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aberrations in CLL. Since the 2010s, the combination of Interleukin 2 (IL-2) and the CpG-oligonucleotide DSP30, which immunostimulates CLL cells in vitro, has been implemented as the gold standard mitogen in CLL and yields abnormal metaphases in up to 65-80% of patients(13). Improved cytogenetic techniques in CLL have prompted renewed interest in the karyotype in this setting.
❯ Complex karyotype. Definition, incidence, genomic complexity
The seminal paper from Juliusson et al.(11) already pointed out that the increasing number of chromosomal abnormalities in the karyotype were associated with a poor outcome. Furthermore, evidence was provided that 25-37% of patients without alterations by FISH carried chromosomal abnormalities not covered by the standard FISH panel and were associated with a poor prognosis(14).
The concept of “complex karyotype” (CK) was firstly described in myelodysplastic syndromes and acute myeloid leukemias(15,16), associated to a negative prognostic impact in these diseases. In CLL, initial studies defined a CK as the presence of 3 or more chromosomal alterations detected by CBA in the same cell clone(13,17). Taking into account this definition, CK are detected in 15% of patients at diagnosis(7,18) and increase up to 30% in relapsed patients after treatment. These are frequently found in Richter Syndrome, and often, but not always, associated with del(17p)/TP53 mutations, del(11q) or U-IGHV(9). Both the detection of CK and the number of anomalies in the karyotype are predictors of an unfavourable clinical outcome in patients treated not only with standard chemoimmunotherapy(7,19) but also in the initial clinical trials with the new mechanism- based therapeutic agents(3,20-22). In this sense, the importance of CBA was recognized by the 2018 Guidelines of the International Workshop on CLL(2), with the aim of identifying patients with CK, which may present shorter time to first treatment, progression free survival and overall survival.
Nevertheless, not all cases with CK are equal regarding genomic aberrations and prognosis. In a Spanish cooperative study (Grupo Cooperativo Español de Citogenética Hematológica y Grupo Español de LLC, Sociedad Española de Hematología y Hemoterapia) led by our group, we demonstrated that
among CLL patients with CK, up to 50% do not present abnormalities of TP53 and/or ATM although they show an aggressive clinical evolution equivalent to those patients with TP53 and/or ATM aberrations who do not have a CK. Furthermore, CK worsens the prognosis of patients with altered TP53 and/or ATM(7,23). Besides, we and other Spanish groups have also participated in a large retrospective study on CLL and CK from the European Research Initiative on CLL (ERIC)(9).The main aim was to define this subgroup of patients from a genetic point of view and the impact of CK in clinical practice. So far, we have shown that the standard criterion for defining a CK (detection of 3 or more chromosomal alterations by CBA) might be refined for the prognostic stratification of patients with CLL, being 5 or more the number of aberrations that best predict a worse prognosis(9). Moreover, we have been able to confirm that patients with multiple trisomies (+12, +18, +19) constitute a particular subgroup who, despite having a CK according to standard criteria, is characterized by a particularly benign clinical course(9,24).
Regarding genomic complexity, a second study has been conducted by the ERIC Cytogenetics Network with the aim of determining the clinical utility of genomic microarrays for copy number alterations (CNA) assessment in CLL diagnostics. The study has revealed that only high genomic complexity (high- GC), defined as ≥ 5 CNAs emerges as an independent adverse prognosticator on multivariable analysis for time to first treatment and overall survival(10). Moreover, our group has conducted a cooperative study with the aim of comparing the performance of CBA and genomic microarrays to detect genomic complexity. Besides, we aimed to compare risk stratification based on genomic complexity measured by both techniques. We have concluded that both methods are helpful for assessing genomic complexity in CLL patients and risk categories established by CBA and genomic microarrays have a significant impact on TTT although they show a moderate agreement. Discordant cases are being investigated to refine genomic complexity criteria equivalent by both techniques(25).
❯ Complex karyotype. Prognostic value
Over the last years, much has changed in the landscape of CLL treatments. Besides chemotherapy,
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