintained or improved molecular responses (MRs) in most patients: as best response, 41 patients (53%) achieved a MR3 or better, with 25 patients (32.5%) reaching deep molecular response (DMR). Greater percentages of intolerant patients achieved MR compared with resistant patients, although the probability of reaching at least a MR3 was not significant between the two groups (p = 0.116). Patients with the T315I mutation responded to asciminib, while ponatinib pre-treated patients showed lower MR improvements compared to naïve patients and had a lower probability to reach a MR3 versus naïve patients (p = 0.0262). These results highlight asciminib remarkable tolerability and efficacy in real-world CML-CP patient population, including heavily pretreated patients, those intolerant and resistant to previous TKIs, and presenting several comorbidities. TRAIL REGISTRATION: The identification code for the MAP is CABL001AIT01M.