From the Guidelines
The exact cause of chronic lymphocytic leukemia (CLL) remains largely unknown, though it involves genetic mutations in the DNA of blood-producing cells that cause them to produce abnormal, ineffective lymphocytes that continue to live and multiply when normal cells would die. While most cases of CLL have no clear cause, certain risk factors have been identified. Environmental factors potentially linked to CLL include exposure to certain herbicides and insecticides, particularly Agent Orange used during the Vietnam War 1. Chemical exposures associated with increased risk include benzene, certain agricultural chemicals, and some industrial solvents. Radiation exposure may also play a role in some cases. However, unlike some other cancers, CLL has fewer established environmental triggers. Family history represents a significant risk factor, with first-degree relatives of CLL patients having a 7-8 times higher risk of developing the disease, suggesting genetic predisposition plays an important role. Age is another major risk factor, with most diagnoses occurring in people over 60. CLL is more common in men than women and occurs more frequently in North America and Europe than in Asia, suggesting both genetic and environmental influences on disease development. Some key points to consider in the diagnosis and management of CLL include:
- The diagnosis of CLL is established by sustained increase of peripheral blood lymphocytes, predominance of small, morphologically mature lymphocytes in the blood smear, and specific immunophenotyping characteristics 1.
- The detection of cytogenetic abnormalities by fluorescent in situ hybridization (FISH) has apparent prognostic value and should be carried out during the initial evaluation of a patient with CLL 1.
- Newer prognostic parameters such as the expression of CD38, ZAP70, and the immunoglobulin mutational status (IgVH mutation) may predict the time to progression from an early stage to advanced disease 1. The most recent and highest quality study, published in 2019, highlights the importance of understanding the molecular characteristics of CLL, including unmutated immunoglobulin heavy-chain variable (IGHV) status, stereotyped B-cell receptor subset 8 combined with VH4-39 use, cytogenetic abnormalities, and genetic abnormalities, in order to better manage the disease and prevent complications such as Richter’s transformation 1.
From the Research
Causes of Chronic Lymphocytic Leukemia (CLL)
- The etiology of CLL is unknown 2
- Leukemic transformation is initiated by specific genomic alterations that interfere with the regulation of proliferation and of apoptosis in clonal B-cells 3
- Leukemic transformation is initiated by specific genomic alterations that impair apoptosis of clonal B-cells 4
Environmental Risk Factors of CLL
- There is no mention of specific environmental risk factors in the provided studies
- However, it is known that CLL typically occurs in elderly patients and has a highly variable clinical course 2, 3, 4
Genetic Risk Factors of CLL
- Deletions of the short arm of chromosome 17 (del[17p]) and/or mutations of the TP53 gene predict resistance to chemoimmunotherapy and a shorter time to progression with most targeted therapies 3, 4
- The CLL international prognostic index integrates genetic, biological, and clinical variables to identify distinct risk groups of patients with CLL 3
- V(H) mutational status and associated ZAP-70 overexpression, disrupted p53 function, and chromosomal aberrations have led to the ability to identify patients at high risk for early disease progression and inferior survival 5