Complex karyotype defined as ≥3 cytogenetic abnormalities is prognostic of survival in patients treated with ibrutinib or venetoclax in relapsed/refractory (RR) chronic lymphocytic leukemia (CLL). Recent studies re-evaluating this dichotomous variable have shown that higher numbers of cytogenetic abnormalities (i.e. ≥5) have a worse overall survival in patients treated with chemoimmunotherapy. We sought to determine if increasing karyotypic complexity, treated as a continuous variable, was prognostic of survival for patients treated with ibrutinib for CLL. We conducted a retrospective analysis of all patients with CLL treated with single-agent ibrutinib or in combination with an anti-CD20 antibody at our institution. We included 456 patients with both treatment-naïve (TN) and RR disease. Median number of prior therapies was 2 (range 0-13), 30% of patients had del(17p), and 75% were IGHV unmutated. 50% had ≥3 cytogenetic abnormalities including 30% with ≥5. In a multivariable analysis, increasing karyotypic complexity was an independent predictor of shorter progression-free survival (HR 1.07 (95% CI 1.04-1.10), p<0.0001) and overall survival (HR 1.09 (95% CI 1.05-1.12), p<0.0001). Furthermore, we found that presence of clonal evolution determined by cytogenetic analysis at progression was prognostic of subsequent survival (p=0.02). This solidifies karyotypic complexity as an important prognostic factor for CLL patients treated with ibrutinib. Further research should consider sequential karyotypic analysis as a determination of risk of progression and death in patients with CLL.
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