Probability of Switch of TKIs Treatment According to Baseline Features in a Large Chronic Myeloid Leukemia (CML) Population: Italian CML Network
Authors: Breccia Massimo , Giai Valentina , Rosso Tiziana , Pregno Patrizia , Castagnetti Fausto , Bonifacio Massimiliano , Capodanno Isabella , Tiribelli Mario , Stagno Fabio , Mulas Olga , Gozzini Antonella , Luciano Luigiana , Galimberti Sara , Patriarca Andrea , Lanzarone Giuseppe , Martino Bruno , Guella Anna , Scortechini Anna Rita , Fava Carmen , Fozza Claudio , Sorà Federica , Maggi Alessandro , Pizzuti Michele , Freducci Sara , Loglisci Giuseppina , Russo Rossi Antonella , Di Noi Maria Laura , Spinosa Giuseppina , Santeramo Maria Teresa , Sanpaolo Grazia , Pietrantuono Giuseppe , Mannarella Clara , Calistri Elisabetta , Prete Eleonora , Rosti Gianantonio , Pane Fabrizio , Saglio Giuseppe , Ciccone Giovannino , Specchia Giorgina 
Published: December 2024

Introduction
The outcome of CML patients in chronic phase (CP) has deeply changed over time after the introduction of TKIs and life expectancy is near to that of general population. Although the outstanding results obtained, 20-30% of patients still experienced resistance and/or intolerance and need a change of treatment. How to identify those patients at risk of therapeutic switch during treatment remain a matter of discussion.
Methods
The CML Italian network (including 68 Hematology Centers from 19 Italian regions) prospectively recorded in a dedicated web-based database (https://www.epiclin.it/lmc) the clinical and biological features of all newly diagnosed Italian adult (&gt;18 years) Ph+ CML patients in each phase of disease, diagnosed from January 2013 onwards. All consecutive patients were included, without any exclusion criteria and regardless of their participation in any other clinical trial, to limit the eligibility criteria selection typical of experimental studies. Baseline information included sociodemographic, clinical, and standard laboratory data. For this analysis, patients prospectively collected from 33 centers with updated follow-up data were considered. Fine and Gray multivariable models were used to estimate the adjusted sub hazard ratios (HR) of the first and second change of therapy, considering competitive events.
Results
1433 patients (57% males) prospectively enrolled were analyzed: of them, 702 initially treated with imatinib and 731 with second generation TKIs (2gen TKI). ELTS stratification showed 59.4% of patients as low risk, 28% as intermediate and 12% as high risk. The baseline Charlson comorbidity index detected 71% as score 2 and the remaining as score ≥ 3. The median follow-up was 4.6 years with most patients aged 61-70 years (23%). In the whole cohort, 55% of patients presented concomitant comorbidities, with most represented being cardiovascular (CV) in 27% of patients. Two-hundreds and nine patients (14.5%) had cytogenetic aberrations at baseline. In the imatinib treated cohort, 32% of patients were aged 71-80 years and 39% presented CV initial comorbidities. In the 2gen TKI cohort, 56.8% of patients aged between 41 and 60 years received frontline nilotinib or dasatinib with only 15% of them presenting baseline CV comorbidities. The overall survival of the whole cohort at 5 years was 88%. Out of 428 patients who deserve a second line, 212 (49.5%) switched for resistance to 1st line (at 2 years: 18.7% for Imatinib and 8.9% for 2gen TKI). The statistical analysis revealed a hazard ratio (HR) for first switching for resistance of 0.34 (0.25-0.47, p&lt;0.0001) for those starting with a 2gen TKI, a reduction of the risk with increasing age (HR 0.97 per year, 0.96-0.98, p&lt;0.0001), and increased risk for intermediate (1.79, 1.27-2.53, p=0.001) and high ELTS risk (2.87, 1.90-4.34, p&lt;0.0001) compared to low risk. One hundred and forty-three patients (33.5%) switched for intolerance. The analysis showed an increased risk for patients who started with a 2gen TKI (1.90, 1.26-2.84, p=0.002), and a trend for a positive association for females (1.37, 0.98-1.91, p=0.064) and for increasing age (1.1 per year, 0.99-1.03, p=0.056).
A second change of treatment was recorded in 119 patients (40% for resistance). Factors predicting a lower risk of resistance were starting with 2gen TKI vs imatinib (0.45, 0.21-0.95, p=0.035), and increasing age (0.96 per year, 0.94-0.98, p&lt;0.0001), while high ELTS risk (3.64, 1-76-7.54, p=0.001) was predictive for a second change. Fifty-five patients changed for intolerance and the analysis revealed a significant reduction in those starting with 2gen TKI vs imatinib (0.48, 0.25-0.93, p=0.030) and high ELTS risk vs low (2.75, 1.33-5.70, p=0.006).
Conclusions
The results of the analysis showed that the time to first treatment switch for resistance is shorter for younger patients, for those initially treated with imatinib, and for intermediate/high ELTS risks. The risk of switch for intolerance is higher for patients initially treated with 2genTKIs and, possibly, for females and with increasing age. The different factors associated to treatment switch for resistance or intolerance may help physicians and patients to make more informed decisions in the choice of the initial treatment.