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CYTOGENETIC COMPLEXITY IN CHRONIC LYMPHOCYTIC LEUKEMIA: DEFINITIONS, ASSOCIATIONS WITH OTHER BIOMARKERS AND CLINICAL IMPACT; A RETROSPECTIVE STUDY ON BEHALF OF ERIC
Author(s):
Panagiotis Baliakas
,
Panagiotis Baliakas
Affiliations:
Department of Immunology, Genetics and Pathology, Science for Life Laboratory,Uppsala University,Uppsala,Sweden
Sabine Jeromin
,
Sabine Jeromin
Affiliations:
MLL Munich Leukemia Laboratory,Munich,Germany
Michalis Iskas
,
Michalis Iskas
Affiliations:
Hematology Department and HCT Unit,G. Papanicolaou Hospital,Thessaloniki,Greece
Anna Puiggros
,
Anna Puiggros
Affiliations:
Laboratori de Citogenètica Molecular, Servei de Patologia,Hospital del Mar,Barcelona,Spain;Grup de Recerca Translacional en Neoplàsies Hematològiques, Programa de Recerca en Càncer,Institut Hospital del Mar d'Investigacions Mèdiques (IMIM),Barcelona,Spain
Karla Plevova
,
Karla Plevova
Affiliations:
Central European Institute of Technology (CEITEC),Masaryk University,Brno,Czech Republic;Department of Internal Medicine - Hematology and Oncology,University Hospital Brno and Faculty of Medicine, Masaryk University,Brno,Czech Republic
Aliki Xochelli
,
Aliki Xochelli
Affiliations:
Institute of Applied Biosciences, Center for Research and Technology Hellas,Thessaloniki,Greece
Julio Delgado
,
Julio Delgado
Affiliations:
Secció d'Hematopatologia, Hospital Clínic,Institut d'Investigacions Biomèdiques Augustí Pi i Sunyer (IDIBAPS), Universitat de Barcelona,Barcelona,Spain
Jana Kotaskova
,
Jana Kotaskova
Affiliations:
Central European Institute of Technology (CEITEC),Masaryk University,Brno,Czech Republic;Department of Internal Medicine - Hematology and Oncology,University Hospital Brno and Faculty of Medicine, Masaryk University,Brno,Czech Republic
Evaggelia Stalika
,
Evaggelia Stalika
Affiliations:
Institute of Applied Biosciences, Center for Research and Technology Hellas,Thessaloniki,Greece
Pau Abrisqueta
,
Pau Abrisqueta
Affiliations:
Servei d'Hematología,Hospital Vall d'Hebron,Barcelona,Spain
Kristina Durechova
,
Kristina Durechova
Affiliations:
Department of Internal Medicine - Hematology and Oncology,University Hospital Brno and Faculty of Medicine, Masaryk University,Brno,Czech Republic
Giwrgos Papaioannou
,
Giwrgos Papaioannou
Affiliations:
Hematology Department and HCT Unit,G. Papanicolaou Hospital,Thessaloniki,Greece
Rosa Collado
,
Rosa Collado
Affiliations:
Servicio de Hematología,Consorcio Hospital General Universitario,Valencia,Spain
Michael Doubek
,
Michael Doubek
Affiliations:
Central European Institute of Technology (CEITEC),Masaryk University,Brno,Czech Republic;Department of Internal Medicine - Hematology and Oncology,University Hospital Brno and Faculty of Medicine, Masaryk University,Brno,Czech Republic
M Jose Calasanz
,
M Jose Calasanz
Affiliations:
Servicio de Citogenética, Departamento de Genética,Universidad de Navarra,Pamplona,Spain
Neus Ruiz-Xiville
,
Neus Ruiz-Xiville
Affiliations:
Servei Laboratori Hematologia,ICO-Hospital Germans Trias i Pujol, Institut de Recerca Contra la Leucèmia Josep Carreras (IJC), Universitat Autònoma de Barcelona,Badalona,Spain
Carolina Moreno
,
Carolina Moreno
Affiliations:
Servei d'Hematologia,Hospital Universitari de la Santa Creu i Sant Pau,Barcelona,Spain
Alexander C. Leeksma
,
Alexander C. Leeksma
Affiliations:
Department of Hematology,Academic Medical Center Amsterdam, University of Amsterdam,Amsterdam,Netherlands
Achilles Anagnostopoulos
,
Achilles Anagnostopoulos
Affiliations:
Hematology Department and HCT Unit,G. Papanicolaou Hospital,Thessaloniki,Greece
Paolo Ghia
,
Paolo Ghia
Affiliations:
Università Vita-Salute San Raffaele,MIlan,Italy;Strategic Research Program in CLL, Division of Experimental Oncology,IRCCS San Raffaele Scientific Institute,Milan,Italy
Niki Stavroyianni
,
Niki Stavroyianni
Affiliations:
Hematology Department and HCT Unit,G. Papanicolaou Hospital,Thessaloniki,Greece
Arnon P. Kater
,
Arnon P. Kater
Affiliations:
Department of Hematology,Academic Medical Center Amsterdam, University of Amsterdam,Amsterdam,Netherlands
Blanca Espinet
,
Blanca Espinet
Affiliations:
Laboratori de Citogenètica Molecular, Servei de Patologia,Hospital del Mar,Barcelona,Spain;Grup de Recerca Translacional en Neoplàsies Hematològiques, Programa de Recerca en Càncer,Institut Hospital del Mar d'Investigacions Mèdiques (IMIM),Barcelona,Spain
Sarka Pospisilova
,
Sarka Pospisilova
Affiliations:
Central European Institute of Technology (CEITEC),Masaryk University,Brno,Czech Republic;Department of Internal Medicine - Hematology and Oncology,University Hospital Brno and Faculty of Medicine, Masaryk University,Brno,Czech Republic
Anastasia Athanasiadou
,
Anastasia Athanasiadou
Affiliations:
Hematology Department and HCT Unit,G. Papanicolaou Hospital,Thessaloniki,Greece
Kostas Stamatopoulos
,
Kostas Stamatopoulos
Affiliations:
Institute of Applied Biosciences, Center for Research and Technology Hellas,Thessaloniki,Greece;Department of Immunology, Genetics and Pathology, Science for Life Laboratory,Uppsala University,Uppsala,Sweden
Claudia Haferlach
Claudia Haferlach
Affiliations:
MLL Munich Leukemia Laboratory,Munich,Germany
(Abstract release date: 05/18/17) EHA Library. Baliakas P. 06/24/17; 181748; S461
Dr. Panagiotis Baliakas
Dr. Panagiotis Baliakas
Contributions
PDF Abstract
Abstract

Abstract: S461

Type: Oral Presentation

Presentation during EHA22: On Saturday, June 24, 2017 from 16:00 - 16:15

Location: Hall B

Background

Recent evidence suggests that complex karyotype (CK) identified by chromosome banding analysis (CBA) may be a relevant biomarker for treatment decisions in CLL, especially regarding the response to signaling inhibitors. However, many challenges towards routine clinical application of CBA still need to be overcome. 

Aims
Reappraisal of definitions for CK in CLL and systematic investigation of clinicobiological associations and prognostic impact. 

Methods
3580 CLL and monoclonal B-cell lymphocytosis (MBL) patients (CLL=3322, 93% and MBL=258, 7%, respectively) were analysed with CpG-oligodeoxynucleotides/interleukin 2 (CPG/IL2, n=379, 11%), phorbol-12-myristate-13-acetate (TPA, n=1846, 52%) or both (n=1355, 37%). CBA was mostly performed within the first year from diagnosis and before treatment administration (79% and 88%, respectively). Main features of the studied cohort: median age: 65.6 years/ males: 2252 (63%)/ Binet A/B/C: 2356/357/258 (79%/12%/9%: MBL and Binet A were grouped together)/ IG-unmutated CLL (U-CLL): 829/2051 (40%)/del(13q), 1769/3271 (54%)/ trisomy 12, 507/3260, 16%/ del(11q): 377/3256 (12%)/ TP53 abnormality (TP53abn i.e. del(17p) and/or TP53 mutations): 299/3308 (12%).

Results

Following the current definition for CK i.e. ≥3 structural and/or numerical aberrations, 381/3580 cases (11%) displayed CK, with no difference in the detection rate between different cell stimulation protocols. CK was significantly associated (p<0.05) with male gender, advanced clinical stage (Binet B/C), U-CLL, del(13q), +12, del(11q) and TP53abn. On univariate analysis, CK was associated with inferior OS (median: 11.5 years); CK remained significant also on multivariate analysis along with older age, Binet B/C stage, U-CLL and TP53abn. Considering earlier evidence in smaller series that CLL cases with ≥3 structural and/or numerical cytogenetic aberrations are not equivalent, we assessed the relevance of other numerical cut-offs for CK, while also investigating the impact of the type of aberrations (i.e. structural versus numerical). CK cases were stratified into those with 3 (‘low-CK’, n=200, 52%), 4 (‘intermediate-CK’, n=82, 22%) and ≥5 (‘high-CK’, n=99, 26%) aberrations. High-CK cases differed significantly (p<0.05) from the other two subgroups, being enriched for U-CLL and TP53abn (79% and 57%, respectively). The median OS was 5.1 years for the high-CK vs not reached for the low- and intermediate-CK groups (p<0.0001). We also identified 46 cases (12% of those with ≥3 aberrations) who carried +12,+19 plus other numerical and/or structural abnormalities and displayed extremely indolent clinical course (median OS not yet reached and only 4 deaths at a median follow-up of 5.2 years). When high-CK was assessed as an independent parameter, it was correlated with inferior OS in the univariate analysis, retaining significance also in the multivariate analysis (p=0.012) independently of the remaining parameters, including clinical stage, U-CLL and TP53 status. In contrast, low/intermediate-CK had no impact on OS, not even in univariate analysis (p=0.57).

Conclusion

CK defined by the presence of ≥3 numerical and/or structural abnormalities should not be axiomatically considered unfavorable in CLL, representing a heterogeneous group with variable clinical behavior. High-CK with ≥5 chromosomal aberrations emerges as prognostically adverse, independently of clinical stage, IG somatic hypermutation and TP53 status. Prospective clinical validation is warranted before finally incorporating high-CK in risk stratification in CLL.

Session topic: 6. Chronic lymphocytic leukemia and related disorders - Clinical

Keyword(s): prognosis, Complex aberrant karyotype, Chronic Lymphocytic Leukemia

Abstract: S461

Type: Oral Presentation

Presentation during EHA22: On Saturday, June 24, 2017 from 16:00 - 16:15

Location: Hall B

Background

Recent evidence suggests that complex karyotype (CK) identified by chromosome banding analysis (CBA) may be a relevant biomarker for treatment decisions in CLL, especially regarding the response to signaling inhibitors. However, many challenges towards routine clinical application of CBA still need to be overcome. 

Aims
Reappraisal of definitions for CK in CLL and systematic investigation of clinicobiological associations and prognostic impact. 

Methods
3580 CLL and monoclonal B-cell lymphocytosis (MBL) patients (CLL=3322, 93% and MBL=258, 7%, respectively) were analysed with CpG-oligodeoxynucleotides/interleukin 2 (CPG/IL2, n=379, 11%), phorbol-12-myristate-13-acetate (TPA, n=1846, 52%) or both (n=1355, 37%). CBA was mostly performed within the first year from diagnosis and before treatment administration (79% and 88%, respectively). Main features of the studied cohort: median age: 65.6 years/ males: 2252 (63%)/ Binet A/B/C: 2356/357/258 (79%/12%/9%: MBL and Binet A were grouped together)/ IG-unmutated CLL (U-CLL): 829/2051 (40%)/del(13q), 1769/3271 (54%)/ trisomy 12, 507/3260, 16%/ del(11q): 377/3256 (12%)/ TP53 abnormality (TP53abn i.e. del(17p) and/or TP53 mutations): 299/3308 (12%).

Results

Following the current definition for CK i.e. ≥3 structural and/or numerical aberrations, 381/3580 cases (11%) displayed CK, with no difference in the detection rate between different cell stimulation protocols. CK was significantly associated (p<0.05) with male gender, advanced clinical stage (Binet B/C), U-CLL, del(13q), +12, del(11q) and TP53abn. On univariate analysis, CK was associated with inferior OS (median: 11.5 years); CK remained significant also on multivariate analysis along with older age, Binet B/C stage, U-CLL and TP53abn. Considering earlier evidence in smaller series that CLL cases with ≥3 structural and/or numerical cytogenetic aberrations are not equivalent, we assessed the relevance of other numerical cut-offs for CK, while also investigating the impact of the type of aberrations (i.e. structural versus numerical). CK cases were stratified into those with 3 (‘low-CK’, n=200, 52%), 4 (‘intermediate-CK’, n=82, 22%) and ≥5 (‘high-CK’, n=99, 26%) aberrations. High-CK cases differed significantly (p<0.05) from the other two subgroups, being enriched for U-CLL and TP53abn (79% and 57%, respectively). The median OS was 5.1 years for the high-CK vs not reached for the low- and intermediate-CK groups (p<0.0001). We also identified 46 cases (12% of those with ≥3 aberrations) who carried +12,+19 plus other numerical and/or structural abnormalities and displayed extremely indolent clinical course (median OS not yet reached and only 4 deaths at a median follow-up of 5.2 years). When high-CK was assessed as an independent parameter, it was correlated with inferior OS in the univariate analysis, retaining significance also in the multivariate analysis (p=0.012) independently of the remaining parameters, including clinical stage, U-CLL and TP53 status. In contrast, low/intermediate-CK had no impact on OS, not even in univariate analysis (p=0.57).

Conclusion

CK defined by the presence of ≥3 numerical and/or structural abnormalities should not be axiomatically considered unfavorable in CLL, representing a heterogeneous group with variable clinical behavior. High-CK with ≥5 chromosomal aberrations emerges as prognostically adverse, independently of clinical stage, IG somatic hypermutation and TP53 status. Prospective clinical validation is warranted before finally incorporating high-CK in risk stratification in CLL.

Session topic: 6. Chronic lymphocytic leukemia and related disorders - Clinical

Keyword(s): prognosis, Complex aberrant karyotype, Chronic Lymphocytic Leukemia

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