CLINICAL IMPACT OF RECURRENT GENE MUTATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA: A RETROSPECTIVE, MULTI-CENTER COHORT STUDY BY ERIC, THE EUROPEAN RESEARCH INITIATIVE ON CLL, IN HARMONY
Author(s): ,
Larry Mansouri
Affiliations:
Molecular Medicine and Surgery,Karolinska Institutet,Stockholm,Sweden
,
Birna Thorvaldsdottir
Affiliations:
Molecular Medicine and Surgery,Karolinska Institutet,Stockholm,Sweden
,
Lesley-Ann Sutton
Affiliations:
Molecular Medicine and Surgery,Karolinska Institutet,Stockholm,Sweden
,
Manja Meggendorfer
Affiliations:
MLL,Munich Leukemia Laboratory,Munich,Germany
,
Helen Parker
Affiliations:
Cancer Genomics, School for Cancer Sciences, Faculty of Medicine,University of Southampton,Southampton,United Kingdom
,
Ferran Nadeu
Affiliations:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS),Barcelona,Spain
,
Christian Brieghel
Affiliations:
Department of Hematology,Rigshospitalet, Copenhagen University Hospital,Copenhagen,Denmark
,
Stamatia Laidou
Affiliations:
Centre for Research and Technology Hellas, Institute of Applied Biosciences,Thessaloniki,Greece
,
Riccardo Moia
Affiliations:
Division of Hematology, Department of Translational Medicine,University of Eastern Piedmont,Novara,Italy
,
Davide Rossi
Affiliations:
Division of Hematology, Oncology Institute of Southern Switzerland,Bellinzona,Switzerland
,
Mark Catherwood
Affiliations:
Centre for Cancer Research and Cell Biology,Queens University,Belfast,United Kingdom
,
Jana Kotaskova
Affiliations:
Department of Internal Medicine - Hematology & Oncology,University Hospital Brno and Faculty of Medicine, Masaryk University,Brno,Czech Republic
,
Julio Delgado
Affiliations:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS),Barcelona,Spain
,
Ana E Rodríguez-Vicente
Affiliations:
Cancer Research Center (IBMCC) CSIC-University of Salamanca,Salamanca,Spain
,
Rocío Benito
Affiliations:
Cancer Research Center (IBMCC) CSIC-University of Salamanca,Salamanca,Spain
,
Gian Matteo Rigolin
Affiliations:
Hematology - Department of Medical Sciences,University of Ferrara,Ferrara,Italy
,
Silvia Bonfiglio
Affiliations:
Università Vita Salute San Raffaele and IRCCS Ospedale San Raffaele,Milano,Italy
,
Lydia Scarfo
Affiliations:
Università Vita Salute San Raffaele and IRCCS Ospedale San Raffaele,Milano,Italy
,
Mattias Mattsson
Affiliations:
Department of Immunology, Genetics and Pathology,Uppsala University,Uppsala,Sweden
,
Zadie Davis
Affiliations:
Molecular Pathology, Royal Bournemouth Hospital,Bournemouth,United Kingdom
,
Ajay Gogia
Affiliations:
All India Institute of Medical Sciences (AIIMS),New Delhi,India
,
Lata Rani
Affiliations:
All India Institute of Medical Sciences (AIIMS),New Delhi,India
,
Panagiotis Baliakas
Affiliations:
Department of Immunology, Genetics and Pathology,Uppsala University,Uppsala,Sweden
,
Cecilia Jylhä
Affiliations:
Molecular Medicine and Surgery,Karolinska Institutet,Stockholm,Sweden
,
Aron Skaftason
Affiliations:
Molecular Medicine and Surgery,Karolinska Institutet,Stockholm,Sweden
,
Inmaculada Rapado
Affiliations:
Hospital Universitario 12 Octubre Madrid, Spain,Madrid,Spain
,
Fatima Miras
Affiliations:
Hospital Universitario 12 Octubre Madrid,Madrid,Spain
,
Joaquín Martinez-Lopez
Affiliations:
Hospital Universitario 12 Octubre Madrid,Madrid,Spain
,
Javier de la Serna
Affiliations:
Hospital Universitario 12 Octubre Madrid,Madrid,Spain
,
Jesús María Hernández Rivas
Affiliations:
Cancer Research Center (IBMCC) CSIC-University of Salamanca,Salamanca,Spain
,
Patrick Thornton
Affiliations:
Haematology Department,Beaumont Hospital Dublin,Dublin,Ireland
,
María José Larráyoz
Affiliations:
Hematological Diseases Laboratory, CIMA LAB Diagnostics, University of Navarra,Pamplona,Spain
,
María José Calasanz
Affiliations:
Hematological Diseases Laboratory, CIMA LAB Diagnostics, University of Navarra,Pamplona,Spain
,
Zoltán Mátrai
Affiliations:
MTA-SE Momentum Molecular Oncohematology Research Group, First Department of Pathology and Experimental Cancer Research,Semmelweis University,Budapest,Hungary
,
Csaba Bödör
Affiliations:
MTA-SE Momentum Molecular Oncohematology Research Group, First Department of Pathology and Experimental Cancer Research,Semmelweis University,Budapest,Hungary
,
Karin E. Smedby
Affiliations:
Clinical Epidemiology Division, Department of Medicine Solna,Karolinska Institutet,Stockholm,Sweden
,
Blanca Espinet
Affiliations:
Molecular Cytogenetics Laboratory, Pathology Department,Hospital del Mar,Barcelona,Spain
,
Anna Puiggros
Affiliations:
Molecular Cytogenetics Laboratory, Pathology Department,Hospital del Mar,Barcelona,Spain
,
Ritu Gupta
Affiliations:
All India Institute of Medical Sciences (AIIMS),New Delhi,India
,
Lars Bullinger
Affiliations:
Department of Hematology, Oncology and Tumour Immunology,Charité University Medicine,Berlin,Germany
,
Francesc Bosch
Affiliations:
Department of Hematology,Hospital Universitari Vall d'Hebron (HUVH),Barcelona,Spain
,
Bárbara Tazón-Vega
Affiliations:
Department of Hematology,Hospital Universitari Vall d'Hebron (HUVH),Barcelona,Spain
,
Fanny Baran-Marszak
Affiliations:
Service d’hématologie biologique Hôpital Avicenne Assistance Publique des Hôpitaux de Paris Bobigny,Paris,France
,
David Oscier
Affiliations:
Molecular Pathology, Royal Bournemouth Hospital,Bournemouth,United Kingdom
,
Florence Nguyen-Khac
Affiliations:
Sorbonne Université, Service d'Hématologie Clinique, Hôpital Pitié-Salpêtrière,Paris,France
,
Thorsten Zenz
Affiliations:
Department of Oncology and Haematology,University Hospital and University of Zurich,Zurich,Switzerland
,
Maria Jose Terol
Affiliations:
Department of Hematology,INCLIVA Research Insitute, University of Valencia,Valencia,Spain
,
Paolo Ghia
Affiliations:
Università Vita Salute San Raffaele and IRCCS Ospedale San Raffaele,Milano,Italy
,
Antonio Cuneo
Affiliations:
Hematology - Department of Medical Sciences,University of Ferrara,Ferrara,Italy
,
María Hernández-Sánchez
Affiliations:
Cancer Research Center (IBMCC) CSIC,University of Salamanca,Salamanca,Spain
,
Sarka Pospisilova
Affiliations:
Department of Internal Medicine - Hematology & Oncology, University Hospital Brno and Faculty of Medicine,Masaryk University,Brno,Czech Republic
,
Ken Mills
Affiliations:
Centre for Cancer Research and Cell Biology,Queens University Belfast,Belfast,United Kingdom
,
Gianluca Gaidano
Affiliations:
Division of Hematology, Department of Translational Medicine,University of Eastern Piedmont,Novara,Italy
,
Carsten U. Niemann
Affiliations:
Department of Hematology,Rigshospitalet, Copenhagen University Hospital,Copenhagen,Denmark
,
Elias Campo
Affiliations:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS),Barcelona,Spain
,
Jonathan C Strefford
Affiliations:
Cancer Genomics, School for Cancer Sciences, Faculty of Medicine,University of Southampton,Southampton,United Kingdom
,
Kostas Stamatopoulos
Affiliations:
Centre for Research and Technology Hellas, Institute of Applied Biosciences,Thessaloniki,Greece
Richard Rosenquist
Affiliations:
Molecular Medicine and Surgery,Karolinska Institutet,Stockholm,Sweden
EHA Library. Mansouri L. 06/09/21; 324551; S143
Larry Mansouri
Larry Mansouri
Contributions
Abstract
Presentation during EHA2021: All Oral presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: S143

Type: Oral Presentation

Session title: New biological and translational insights in CLL

Background

The introduction of next-generation sequencing (NGS) rapidly uncovered the genomic landscape of chronic lymphocytic leukemia (CLL). Using whole-genome and/or exome sequencing, a limited number of recurrently mutated genes was observed in more than 10% of patients, while a very long tail comprising hundreds of genes mutated only in a fraction of patients (<5%) has been demonstrated. Several of the more frequent gene mutations have been linked to worse outcomes with shorter time-to-first-treatment (TTFT) and overall survival.

Aims

To assess the prognostic strength of recurrent gene mutations, we collected a large, multi-center cohort including 4,674 well-characterized CLL patients [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 (n=2,498, 56%) and IGHV-unmutated (n=1,927, 44%); del(13q) only (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%)].

Methods

We performed NGS and/or Sanger sequencing of 9 genes (BIRC3, EGR2, NFKBIE, MYD88, NOTCH1, POT1, SF3B1, TP53, and XPO1) on pre-treatment samples in order to study their clinical impact in CLL.

Results

Overall, mutations in any of these genes were detected in 1,720 of 4,674 patients (36.8%, using a variant allele frequency cutoff of 5% for NGS), while the remaining patients were wildtype; two mutations were seen in 361 patients (7.7%) and three 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%), SF3B1 (9.3%), XPO1 (3.9%), POT1 (3.8%), NFKBIE (3.7%), BIRC3 (3.0%), EGR2 (2.5%) and MYD88 (2.5%; Figure 1A). We observed that certain gene mutations appeared almost mutually exclusive, such as BIRC3 and SF3B1 mutations (10 BIRC3mut/433 (2.3%) SF3B1mut  cases), and TP53 aberrations and XPO1 mutations (18 XPO1mut/488 (3.7%) TP53abn cases) or BIRC3 mutations (14 BIRC3mut/488 (2.9%) TP53abn cases). Except for MYD88, mutations in each of the investigated genes were associated with significantly shorter TTFT in univariate analysis. On multivariable analysis (including all genes, unmutated IGHV genes, Binet stage B/C, age > median at diagnosis and male gender), SF3B1 (Hazard Ratio 1.58; p<0.001), EGR2 (HR 1.39; p=0.003), XPO1 (HR 1.26; p=0.006), BIRC3 mutations (HR 1.25; p=0.031) and TP53 aberrations (HR 1.20; p=0.004), along with Binet stage B/C (HR 3.73; p-value <0.001) and unmutated IGHV genes (HR 2.95; p<0.001), remained as independent factors for shorter TTFT. As earlier studies have indicated different prognostic importance of genetic aberrations in IGHV-mutated (M-CLL) and IGHV-unmutated CLL (U-CLL), we next studied the impact of gene mutations in relation to IGHV gene mutation status. While TP53 aberrations, SF3B1 (Figure 1B) and BIRC3 mutations were associated with a worse outcome in both U-CLL and M-CLL, NOTCH1, POT1 and XPO1 mutations were only linked to a worse outcome in M-CLL, whereas EGR2 mutations correlated with a poor outcome only in U-CLL.

Conclusion

Based on these results, we conclude that SF3B1, EGR2, XPO1 and BIRC3 mutations independently predicted short TTFT and should be considered for extended molecular testing in CLL. However, considering the different impact of gene mutations in M-CLL and U-CLL, the IGHV mutation status must be taken into account when constructing future prognostic models including recurrent gene mutations.

Keyword(s): Chronic lymphocytic leukemia, Mutation

Presentation during EHA2021: All Oral presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: S143

Type: Oral Presentation

Session title: New biological and translational insights in CLL

Background

The introduction of next-generation sequencing (NGS) rapidly uncovered the genomic landscape of chronic lymphocytic leukemia (CLL). Using whole-genome and/or exome sequencing, a limited number of recurrently mutated genes was observed in more than 10% of patients, while a very long tail comprising hundreds of genes mutated only in a fraction of patients (<5%) has been demonstrated. Several of the more frequent gene mutations have been linked to worse outcomes with shorter time-to-first-treatment (TTFT) and overall survival.

Aims

To assess the prognostic strength of recurrent gene mutations, we collected a large, multi-center cohort including 4,674 well-characterized CLL patients [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 (n=2,498, 56%) and IGHV-unmutated (n=1,927, 44%); del(13q) only (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%)].

Methods

We performed NGS and/or Sanger sequencing of 9 genes (BIRC3, EGR2, NFKBIE, MYD88, NOTCH1, POT1, SF3B1, TP53, and XPO1) on pre-treatment samples in order to study their clinical impact in CLL.

Results

Overall, mutations in any of these genes were detected in 1,720 of 4,674 patients (36.8%, using a variant allele frequency cutoff of 5% for NGS), while the remaining patients were wildtype; two mutations were seen in 361 patients (7.7%) and three 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%), SF3B1 (9.3%), XPO1 (3.9%), POT1 (3.8%), NFKBIE (3.7%), BIRC3 (3.0%), EGR2 (2.5%) and MYD88 (2.5%; Figure 1A). We observed that certain gene mutations appeared almost mutually exclusive, such as BIRC3 and SF3B1 mutations (10 BIRC3mut/433 (2.3%) SF3B1mut  cases), and TP53 aberrations and XPO1 mutations (18 XPO1mut/488 (3.7%) TP53abn cases) or BIRC3 mutations (14 BIRC3mut/488 (2.9%) TP53abn cases). Except for MYD88, mutations in each of the investigated genes were associated with significantly shorter TTFT in univariate analysis. On multivariable analysis (including all genes, unmutated IGHV genes, Binet stage B/C, age > median at diagnosis and male gender), SF3B1 (Hazard Ratio 1.58; p<0.001), EGR2 (HR 1.39; p=0.003), XPO1 (HR 1.26; p=0.006), BIRC3 mutations (HR 1.25; p=0.031) and TP53 aberrations (HR 1.20; p=0.004), along with Binet stage B/C (HR 3.73; p-value <0.001) and unmutated IGHV genes (HR 2.95; p<0.001), remained as independent factors for shorter TTFT. As earlier studies have indicated different prognostic importance of genetic aberrations in IGHV-mutated (M-CLL) and IGHV-unmutated CLL (U-CLL), we next studied the impact of gene mutations in relation to IGHV gene mutation status. While TP53 aberrations, SF3B1 (Figure 1B) and BIRC3 mutations were associated with a worse outcome in both U-CLL and M-CLL, NOTCH1, POT1 and XPO1 mutations were only linked to a worse outcome in M-CLL, whereas EGR2 mutations correlated with a poor outcome only in U-CLL.

Conclusion

Based on these results, we conclude that SF3B1, EGR2, XPO1 and BIRC3 mutations independently predicted short TTFT and should be considered for extended molecular testing in CLL. However, considering the different impact of gene mutations in M-CLL and U-CLL, the IGHV mutation status must be taken into account when constructing future prognostic models including recurrent gene mutations.

Keyword(s): Chronic lymphocytic leukemia, Mutation

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