Survival Outcomes of Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) Treated in the Chemoimmunotherapy Vs BTK Inhibitor (BTKi) Eras: A European Research Initiative on CLL (ERIC) Study
Authors: C T , Minga Eva , Karakatsoulis Georgios , Albi Elisa , Alcoceba Miguel , Allsup David , Bacchiarri Francesca , Besikli-Dimou Sotiria , Chatzileontiadou Sofia , Collado Rosa , Davis Zadie , Dimou Maria , Donaldson David , Efstathopoulou Maria , Galimberti Sara , Galitzia Andrea , Gimeno Eva , Guarente Valerio , Hatzimichael Eleftheria , Hernandez-Rivas Jose-Angel , Iacoboni Gloria , Konstantinou Iliana , Kotsianidis Ioannis , Kotaskova Jana , Koumpis Andreas Epameinondas , Kubova Zuzana , Labrador Jorge , Laurenti Luca , Marquet Juan , Maslejova Stanislava , Mayor-Bastida Carlota , Miras Fatima , Moia Riccardo , Navarro-Bailon Almudena , Olivieri Jacopo , Papaioannou Maria , Puiggros Anna , Rigolin Gian Matteo , Schipani Mattia , Shokralla Tereza , Simkovic Martin , Tranidou Antigoni , Vassilakopoulos Theodoros , Visentin Andrea , Vitale Candida , Vrachiolias George , Walewska Renata , Yanez San Segundo Lucrecia , Zuchnicka Jana , Oscier David Graham , Gozzetti Alessandro , Panayiotidis Panayiotis , Bosch Francesc , Sportoletti Paolo , Espinet Blanca , Pangalis Gerassimos , Angelopoulou Maria , Papajik Tomas , Murru Roberta , Coscia Marta , Cuneo Antonio , Gaidano Gianluca , Stavrogianni Niki , Trentin Livio , Smolej Lukas , Caterwood Mark , Spacek Martin , Pospisilova Sarka , Doubek Michael , Chatzidimitriou Anastasia , Stamatopoulos Kostas , Ghia Paolo , Scarfo Lydia 
Published: December 2024

Introduction:
The introduction of targeted agents has radically changed the management of patients with chronic lymphocytic leukemia (CLL). Randomized controlled trials have shown the superiority of targeted agents over chemoimmunotherapy (CIT) in patients with relapsed/refractory (R/R) CLL. Following these trials, the treatment paradigm of CLL in daily practice shifted from CIT to targeted agents in any line of treatment. However, it is largely unknown if this has improved the overall survival (OS) of patients with R/R CLL in the real world.
Methods:
This is a retrospective, observational study that aimed to explore differences in the OS of patients with CLL in a real-world setting.
Patients who received second-line treatment for CLL between 2010 and 2019 in five European countries (Czech Republic, Greece, Italy, Spain, and the United Kingdom) were eligible for the study. The patients were allocated to two different groups (CIT-era and BTKi-era groups) according to the actual use of BTKis in R/R settings in each country.
The year when the use of BTKis surpassed 30% in any line was defined as the cutoff year for each country. Cases treated before the cutoff year were allocated to the CIT-era group, and cases treated after the cutoff year were allocated to the BTKi-era group.
We compared the OS from the initial date of second line treatment between the two groups. The analysis was also done after adjusting for age at second line treatment through propensity score matching.
Results:
A total of 1877 patients (1384 in the CIT-era group and 493 in the BTKi-era group) from 38 centers were eligible for the study. The cutoff year was 2019, 2018, 2017, 2016, and 2014 for the Czech Republic, Greece, Italy, Spain, and the United Kingdom, respectively. In both groups, most patients were males [919 (66.4%) in the CIT-era and 337 (68.4%) in the BTKi-era group, p=0.461]. Patients in the CIT-era group were younger at both diagnosis [64 years (interquartile range (IQR)=57-71) vs 66 (IQR=59-74), p=0.001 for CIT-era and BTKi-era groups, respectively] and the start of second-line treatment [69 years (IQR=63-76) vs 73 (IQR=65, 79) p=0.001 for the CIT-era and BTKi-era groups, respectively]. The CIRS score was higher in the BTKi-era group [3 (IQR=1.25-6) vs 4 (IQR=2-6), p=0.053 for the CIT-era and BTKi-era groups, respectively]. Unfavorable disease biomarkers were similarly distributed among the two groups [del(11q): 215 (27.7%) vs. 80 (24.2%), p=0.26 | del(17p): 117 (14.7%) vs. 54 (15.7%), p=0.7 | TP53 mutations: 94 (19%) vs. 41 (17.3%), p=0.66 | unmutated immunoglobulin heavy variable (IGHV) gene status: 792 (78.8%) vs 276 (76.2%), p=0.35 for the CIT-era and BTKi-era groups, respectively]. The follow-up time from diagnosis (153 months [95% confidence intervals (CI):149-160) vs 106.6 (95% CI:98-115) for CIT-era and BTKi-era groups, respectively] and second-line treatment [81 months (95% CI:77-86) vs 30 (95% CI:27- 33) for CIT-era and BTKi-era groups, respectively] were longer for the CIT-era group.
Patients in the BTKi-era group had statistically significantly better OS compared to the CIT-era group (Hazard ratio (HR): 0.74 95% CI: 0.61-0.91, p=0.003). This difference was even more pronounced when comparing OS using propensity score matching (HR: 0.71, 95% CI: 0.58-0.88, p=0.001). The median OS for the CIT-era group was 65 months (95% CI=57-71), while the median OS for the BTKi-era group was not reached (95% CI=not estimable, not estimable).
Finally, we performed a univariable and multivariable analysis (MVA) to assess the risk factors for death in the entire population. TP53 aberrations and unmutated IGHV gene status remained the only statistically significant risk factors for death in the MVA (HR: 1.7, 95% CI: 1.03-3.13, p=0.039, HR: 2.48, 95% CI: 1.08-5.66, p=0.032, respectively). The only protective factor against death was treatment with BTKis in the R/R setting (HR: 0.5, 95% CI: 0.28-0.88, p=0.017).
Conclusion:
Our findings demonstrated that the availability of BTKis has improved the OS of patients with R/R CLL in the real-world setting.