Chronic Lymphocytic Leukemia (CLL) is a genetically and clinically heterogeneous disease, characterized by a wide range of genetic mutations and chromosomal abnormalities that contribute to its variable clinical course and response to treatment. This heterogeneity makes CLL a complex disease to manage, with genetic factors playing a crucial role in prognosis and treatment decisions. Approximately 80% of patients with CLL have at least one of the chromosomal abnormalities: del(13q), del(11q), del(17p), or trisomy 12. The most commonly used genetic tests are FISH (Fluorescence In Situ Hybridization) and next-generation sequencing (NGS). Conventional cytogenetics is not preferred in CLL due to its lower sensitivity for detecting smaller chromosomal abnormalities and subtle genetic mutations. FISH is highly effective at detecting specific chromosomal abnormalities, such as del(13q), del(11q), del(17p), or trisomy 12, while NGS provides a detailed analysis of molecular mutations, including those in genes like TP53,NOTCH1 and SF3B1. The immunoglobulin heavy chain variable region (IGHV) mutation status plays a critical role in prognosis. IGHV mutation status is typically assessed using Sanger sequencing or NGS. The prognostic significance of the chromosomal abnormalities and mutations described above in CLL is well-established(Gaidano& Rossi, 2017; Hallek et al.,2021).

Multiple studies have shown that del(17p), TP53 mutations, and/or unmutated IGHV status are associated with poor prognosis in CLL. In addition to poor survival outcomes, these factors also carry a high risk of poor response to initial chemoimmunotherapy and earlier relapse after achieving remission(Eichhorst et al.,2021; Mato et al.,2022; Tausch et al.,2020). Currently, treatment guidelines for CLL include prognostic evaluations and treatment planning based on these three mutation statuses(Eichhorst et al.,2021; Eichhorst et al.,2024; Hampel & Parikh,2022)

NOTCH1 mutations have been identified as potential biomarkers of resistance to anti-CD20 monoclonal antibodies, such as rituximab and ofatumumab, in CLL, with further clinical validation needed to confirm their role and assess the efficacy of obinutuzumab in overcoming this resistance(Estenfelder et al., 2016). While other mutations, such as NOTCH1, are being investigated, they are not yet ready for widespread use in clinical practice or treatment decision-making.

In CLL, the use of measurable (previously referred to as ''minimal’’) residual disease (MRD) is still largely limited to clinical trials. MRD is commonly used as a marker of treatment efficacy. Flow cytometry, PCR, and NGS are the primary methods employed to detect MRD. The threshold for MRD detection remains a subject of debate. The current international consensus defines "undetectable" MRD as U-MRD4, though some studies report data at MRD5 or lower levels. Currently, MRD is associated with disease prognosis and is utilized to adjust the duration of treatment. However, it is still unclear whether therapeutic decisions based on MRD will consistently provide clinical benefits or be sufficient to challenge established treatment strategies for CLL(Fisher et al.,2023; Wierda et al.,2021; Yang et al,2021).

Complex karyotype (CK) in CLL is defined by at least three numerical or structural abnormalities in two or more metaphases within the same clone. CK is linked to advanced disease, unmutated IGHV, TP53 mutations, adverse FISH abnormalities, and telomere dysfunction. Even within the CK subgroup, heterogeneity exists in the number and type of aberrations. While CK is a significant prognostic marker, its predictive value and role in treatment remain uncertain. (Chatzikonstantinou et al., 2021). Advances in understanding epigenetics in CLL, including DNA methylation and microRNAs, may lead to targeted therapies(Zhang et al., 2024).

In conclusion, CLL's genetic and epigenetic landscape is complex, with numerous chromosomal abnormalities and molecular mutations playing a critical role in disease progression, prognosis, and treatment outcomes. Ongoing studies into genetic biomarkers and MRD monitoring continue to refine our understanding of the disease, thereby providing the foundation for more individualized and potentially more effective treatment approaches in the future.