Genomic arrays for the identification of high-risk chronic lymphocytic leukemia: ready for prime time?

Abstract

Hematopoietic tumors develop through the acquisition of multiple molecular cytogenetic lesions, which confer growth advantage to the neoplastic cells, favoring the emergence of clones resistant to treatment. Not surprisingly, a high number of chromosome aberrations represents an unfavorable prognostic factor in several hematologic neoplasias, including acute myeloid leukemia, myelodysplastic syndrome, myelofibrosis and chronic lymphocytic leukemia (CLL). Conventional banding analysis (CBA) is a well-established method allowing for a complete overview of the cell genome, with high specificity and low sensitivity. The presence of three or more chromosome lesions in the same clone, usually referred to as complex karyotype, was associated with a shorter overall survival in CLL as early as 1990. Since then, reports have documented the negative prognostic significance of a complex karyotype in patients treated with chemoimmunotherapy and with novel mechanism-based therapy. While prognostic factors associate with outcome independently of the treatment, predictive factors are able to identify patients who are likely to obtain improved survival with a specific therapy and can only be identified in comparative trials. Because different types of treatment can be offered to CLL patients, biological factors predicting outcome with a specific drug are very useful in clinical practice and CBA was proposed as a desirable procedure in the diagnostic workup within prospective clinical studies. Interestingly, high efficacy of venetoclax plus obinutuzumab in patients with a complex karyotype and CLL was recently documented in the CLL14 trial, pointing to a possible role of complex karyotype as a predictive marker. Despite the introduction of effective mitogens, CBA is quite a cumbersome procedure requiring fresh dividing cells. For this reason, molecular methods such as array comparative genomic hybridization (CGH), single nucleotide insertional polymorphisms and next-generation sequencing have been applied in CLL, consistently showing that a high number of genetic lesions is associated with an inferior outcome.