Survival differences of patients with treatment-naive CLL between the chemoimmunotherapy and BTKi eras: An eric study.

Abstract Introduction: Several randomized controlled trials have demonstrated superiority of BTK inhibitors (BTKis) over chemoimmunotherapy (CIT) in patients with treatment naïve (TN) CLL. In some of these trials, BTKis have also led to a statistically significant improvement in overall survival (OS). However, it is largely unknown if the adoption of BTKis in TN CLL has improved OS of patients with CLL in the real world (RW). Methods: This is a retrospective, observational study that aimed to explore differences in the OS of patients with TN CLL treated a) in different eras [CIT-era group vs BTKi-era] and b) with BTKis vs fludarabine-cyclophosphamide-rituximab (FCR) in a RW setting. In the latter comparison, we excluded patients >70 years at first-line (1L) treatment and patients with TP53 aberrations. Patients who received 1L treatment for CLL between 2010 and 2020 in 14 countries were included in the study. Patients were allocated to two different groups (CIT-era and BTKi-era groups) according to the actual use of BTKis in each country. The year when the use of BTKis surpassed 25% 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. OS was defined as the time from CLL-directed treatment to death (event) or last follow-up date (censoring). For the propensity score matching (PSM), we matched patients based on age at 1L initiation, biological sex, and TP53 aberrations for the group comparison and on age at 1L initiation and biological sex for the BTKis vs FCR comparison. Results: A total of 5642 patients (CIT-era group: 4321 and BTKi-era group: 1321) from 37 centers were eligible for the study. The cutoff year was 2020 for the Czech Republic and Russia, 2019 for Brazil, Croatia, Germany, Greece, 2018 for Israel and Turkey, 2017 for Italy and Spain, and 2016 for Switzerland and the United Kingdom. Cases treated in India and Serbia did not reach the 25% cut-off and were allocated to the CIT-era group. BTKis represented the most common treatment in 1L for the BTKi-era group [484 (37%), ibrutinib-based: 443 (91.5%), acalabrutinib-based: 34 (7%), and zanubrutinib-based: 7 (1.5%)], while only 67 (5.1%) cases were treated with venetoclax-based regimens, reflecting the later approval of these regimens in 1L. In the CIT-era group, FCR (1478, 34.1%) chlorambucil-based (1131, 26.2%) and bendamustine plus anti-CD20 antibody (549, 12.7%) were the most common treatments. The use of BTKis in 1L in the CIT-era group was minimal (141, 3.3%). In both groups, most patients were males [2755 (64%) in the CIT-era group and 836 (63%) in the BTKi-era group, p=0.8]. Patients in the CIT group were younger at the start of 1L treatment [67 years (IQR=59-74) vs 69 (IQR=62, 76) p=0.001 for the CIT and BTKi-era groups, respectively]. TP53 mutations and del(17p) were similarly distributed among the two groups [del(17q): 304 (11%) vs. 130 (13%), p=0.09 | TP53 mutations: 202 (15%) vs. 100 (12%), p=0.09]. Unmutated immunoglobulin heavy variable (IGHV) gene status and del(11q) were more frequent in the CIT-era group [449 (19%) vs 126 (15%), p= 0.02 | 1.209 (65%) vs 532 (59%), p= 0.003, respectively]. The follow-up time from 1L treatment was longer for the CIT group [64 months (IQR: 31-98) vs 48 (IQR: 22- 63)] for CIT and BTKi groups, respectively. OS was similar between the two groups [HR: 0.98 (95%CI: 0.88-1.10), p=0.8), median OS: CIT-era group: 7.8 years (95% CI: 7.5, 8) vs BTKi-era group: not reached (7.5, not estimable (NE)]. However, the OS difference was statistically significantly better for the BTKi-era group when we compared OS with PSM for age at 1L initiation and biological sex (HR=0.88 (95%CI: 0.79-0.99), p= 0.04) and for age at 1L initiation, biological sex, and TP53 aberrations [HR:0.73 (95%CI: 0.61-0.88), p< 0.001]. Finally, in the PMS analysis, the OS of patients treated with BTKis was not statistically significantly different compared to cases treated with FCR in 1L (HR: 0.80 (95%CI: 0.56, 1.15), p= 0.2). The median OS for patients treated with BTKis (n=211) and FCR (n=1259) was 10 years (95% CI: 10, NE) and 10.8 years (95% CI: 9.8-11.9), respectively. Conclusion: Our findings show that the availability of BTKis has improved the OS of patients with TN CLL. Patients treated with BTKis had a similar OS with cases treated with FCR in the RW setting.

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Journal
Blood
Published
2025-11-03
DOI
https://doi.org/10.1182/blood-2025-5664
Primary Topic
Chronic Lymphocytic Leukemia Research
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article
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article

Survival differences of patients with treatment-naive CLL between the chemoimmunotherapy and BTKi eras: An eric study.

Niki Stavrogianni, Candida Vitale, Šárka Pavlová, Talita Silveira et al.
Blood
Chronic Lymphocytic Leukemia Research
article

Survival differences of patients with treatment-naive CLL between the chemoimmunotherapy and BTKi eras: An eric study.

Niki Stavrogianni, Candida Vitale, Šárka Pavlová, Talita Silveira, Livio Trentin, Davide Rossi, Ιoannis Kotsianidis, Yair Herishanu, Rosa Collado, Εliana Konstantinou, Alessandro Cellini, Ana Muntanola Prat, Riccardo Moia, Alexandros Machairas, Antonio Cuneo, Rocío García‐Serra, Luca Laurenti, Alessandro Gozzetti, Lydia Scarfò, Ritu Gupta, George Vrachiolias, Carolyn Rainer, Leila Perobelli, Celso Arrais‐Rodrigues, Anastasia Chatzidimitriou, Münci Yağcı, Marta Coscia, Gian Matteo Rigolin, Maria Dimou, Darko Antić, Anna Puiggros, Gianluca Gaïdano, Andrea Visentin, Michael Doubek, Κώστας Σταματόπουλος, Eleftheria Hatzimichael, Kristina Tomić, Rocio Nieves Salgado Sanchez, Mark Catherwood, Zadie Davis, Francesc Bosch, Blanca Espinet, Maria Kislova, Roberta Murru, Carlos Chiattone, Thomas Chatzikonstantinou, Theodoros P. Vassilakopoulos, Gerassimos A. Pangalis, Šárka Pospı́šilová, Rodrigo Santucci, Lata Rani, Marina P. Siakantaris, Eva Minga, Maria K. Angelopoulou, Ozren Jakšić, Maria Efstathopoulou, Ángel Serna, Samir Mouhssine, Paolo Sportoletti, Sophia Chatzileontiadou, Paolo Ghia, Ilaria Romano, Andreas Epameinondas Koumpis, Sérgio Ramos, Şeyma Yıldız, Maria Papaioannou, Francesca Martini, Maya Koren Michowitz, Annamaria Tomasso, S. Konstantinou, Marta Campreciós Crespo, Miguel Argüello De Tomás, Caterina Chessa, Persefoni Talimtzi, Marcello Bradaschia
article en

Abstract

Abstract Introduction: Several randomized controlled trials have demonstrated superiority of BTK inhibitors (BTKis) over chemoimmunotherapy (CIT) in patients with treatment naïve (TN) CLL. In some of these trials, BTKis have also led to a statistically significant improvement in overall survival (OS). However, it is largely unknown if the adoption of BTKis in TN CLL has improved OS of patients with CLL in the real world (RW). Methods: This is a retrospective, observational study that aimed to explore differences in the OS of patients with TN CLL treated a) in different eras [CIT-era group vs BTKi-era] and b) with BTKis vs fludarabine-cyclophosphamide-rituximab (FCR) in a RW setting. In the latter comparison, we excluded patients >70 years at first-line (1L) treatment and patients with TP53 aberrations. Patients who received 1L treatment for CLL between 2010 and 2020 in 14 countries were included in the study. Patients were allocated to two different groups (CIT-era and BTKi-era groups) according to the actual use of BTKis in each country. The year when the use of BTKis surpassed 25% 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. OS was defined as the time from CLL-directed treatment to death (event) or last follow-up date (censoring). For the propensity score matching (PSM), we matched patients based on age at 1L initiation, biological sex, and TP53 aberrations for the group comparison and on age at 1L initiation and biological sex for the BTKis vs FCR comparison. Results: A total of 5642 patients (CIT-era group: 4321 and BTKi-era group: 1321) from 37 centers were eligible for the study. The cutoff year was 2020 for the Czech Republic and Russia, 2019 for Brazil, Croatia, Germany, Greece, 2018 for Israel and Turkey, 2017 for Italy and Spain, and 2016 for Switzerland and the United Kingdom. Cases treated in India and Serbia did not reach the 25% cut-off and were allocated to the CIT-era group. BTKis represented the most common treatment in 1L for the BTKi-era group [484 (37%), ibrutinib-based: 443 (91.5%), acalabrutinib-based: 34 (7%), and zanubrutinib-based: 7 (1.5%)], while only 67 (5.1%) cases were treated with venetoclax-based regimens, reflecting the later approval of these regimens in 1L. In the CIT-era group, FCR (1478, 34.1%) chlorambucil-based (1131, 26.2%) and bendamustine plus anti-CD20 antibody (549, 12.7%) were the most common treatments. The use of BTKis in 1L in the CIT-era group was minimal (141, 3.3%). In both groups, most patients were males [2755 (64%) in the CIT-era group and 836 (63%) in the BTKi-era group, p=0.8]. Patients in the CIT group were younger at the start of 1L treatment [67 years (IQR=59-74) vs 69 (IQR=62, 76) p=0.001 for the CIT and BTKi-era groups, respectively]. TP53 mutations and del(17p) were similarly distributed among the two groups [del(17q): 304 (11%) vs. 130 (13%), p=0.09 | TP53 mutations: 202 (15%) vs. 100 (12%), p=0.09]. Unmutated immunoglobulin heavy variable (IGHV) gene status and del(11q) were more frequent in the CIT-era group [449 (19%) vs 126 (15%), p= 0.02 | 1.209 (65%) vs 532 (59%), p= 0.003, respectively]. The follow-up time from 1L treatment was longer for the CIT group [64 months (IQR: 31-98) vs 48 (IQR: 22- 63)] for CIT and BTKi groups, respectively. OS was similar between the two groups [HR: 0.98 (95%CI: 0.88-1.10), p=0.8), median OS: CIT-era group: 7.8 years (95% CI: 7.5, 8) vs BTKi-era group: not reached (7.5, not estimable (NE)]. However, the OS difference was statistically significantly better for the BTKi-era group when we compared OS with PSM for age at 1L initiation and biological sex (HR=0.88 (95%CI: 0.79-0.99), p= 0.04) and for age at 1L initiation, biological sex, and TP53 aberrations [HR:0.73 (95%CI: 0.61-0.88), p< 0.001]. Finally, in the PMS analysis, the OS of patients treated with BTKis was not statistically significantly different compared to cases treated with FCR in 1L (HR: 0.80 (95%CI: 0.56, 1.15), p= 0.2). The median OS for patients treated with BTKis (n=211) and FCR (n=1259) was 10 years (95% CI: 10, NE) and 10.8 years (95% CI: 9.8-11.9), respectively. Conclusion: Our findings show that the availability of BTKis has improved the OS of patients with TN CLL. Patients treated with BTKis had a similar OS with cases treated with FCR in the RW setting.

BloodVol. 146(Supplement 1)
University of Siena (IT), Università Cattolica del Sacro Cuore (IT), Hebron University (PS), Universitat Autònoma de Barcelona (ES), Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT), Belfast Health and Social Care Trust (GB), University of Padua (IT), Democritus University of Thrace (GR), Ankara University (TR), Vita-Salute San Raffaele University (IT), University of Augsburg (DE), University of Ioannina (GR), University of Ferrara (IT), Masaryk University (CZ), University of Perugia (IT), Tel Aviv Sourasky Medical Center (IL), Royal Bournemouth Hospital (GB), University Hospital Dubrava (HR), AHEPA University Hospital (GR), Ospedale di Circolo e Fondazione Macchi (IT), Hospital de Sant Pau (ES), University Hospital Augsburg (DE), Agostino Gemelli University Polyclinic (IT), Universidade Nove de Julho (BR), AC Camargo Hospital (BR), University of Belgrade (RS), Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT), Josep Carreras Leukaemia Research Institute (ES), Institute of Oncology Research (CH), University Hospital Brno (CZ), Vall d'Hebron Institut de Recerca (ES), Faculdade de Ciências Médicas da Santa Casa de São Paulo (BR), Centar za Promociju Nauke (RS), Assaf Harofeh Medical Center (IL), Laiko General Hospital of Athens (GR), Botkin Hospital (RU), Vall d'Hebron Hospital Universitari (ES), Hospital General Universitario De Valencia (ES), Hospital Universitario Fundación Jiménez Díaz (ES), Hospital Del Mar (ES), IRCCS Ospedale San Raffaele (IT), Athens Medical Center (GR), Centre for Research and Technology Hellas (GR), Dr. Euryclides Hospital de Jesus Zerbini (BR), University General Hospital Attikon (GR), Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (BR), Piedmont University (US), G. Papanikolaou General Hospital (GR), DR. B.R.A. Institute Rotary Cancer Hospital (IN), University Hospital of Alexandroupolis (GR), Hospital São Paulo (BR), Instituto de Hematología e Inmunología (CU), All India Institute of Medical Sciences (IN), Gazi University (TR)
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Chronic Lymphocytic Leukemia Research
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