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

Complex karyotypes have been associated with inferior outcomes in chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy (CIT) while 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 [CA], CKT) and highly complex karyotypes (≥5 CA, hCKT) 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 (96.7%) patients of whom 153 (17%) had a CKT and 43 (5%) hCKT. In the CIT arm, CKT was associated with shorter PFS (HR 2.58, 95%CI 1.54-4.32, p<0.001) and OS (HR 3.25, 95%CI 1.03-10.26, p=0.044). In the pooled venetoclax arms a multivariable analysis identified hCKT (HR 1.96, 95%CI 1.03-3.72, p=0.041) but not CKT as independent adverse prognosticators for PFS. The presence of translocations (unbalanced and/or balanced) was also independently associated with shorter PFS in the venetoclax arms. CIT led to the acquisition of additional CA (mean CA: 2.0 to 3.4, baseline to CLL progression) while 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 work-up of CLL as it identifies patients at high risk for poor treatment outcomes and thereby improves prognostication.