High karyotypic complexity is an independent prognostic factor in patients with CLL treated with venetoclax combinations

Author:

Fürstenau Moritz1ORCID,Thus Yvonne J.2ORCID,Robrecht Sandra1,Mellink Clemens H. M.3,van der Kevie-Kersemaekers Anne-Marie3ORCID,Dubois Julie2,von Tresckow Julia4,Patz Michaela1,Gregor Michael56,Thornton Patrick7,Staber Philipp B.8ORCID,Tadmor Tamar9,Levin Mark-David10,da Cunha-Bang Caspar11ORCID,Schneider Christof12,Poulsen Christian Bjoern13ORCID,Illmer Thomas14,Schöttker Björn15,Janssens Ann16ORCID,Christiansen Ilse17,Nösslinger Thomas18,Baumann Michael619,Hebart Holger20,Gaska Tobias21,Regelink Josien C.22,Dompeling Ellen C.23,Lindström Vesa24,Juliusson Gunnar25,Widmer Anouk626,Goede Jeroen627,Goldschmidt Neta28,Simon Florian1ORCID,De Silva Nisha1,Fink Anna-Maria1,Fischer Kirsten1,Wendtner Clemens-Martin29,Ritgen Matthias30,Brüggemann Monika30,Tausch Eugen12,Spaargaren Marcel2ORCID,Eldering Eric2ORCID,Stilgenbauer Stephan12,Niemann Carsten U.11ORCID,Hallek Michael1ORCID,Eichhorst Barbara1,Kreuzer Karl-Anton1,Kater Arnon P.2ORCID

Affiliation:

1. 1Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, German CLL Study Group, University of Cologne, Cologne, Germany

2. 2Department of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands

3. 3Genome Diagnostics Laboratory, Section Cytogenetics, Department of Human Genetics, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands

4. 4Clinic for Hematology and Stem Cell Transplantation, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

5. 5Division of Hematology, Cantonal Hospital of Lucerne, Lucerne, Switzerland

6. 6Swiss Group for Clinical Cancer Research, Berne, Switzerland

7. 7Department of Haematology, Beaumont Hospital, RCSI University of Medicine and Health Sciences, Cancer Trials Ireland, Dublin, Ireland

8. 8Department of Medicine I, Medical University of Vienna, Vienna, Austria

9. 9Hematology, Bnai-Zion Medical Center, Haifa, Israel

10. 10Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, The Netherlands

11. 11Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

12. 12Division of CLL, Department of Internal Medicine III, University of Ulm, Ulm, Germany

13. 13Department of Hematology, Zealand University Hospital, Roskilde, Roskilde, Denmark

14. 14BAG Freiberg-Richter, Jacobasch, Wolf, Illmer, Dresden, Germany

15. 15Hämatologisch-onkologische Schwerpunktpraxis Würzburg, Würzburg, Germany

16. 16Department of Hematology, Universitaire Ziekenhuizen Leuven, Leuven, Belgium

17. 17Department of Hematology, Aalborg University Hospital, Aalborg, Denmark

18. 18Department of Internal Medicine III, Hanusch Hospital, Vienna, Austria

19. 19Department of Oncology, Kantonsspital St. Gallen, St. Gallen, Switzerland

20. 20Department of Oncology, Stauferklinikum, Mutlangen, Germany

21. 21Hematology and Oncology, Brüderkrankenhaus, Paderborn, Germany

22. 22Department of Haematology, Meander Medisch Centrum, Amersfoort, The Netherlands

23. 23Department of Hematology, Isala Ziekenhuis, Zwolle, The Netherlands

24. 24Department of Hematology, Comprehensive Cancer Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland

25. 25Department of Hematology, Skåne University Hospital, Lund, Sweden

26. 26Department of Medical Oncology and Haematology, Universitätsspital Zürich, Zürich, Switzerland

27. 27Clinic for Medical Oncology and Hematology, Cantonal Hospital of Winterthur, Winterthur, Switzerland

28. 28Department of Hematology, Hadassah Medical Center, Jerusalem, Israel

29. 29Department of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases and Tropical Medicine, German CLL Study Group, Munich Clinic Schwabing, Munich, Germany

30. 30Department II of Internal Medicine, University of Schleswig-Holstein, Kiel, Germany

Abstract

Abstract Complex karyotypes have been associated with inferior outcomes in chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy (CIT), whereas their prognostic impact in the context of venetoclax-based treatments is still debated. In this prospective analysis on karyotype complexity in CLL, we evaluated the impact of complex (≥3 chromosomal aberrations [CAs], CKTs) and highly complex karyotypes (≥5 CAs; hCKTs) as well as specific aberrations in previously untreated patients without TP53 aberrations undergoing either CIT or time-limited venetoclax-based therapies in the phase 3 GAIA/CLL13 trial. Karyotype analyses were available for 895 of 926 patients (96.7%), of whom 153 (17%) had a CKT and 43 (5%) hCKT. In the CIT arm, CKT was associated with shorter progression-free survival (PFS) (hazard ratio [HR] 2.58; 95% confidence interval [95% CI], 1.54-4.32; P < .001) and overall survival (HR, 3.25; 95% CI, 1.03-10.26; P = .044). In the pooled venetoclax arms, a multivariable analysis identified hCKTs (HR, 1.96; 95% CI, 1.03-3.72; P = .041), but not CKTs, as independent adverse prognosticators for PFS. The presence of translocations (unbalanced and/or balanced) was also independently associated with shorter PFSs in the venetoclax arms. CIT led to the acquisition of additional CAs (mean CAs, 2.0-3.4; from baseline to CLL progression), whereas karyotype complexity remained stable after venetoclax-based treatments (2.0, both time points). This analysis establishes highly complex karyotypes and translocations as adverse prognostic factors in the context of venetoclax-based combination treatments. The findings of this study support the incorporation of karyotyping into the standard diagnostic workup of CLL, because it identifies patients at high risk of poor treatment outcomes and thereby improves prognostication. This trial was registered at www.clinicaltrials.gov as #NCT02950051.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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