Complex Karyotype in <scp>CLL</scp> —How to Count Cytogenetic Aberrations Consistently and Efficiently

Complex karyotype (CK) in chronic lymphocytic leukemia (CLL), defined by ≥ 3 or ≥ 5 (high-CK) chromosomal aberrations, is an established adverse prognostic marker. However, different methods for counting aberrations are used in the literature and clinical trials, potentially affecting CK classification and risk stratification. We systematically compared two established counting methods: the approach by Jondreville et al., which counts one aberration per item separated by commas, and the International System for Human Cytogenomic Nomenclature (ISCN) method, which counts unbalanced aberrations involving multiple chromosomes as two aberrations. Chromosome banding analyses from 1605 CLL patients were evaluated using both counting methods. This revealed that CK classification by the two methods disagreed in 7.5% of all cases. However, both methods performed similarly in prognostic stratification of these ambiguous cases. This suggests that the method proposed by Jondreville et al. should be adopted, as it is simpler to perform and less ambiguous. Furthermore, we compared how cases were stratified if aberrations are counted across all (sub)clones (as suggested both by Jondreville et al. and the ISCN) or only in the clone with the most aberrations. In total, 3.5% of all cases were differentially classified depending on whether aberrations were counted across all clones or only in the most complex clone. Importantly, these ambiguous cases were better stratified by counting aberrations in the most complex clone only. We therefore suggest the method proposed by Jondreville et al. to determine CK status in CLL and to count aberrations only in the clone with the most aberrations.