Background: Improved outcome has been reported in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs) in sponsored trials. Methods: This is a multicenter prospective cohort study of consecutive patients with newly diagnosed chronic phase CML from 19 regions in Italy. Baseline treatments and prognostic factors on time to first optimal molecular response (≥ molecular response 3, MR3), time to disease progression, time to death from CML, and overall survival (OS) were analyzed using multivariable Fine and Gray models. Results: The authors included 1433 CML patients: 49% (median age, 70 years) treated with frontline imatinib (IMA), and 51% treated with second-generation TKIs (2G-TKIs; median age, 52 years). EUTOS long-term survival (ELTS) was low in 68.1% of 2G-TKIs patients, compared to 50.4% of IMA patients. Faster molecular responses were observed with 2G-TKIs within the first 6 months and maintained thereafter (subhazard ratio [sHR], 1.31; 95% confidence interval [CI], 1.15–1.50). Female gender and low ELTS risk had faster time of response. Achieving major molecular response (MMR or MR3) was associated with reduced risk of progression at 6 and 12 months. Overall, 41 patients progressed without differences between IMA and 2G-TKIs. Intermediate and high risk ELTS showed higher risk of progression and death from CML. Twenty-two CML-related deaths (16.5%) occurred mostly in the first 2 years from diagnosis, higher in 2G-TKIs patients (sHR, 1.75; 95% CI, 0.52–5.87). OS at 5 years was 88% with no clear differences between IMA and 2G-TKIs treatment after adjustment for potential confounders. Conclusions: The study confirms faster responses with 2G-TKIs compared to IMA but similar clinical outcomes and a strong prognostic effect of ELTS.
