Etiology

The exact cause of CLL is unclear, but it is thought to develop as a result of an accumulation of multiple genetic events affecting oncogenes and tumor suppressor genes, which leads to increased cell survival and resistance to apoptosis.[10]

Monoclonal B-cell lymphocytosis (MBL; an absolute monoclonal B-lymphocyte count <5000 cells/microliter [<5 × 10⁹/L] that persists more than 3 months) is a precursor to CLL.[11][12]​ The majority of individuals with MBL will not, however, develop a malignancy.[13][14]

Hereditary factors may contribute. Approximately 5% to 10% of cases are familial.[15][16]​ MBL and CLL likely share genetic risk factors.[17][18][19]

Pathophysiology

CLL is a lymphoid malignancy characterized by the proliferation and accumulation of mature monoclonal B cells in the lymphatic system and hematopoietic organs (e.g., liver, spleen, bone marrow). As a result, CLL can present with lymphadenopathy, hepatosplenomegaly, and bone marrow suppression. In small lymphocytic lymphoma (SLL), the CLL cells are found predominantly in lymph nodes.

Recurrent infections can occur because CLL cells are immunologically dysfunctional. With increasing duration of disease, many patients will develop hypogammaglobulinemia due to defective functioning of nonclonal CD5-negative B-cells.[20]

CLL cells may be involved in initiating autoantibody production by normal B cells, leading to autoimmune complications (e.g., autoimmune hemolytic anemia, immune thrombocytopenic purpura).[21]

Genetic abnormalities and molecular markers

Gene mutations of potential clinical relevance include TP53, NOTCH1, SF3B1, ATM, and BIRC3.[22] TP53 or NOTCH1 gene mutations are associated with a poor prognosis.[23][24]​ 

Cytogenetic abnormalities identified in CLL include del(13q) (55%), del(11q) (18%), trisomy 12 (16%), and del(17p) (7%).[25] Del(13q) is associated with a favorable prognosis.[25] Del(11q) and del(17p) are associated with rapid disease progression and a poor prognosis.[25] Trisomy 12 is associated with an intermediate prognosis (i.e., worse than del(13q) but better than del(11q) and del(17p)).[25]

Important molecular markers identified in CLL include mutated immunoglobulin heavy chain (IgHV), zeta-associated protein (ZAP-70), and expression of CD38 or CD49d. The presence of mutated IgHV gene is associated with slower disease progression and better prognosis.[26][27]​ ZAP-70 is a tyrosine kinase that is essential for T-cell receptor signaling, but is not found in normal B cells. Overexpression of ZAP-70 has been found to correlate with the presence of unmutated IgHV and worse prognosis.[28] CD38 expression correlates with the presence of unmutated IgHV and denotes a poor-risk group.[29] CD49d expression is also a strong predictor for a poor prognosis.[30]

Classification

The 5th edition of the World Health Organization (WHO) classification of haematolymphoid tumours: lymphoid neoplasms[1]

The WHO classifies CLL and small lymphocytic lymphoma (SLL) as the same disease entity, under the group "mature B-cell neoplasms: preneoplastic and neoplastic small lymphocytic proliferations."

The group also includes the disease entity monoclonal B-cell lymphocytosis (MBL), a premalignant condition that precedes CLL/SLL. The WHO recognizes three subtypes of MBL.

  • Low-count MBL or clonal B-cell expansion: clonal CLL/SLL-phenotype B-cell count <500 cells/microliter (<0.5 × 10⁹/L) with no other features diagnostic of B-lymphoproliferative disorder. The arbitrary threshold is based on the distribution of clonal B-cell counts in population studies compared with clinical cohorts.

  • CLL/SLL-type MBL: monoclonal CLL/SLL-phenotype B-cell count ≥500 cells/microliter (≥0.5 × 10⁹/L) and <5000 cells/microliter (<5 × 10⁹/L) with no other features diagnostic of CLL/SLL. The threshold of <5000 cells/microliter (<5 × 10⁹/L) is arbitrary but identifies a group with a very low likelihood of requiring treatment compared with individuals with B-cell counts between 5000 cells/microliter (5 × 10⁹/L) and 10,000 cells/microliter (10 × 10⁹/L).

  • Non-CLL/SLL-type MBL: any monoclonal non-CLL/SLL phenotype B-cell expansion with no symptoms or features diagnostic of another mature B-cell neoplasm. The majority of cases have features consistent with a marginal zone origin.

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