Real-world treatment patterns and outcomes in patients with CLL and cardiovascular comorbidities: Interim analysis of the multicenter study conducted by eric.
Abstract
Abstract Introduction Management of chronic lymphocytic leukemia (CLL) has advanced significantly over the past decade with the introduction of targeted therapies (TT). Despite that, important challenges persist in optimizing treatment, especially for patients (pts) with concurrent cardiovascular comorbidities (CVC). We examined real-world treatment patterns and outcomes among pts with CLL and CVC, aiming to better understand therapeutic approaches and effectiveness in this complex population. Methods This retrospective multicenter longitudinal study included pts diagnosed with CLL between 2010 and 2020 (index period), who had at least one CVC at diagnosis or prior to first-line treatment (1L) initiation. Demographic and clinical variables were collected from physician-reported records. Pts were followed from the index date until the last follow-up (f/u), end of study (September 2024), or death, whichever came first. Clinical outcomes were assessed following 1L initiation and were described for both the overall study population and pts who received only TT. Results A total of 1393 pts from 20 centers in 7 countries were included. Most pts were male (898/1393, 64.5%) and had received at least 1 line of CLL-directed treatment (857/1393, 61.6%). The median f/u from diagnosis and 1L initiation were 8.4 years (yrs) [IQR=8-9] and 4 yrs [IQR=1.9-6.9], respectively. The median age (mAge) at diagnosis and 1L was 69 (IQR=62-76) and 71 (IQR=64-78) yrs, respectively. Most pts were diagnosed with arterial hypertension (1112/1393, 79.8%), followed by atrial fibrillation/flutter (AF) (180, 12.9%). Ischemic heart disease [excluding myocardial infarction (MI)], stroke, cardiomyopathy, MI, heart failure, other cardiac arrythmias (excluding AF), and cardiac valve disease were present in 139 (10%), 85 (6.1%), 61 (4.4%), 59 (4.2%), 52 (3.7%), 41 (2.9 %), 31 (2.2%), respectively. At the time of 1L initiation, most pts had unmutated IGHV genes (316/547, 57.8%), while 94/641 (14.7%) had TP53 aberrations. The most common 1L treatments were chlorambucil-based (CHL) regimens [295/857 (34.4%), CHL monotherapy: 117 (13.7%) and CHL plus anti-CD20 monoclonal antibody: 178 (20.1%)] and BTK inhibitors (BTKis) [141/857 (16.5%), ibrutinib (I): 92 (10.7%), acalabrutinib (A): 45 (5.3%), zanubrutinib (Z): 4 (0.5%)]. Fludarabine-cyclophosphamide-rituximab (FCR) and bendamustine-rituximab (BR) were used in 133 (15.6%) and 53 (6.2%), respectively. Venetoclax-based (ven) regimens were used in 55 [6.4%, 50 (5.8%) received ven-obinutuzumab] pts. I plus ven was used in 7 (0.8%) pts. After 2020, the use of BTKis [86/234 (36.7%), A: 43 (18.8%), I: 39 (16.7%), Z: 4 (1.7%)] and ven regimens (48, 20.5%) increased markedly, while chemoimmunotherapy use declined [CHL regimens: 43 (18.4%), BR: 12 (5.1%) and FCR: 5 (2.1%)]. The overall survival (mOS) and time to next treatment or death (mTTNTD) from 1L initiation were 8.4 yrs (95%CI=7.7-9.4) and 3.6 yrs (95%CI=3.2-4), respectively. Of the pts who received TT only, the mOS was not reached [95%CI=5.6 yrs, not estimable (NE)], and mTTNTD was 5.6 yrs (95%CI=4.5-NE). The 3-year-TTNTD for BTKis [mAge: 73yrs], ven regimens (mAge: 69yrs), FCR (mAge: 61), and CHL regimens (mAge: 75yrs) was 71% (95%CI=62-80), 87.1% (95%CI=74-100), 67.5% (95%CI=60-76) and 44.2% (95%CI=39-51), respectively. Overall, 54/141 (38.3%) pts discontinued BTKis in 1L. The reasons were toxicity (tox) (20, 14.2%, CV tox: 9/20 and non-CV tox: 11/20), disease progression (PD) (15, 10.6%), CLL-unrelated (CLL-u) deaths (13, 9.2%) and other reasons (6, 4.2%). Of the 55 pts who received ven regimens, 6 (10.9%) discontinued treatment earlier than scheduled [non-CV tox: 3 (5.5%), other reasons: 2 (3.6%), and CLL-u death: 1 (1.8%)]. FCR (n=133) was discontinued earlier than scheduled in 15 (11.3%) pts [non-CV tox: 12 (9%), PD: 1 (0.8%), other reasons: 2 (1.5%)]. Finally, CHL regimens (n=295) were discontinued in 36 (12.2%) pts [non-CV tox: 14 (4.7%), PD: 12 (4.1%), other reasons: 9 (0.8%), CLL-u death: 1 (0.3%)]. Conclusion We highlight a shift toward the use of TT in pts with CLL and CVC and illustrate differential patterns in TTNTD and discontinuation according to regimen. Differences in pts age and treatment duration across regimens may have contributed to the varying incidence of CV tox leading to discontinuation, especially in pts receiving BTKi. The study's retrospective nature, age and f/u differences preclude any comparison of TTNTD between treatments.
Article Details
Authors (48)
Thomas Chatzikonstantinou
1Institute of Applied Biosciences, Center for Research and Technology, Thessaloniki, Greece
Sevasti Konstantinou
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
Francesco Angotzi
3Hematology Unit, Department of Medicine, University of Padova, Padova, Italy
Marcello Bradaschia
7Hematology, University of Siena, AOUS, Policlinico Le Scotte, Siena, Italy
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
Marta Crespo
Maria Dimou
18Hematology, University of Athens, Laikon General Hospital, Athens, Greece
Alessandro Gozzetti
University of Siena, Siena, Italy
Ritu Gupta
Eliana Konstantinou
18Hematology, University of Athens, Laikon General Hospital, Athens, Greece
Andreas Epameinondas Koumpis
24Department of Haematology, Faculty of Medicine, University of Ioannina,Greece, Ioannina, Greece
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
Roberta Murru
11Hematology and Stem Cell Transplantation Unit, Ospedale Oncologico A. Businco, ARNAS “G. Brotzu”, Cagliari, Italy
Leila Perobelli
35Hospital de Transplantes Euryclides de Jesus Zerbini – Hospital Brigadeiro, Sao Paulo, Brazil
Lata Rani
23Laboratory Oncology Unit, Dr. B.R.A. IRCH, All India Institute of Medical Sciences (AIIMS), New Delhi, India
Ilaria Romano
37Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
Gian Matteo Rigolin
16St. Anna University Hospital - Department of Medical Sciences, University of Ferrara, l, Ferrara, Italy
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
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
Celso Arrais-Rodrigues
Rodrigo Santucci da Silva
20Instituto Hemomed de Oncologia e Hematologia, Sao Paulo, Brazil
Carlos Chiattone
4Department of Medicine, Santa Casa Medicine School, Sao Paulo, Brazil
Francesc Bosch Albareda
5Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain
Anastasia Chatzidimitriou
1Institute of Applied Biosciences, Center for Research and Technology, Thessaloniki, Greece
Marta Coscia
15Division of Hematology, Ospedale di Circolo e Fondazione Macchi ASST Sette Laghi, University of Insubria, Varese, Italy
Antonio Cuneo
1University of Ferrara
Gianluca Gaidano
13Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
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
Ioannis Kotsianidis
29Department of Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
Panagiotis Panagiotidis
2Hematology, University of Athens, Laikon General Hospital, Athens, Greece
Maria Papaioannou
10Hematology Unit, 1st Dept of Internal Medicine, AUTH, AHEPA Hospital, Thessaloniki, Greece
Davide Rossi
Institute of Oncology Research, Bellinzona, Switzerland
Niki Stavrogianni
41Hematology Department and HCT Unit G. Papanicolaou Hospital, Thessaloniki, Greece
Livio Trentin
Hematology Unit, Department of Medicine, University of Padua
Theodoros Vassilakopoulos
18Hematology, University of Athens, Laikon General Hospital, Athens, 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