-Author name in bold denotes the presenting author
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2617 Different Prognostic Impact of Recurrent Gene Mutations in IGHV-Mutated and IGHV-Unmutated Chronic Lymphocytic Leukemia: A Retrospective, Multi-Center Cohort Study By Eric, the European Research Initiative on CLL, in Harmony

Program: Oral and Poster Abstracts
Session: 641. Chronic Lymphocytic Leukemias: Basic and Translational: Poster II
Hematology Disease Topics & Pathways:
Translational Research
Sunday, December 12, 2021, 6:00 PM-8:00 PM

Larry Mansouri, PhD1*, Birna Thorvaldsdottir, PhD1*, Lesley-Ann Sutton, PhD1*, Manja Meggendorfer, PhD2, Ferran Nadeu, PhD3*, Christian Brieghel, MD, PhD4*, Helen Parker, PhD5*, Stamatia Laidou6*, Riccardo Moia, MD7*, Davide Rossi, MD, PhD8, Mark Catherwood, PhD9*, Jana Kotaskova10*, Julio Delgado, MD3, Ana E Rodríguez-Vicente11*, Rocio Benito, PhD12*, Gian Matteo Rigolin13*, Silvia Bonfiglio14*, Lydia Scarfo15*, Mattias Mattsson, MD16*, Zadie Davis17*, Ajay Gogia18*, Lata Rani, PhD19*, Panagiotis Baliakas20*, Cecilia Jylhä1*, Aron Skaftason1*, Inmaculada Rapado, PhD21*, Fatima Miras22*, Joaquin Martinez-Lopez23*, Javier de la Serna, MD24*, Jesús M Hernández Rivas, MD, PhD25, Patrick Thornton, MB, FRCPath26*, Maria Jose Larrayoz, BSc27*, María José Calasanz, PhD28*, Zoltán Mátrai, MD, PhD29*, Csaba Bodor, PhD29*, Karin E. Smedby, MD, PhD30*, Blanca Espinet, PhD31*, Anna Puiggros, PhD32*, Ritu Gupta, MD33*, Lars Bullinger34, Francesc Bosch35, Bárbara Tazón, PhD36*, Fanny Baran-Marszak37*, David Oscier17, Florence Nguyen-Khac, MD, PhD38*, Thorsten Zenz, MD39, María José Terol, MD PhD40*, Antonio Cuneo, MD41*, María Hernández-Sánchez, PhD42*, Sarka Pospisilova, Prof PhD43*, Ken I Mills44, Gianluca Gaidano, MD45, Carsten Utoft Niemann, MD, PhD46, Elías Campo47, Jonathan C Strefford, PhD48, Paolo Ghia, MD, PhD14, Kostas Stamatopoulos49,50 and Richard Rosenquist1

1Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
2MLL Munich Leukemia Laboratory, Munich, Bavaria, Germany
3Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
4Department of Hematology, Rigshospitalet, Copenhagen University Hospital, København Ø, Denmark
5Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom
6Centre for Research and Technology Hellas, Thessaloniki, Greece
7Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
8Amedeo Avorgadro Univ. of Eastern Piedmont, Bellinzona, Italy
9Haematology Department, Belfast Health and Social Care Trust, Belfast, United Kingdom
10Masaryk University, University Hospital Brno, Brno, Czech Republic
11Cancer Research Center (IBMCC) CSIC, University of Salamanca, Salamanca, Spain
12IBSAL, IBMCC, CIC, Universidad de Salamanca-CSIC, Salamanca, Spain
13Hematology section, Department of Medical Sciences, Azienda Ospedaliera- Universitaria, Arcispedale S. Anna, University of Ferrara, Ferrara, Italy
14Division of Experimental Oncology, Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milano, Italy
15Strategic Research Program on CLL, Università Vita Salute San Raffaele and IRCCS San Raffaele, Milan, Italy
16Department of Hematology, Uppsala University Hospital, Uppsala, Sweden
17Royal Bournemouth Hospital, Bournemouth, United Kingdom
18Medical Oncology, Dr. B.R.A. IRCH, All India Institute of Medical Sciences, New Delhi, India
19Laboratory Oncology, Dr. B.R.A. IRCH, All India Institute of Medical Sciences, New Delhi, India
20Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Uppsala, Sweden
21Hematology Department, Hospital Universitario 12 de Octubre, CNIO, Complutense University, Madrid, Spain
22University Hospital Doce De Octubre, Madrid, Spain
23Department of Hematology, Hospital 12 de Octubre, Complutense University, CNIO, Madrid, Spain
24Hospital Universitario 12 de Octubre, Madrid, Spain
25Universidad de Salamanca, IBSAL, Centro de Investigación del Cáncer, IBMCC-CSIC, Salamanca, Spain
26Department of Haematology, Beaumont Hospital, Dublin, Ireland
27Centro de Investigación Médica Aplicada, University of Navarra, CIMA LAB Diagnostics-Universidad de Navarra, IdiSNA: Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain
28CIMA LAB Diagnostics-Universidad de Navarra, IdiSNA: Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain
29HCEMM-SE Molecular Oncohematology Research Group, First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
30Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
31Pathology Department, Hospital del Mar, Barcelona, Spain
32Laboratori de Citologia Hematològica i Citogenètica, Servei de Patologia, Hospital del Mar. GRETNHE- Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain
33All India Institute of Medical Sciences (AIIMS), New Delhi, India
34Department of Hematology, Oncology and Tumor Immunology, Campus Virchow, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
35Department of Hematology, Vall d’Hebron University Hospital. Experimental Hematology Unit, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
36Department of Hematology. Vall d’Hebron Institute of Oncology (VHIO), University Hospital Vall d’Hebron., Barcelona, Spain, Barcelona, Spain
37Hematology Laboratory, Avicenne Hospital, APHP, Bobigny, France
38Hematologie Biologique, APHP Pitié Salpêtrière, Paris, France
39Department of Medical Oncology and Hematology, University Hospital and University of Z, Zurich, Switzerland
40Department of Hematology, Hospital Clínico Universitario de Valencia, INCLIVA, Valencia, Spain
41Hematology, Azienda Ospedaliero Universitaria di Ferrara – University of Ferrara, Ferrara, ITA
42University of Salamanca, IBSAL, IBMCC, CSIC, Cancer Research Center, Salamanca, Spain
43Department of Internal Medicine - Hematology and Oncology / Center of Molecular Biology and Gene Therapy, University Hospital Brno and Faculty of Medicine, Brno, Czech Republic
44Patrick G Johnston Centre for Cancer Research, Queens University Belfast, Belfast, United Kingdom
45Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
46Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
47Hematopathology Unit, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Universitat de Barcelona, Barcelona, Spain
48Academic Unit of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
49Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
50Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece

The mutational status of the immunoglobuin heavy variable (IGHV) genes is an undisputable strong prognostic factor that subdivides patients with chronic lymphocytic leukemia (CLL) into 2 subgroups, i.e. IGHV-unmutated CLL (U-CLL) and IGHV-mutated CLL (M-CLL). U-CLL and M-CLL have distinct landscapes of genomic aberrations as well as distinct prognosis, since U-CLL is considerably more aggressive than M-CLL. That said, there is considerable clinical heterogeneity among M-CLL patients, ranging from patients without need of treatment to patients requiring early therapeutic intervention, indicating the need to further refine prognosis in this subgroup. In recent years, it has become evident that the prognostic impact of genomic aberrations may differ depending on IGHV gene mutational status. Hence, defining genomic aberrations with prognostic impact in M-CLL patients may help identifying patients with an predicted unfavorable prognosis within this subgroup, with obvious implications for management of follow up and therapy choice.

To study the clinical impact of recurrent gene mutations in relation to IGHV gene mutational status, we collected a large, multi-center cohort including 4,674 patients with CLL [median age at diagnosis, 64.5 years; male/female, n=2,962 (63%)/n=1,712 (37%); Binet stage A (n=3,369, 74%), B (n=827, 18%), and C (n=387, 8%); IGHV-mutated (M-CLL, n=2,498, 56%) and IGHV-unmutated (U-CLL, n=1,927, 44%); isolated del(13q) (n=1,868, 41%), trisomy 12 (n=571, 13%), del(11q) (n=503, 11%), and del(17p) (n=249, 5.5%); treated (n=2,745, 59%) and untreated (n=1,929, 41%)] and performed next-generation sequencing (NGS) and/or Sanger sequencing of 9 genes (BIRC3, EGR2, NFKBIE, MYD88, NOTCH1, POT1, SF3B1, TP53, and XPO1) on pre-treatment samples. Overall, pathogenic mutations in any of these genes were detected in 1720/4674 patients (36.8%, using a variant allele frequency cutoff of 5% for NGS), while the remaining patients were wildtype; 2 mutations were observed in 361 patients (7.7%) and 3 or more mutations in 58 patients (1.2%). The mutation frequency for the individual genes was: TP53 (10.4%, including TP53 mutations and/or del(17p)), NOTCH1 (10.1%, 3’UTR mutations not included), SF3B1 (9.3%), XPO1 (3.9%), POT1 (3.8%), NFKBIE (3.7%), BIRC3 (3.0%), EGR2 (2.5%) and MYD88 (2.5%; Figure 1A). Except for MYD88, gene mutations in each of the investigated genes were associated with significantly shorter time-to-first-treatment (TTFT) in univariate analysis. In multivariate analysis of Binet stage A patients (n=3,369; including all genes, IGHV gene mutational status, age at diagnosis and gender), SF3B1 (Hazard Ratio (HR) 1.79; p<0.001), BIRC3 mutations (HR 1.50; p=0.004), XPO1 (HR 1.29; p=0.020), EGR2 (HR 1.42; p=0.021) and TP53 aberrations (HR 1.21; p=0.028), along with unmutated IGHV genes (HR 4.21; p<0.001) and male gender (HR 1.12; p=0.027) remained as independent factors for shorter TTFT. In a multivariate model focusing on M-CLL Binet stage A patients (n=2,049), SF3B1 (HR 2.72; p<0.001), NOTCH1 (HR 1.65; p=0.006), XPO1 (HR 2.21; p=0.021) and NFKBIE mutations (HR 1.74; p=0.025) were independent markers of poor TTFT (Figure 1B), while conversely in U-CLL Binet stage A cases (n=1157), SF3B1 mutations (HR 1.49; p<0.001), TP53 aberrations (HR 1.30; p=0.011), BIRC3 mutations (HR 1.49; p=0.016) and male gender (HR 1.20; p=0.012) were significant factors for shorter TTFT (Figure 1C).

In summary, different spectra of genetic mutations independently predicted short TTFT in M-CLL and U-CLL, respectively, with SF3B1 mutations as the only aberration found to be significant predictor of shorter time to first treatment in both subgroups. Importantly, mutations within several genes (i.e. SF3B1, NOTCH1, XPO1 and NFKBIE) identified patients in the M-CLL subgroup with a high-risk profile; conversely, TP53 mutations did not affect TTFT in this subgroup. On these grounds, we suggest to include analysis of recurrent gene mutations to identify high-risk patients within the M-CLL subgroup.

Disclosures: Brieghel: AstraZeneca: Consultancy. Rossi: Roche: Honoraria, Research Funding; Verastem: Honoraria, Research Funding; Cellestia: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Scarfo: Astra Zeneca: Honoraria; Abbvie: Honoraria; Janssen: Honoraria, Other: Travel grants. Mattsson: Gilead: Research Funding. Baliakas: Janssen: Honoraria; Gilead: Honoraria, Research Funding; Abbvie: Honoraria. Martinez-Lopez: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees. de la Serna: AbbVie, AstraZeneca, Beigene, Gilead, GSK, Janssen, Jazzpharma, Novartis, Roche: Consultancy; ABBVIE, ASTRAZENECA,ROCHE: Research Funding; AbbVie, AstraZeneca, Roche: Speakers Bureau. Hernández Rivas: Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Smedby: Jansen-Cilag: Other: part of a research collaboration between Karolinska Institutet and Janssen Pharmaceutica NV for which Karolinska Institutet has received grant support. Bullinger: Seattle Genetics: Honoraria; Gilead: Consultancy; Pfizer: Consultancy, Honoraria; Astellas: Honoraria; Sanofi: Honoraria; Bayer: Research Funding; Amgen: Honoraria; Novartis: Consultancy, Honoraria; Menarini: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Hexal: Consultancy; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Bosch: TAKEDA: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel. Terol: BMS: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Roche: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Hospital Clinico Valencia: Current Employment. Cuneo: AstraZeneca: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau. Gaidano: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Niemann: Abbvie, Janssen, AstraZeneca, Novo Nordisk Foundation: Research Funding; Abbvie, Janssen, Roche, AstraZeneca, CSL Behring, Genmab, Takeda, Octapharma: Consultancy. Ghia: AstraZeneca: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Research Funding; Celgene/Juno/BMS: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; ArQule/MSD: Consultancy, Honoraria; Sunesis: Research Funding. Stamatopoulos: AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Rosenquist: Roche: Honoraria; Janssen: Honoraria; Illumina: Honoraria; Abbvie: Honoraria; AstraZeneca: Honoraria.

*signifies non-member of ASH