Outcomes and Clinical Practice Among Patient with Chronic Lymphocytic Leukemia Treated with Ibrutinib in China: A Real-World Experience
Authors: Yang Shenmiao , Feng Ru , Guo Xutao , Li Zhenling , Ju Qianqian , Dong Yujun , Wang Bingjie , Zhao Yu , Wang Liang , Sun Wanling , Fang Fang , Wang Liru , Su Liping , Huang Xiaojun 
Published: December 2024

Introduction
The incidence of CLL in China is estimated at 1/10 to 1/20 of its incidence in Western countries. Moreover, the geographic diversity in CLL biology was noticed. Ibrutinib, the first-in class Bruton tyrosine kinase inhibitor (BTKi) was approved in China in 2017. The long-term efficacy and safety of BTKi in Chinese CLL patients has rarely been reported. This real world study aims to analyze long-term survival and outcomes of ibrutinib in Chinese patients with CLL and explore the risk factors for PFS and OS.
Methods
This study (NCT06489184) included 257 CLL patients aged 18 years and older who received ibrutinib monotherapy for at least one month from Mar.18, 2014.to Apr.1, 2024. The Kaplan-Meier curves were constructed to evaluate PFS, OS, and the differences between the treatment groups were compared using the log-rank test. Cox proportional hazards model comparisons were also conducted to explore the prognostic factors of PFS and OS, and backward stepwise logistic regression method was used in the multivariate analysis to identify independent predictors. A P &lt; 0.05 was considered statistically significant; all P values were two-sided. TP53 aberration includes either TP53 mutation or del17p.
Results
A total of 257 patients were enrolled in the study, with 137 treatment-naïve (TN) patients and 120 R/R CLL. The median age was 64(range: 34-92) and 180 (70.0%) were male. Regarding the biological characteristics, 59.1% (152) of the patients were at Rai stage III/IV, 34.6% (89/257) with complex karyotype (CK), 36.6% (94/257) with unmutated IGHV. TP53 mutation was detected in 27.2% (70/257) patients, del17p was 20.6%(53/257), and TP53 aberration was 34.2%(88/257).
The median follow up was 40 months in the overall population, the longest follow up was till to 122 months, median estimated PFS and OS were 83 and 104 months respectively.
For TN patients, the median follow-up was 38(1-122) months, and median PFS and OS was not reached. In TN group 51 patients discontinued the drug, 21(41.2%) due to PD, 17(33.3%) due to AE, 12 (23.5%) due to patient decision, and 1(2.0%) due to unknown reason. Univariate analysis identified TP53 aberration and unmutated IGHV associated with impaired PFS and OS, on the other hand, del(13q) was favorable prognostic parameter for PFS and OS. Using multivariate analysis, TP53 aberrations (HR:2.732; 95%CI:0.108-0.860; P= 0.020), del(13q) (HR:0.304; 95%CI:0.108-0.860; P=0.025) and unmutated IGHV(HR:2.777; 95%CI:1.151-6.701; P=0.023) was the independent adverse risk factors for PFS, and del(13q) (HR:0.283; 95%CI:0.087-0.917; P= 0.025) and unmutated IGHV(HR:3.389; 95%CI:1.242-9.253; P=0.017) was the independent adverse risk factors for PFS.
For R/R patients, the median follow-up was 40.5 (1-119) months. Median PFS and OS were 55 and 83 months, respectively. In R/R group, 79 patients discontinued the drug. 34(43%) due to PD, 19(24.1%) due to AE, 13(16.5%) due to the patients' decision, 11(13.9%) due to death, and 2(2.5%) due to unknown reasons. Univariate analysis identified TP53 aberration, IGHV unmutated and RAI III/IV associated with impaired PFS and OS, and del(13q) was favorable factor for PFS and OS. Multivariate analysis showed that TP53 aberration (HR:1.988; 95%CI:1.043-3.789; P=0.037) and unmutated IGHV (HR:0.488; 95%CI:0.247-0.963; P=0.038) were independent adverse risk factors for PFS, and Rai stage III/IV (HR:2.541; 95%CI:1.015-6.360; P=0.046) and unmutated IGHV (HR:0.440; 95%CI:0.206-0.939; P=0.034) were independent adverse risk factors for PFS.
Among the 73 dead patients, 23 were in TN group and 50 in R/R group. The causes of deaths in TN group were CLL PD (6, 26.1%), Richter Transformation (RT) (3,13%) COVID-19 and infection (6, 26.1%), other (4,17.4%), cardiovascular disease (CVD, 3,13%), and unknown (1,4.3%). However, COVID-19 and infection (13, 26%) was the most common death reason in R/R group, and CLL PD (12, 24%), RT (7,14%), unknown (7,14%), other (4,8%), cardiovascular disorders (3,6%), secondary malignancies (SM, 3,6%) and cerebral infarction (1,2%).
Conclusion
To our best of knowledge, this is the first multicenter real-world data in China to analysis ibrutinib monotherapy in CLL patients. Ibrutinib showed long-term effect in both TN and R/R CLL, but discontinuation due to patient decision remains a noteworthy issue in CLL treatment in China.