TY - JOUR
T1 - High karyotypic complexity is an independent prognostic factor in patients with CLL treated with venetoclax combinations
AU - Fürstenau, Moritz
AU - Thus, Yvonne J.
AU - Robrecht, Sandra
AU - Mellink, Clemens H.M.
AU - van der Kevie-Kersemaekers, Anne Marie
AU - Dubois, Julie
AU - von Tresckow, Julia
AU - Patz, Michaela
AU - Gregor, Michael
AU - Thornton, Patrick
AU - Staber, Philipp B.
AU - Tadmor, Tamar
AU - Levin, Mark David
AU - da Cunha-Bang, Caspar
AU - Schneider, Christof
AU - Poulsen, Christian Bjoern
AU - Illmer, Thomas
AU - Schöttker, Björn
AU - Janssens, Ann
AU - Christiansen, Ilse
AU - Nösslinger, Thomas
AU - Baumann, Michael
AU - Hebart, Holger
AU - Gaska, Tobias
AU - Regelink, Josien C.
AU - Dompeling, Ellen C.
AU - Lindström, Vesa
AU - Juliusson, Gunnar
AU - Widmer, Anouk
AU - Goede, Jeroen
AU - Goldschmidt, Neta
AU - Simon, Florian
AU - De Silva, Nisha
AU - Fink, Anna Maria
AU - Fischer, Kirsten
AU - Wendtner, Clemens Martin
AU - Ritgen, Matthias
AU - Brüggemann, Monika
AU - Tausch, Eugen
AU - Spaargaren, Marcel
AU - Eldering, Eric
AU - Stilgenbauer, Stephan
AU - Niemann, Carsten U.
AU - Hallek, Michael
AU - Eichhorst, Barbara
AU - Kreuzer, Karl Anton
AU - Kater, Arnon P.
N1 - Funding Information: The trial was sponsored by the German CLL Study Group with financial support and study drug provision from Roche , AbbVie , and Janssen . This analysis was partly supported by a Dutch Cancer Foundation grant (Coherent: 13650/2021-Infra). Publisher Copyright: © 2023 The American Society of Hematology
PY - 2023/8/3
Y1 - 2023/8/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85161324651&partnerID=8YFLogxK
U2 - https://doi.org/10.1182/blood.2023019634
DO - https://doi.org/10.1182/blood.2023019634
M3 - Article
C2 - 37172204
SN - 0006-4971
VL - 142
SP - 446
EP - 459
JO - Blood
JF - Blood
IS - 5
ER -