GENOMIC ARRAYS IDENTIFY HIGH-RISK CHRONIC LYMPHOCYTIC LEUKEMIA WITH GENOMIC COMPLEXITY: A MULTI-CENTER STUDY
Author(s): ,
Alexander Leeksma
Affiliations:
Experimental Immunology,AMC,Amsterdam,Netherlands;Dept of Hematology and Lymphoma and Myeloma Center Amsterdam (LYMMCARE),Amsterdam University Medical Centers, University of Amsterdam,Amsterdam,Netherlands;Cancer Center Amsterdam and Amsterdam Infection and Immunity Institute,Amsterdam,Netherlands
,
Panagiotis Baliakas
Affiliations:
Dept of Immunology, Genetics and Pathology,Science for Life Laboratory, Uppsala University,Uppsala,Sweden
,
Theodoros Moysiadis
Affiliations:
Institute of Applied Biosciences,Center for Research and Technology Hellas,Thessaloniki,Greece
,
Clemens Mellink
Affiliations:
Dept of Clinical Genetics,Amsterdam University Medical Centers, University of Amsterdam,Amsterdam,Netherlands
,
Anna Puiggros
Affiliations:
Laboratori de Citogenètica Molecular, Servei de Patologia,Hospital del Mar,Barcelona,Spain
,
Karla Plevova
Affiliations:
Dept of Internal Medicine - Hematology and Oncology,University Hospital Brno and Faculty of Medicine, Masaryk University,Brno,Czech Republic
,
Anne-Marie van der Kevie
Affiliations:
Dept of Clinical Genetics,Amsterdam University Medical Centers, University of Amsterdam,Amsterdam,Netherlands
,
Anh Nhi Tran
Affiliations:
Dept of Molecular Medicine and Surgery,Karolinska Institutet,Stockholm,Sweden
,
Rebeqa Gunnarsson
Affiliations:
Division of Clinical Genetics,Dept of Laboratory Medicine, Lund University,Lund,Sweden
,
Helen Parker
Affiliations:
Cancer Genomics, Academic Unit of Cancer Sciences,Faculty of Medicine, University of Southampton,Southampton,United Kingdom
,
Eva van den Berg
Affiliations:
Dept of Genetics,University Medical Center Groningen, University of Groningen,Groningen,Netherlands
,
Paolo Ghia
Affiliations:
Division of Experimental Oncology,IRCCS Istituto Scientifico San Raffaele e Università Vita-Salute San Raffaele,Milan,Italy
,
Blanca Espinet
Affiliations:
Laboratori de Citogenètica Molecular,Servei de Patologia, Hospital del Mar,Barcelona,Spain
,
Sarka Pospisilova
Affiliations:
Dept of Internal Medicine - Hematology and Oncology,University Hospital Brno and Faculty of Medicine, Masaryk University,Brno,Czech Republic
,
Constantine Tam
Affiliations:
Dept of Haematology, St Vincent Hospital Melbourne and Peter MacCallum Cancer Center; University of Melbourne,Melbourne,Australia
,
Loïc Ysebaert
Affiliations:
Institut Universitaire du Cancer de Toulouse-Oncopôle, Toulouse-Oncopôle,Toulouse,France
,
Marie Jarosova
Affiliations:
Dept of Internal Medicine- Hematology and Oncology,University Hospital Brno and Faculty of Medicine,Brno,Czech Republic
,
Florence Nguyen-Khac
Affiliations:
INSERM U1138; Université Pierre et Marie Curie-Paris,Service d'Hématologie Biologique, Hôpital Pitié-Salpêtrière, APHP,Paris,France
,
David Oscier
Affiliations:
Dept of Molecular Pathology,Royal Bournemouth Hospital,Bournemouth,United Kingdom
,
Claudia Haferlach
Affiliations:
MLL Munich Leukemia Laboratory,Munich,Germany
,
Jacqueline Schoumans
Affiliations:
Oncogenomic laboratory, Department of Hematology,Lausanne University Hospital (CHUV),Lausanne,Switzerland
,
Marian Stevens-Kroef
Affiliations:
Dept of Human Genetics,Radboud University Medical Center,Nijmegen,Netherlands
,
Eric Eldering
Affiliations:
Dept of Experimental Immunology,Amsterdam University Medical Centers, University of Amsterdam,Amsterdam,Netherlands
,
Kostas Stamatopoulos
Affiliations:
Institute of Applied Biosciences, Center for Research and Technology Hellas,Thessaloniki,Greece
,
Richard Rosenquist
Affiliations:
Dept of Molecular Medicine and Surgery,Karolinska Institutet,Stockholm,Sweden
,
Jonathan Strefford
Affiliations:
Cancer Genomics, Academic Unit of Cancer Sciences, Faculty of Medicine, University of Southampton,Southampton,United Kingdom
Arnon Kater
Affiliations:
Dept of Hematology and Lymphoma and Myeloma Center Amsterdam (LYMMCARE),Amsterdam University Medical Centers, University of Amsterdam,Amsterdam,Netherlands
EHA Library. Leeksma A. Jun 15, 2019; 266750; PS1133
Mr. Alexander Leeksma
Mr. Alexander Leeksma
Contributions
Abstract

Abstract: PS1133

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background

Cytogenetic complexity assessed by chromosome banding analysis is linked to survival in chronic lymphocytic leukemia (CLL) patients treated with chemoimmunotherapy and targeted agents. Array-based copy number profiling uses isolated DNA as input and offers high-resolution genome-wide detection of copy-number alterations (CNAs). Although genomic arrays have been introduced clinically, their precise role in the prognostic assessment of CLL remains inconclusive.  

Aims

To determine the prognostic relevance of CNA assessment by genomic arrays in the clinical work-up of CLL.

Methods

In total, genomic array data of 2293 CLL patients from 13 diagnostic laboratories were analyzed retrospectively. Analyses were performed according to established standards [5 megabase (Mb) size cutoff for aberrations other than del(13)(q14), del(11)(q22.3) (ATM) and del(17)(p13.1) (TP53)]. In a subgroup of patients (n=260) genomic array results were compared with simultaneous FISH data.

Results

Analysis of genomic arrays identified CNAs outside regions captured by CLL FISH probes in 34.1% of patients and included chromosomal deletions (n=994), chromosomal gains (n=589), monosomies (n=69), and trisomies (n=62). Also, complex patterns (n=32) putative for chromothripsis were detected. In patients with simultaneous FISH data available, genomic array findings were overlapping with FISH in 92.2% (906/983) for regions captured by CLL FISH probes. In addition to confirming the adverse prognostic impact of gains of 2p (p<0.001) and 8q  (p<0.001) and loss of 6q (p=0.05) on overall survival, we showed that losses of 4p (p=0.01), 9p (p<0.001), 18p (p<0.001), 20p (p=0.03), and gain of 17q (p=0.03) were also linked to poor outcome. CLL patients could be grouped into three distinct prognostic subgroups based on the number of CNAs: 'low' genomic complexity (GC;0-2 CNAs; n=799), intermediate-GC (3-4 CNAs; n=123) and high-GC (≥5 CNAs; n=57). Low-GC was associated with a favorable clinical outcome (median OS: 10.17 years, 95% CI: 8.92-11.42 years) compared to intermediate-GC (median OS: 7.02 years, 95% CI 4.79-9.25 years, p=0.001) and high-GC, which displayed the shortest OS (median OS: 3.05 years, 95% CI: 1.14-4.96 years, p<0.001) (Figure). Similar results were observed for TTFT between the three different prognostic subgroups (p=0.001). Low-GC cases were associated with indolent disease (low incidence of TP53abn (del(17)(p13.1) and/or TP53 mutation) and del(11)(q22.3)) (p<0.001). Intermediate-GC cases were associated with a more advanced clinical stage compared to low-GC cases (p<0.001). High-GC cases were enriched for TP53abn (p<0.001) compared to intermediate-GC, and emerged as an independent adverse prognosticator in multivariable analysis for both time to first treatment (Hazard ratio: 2.15, 95% CI: 1.36-3.41; p=0.001) and overall survival (Hazard ratio: 2.54, 95% CI: 1.54-4.17; p<0.001). 

Conclusion

Our findings support genomic array as an accurate tool for CLL risk stratification. High-GC appears as a separate prognostically adverse risk group independent of other well-established CLL biomarkers. We, therefore, recommend implementation of comprehensive genomic profiling in future clinical trials.

Session topic: 5. Chronic lymphocytic leukemia and related disorders - Biology & Translational Research

Keyword(s): Complex aberrant karyotype, Cytogenetics, Prognostic factor

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