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 - Publisher Copyright: © 2023 The American Society of Hematology

PY - 2023

Y1 - 2023

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.

U2 - 10.1182/blood.2023019634

DO - 10.1182/blood.2023019634

M3 - Journal article

C2 - 37172204

AN - SCOPUS:85161324651

VL - 142

SP - 446

EP - 459

JO - Blood

JF - Blood

SN - 0006-4971

IS - 5

ER -