Dissecting the heterogeneity of IGHV-mutated CLL: An eric study.
Abstract
Abstract Introduction: Patients with CLL and mutated immunoglobulin heavy variable (IGHV) genes (M-CLL) are clinically heterogeneous. While genomic aberrations contribute to adverse outcomes in certain M-CLL subgroups, they do not fully account for M-CLL heterogeneity, suggesting the need for further research. Methods: This is a retrospective, observational study aiming to identify factors associated with shorter overall survival (OS) after first-line (1L) treatment in M-CLL. The study included patients diagnosed with M-CLL between 2000-2022 in 26 centers with a follow-up >6 months after 1L treatment. Special attention was given to immunogenetic features, including BcR stereotypy. Besides, we developed a novel immunogenetic metric that considers the amino acid composition of the germline IGHV genes, following the IMGT physicochemical classification table. Each aligned position across the IGHV gene sequences was assigned different scores based on the relation between the assessed amino acids: 0 if identical, 1 if in the same physicochemical group, and 2 if in different groups. This scoring system enabled the generation of a distance matrix for all IGHV genes, which was then used as input for hierarchical clustering, leading to the creation of 15 clusters. Univariable (UVA) and multivariable (MVA) analyses were performed to identify risk factors associated with shorter OS. The variables assessed in the UVA were age at 1L initiation, biological sex, type of 1L treatment, TP53 mutations, FISH aberrations, and karyotype. Results: 1933 patients from 26 centers in 12 countries were evaluated. The median age at 1L treatment was 69 years (IQR: 62-76). Most patients were males (1184, 61.3%) and 1249 (64.7%) were alive at last follow up. The median follow-up from 1L treatment was 4.6 years (IQR: 1.8-8.1). Before 1L treatment, 623/1090 (57.2%), 195/1077 (18.1%), 107/1342 (8%) and 103/1240 (8.3%) carried del(13q), trisomy 12, del(17p) and del(11q) detected by FISH, respectively. TP53 mutations were detected in 118/1012 (11.7%) cases and karyotype with ≥3 and ≥5 (CK5) aberrations in 82/610 (13.4%) and 17/610 (2.8%) cases, respectively. The most common stereotyped subsets were #2 (59/1112, 5.3%) and #4 (11/1112, 1%). Most patients (1346, 69.8%) received 1 line of treatment, while 344 (17.8%), 138 (7.2%) and 101 (5.2%) received 2, 3, and ≥4 lines, respectively. FCR was the most common 1L treatment (395, 20.8%) followed by chlorambucil (Chl) monotherapy (320, 16.9%). BTK inhibitors (BTKis) were used in 241 cases [12.5%; ibrutinib: 162 (8.3%), acalabrutinib 65 (3.4%), zanubrutinib: 10 (0.5%), pirtobrutinib 4 (0.2%)]. BR, Chl-rituximab and Chl-obinutuzumab were used in 185 (9.8%), 126 (6.6%) and 98 (5.2%) cases, respectively. Finally, 70 (3.6%) received venetoclax-obinutuzumab 1L treatment and 33 (1.7%) received ibrutinib-venetoclax. The median OS was 11 years (95% CI: 10.4-11.8). In UVA, older age at 1L, male sex, TP53 aberrations (TP53-abs), del(11q) and CK5 were associated with shorter OS (p<0.001, p=0.03, p<0.001, p<0.001, p=0.001, respectively). Compared to FCR/BR, targeted treatments led to a similar OS (p=0.3), while other non-targeted treatments resulted in shorter OS (p<0.001). Regarding the new immunogenetic metric, clusters 13 (IGHV1-24 and IGHV1-69-2 genes), 4 (IGHV2 genes) and 8 (IGHV3-13) associated with shorter OS (p=0.07, p=0.02, and p=0.002, respectively). To assess the relevance of this finding, we scanned our immunogenetic database consisting of 42,154 M-CLL IG rearrangements. While the IGHV1-24, IGHV1-69-2 and IGHV3-13 genes were very rare (0.6%), IGHV2 gene rearrangements represented a sizeable M-CLL subgroup (1969 cases, 4.7%). In MVA, only age at 1L and CK5 retained statistical significance for OS (HR: 1.08, 95% CI: 1.04-1.3, p<0.001, HR: 2.5, 95% CI: 1.04-6.2, p=0.04, respectively). In patients <70 years, older age at 1L, TP53-abs, del(11q), and clusters 4 and 8 were associated with shorter OS (p<0.001, p=0.01, p=0.007, p=0.01, and p=0.01, respectively). The type of treatment effect was similar to the whole cohort. In MVA, age at 1L andTP53-absretained statistical significance (HR:1.07, 95% CI:1.02-1.11, p=0.003, HR:1.9, 95% CI:1.02-3.5, p=0.04, respectively). Conclusion: Older age, CK5 and TP53 aberrations are independent high-risk factors for shorter OS in M-CLL. Utilization of IGHV2 subgroup genes emerged as adverse-prognostic for OS and merits further evaluation.
Article Details
Authors (64)
Thomas Chatzikonstantinou
1Institute of Applied Biosciences, Center for Research and Technology, Thessaloniki, Greece
Andreas Agathangelidis
Persefoni Talimtzi
1Institute of Applied Biosciences, Center for Research and Technology, Thessaloniki, Greece
Stamatia Laidou
1Institute of Applied Biosciences, Center for Research and Technology, Thessaloniki, Greece
Eva Minga
1Institute of Applied Biosciences, Center for Research and Technology, Thessaloniki, Greece
Athanasios Roussos
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
Fanny Baran-Marszak
6Département de recherche Clinique, Hôpital Avicenne, APHP, Bobigny, France
Csaba Bödör
Francesc Bosch Albareda
5Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain
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
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
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
Thalia Karamanli
1Institute of Applied Biosciences, Center for Research and Technology, Thessaloniki, Greece
Eliana Konstantinou
18Hematology, University of Athens, Laikon General Hospital, Athens, Greece
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
Tamas Laszlo
7HCEMM-SE Molecular Oncohematology Research Group, MTA-SE Lendulet Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
Vincent Levy
6Département de recherche Clinique, Hôpital Avicenne, APHP, Bobigny, France
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
Eugenia Mpalaoura
1Institute of Applied Biosciences, Center for Research and Technology, Thessaloniki, Greece
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
Karla Plevova
15Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University; CEITEC MU, Brno, Czech Republic, Brno, Czech Republic
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
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
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
Martin Simkovic
254th Department of Internal Medicine-Hematology, Faculty of Medicine in Hradec Kralove, University Hospital and Charles University, Hradec Kralove, Hradec Kralove, Czech Republic
Lukas Smolej
254th Department of Internal Medicine-Hematology, Faculty of Medicine in Hradec Kralove, University Hospital and Charles University, Hradec Kralove, Hradec Kralove, Czech Republic
Niki Stavrogianni
41Hematology Department and HCT Unit G. Papanicolaou Hospital, Thessaloniki, Greece
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
Lydia Scarfò
School of Medicine, Università Vita Salute San Raffaele, Milan
Anastasia Chatzidimitriou
1Institute of Applied Biosciences, Center for Research and Technology, Thessaloniki, Greece
Paolo Ghia
School of Medicine, Università Vita Salute San Raffaele, Milan
Kostas Stamatopoulos
Institute of Applied Biosciences at the Centre for Research and Technology Hellas