REFINING PROGNOSIS OF CHRONIC LYMPHOCYTIC LEUKEMIA WITH SOMATICALLY HYPERMUTATED B-CELL RECEPTORS: A NOVEL PROGNOSTIC INDEX ON BEHALF OF THE EUROPEAN RESEARCH INITIATIVE ON CLL (ERIC)
Author(s): ,
Panagiotis Baliakas
Affiliations:
Department of Immunology, Genetics and Pathology, Science for Life Laboratory,Uppsala University,Uppsala,Sweden
,
Anastasia Hadzidimitriou
Affiliations:
Department of Immunology, Genetics and Pathology, Science for Life Laboratory,Uppsala University,Uppsala,Sweden;Institute of Applied Biosciences, Center for Research and Technology Hellas,Thessaloniki,Greece
,
Mattias Mattsson
Affiliations:
Department of Immunology, Genetics and Pathology, Science for Life Laboratory,Uppsala University,Uppsala,Sweden
,
Aliki Xochelli
Affiliations:
Department of Immunology, Genetics and Pathology, Science for Life Laboratory,Uppsala University,Uppsala,Sweden;Institute of Applied Biosciences, Center for Research and Technology Hellas,Thessaloniki,Greece
,
Lesley-Ann Sutton
Affiliations:
Department of Immunology, Genetics and Pathology, Science for Life Laboratory,Uppsala University,Uppsala,Sweden
,
Eva Minga
Affiliations:
Institute of Applied Biosciences, Center for Research and Technology Hellas,Thessaloniki,Greece
,
Lydia Scarfò
Affiliations:
Division of experimental Oncology and Department of Onco-Hematology,Instituto Scientifico San Raffaele e Fondazione Centro San Raffaele,Milan,Italy;Università Vita-Salute San Raffaele,Milan,Italy
,
Davide Rossi
Affiliations:
Division of Hematology, Department of Translational Medicine,Amedeo Avogadro University of Eastern Piedmont,Novara,Italy
,
Zadie Davis
Affiliations:
Department of Haematology,Royal Bournemouth Hospital,Bournemouth,United Kingdom
,
Andreas Agathangelidis
Affiliations:
Division of experimental Oncology and Department of Onco-Hematology,Instituto Scientifico San Raffaele e Fondazione Centro San Raffaele,Milan,Italy;Università Vita-Salute San Raffaele,Milan,Italy
,
Neus Villamor
Affiliations:
Hemopathology Unit,Hospital Clinic,Barcelona,Spain
,
Helen Parker
Affiliations:
Cancer Sciences, Faculty of Medicine,University of Southampton,Southampton,United Kingdom
,
Jana Kotaskova
Affiliations:
Central European Institute of Technology,Masaryk University and University Hospital Brno,Brno,Czech Republic
,
Evangelia Stalika
Affiliations:
Institute of Applied Biosciences, Center for Research and Technology Hellas,Thessaloniki,Greece;Hematology Department and HCT Unit,G. Papanicolaou Hospital,Thessaloniki,Greece
,
Karla Plevova
Affiliations:
Central European Institute of Technology,Masaryk University and University Hospital Brno,Brno,Czech Republic
,
Larry Mansouri
Affiliations:
Department of Immunology, Genetics and Pathology, Science for Life Laboratory,Uppsala University,Uppsala,Sweden
,
Diego Cortese
Affiliations:
Department of Immunology, Genetics and Pathology, Science for Life Laboratory,Uppsala University,Uppsala,Sweden
,
Alba Navarro Lopez
Affiliations:
Hemopathology Unit,Hospital Clinic,Barcelona,Spain
,
Julio Delgado
Affiliations:
Hematology Department,Hospital Clinic,Barcelona,Spain
,
Marta Larrayoz
Affiliations:
Cancer Sciences, Faculty of Medicine,University of Southampton,Southampton,United Kingdom
,
Achilles Anagnostopoulos
Affiliations:
Hematology Department and HCT Unit,G. Papanicolaou Hospital,Thessaloniki,Greece
,
Chrysoula Belessi
Affiliations:
Hematology Department,Nikea General Hospital,Pireaus,Greece
,
Karin E Smedby
Affiliations:
Department of Medicine, Solna, Clinical Epidemiology Unit,Karolinska Institutet,Stockholm,Sweden
,
Gunnar Juliusson
Affiliations:
Lund University and Hospital Department of Hematology,Lund Stem Cell Center,Lund,Sweden
,
Jonathan C. Strefford
Affiliations:
Cancer Sciences, Faculty of Medicine,University of Southampton,Southampton,United Kingdom
,
Sarka Pospisilova
Affiliations:
Central European Institute of Technology,Masaryk University and University Hospital Brno,Brno,Czech Republic
,
David Oscier
Affiliations:
Department of Haematology,Royal Bournemouth Hospital,Bournemouth,United Kingdom
,
Gianluca Gaidano
Affiliations:
Division of Hematology, Department of Translational Medicine,Amedeo Avogadro University of Eastern Piedmont,Novara,Italy
,
Elias Campo
Affiliations:
Hemopathology Unit,Hospital Clinic,Barcelona,Spain;Department of Pathology,University of Barcelona,Barcelona,Spain
,
Paolo Ghia
Affiliations:
Division of experimental Oncology and Department of Onco-Hematology,Instituto Scientifico San Raffaele e Fondazione Centro San Raffaele,Milan,Italy;Università Vita-Salute San Raffaele,Milan,Italy
,
Richard Rosenquist
Affiliations:
Department of Immunology, Genetics and Pathology, Science for Life Laboratory,Uppsala University,Uppsala,Sweden
Kostas Stamatopoulos
Affiliations:
Department of Immunology, Genetics and Pathology, Science for Life Laboratory,Uppsala University,Uppsala,Sweden;Institute of Applied Biosciences, Center for Research and Technology Hellas,Thessaloniki,Greece
EHA Learning Center. Baliakas P. Jun 12, 2015; 100463
Disclosure(s): Uppsala University
Immunology, Genetics and Pathology
Dr. Panagiotis Baliakas
Dr. Panagiotis Baliakas

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Abstract
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Abstract: P209

Type: Poster Presentation

Presentation during EHA20: From 12.06.2015 17:15 to 12.06.2015 18:45

Location: Poster area (Hall C)

Background
Chronic lymphocytic leukemia (CLL) patients with somatically hypermutated IGHV genes (M-CLL) within their B-cell receptor immunoglobulin (BcR IG) generally display favorable biological profiles with an indolent disease course. However, neither the biological background nor the clinical presentation and outcome of M-CLL is uniform, thus justifying the quest for parameters that would assist in refining prognosis. 

Aims

Development of a novel prognostic index tailored to M-CLL.



Methods
Cox-regression models were used to assess the impact of demographic, clinical, genomic and immunogenetic features on time-to-first-treatment (TTFT) in 1359 M-CLL cases. 

Results
Main features of the studied cohort were as follows: median age: 64 years (22-92); males: 810/1359 (60%), Binet A/B/C: 1169/79/53 (90%/6%/4%); CD38 expression (CD38+): 161/1225 (13%). Except for del(13q) (494/836, 59%) and trisomy 12 (+12, 142/1072, 13%), other genomic aberrations were relatively rare [del(11q): 49/1076 (4.5%), TP53 abnormality (TP53abn) i.e. del(17p) and/or TP53 mutations: 52/1144 (4.5%), NOTCH1 mutations (NOTCH1m): 23/1333 (2%), SF3B1m: 33/897 (4%), MYD88m: 23/556 (4%)]. Borderline mutated IGHV genes (germline identity, GI: 97-97.99%) were expressed by 101 cases (7%). Thirty-three (2.5%) and 26 (2%) patients were assigned to stereotyped subsets #4 (IGHV4-34/IGKV2-30) and #2 (IGHV3-21/IGLV3-21), respectively. All the aforementioned parameters were evaluated for their impact on TTFT, using  univariate regression analysis. As expected, Binet stage C at diagnosis emerged as the most powerful marker (HR: 9.44, 95% CI, 7.45-11.97, p<0.0001). Among the remaining cases (Binet A/B), representing 96% of the cohort, the following parameters were significantly associated with shorter TTFT: Binet B (HR: 7.35, 5.51-9.81, p<0.0001), subset #2 membership (HR: 4.24, 2.32-7.76, p=0.0001), CD38+ (HR: 2.62, 1.98-3.50, p<0.0001), TP53abn (HR: 2.56, 1.64-4, p=0.0003), +12 (HR: 1.75, 1.27-2.41, p=0.002), male gender (HR: 1.52, 1.2-1.9, p=0.004). In contrast, a trend for favorable outcome was observed for subset #4 membership (HR: 0.43, 0.16-1.18, p=0.06). Taking into consideration the above HRs as well as median TTFT, we defined 4 groups among Binet A/B patients (n=934) with different TTFT (Figure 1): (i) high risk (n=88, 9%): Binet B or subset #2 membership (median TTFT: 2.1 years, 65% and 85% probability of treatment initiation (TI) at 5 and 10 years from diagnosis, respectively); (ii) intermediate risk (n=199, 22%): Binet A and occurence of one or more of: CD38 expression/TP53abn/+12 (median TTFT: 12 years, 33% and 45% TI at 5 and 10 years, respectively); (iii) low risk (n=619, 66%): Binet A with no CD38+/TP53abn/+12 (median TTFT: not yet reached, 15% and 25% TI at 5 and 10 years, respectively); and (iv) very low risk (n=28, 3%): subset #4 membership (median TTFT not yet reached,  0% and 10% TI at 5 and 10 years, respectively). 

Summary

We report a simple prognostic index for M-CLL capable of identifying patients who will experience short TTFT as well as those who will probably never require treatment, applicable even within early clinical stage CLL. At the ends of the clinical spectrum described by this novel index lie stereotyped subsets #2 (aggressive) and #4 (indolent). This further highlights the importance of distinct BcR IG configuration, likely linked to distinct immune signaling, for CLL ontogeny and evolution and indicates that subclassifying M-CLL based on stereotypy is relevant in the context of everyday routine practice. 



Keyword(s): Chronic lymphocytic leukemia, Prognosis



Session topic: Chronic lymphocytic leukemia - Clinical 1
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