Sex-Related Differences in CML Outcomes in a Real-World Prospective Registry (GQR LMC-NMP)
Authors: Beaudet Marc-Etienne , Szuber Natasha , Moussa Hanane , Harnois Michaël , Assouline Sarit E. , Busque Lambert 
Published: December 2024

Introduction
Women are underrepresented in clinical trials and specifically in phase 3 leukemia trials (Noyola-Perez A, et al. Blood 2023). Conversely, they are overrepresented when looking at side effects in numerous studies in medicine. Several reports looking at treatment free remission (TFR) in chronic myelogenous leukemia (CML) identified female sex as a predictor of durable deep molecular response. We aimed to explore sex-driven differences in CML regarding baseline characteristics, treatment efficacy and intolerance in a real-world setting.
Method
Data was queried from the Quebec CML-MPN Research Group (GQR LMC-NMP) prospective registry which includes CML patients recruited since 2009 from 20 different academic and community centers. Exclusion criteria for this analysis were a CML diagnosis prior to 2008, accelerated/blastic phase at diagnosis and ponatinib as first line (1L) treatment. Data were abstracted in April 2024. Patients were evaluated for baseline characteristics, choice of tyrosine kinase inhibitor (TKI), reasons for TKI discontinuation in 1L and second line (2L) and major molecular response (MMR) achievement. Categorical variables were compared using the Chi-square test and continuous variables using Mann-Whitney U test. Failure-free survival (FFS) was defined form the date of treatment start to the date of death or any events leading to treatment discontinuation except for TFR. Overall survival (OS) was defined from the date of treatment start to the date of death from any cause. Time-to-event Kaplan-Meier curves were generated and compared using the log-rank test. The cumulative incidence of intolerance leading to TKI discontinuation in 1L was assessed with a competing risk model including resistance leading to TKI discontinuation and death.
Results
A total of 663 patients were included with 303 women (45.7%). The median follow-up was 6.5 years. Imatinib was the 1L TKI in a similar proportion of women (n=217; 71.6%) and men (n=257; 71.4%). There was no difference in overall survival (p=0.24) and FFS (p=0.47) between women and men. MMR rates were similar across sexes (88.4% vs 86.7%) but median time to achieve MMR was shorter in women: 262 days compared to 343 days in men (p=0.01). Differences were observed in frequency of reasons leading to TKI discontinuation in 1L between women and men, respectively, in regard to intolerance (33.0% vs 23.6%), resistance (14.5% vs 22.8%) and TFR (7.3% vs 2.2%) (p&lt;0.01). The same pattern was seen in 2L between women and men for intolerance (37.5% vs 28.7%) resistance (7.6% vs 12.6 %) and TFR (6.9% vs 4.0%) but did not reached statistical significance (p=0.21). At 10 years, the estimated cumulative incidence of intolerance leading to TKI discontinuation in 1L was 0.42 (IC 95 %,0.34-0.50) in women and 0.27 (IC 95 %, 0.22-0.33) in men (p&lt; 0.01). The median time to intolerance leading to TKI switching was 177 days in 1L and 267 days in 2L in women compared to 214 days in 1L and 156 days in 2L in men. Gastro-intestinal toxicities were the most common side effect leading to TKI switching in 1L and 2L in women (17.5% vs 11.8%) and pleural effusion was the most common side effect leading to TKI switching in 1L and 2L in men (11.7% vs 16.2%).
Conclusion
In our prospective cohort, women achieved MMR faster, attempted TFR more frequently and showed less resistance to treatment leading to TKI switching. Even though they showed a favorable response profile, FFS was the same compared to men due to a higher cumulative rate of intolerance leading to TKI switching. These results shed light on disparities between sexes in regard to CML clinical trajectories. This could potentially be leveraged to tailor toxicity management and dose reduction for women, especially when MMR is obtained or when TFR is not an objective.