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Ferrata Storti Foundation
Haematologica 2020 Volume 105(11):2598-2607
Chronic Lymphocytic Leukemia
Prognostic impact of prevalent chronic lymphocytic leukemia stereotyped subsets: analysis within prospective clinical trials of the German CLL Study Group
Sonia Jaramillo,1 Andreas Agathangelidis,2 Christof Schneider,1
Jasmin Bahlo,3 Sandra Robrecht,3 Eugen Tausch,1 Johannes Bloehdorn,1 Manuela Hoechstetter,4 Kirsten Fischer,3 Barbara Eichhorst,3 Valentin Goede,3 Michael Hallek,3 Hartmut Döhner,1 Richard Rosenquist,5 Paolo Ghia,6
Kostas Stamatopoulos2,5 and Stephan Stilgenbauer1
1Department of Internal Medicine III, Ulm University, Ulm, Germany; 2Institute of Applied Biosciences, Centre for Research and Technology, Thessaloniki, Greece; 3Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University of Cologne, Cologne, Germany; 4Department of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases and Tropical Medicine, München Klinik Schwabing, Munich, Germany; 5Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden and 6Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan, Italy
ABSTRACT
Almost one-third of all patients with chronic lymphocytic leukemia (CLL) express stereotyped B-cell receptor immunoglobulins (BcR IG) and can be assigned to distinct subsets, each with a particular BcR IG. The largest stereotyped subsets are #1, #2, #4 and #8, associated with specific clinico-biological characteristics and outcomes in retrospective studies. We assessed the associations and prognostic value of these BcR IG in prospective multicenter clinical trials reflective of two different clinical situations: (i) early-stage patients ('watch and wait' arm of the CLL1 trial) (n=592); (ii) patients in need of treatment, enrolled in three phase III trials (CLL8, CLL10, CLL11), treated with different chemo-immunotherapies (n=1,861). Subset #1 was associated with del(11q), higher CLL International Prognostic Index (CLL-IPI) scores and similar clinical course to CLL with unmutated immunoglobulin heavy variable (IGHV) genes (U-CLL) in both early and advanced stage groups. IGHV-mutated (M-CLL) subset #2 cases had shorter time-to-first-treatment (TTFT) versus other M-CLL cases in the early-stage cohort (hazard ratio [HR]: 4.2, confidence interval [CI]: 2-8.6, P<0.001), and shorter time-to-next-treatment (TTNT) in the advanced- stage cohort (HR: 2, CI: 1.2-3.3, P=0.005). M-CLL subset #4 was associated with lower CLL-IPI scores and younger age at diagnosis; in both cohorts, these patients showed a trend towards better outcomes versus other M- CLL. U-CLL subset #8 was associated with trisomy 12. Overall, this study shows that major stereotyped subsets have distinctive characteristics. For the first time in prospective multicenter clinical trials, subset #2 appeared as an independent prognostic factor for earlier TTFT and TTNT and should be proposed for risk stratification of patients. (Trials registered at clinical tri- als.gov identifiers: NCT00262782, NCT00281918, NCT2000769522, and NCT01010061).
Introduction
Chronic lymphocytic leukemia (CLL) is a clinically and biologically heteroge- neous disease.1 Important prognostic markers include clinical stage (Rai and Binet), presence of deletions in the long arm of chromosome 11 (del(11q)) and in the short arm of chromosome 17(del(17p)), TP53 gene mutations, complex karyotype (CK) as defined by ≥3 chromosomal abnormalities by conventional cytogenetics, markers of tumor load (e.g., thymidine kinase [TK], and 2-microglobulin [β2MG], and genetic parameters such as immunoglobulin heavy variable (IGHV) gene somatic
Correspondence:
STEPHAN STILGENBAUER
stephan.stilgenbauer@uniklinik-ulm.de
Received: July 8 2019.
Accepted: December 18, 2019. Pre-published: December26,2019.
doi:10.3324/haematol.2019.231027 ©2020 Ferrata Storti Foundation
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