Survival differences of patients with treatment-naive CLL between the chemoimmunotherapy and BTKi eras: An eric study.
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.
Article Details
Authors (75)
Thomas Chatzikonstantinou
1Institute of Applied Biosciences, Center for Research and Technology, Thessaloniki, Greece
Persefoni Talimtzi
1Institute of Applied Biosciences, Center for Research and Technology, Thessaloniki, Greece
Eva Minga
1Institute of Applied Biosciences, Center for Research and Technology, Thessaloniki, Greece
Maria Angelopoulou
2Department of Haematology, University of Athens, Laikon General Hospital, Athens, Greece
Miguel Arguello De Tomas
3Hematology Department, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau and José Carreras Leukemia Research Institutes, Departamento de Medicina, Universidad Autónoma de Barcelona, Barcelona, Spain
Darko Antic
4Clinic for Hematology, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
Celso Arrais-Rodrigues
Francesc Bosch Albareda
5Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain
Marcello Bradaschia
7Hematology, University of Siena, AOUS, Policlinico Le Scotte, Siena, Italy
Alessandro Cellini
8Hematology Unit, Department of Medicine, University of Padova, Padova, Italy
Mark Catherwood
9Regional Molecular Diagnostics Service, Belfast Health and Social Care Trust, Belfast, Ireland
Sophia Chatzileontiadou
10Hematology Unit, 1st Dept of Internal Medicine, AUTH, AHEPA Hospital, Thessaloniki, Greece
Caterina Chessa
11Hematology and Stem Cell Transplantation Unit, Ospedale Oncologico A. Businco, ARNAS “G. Brotzu”, Cagliari, Italy
Carlos Chiattone
4Department of Medicine, Santa Casa Medicine School, Sao Paulo, Brazil
Rosa Collado
14Department of Hematology, Consorcio Hospital General Universitario de Valencia. Fundación de Investigación Hospital General Universitario de Valencia, Valencia, Spain
Marta Coscia
15Division of Hematology, Ospedale di Circolo e Fondazione Macchi ASST Sette Laghi, University of Insubria, Varese, Italy
Marta Crespo
Antonio Cuneo
1University of Ferrara
Zadie Davis
17Department of Haematology, Royal Bournemouth Hospital, Bournemouth, United Kingdom
Maria Dimou
18Hematology, University of Athens, Laikon General Hospital, Athens, Greece
Michael Doubek
19Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University; CEITEC MU, Brno, Czech Republic, Brno, Czech Republic
Maria Efstathopoulou
20Department of Haematology, Athens Medical Center, Psychikon Branch, Athens, Greece
Blanca Espinet
21Molecular Cytogenetics Laboratory, Pathology Department, Hospital del Mar and Translational Research on Hematological Neoplasms Group, Hospital del Mar Research Institute (IMIM), Barcelona, Spain
Gianluca Gaidano
13Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
Rocio Garcia-Serra
14Department of Hematology, Consorcio Hospital General Universitario de Valencia. Fundación de Investigación Hospital General Universitario de Valencia, Valencia, Spain
Alessandro Gozzetti
University of Siena, Siena, Italy
Ritu Gupta
Eleftheria Hatzimichael
24Department of Haematology, Faculty of Medicine, University of Ioannina,Greece, Ioannina, Greece
Yair Herishanu
13Faculty of Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel
Ozren Jaksic
26Division of Hematology, Department of Internal Medicine, University Hospital Dubrava and Medical School, University of Zagreb, Zagreb, Croatia
Maria Kislova
27Department of Hematology, Oncology, and Chemotherapy, S. P. Botkins City Hospital, Moscow, Russian Federation
Eliana Konstantinou
18Hematology, University of Athens, Laikon General Hospital, Athens, Greece
Sevasti Konstantinou
1Institute of Applied Biosciences, Center for Research and Technology, Thessaloniki, Greece
Maya Koren Michowitz
28Department of Hematology, Shamir Medical Center, Zerifin, Israel
Ioannis Kotsianidis
29Department of Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
Andreas Epameinondas Koumpis
24Department of Haematology, Faculty of Medicine, University of Ioannina,Greece, Ioannina, Greece
Luca Laurenti
2Department of Diagnostic Imaging, Oncological Radiotherapy and Hematology, Agostino Gemelli University Hospital Foundation IRCCS, Rome, Italy
Alexandros Machairas
18Hematology, University of Athens, Laikon General Hospital, Athens, Greece
Francesca Martini
Dipartimento di Chimica e Chimica Industriale
Riccardo Moia
32Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
Samir Mouhssine
32Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
Ana Muntanola Prat
33Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
Roberta Murru
11Hematology and Stem Cell Transplantation Unit, Ospedale Oncologico A. Businco, ARNAS “G. Brotzu”, Cagliari, Italy
Rocio Nieves Salgado Sanchez
34Fundacion Jimenez Díaz University Hospital, Health Research Institute IIS-FJD, Madrid, Spain
Gerassimos Pangalis
20Department of Haematology, Athens Medical Center, Psychikon Branch, Athens, Greece
Maria Papaioannou
10Hematology Unit, 1st Dept of Internal Medicine, AUTH, AHEPA Hospital, Thessaloniki, Greece
Sarka Pavlova
Leila Perobelli
35Hospital de Transplantes Euryclides de Jesus Zerbini – Hospital Brigadeiro, Sao Paulo, Brazil
Sarka Pospisilova
19Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University; CEITEC MU, Brno, Czech Republic, Brno, Czech Republic
Anna Puiggros
21Molecular Cytogenetics Laboratory, Pathology Department, Hospital del Mar and Translational Research on Hematological Neoplasms Group, Hospital del Mar Research Institute (IMIM), Barcelona, Spain
Claus Rainer
36Comprehensive Cancer Center Augsburg, Ausburg, Germany
Sergio Ramos
34Fundacion Jimenez Díaz University Hospital, Health Research Institute IIS-FJD, Madrid, Spain
Lata Rani
23Laboratory Oncology Unit, Dr. B.R.A. IRCH, All India Institute of Medical Sciences (AIIMS), New Delhi, India
Gian Matteo Rigolin
16St. Anna University Hospital - Department of Medical Sciences, University of Ferrara, l, Ferrara, Italy
Ilaria Romano
37Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
Davide Rossi
Institute of Oncology Research, Bellinzona, Switzerland
Rodrigo Santucci
38Instituto Hemomed de Oncologia e Hematologia, Sao Paulo, Brazil
Angel Serna
6Department of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Servei d'Hematologia, Vall d'Hebron Hospital Universitari, Experimental Hematology, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
Marina Siakantaris
18Hematology, University of Athens, Laikon General Hospital, Athens, Greece
Talita Silveira
2AC Camargo Cancer Center, Hematology, São Paulo, Brazil
Paolo Sportoletti
Department of Medicine and Surgery, Institute of Hematology and Center for Hemato-Oncology Research (CREO), University of Perugia, Santa Maria della Misericordia Hospital, Perugia, Italy
Niki Stavrogianni
41Hematology Department and HCT Unit G. Papanicolaou Hospital, Thessaloniki, Greece
Annamaria Tomasso
30Università Cattolica del Sacro Cuore, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
Kristina Tomic Vujovic
4Clinic for Hematology, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
Livio Trentin
Hematology Unit, Department of Medicine, University of Padua
Theodoros Vassilakopoulos
18Hematology, University of Athens, Laikon General Hospital, Athens, Greece
Andrea Visentin
8Hematology Unit, Department of Medicine, University of Padova, Padova, Italy
Candida Vitale
42Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino and Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
George Vrachiolias
29Department of Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
Munci Yagci
43Gazi University, Ankara, Türkiye
Seyma Yildiz
Anastasia Chatzidimitriou
1Institute of Applied Biosciences, Center for Research and Technology, Thessaloniki, Greece
Kostas Stamatopoulos
Institute of Applied Biosciences at the Centre for Research and Technology Hellas
Paolo Ghia
School of Medicine, Università Vita Salute San Raffaele, Milan
Lydia Scarfò
School of Medicine, Università Vita Salute San Raffaele, Milan