CLL: The more complex the karyotype, the less favorable the prognosis
Chronic lymphocytic leukemia (CLL) is the most common leukemic disease in Central Europe. In addition to clinical prognostic factors, a number of genetic risk factors have a negative impact on response rate and overall survival.
Genetic Risk Factors of CLL
The Onkopedia guidelines1 recommend
testing for the following genetic risk factors before initiating therapy:
1. TP53 deletion (del(17p13))
2. TP53 mutation
3. Complex karyotype
4. Unmutated IGHV status
The presence of at least one of these risk factors influences the therapy of patients, because in these cases the use of BTK inhibitors (e.g. ibrutinib) or the combination of venetoclax/obinutuzumab is recommended in first-line therapy1.
Complex Karyotype as a Prognostic Factor
Approximately 20% of all CLL patients exhibit a complex karyotype, but the number of aberrations starting from which the strongest prognostic effect is observed has long been debated2,3. New data now further breaks down this relationship by examining the survival of 456 CLL patients treated with ibrutinib based on the number of chromosomal alterations4. The patients were divided into subgroups based on the number of aberrations at initial diagnosis (0, 1-2, 3-4, 5-9, 10-14, ≥15). The authors were then able to show that karyotype complexity is a continuous variable for survival: Patients with 1-2 aberrations showed a progression-free survival of 67 months, the presence of 5-9 aberrations reduced this to 45 months, and with ≥15 alterations it further decreased to 19 months. Thus, it is clear that it is not only the presence of a complex karyotype per se, but also the number of alterations which has an influence on the prognosis. For some patients, samples were also analyzed during the course of the disease. Here it also became clear that an increase in chromosomal alterations was associated with a poorer prognosis.
The Role of Chromosomal Analysis in Risk Stratification for CLL
Although several guidelines (e.g., Onkopedia) recommend analysis of the complex karyotype before initiating therapy, chromosomal analysis has not yet been established as an integral part of CLL diagnostics. FISH (fluorescence in situ hybridization) analyses to detect frequent or prognostically relevant alterations are routinely performed, but cannot determine the total number of aberrations because a genome-wide analysis is not possible with FISH. The new data not only demonstrates the importance of the complex karyotype as a continuous prognostic marker, but also underscores the role of chromosomal analysis in CLL diagnostics, both for the initial diagnosis and over the course of the disease. In principle, whole-genome sequencing (WGS) analyses can be considered as an alternative method. However, this is currently not yet a standard option in CLL diagnostics for cost reasons.
2Haferlach C, Dicker F, Schnittger S, Kern W, Haferlach T. Comprehensive genetic characterization of CLL: a study on 506 cases analysed with chromosome banding analysis, interphase FISH, IgV(H) status and immunophenotyping. Leukemia. 2007; 21(12):2442-2451.
3Baliakas P, Jeromin S, Iskas M, et al; ERIC, the European Research Initiative on CLL. Cytogenetic complexity in chronic lymphocytic leukemia: definitions, associations, and clinical impact. Blood. 2019;133(11):1205-1216.
4Kittai AS, Miller C, Goldstein D, et al. The impact of increasing karyotypic complexity and evolution on survival in patients with CLL treated with ibrutinib. Blood. 2021;138(23):2372-2382.