Chronic Lymphocytic Leukaemia (CLL)

Overview

• Chronic lymphocytic leukaemia (CLL) is a slowly progressive, indolent lymphoproliferative disorder.
• Characterised by the clonal expansion and accumulation of mature but functionally incompetent B lymphocytes.
• These malignant lymphocytes primarily affect the peripheral blood, bone marrow, spleen, and lymph nodes.
• Small lymphocytic lymphoma (SLL) and CLL are considered different clinical manifestations of the same underlying disease.
  
  
  

Diagnostic Criteria

• Peripheral Blood: Diagnosis of CLL is based on a persistent absolute monoclonal B lymphocytosis of ≥5 × 10⁹/L (≥5000/μL) sustained for at least three months.
• Clonality: Confirmed by flow cytometry, showing a typical immunophenotype (CD5+, CD19+, CD20dim, CD23+, and surface immunoglobulin with kappa or lambda light chain restriction).
• Distinction from SLL: SLL is defined by the presence of clonal B lymphocytes predominantly in lymph nodes (absolute lymphocyte count <5 × 10⁹/L), with minimal or no blood involvement and no disease-related cytopenias.
• Morphology: Peripheral smear typically shows small, mature-appearing lymphocytes with clumped chromatin and indistinct nucleoli; smudge (basket) cells are commonly seen but not pathognomonic.
  
  

Disease Spectrum and Classification

• CLL/SLL Spectrum: The World Health Organization classifies CLL and SLL together within mature B-cell neoplasms.
• Monoclonal B-cell Lymphocytosis (MBL): A precursor state with <5 × 10⁹/L monoclonal B lymphocytes in peripheral blood, absent other features of lymphoproliferative disease. MBL may progress to CLL at a rate of 1–2% per year.
• Immunophenotype: Both CLL and SLL share the same immunophenotypic features on flow cytometry.
• Disease Progression: CLL typically presents with a leukemic phase, while SLL is primarily nodal.
  
  

Genetic Susceptibility

• The precise cause of CLL remains uncertain, but current evidence points strongly to a genetic basis.
• Genome-wide association studies have identified multiple risk loci associated with CLL. Many of these are located near genes involved in apoptosis, supporting a biologically plausible mechanism for disease susceptibility.
• Familial clustering is recognised, with approximately 5% to 10% of cases having a positive family history. The risk of CLL in first-degree relatives is higher than in the general population.
• Monoclonal B-cell lymphocytosis (MBL), which is defined by a persistent absolute monoclonal B-lymphocyte count of less than 5 × 10⁹/L, is considered a precursor state to CLL. Although most with MBL will not progress to CLL, both conditions likely share underlying genetic risk factors.
• Some hereditary factors linked to both CLL and MBL have been described, but truly familial CLL is uncommon.
  
  

Environmental and Occupational Factors

• Environmental exposures have been investigated, but most have not been proven as definitive causes.
• Occupational exposure to certain chemicals (e.g. benzene, solvents), and rubber manufacturing industries has been linked in some reports to a higher incidence of CLL. However, these associations remain unproven and inconsistent across studies.
• Radiation exposure, both ionising and non-ionising, has been explored:
  • Uranium miners have shown a modestly increased risk of CLL, though this is not a consistent finding in all populations.
  • Importantly, atomic bomb survivors have not demonstrated increased rates of CLL, despite an increased incidence of other types of leukaemia.
• Tobacco use is associated with a modestly increased risk of CLL compared to non-tobacco users.
• Exposure to certain herbicides, including Agent Orange during military service, has been officially recognised by some authorities as a potential risk factor for CLL.
  
  

Molecular Pathogenesis

• The development of CLL is considered to be a multistep process involving an accumulation of genetic abnormalities affecting both oncogenes and tumour suppressor genes.
• These genetic changes enhance the survival of B lymphocytes and confer resistance to apoptosis, leading to their progressive accumulation.
  
  

Stepwise Disease Development

• The pathogenesis of CLL/SLL is conceptualised as a two-step process:
  • The first step involves the emergence of monoclonal B-cell lymphocytosis (MBL), attributed to genetic mutations, cytogenetic abnormalities, and chronic antigenic stimulation.
  • The second step involves the transformation of MBL to overt CLL/SLL, usually due to additional genetic changes or alterations in the bone marrow microenvironment. This transition is marked by autonomous, antigen-independent B-cell receptor (BCR) signalling, which drives uncontrolled B-cell proliferation and survival.
    
    

Clonal Expansion and Tissue Distribution

• The malignant clone comprises CD5+ B lymphocytes, which are abnormally activated and evade normal apoptotic signals.
• Clonal B-cell expansion occurs predominantly in lymph nodes, but eventually involves the peripheral blood, spleen, and bone marrow.
• Lymphadenopathy (especially in cervical, supraclavicular, and axillary regions) is common, and as neoplastic cells enter the blood, sustained lymphocytosis becomes evident.
• Infiltration of the spleen and bone marrow can result in splenomegaly, bone marrow hypercellularity, and eventually cytopenias (anaemia and thrombocytopenia).
  
  

Immunological Dysfunction

• CLL cells are functionally abnormal and exhibit impaired antibody production.
• Progressive hypogammaglobulinaemia develops, especially as non-clonal CD5-negative B cells become dysfunctional, resulting in increased susceptibility to recurrent bacterial and viral infections.
• Malignant B cells can also drive the production of autoantibodies by residual normal B cells, predisposing to autoimmune haemolytic anaemia and immune thrombocytopenic purpura.
  
  
  

Genetic and Molecular Abnormalities

• Several gene mutations play a role in disease progression and prognosis, notably TP53, NOTCH1, SF3B1, ATM, and BIRC3.
  • TP53 and NOTCH1 mutations, as well as deletions at chromosome 17p and 11q, are linked to aggressive disease and poor outcomes.
• Cytogenetic abnormalities are highly prevalent:
  • del(13q) (55%): Associated with a favourable prognosis and slower progression.
  • del(11q) (18%) and del(17p) (7%): Linked to rapid progression and adverse prognosis.
  • Trisomy 12 (16%): Intermediate prognosis, often with atypical morphology.
• The most frequent abnormality is deletion of 13q14, leading to loss of miRNA15a and miRNA16-1. These microRNAs regulate Bcl-2, a protein that suppresses apoptosis. Their loss results in Bcl-2 overexpression, conferring survival advantage to malignant B cells.
• Other important molecular markers include mutated immunoglobulin heavy chain variable region (IgHV), ZAP-70 overexpression, and elevated CD38 and CD49d expression. Mutated IgHV confers a more indolent course, whereas unmutated IgHV, ZAP-70, CD38, and CD49d positivity are linked to a poor prognosis and more aggressive disease.
• Over 80% of patients have at least one cytogenetic abnormality detectable by sensitive methods such as FISH, although conventional cytogenetics may be normal in a substantial minority.
  
  

Cellular Phenotype

• CLL B lymphocytes typically display surface markers: CD19, CD20 (dim), CD21, CD23, and the T-cell marker CD5.
• The malignant population is derived from a subset of anergic, self-reactive B cells within the mantle zone of lymphoid follicles, which are devoted to producing polyreactive natural autoantibodies.
• These cells have low surface immunoglobulin (often IgM or IgM/IgD), with monotypic (kappa or lambda) light chain expression.
• A small subset of patients may exhibit a T-cell phenotype, and some display biclonality.
  
  

Clinical Consequences of Pathophysiology

• Cytopenias result from both marrow infiltration and immune-mediated destruction.
• Systemic symptoms such as fevers, night sweats, fatigue, weight loss, and early satiety occur with disease progression.
• Skin manifestations (leukaemia cutis) can include papules, macules, plaques, ulcers, blisters, or nodules, typically involving the face. Nonspecific lesions may occur from vasculitis, bleeding, or infection.
• Exaggerated reactions to insect bites have also been reported in some patients.
  
  

Global and Regional Incidence

• CLL is the most prevalent leukaemia in adults in Western countries, accounting for approximately 25–30% of all leukaemias in the United States.
• In the US, it represents about 1% of all new cancer diagnoses. Recent estimates indicate around 20,700 new cases per year, with about 4,440 related deaths.
• In the UK, approximately 3,952 new cases of CLL are diagnosed annually.
• Worldwide, CLL and small lymphocytic lymphoma (SLL) contribute to an estimated 191,000 new cases and 61,000 deaths each year.
• The incidence of CLL in Western populations (including North America and Europe) is far higher than in Asian (China, Japan), Latin American, or African populations. In Asia, CLL is particularly rare, making up only about 10% of all leukaemias.
• CLL occurs with the greatest frequency among non-Hispanic White populations, with rates substantially lower among Asian and Black individuals. For example, in the US, the age-adjusted annual incidence is 6.3 per 100,000 males and 3.3 per 100,000 females (2017–2021 data).
  
  

Demographic Patterns

• CLL predominantly affects older adults. The median age at diagnosis is about 70 years, with the majority of new diagnoses (approximately 69%) occurring in those aged 65 or older.
• The disease is uncommon in individuals younger than 40 and extremely rare in children.
• A male predominance is consistently observed, with male-to-female ratios ranging from 1.3:1 up to nearly 2:1 in some series.
• Although the incidence is higher in men, several studies suggest women may experience a more aggressive clinical course.

Familial and Genetic Factors

• Familial cases of CLL comprise approximately 5–10% of all diagnoses.
• Individuals with a first-degree relative with CLL have about double the risk compared to the general population.
• Familial CLL tends to present at a younger age, with a median age of 57 years in affected family members.
• Among first-degree relatives of CLL patients, up to 17% may have monoclonal B-cell lymphocytosis (MBL), a precursor state to CLL, although only a minority of these will eventually develop the disease.

Epidemiology in Specific Populations

• The clinical presentation, gender ratio, and age distribution of CLL are generally similar across populations, regardless of geographic region.
• CLL has been found to be more frequent among people of Eastern European Jewish ancestry.
• The true incidence of CLL in some non-Western regions may be underestimated due to underreporting or incomplete cancer registry data.
  
  

Trends in Incidence and Mortality

• The overall incidence of CLL in the US and other Western nations has been relatively stable over recent decades.
• Mortality rates have been declining, reflecting advances in diagnosis and treatment.
• While CLL remains a disease primarily of older adults, improvements in care have led to increased survival.
  
  
  
  

Typical Initial Presentation

• Many patients are asymptomatic at diagnosis, with CLL often discovered incidentally on routine blood tests showing lymphocytosis.
• When symptoms are present, the most common initial complaint is painless, persistent swelling of lymph nodes (lymphadenopathy).
• Up to 80% of cases are identified in the absence of overt clinical symptoms.
  
  

Systemic (B) Symptoms

• A minority of patients (approximately 5–10%) present with B symptoms, which are significant for disease staging and management:
  • Unintentional weight loss (≥10% of body weight over 6 months)
  • Persistent fevers (>38°C for over two weeks, not attributable to infection)
  • Drenching night sweats (not explained by infection)
  • Extreme fatigue
  • Early satiety (often due to splenomegaly)
• B symptoms can also herald transformation to an aggressive lymphoma (Richter syndrome).
  
  
  

Other Common Historical Features

• Recurrent Infections: History of frequent infections (e.g., pneumonia, herpes simplex, herpes zoster), due to immune dysfunction and hypogammaglobulinaemia, especially in advanced or prolonged disease.
• Fatigue and Shortness of Breath: Frequently reported, often due to anaemia or autoimmune haemolytic anaemia, which affects 5–10% of patients.
• Easy Bruising or Mucocutaneous Bleeding: May be described, reflecting underlying thrombocytopenia.
• Early Satiety or Abdominal Discomfort: Associated with splenomegaly, present in a significant proportion of patients.
• Epistaxis and Petechiae: Occur due to thrombocytopenia.
  
  

Predisposing and Risk Factors

• Age: Median age at diagnosis is approximately 70 years, with the majority of cases occurring in individuals over 60.
• Sex: CLL is more common in men than women.
• Ethnicity: White ethnicity, particularly non-Hispanic Whites, have the highest incidence rates.
• Family History: A positive family history increases risk; approximately 5–10% of cases are familial, and first-degree relatives have a higher risk.
• Other Factors: A history of autoimmune conditions or prior malignancy may be relevant, and some patients may have a history suggestive of monoclonal B-cell lymphocytosis preceding CLL diagnosis.
  
  

Transformation and Disease Complications

• Richter Syndrome: Patients may present with sudden, unexplained constitutional symptoms (B symptoms), rapid lymph node enlargement, or new systemic complaints—this indicates possible transformation to a high-grade lymphoma and requires urgent attention.
• Autoimmune Manifestations: Autoimmune cytopenias may present with a history of bruising, pallor, and symptoms attributable to anaemia or thrombocytopenia.

General Considerations

• Many patients with CLL are asymptomatic and may have unremarkable findings on examination at diagnosis, with lymphocytosis typically discovered incidentally.
• Physical signs, when present, often reflect underlying tissue infiltration or complications from cytopenias and immunosuppression.
  
  

Lymphadenopathy

• Localised or generalised lymphadenopathy is present in approximately 50–90% of cases.
• Commonly affected regions include cervical, supraclavicular, and axillary lymph nodes.
• On palpation, lymph nodes tend to be:
  • Firm, round, and non-tender
  • Freely mobile
• Lymphadenopathy is a critical finding for staging and influences management decisions.
  
  

Splenomegaly

• The spleen is typically:
  • Painless and non-tender
  • Smooth, firm surface
• Splenomegaly is often associated with early satiety or abdominal discomfort due to mass effect.

Hepatomegaly

• Hepatomegaly is less common, observed in approximately 14–25% of cases.
• The liver, when enlarged, is:
  • Mildly increased in size (palpable 2–6 cm below the right costal margin)
  • Firm, non-tender, and smooth

Skin Findings

• The skin is the most commonly involved non-lymphoid tissue in CLL.
• Specific lesions (leukaemia cutis) may be seen, especially on the face, and include:
  • Papules, macules, plaques, ulcers, blisters, or nodules
• Secondary cutaneous findings may result from:
  • Bleeding (ecchymoses, petechiae)
  • Vasculitis
  • Infection
• Exaggerated reactions to insect bites may also be observed.
  
  
  

Findings Due to Cytopenias

• Anaemia: Pallor, and in some cases, mild tachycardia or systolic flow murmurs.
• Thrombocytopenia: Petechiae, mucosal bleeding (e.g., epistaxis), or easy bruising may be apparent.
• Neutropenia (less common): Signs of infection, including oral or skin lesions.
  
  

Other Systemic Signs

• Signs associated with disease complications:
  • Recurrent infections: Oral ulcers, pneumonia, or skin infections due to immunosuppression and hypogammaglobulinaemia.
  • Richter Transformation: Rapidly enlarging lymph nodes, new or worsening hepatosplenomegaly, and systemic B symptoms on examination may signal transformation to an aggressive lymphoma.
    
    

Initial Diagnostic Investigations

• Full Blood Count (FBC) with Differential
  • Typically reveals absolute lymphocytosis; a monoclonal B-lymphocyte count of ≥5 × 10⁹/L (≥5000 cells/μL) sustained for at least three months is required for CLL diagnosis.
  • Cytopenias (anaemia, thrombocytopenia) may also be present, which may be due to bone marrow infiltration or autoimmune complications (e.g., autoimmune haemolytic anaemia, immune thrombocytopenic purpura).

• Peripheral Blood Smear
  • Confirms lymphocytosis and shows small, mature lymphocytes with dense chromatin and scant cytoplasm.
  • Smudge cells (damaged lymphocytes) are a classic but non-specific finding; their presence in higher numbers may be associated with a less aggressive disease course.
  • Additional findings may include spherocytes or polychromasia in cases of active haemolysis.
    
    
• Flow Cytometry
  • Essential for confirming clonality and defining the typical CLL immunophenotype (CD5+, CD19+, CD20^dim, CD23+, surface immunoglobulin dim+, light chain restriction).
  • Flow cytometry can also identify prognostic markers such as ZAP-70, CD38, and CD49d, with their presence indicating a poorer prognosis.
    
    

Investigations for Prognosis and Disease Stratification

• Serum Beta-2 Microglobulin
  • Included in the CLL International Prognostic Index (CLL-IPI); elevated levels are associated with a poorer prognosis.

• Cytogenetic and Molecular Genetic Testing
  • Fluorescence In Situ Hybridisation (FISH):
    • Detects cytogenetic abnormalities (del(13q), del(11q), trisomy 12, del(17p)), which inform prognosis and treatment.
    • del(17p) and del(11q) are linked with a more aggressive clinical course and resistance to certain therapies.
  • Molecular Genetic Tests:
    • Identify TP53 and immunoglobulin heavy chain (IgHV) mutation status.
    • TP53 mutations are associated with poor prognosis and resistance to chemoimmunotherapy.
    • Mutated IgHV generally indicates a better prognosis and response to treatment.
    • Additional gene mutations (e.g., NOTCH1, SF3B1, ATM, BIRC3) may also be detected, but their direct role in treatment selection is evolving.
  • MicroRNA Analysis:
    • Remains investigational but has potential to provide additional prognostic information (e.g., decreased miR-181b correlates with progressive disease).
      
      

Other Laboratory and Ancillary Investigations

• Serum Quantitative Immunoglobulin
  • Ordered if there is a history of recurrent infections; hypogammaglobulinaemia is common and predisposes to infection.
    
    
• Direct Antiglobulin Test (DAT)
  • Performed in cases of anaemia to identify autoimmune haemolytic anaemia.
    
    

Imaging and Tissue-Based Investigations

• Bone Marrow Aspiration and Biopsy
  • Not required for diagnosis in most cases but may be indicated if cytopenias are unexplained or if marrow status needs to be clarified before therapy.
  • Helps differentiate marrow infiltration from other causes of cytopenia.
    
    
• Lymph Node Biopsy
  • Indicated if there is suspicion of SLL (lymphadenopathy with <5 × 10⁹/L circulating B-lymphocytes), or if rapid lymph node enlargement suggests transformation (e.g., Richter syndrome).
  • Core needle or fine-needle aspiration may be supportive but excisional biopsy is preferred for diagnosis.
    
    
• Imaging (CT or PET/CT)
  • Not routinely needed for diagnosis or staging.
  • CT may be used to evaluate bulky disease, suspected organ compromise, or to assess risk for tumour lysis syndrome before starting targeted therapy.
  • PET/CT may be indicated if Richter transformation is suspected, guiding biopsy of metabolically active nodes.
    
    

Staging Systems and Prognostic Indices

• Modified Rai and Binet Staging Systems
  • Rai system stratifies patients into low, intermediate, and high-risk groups based on lymphocytosis, lymphadenopathy, hepatosplenomegaly, anaemia, and thrombocytopenia.
  • Binet staging uses the number of involved lymph node groups and the presence of anaemia/thrombocytopenia.
    
    
• International Prognostic Index for CLL (CLL-IPI)
  • Incorporates age, clinical stage, serum beta-2 microglobulin, IgHV mutation status, and TP53/17p status.
  • Defines risk categories that inform prognosis and guide treatment decisions.
    
    
    
    

Overview

• The presence of absolute lymphocytosis in adults warrants evaluation for both reactive (non-neoplastic) and clonal (neoplastic) causes.
• Diagnosis of CLL is confirmed with sustained lymphocytosis (>3 months) and the typical immunophenotype on flow cytometry. Other causes must be excluded by careful clinical and laboratory assessment.
  
  

Key Non-Neoplastic Causes of Lymphocytosis

• Viral and Other Infections:
  • Infectious mononucleosis, pertussis, toxoplasmosis, and other acute infections can cause transient lymphocytosis.
  • Reactive lymphocytosis is not clonal, usually resolves within weeks, and may feature atypical (activated) lymphocytes rather than the mature, small lymphocytes of CLL.
  • These infections typically do not infiltrate the bone marrow, and the immunophenotype differs from that of CLL.
    
    
• Monoclonal B-Cell Lymphocytosis (MBL):
  • Defined by a persistent clonal B-lymphocyte count <5 × 10⁹/L, without lymphadenopathy, organomegaly, or cytopenias.
  • MBL is considered a precursor state to CLL but does not fulfil diagnostic criteria for CLL in the absence of other disease manifestations.
    
    

Other Clonal Lymphoproliferative Disorders

• Prolymphocytic Leukaemia (PLL):
  • Characterised by more than 55% prolymphocytes in peripheral blood, which are larger, with more immature-appearing chromatin and prominent nucleoli compared to CLL cells.
  • PLL cells typically express "bright" surface immunoglobulin and lack CD5, in contrast to CLL’s "dim" SmIg and CD5 positivity.
    
    
• Mantle Cell Lymphoma (MCL):
  • Can mimic CLL in its leukemic phase, also coexpressing CD5 and CD20.
  • MCL cells usually stain strongly for cyclin D1, are negative for CD23, and exhibit a t(11;14) chromosomal abnormality, features not seen in typical CLL.
    
    
• Lymphoplasmacytic Lymphoma (LPL):
  • May be CD5 positive in a minority, but typically features a prominent monoclonal IgM paraprotein spike (>0.5 g/dL) and plasma cell differentiation.
  • The MYD88 L265P mutation is commonly seen in LPL but rare in CLL.
  • Peripheral blood involvement is less prominent and proliferation centres are absent.
    
    
• Hairy Cell Leukaemia (HCL) and Variant (HCL-v):
  • HCL presents with splenomegaly and cytopenias, less frequently with lymphocytosis.
  • Hairy cells have distinct cytoplasmic projections, are CD25+, CD11c+, annexin A1+, CD103+, and usually lack CD5.
  • Variant forms may show lymphocytosis and more immunophenotypic heterogeneity.
    
    
• Follicular Lymphoma (FL):
  • May present with painless peripheral adenopathy and, less commonly, with leukemic disease.
  • FL is CD10+ and usually lacks CD5, and is associated with t(14;18) translocation.
  • FL displays a nodular pattern on lymph node biopsy, in contrast to the diffuse proliferation centres of CLL/SLL.
    
    
• Splenic Marginal Zone Lymphoma (SMZL):
  • Can present with splenomegaly and lymphocytosis, but usually lacks the cytogenetic changes of CLL and has different immunophenotypic features (often bright SmIg and CD20).
    
    
• Large Granular Lymphocytic Leukaemia:
  • Typically expresses NK or T-cell markers (CD2, CD3, CD8, CD16, CD56) rather than B-cell markers.
    
    
• Other B-Cell and T-Cell Neoplasms:
  • Acute lymphoblastic leukaemia, lymphoblastic lymphoma, and diffuse large B-cell lymphoma may be considered in cases with atypical features or aggressive presentation.
    
    

Distinguishing CLL from Other Entities

• Immunophenotyping (Flow Cytometry):
  • The CLL immunophenotype is essential for diagnosis and distinguishes it from other entities.
  • CLL is characteristically CD5+, CD19+, CD20(dim), CD23+, with restricted light chain expression and dim surface immunoglobulin.
    
    
• Morphology and Tissue Biopsy:
  • CLL/SLL features proliferation centres in lymph nodes, which are absent in other small B-cell lymphomas.
  • Biopsy may be required in difficult cases or to assess for transformation.
    
    

Histological Transformation (Richter Syndrome)

• CLL/SLL may transform into a more aggressive lymphoma, most often diffuse large B-cell lymphoma or, less commonly, Hodgkin lymphoma.
• Transformation should be suspected with rapidly enlarging lymph nodes, new B symptoms, or changes in clinical behaviour.
  
  

Summary Table: Important Differential Diagnoses

• Infectious mononucleosis and other infections (transient, reactive lymphocytosis)
• Monoclonal B-cell lymphocytosis (MBL)
• Prolymphocytic leukaemia (PLL)
• Mantle cell lymphoma (MCL)
• Lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinaemia
• Hairy cell leukaemia (HCL, HCL-v)
• Follicular lymphoma (FL)
• Splenic marginal zone lymphoma (SMZL)
• Large granular lymphocytic leukaemia
• Acute lymphoblastic leukaemia (ALL) and other acute leukaemias
• Non-Hodgkin lymphomas
• Richter transformation (histologic transformation of CLL/SLL)
  
  

General Principles

• CLL is considered incurable with current therapies. Management aims to improve quality of life and prolong survival.
• Treatment strategy is individualised and depends on disease stage, presence of symptoms, patient age and fitness, and specific genetic features such as del(17p), TP53 mutation, or IgHV mutation status.
  
  
  

Initial Assessment and Indications for Treatment

• Not all patients with CLL require immediate therapy. Many are managed with active surveillance (“watch and wait”), especially those with early-stage, asymptomatic disease.

• Indications for starting treatment:
  • Symptomatic disease (severe fatigue, night sweats, fever without infection, significant weight loss)
  • Threatened organ function
  • Bulky or progressive disease (spleen >6 cm below costal margin, lymph nodes >10 cm)
  • Rapidly increasing lymphocyte count (≥50% rise in 2 months, or lymphocyte doubling time <6 months)
  • Progressive cytopenias (anaemia or thrombocytopenia)
  • Refractory autoimmune cytopenias (e.g., autoimmune haemolytic anaemia not responding to steroids)
  • Symptomatic or functional extranodal involvement
    
    

Active Surveillance

• Asymptomatic patients with early-stage CLL are closely monitored.
• Routine physical examinations and full blood counts are performed monthly for three months, then every three months to track disease progression.
  
  
  

Therapeutic Options Based on Genetic and Clinical Factors

• First-line targeted therapies:
  • Covalent BTK inhibitor-based regimens (e.g., acalabrutinib, zanubrutinib, or ibrutinib ± obinutuzumab or rituximab)
  • Time-limited BCL2 inhibitor regimens (e.g., venetoclax plus obinutuzumab or acalabrutinib ± obinutuzumab, or venetoclax plus ibrutinib)
• Chemoimmunotherapy:
  • Considered in select younger, fit patients with favourable genetics (e.g., IgHV-mutated, no del(17p) or TP53 mutation); options include FCR (fludarabine, cyclophosphamide, rituximab) or bendamustine plus anti-CD20 monoclonal antibody.
    
    

• Chemoimmunotherapy is not recommended due to poor response and short progression-free survival.
• First-line regimens:
  • Covalent BTK inhibitor-based regimen (acalabrutinib, zanubrutinib, ibrutinib)
  • Time-limited BCL2 inhibitor regimen (venetoclax plus obinutuzumab, venetoclax plus acalabrutinib ± obinutuzumab, or venetoclax plus ibrutinib)
  • High-dose methylprednisolone with rituximab or obinutuzumab may be considered in select cases.
    
    

Relapsed or Refractory Disease

• Treatment is individualised based on previous therapies, remission duration, fitness, and mutational status.
• Options may include:
  • Switching between BTK and BCL2 inhibitors
  • Non-covalent BTK inhibitors (e.g., pirtobrutinib)
  • PI3K inhibitors (e.g., duvelisib, idelalisib ± rituximab)
  • CAR T-cell therapy (e.g., lisocabtagene maraleucel)
  • Lenalidomide (with or without rituximab)
  • High-dose methylprednisolone plus rituximab or obinutuzumab
  • Alemtuzumab (with or without rituximab) for del(17p) or TP53 mutation
  • Allogeneic stem cell transplant for select fit patients
• Clinical trial enrolment is encouraged, especially for those with poor prognosis or refractory disease.
  
  

Supportive and Monitoring Measures

• Patients with recurrent infections may benefit from immunoglobulin replacement if hypogammaglobulinaemia is present.
• Patients should be screened for hepatitis B and C, and vaccination status should be reviewed and updated.
• Regular monitoring for secondary malignancies (e.g., skin cancer) and cardiovascular risk factors, particularly for those on BTK inhibitors.
  
  
  

Toxicity and Complications

• Tumour lysis syndrome (TLS): Increased risk with venetoclax and other potent regimens, requiring prophylactic measures and monitoring.
• Cardiovascular complications: Ibrutinib and other BTK inhibitors are associated with increased risk of hypertension, cardiac arrhythmias, and heart failure.
• PI3K inhibitors: Associated with significant toxicity, including hepatotoxicity, diarrhoea, pneumonitis, infections, and risk of intestinal perforation.
• CAR T-cell therapy: May cause cytokine release syndrome (CRS), neurotoxicity, and T-cell malignancies.
• Lenalidomide: Associated with tumour flare reaction and venous thromboembolism.
  
  
  
  

Survival Trends

• The prognosis of CLL has improved substantially in recent years, largely due to the introduction of targeted therapies.
• Surveillance, Epidemiology, and End Results (SEER) Program data (2000–2020) indicate the following relative survival rates for all stages:
  • 2-year survival: 92.4%
  • 5-year survival: 84.8%
  • 10-year survival: 71.8%
• Median survival is around 10 years, but outcomes are highly variable, ranging from 2 to over 20 years depending on disease biology and patient factors.
  
  

Key Prognostic Factors

• Clinical Stage at Diagnosis:
  • Patients diagnosed with early-stage disease (Rai stage 0–II or Binet stage A–B) may remain treatment-free for years and often have a prolonged survival (5–20 years).
• Lymphocyte Doubling Time:
  • Rapid lymphocyte doubling time (<12 months) is associated with a more aggressive disease course and poorer prognosis.
• Genetic and Molecular Markers:
  • Favourable Prognostic Indicators:
    • Mutated immunoglobulin heavy chain variable region (IgHV)
    • Deletion of chromosome 13q
    • Low expression of ZAP-70 and CD38 on flow cytometry
  • Unfavourable Prognostic Indicators:
    • Deletion of chromosome 17p (del(17p)) or TP53 mutation
    • Deletion of chromosome 11q (del(11q))
    • Presence of extensive lymphadenopathy, hepatosplenomegaly, anaemia, and thrombocytopenia
      
      

Impact of Targeted Therapy

• The use of agents such as Bruton's tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib, zanubrutinib), BCL2 inhibitors (venetoclax), and PI3K inhibitors (duvelisib, idelalisib) has markedly improved the outlook for high-risk patients, particularly those with del(17p), TP53 mutation, or relapsed/refractory disease.
• Survival among patients with traditionally poor prognosis may now exceed eight years with modern targeted regimens.
  
  

Prognostic Scoring Systems

• The International Prognostic Index for Chronic Lymphocytic Leukaemia (CLL-IPI) combines five independent prognostic variables:
  • Age
  • Clinical stage (Rai or Binet)
  • Serum beta-2 microglobulin level
  • Immunoglobulin heavy chain variable region (IgHV) mutational status
  • 17p deletion (by FISH) and/or TP53 mutation
• The CLL-IPI helps stratify patients into risk groups and inform management decisions.
  
  
  
  

Infectious Complications

• Increased Susceptibility to Infection:
  • Patients are prone to recurrent, often severe infections, especially of the respiratory tract.
  • Hypogammaglobulinaemia is frequent due to dysfunctional B lymphocytes, leading to deficiency of IgG, IgA, and/or IgM.
  • Intravenous immunoglobulin (IVIG) is recommended for those with IgG <5 g/L and recurrent infections.
    
    
• Chemotherapy-Induced Neutropenic Fever:
  • Myelosuppressive therapies, such as fludarabine-based chemoimmunotherapy, reduce neutrophil counts, predisposing to bacterial and fungal infections.
  • Prophylactic antibiotics and granulocyte colony-stimulating factor may be indicated in selected patients.
    
    
• Cytomegalovirus (CMV) Reactivation:
  • High risk with agents such as fludarabine, PI3K inhibitors (duvelisib, idelalisib), or alemtuzumab.
  • CMV monitoring and, if necessary, prophylactic or pre-emptive antiviral therapy are advised.
    
    
    

Autoimmune Cytopenias

• Autoimmune Haemolytic Anaemia (AIHA):
  • Occurs in 5–10% of patients.
  • Diagnosis supported by a positive direct antiglobulin (Coombs) test.
  • Treated with corticosteroids or other immunosuppressants.
    
    
• Immune Thrombocytopenic Purpura (ITP):
  • Occurs in 1–5% of cases.
  • Presents as easy bruising, mucosal bleeding, or petechiae.
  • Managed similarly to AIHA.
    
    
    

Treatment-Related Toxicities

• Tumour Lysis Syndrome (TLS):
  • An oncological emergency, particularly with potent therapies such as venetoclax, obinutuzumab, rituximab, lenalidomide, or chemoimmunotherapy.
  • Risk is increased with high tumour burden, renal dysfunction, or rapid cell kill.
  • Prophylactic measures include aggressive hydration, antihyperuricaemics, and close biochemical monitoring during dose titration and initiation of therapy.
    
    
• Interstitial Lung Disease:
  • Rare complication of fludarabine, presenting as cough, dyspnoea, and infiltrates.
  • Responds to drug withdrawal and corticosteroids.
    
    
• Bruton’s Tyrosine Kinase (BTK) Inhibitor Cardiotoxicity:
  • Ibrutinib, and to a lesser extent acalabrutinib or zanubrutinib, are associated with an increased risk of hypertension, atrial fibrillation, other cardiac arrhythmias, and heart failure.
  • Cardiac evaluation and monitoring are recommended, especially in patients with cardiac risk factors.
    
    

Secondary Malignancies

• Increased Risk of Second Cancers:
  • CLL patients have a higher incidence of secondary solid tumours (skin, lung, gastrointestinal, breast, prostate) and haematological malignancies (e.g., myelodysplastic syndrome, acute myeloid leukaemia after FCR therapy).
  • Chimeric antigen receptor (CAR) T-cell therapy may rarely cause T-cell malignancies.
    
    
    

Richter Transformation

• Histologic Transformation:
  • Up to 15% of CLL cases may transform into a high-grade non-Hodgkin lymphoma (Richter syndrome), most commonly diffuse large B-cell lymphoma.
  • Presents with rapid clinical deterioration: new or worsening B symptoms, rapidly progressive lymphadenopathy, and elevated serum lactate dehydrogenase.
  • Diagnosis confirmed by PET/CT-guided lymph node biopsy and histopathological review.
  • Prognosis is generally poor.
    
    
    

Other Complications

• Graft-versus-Host Disease (GVHD):
  • A potential complication following allogeneic haematopoietic stem cell transplantation.
  • Managed with systemic corticosteroids and immunosuppressants.
    
    
• Tumour Flare Reaction:
  • Lenalidomide may trigger acute, painful lymph node swelling, usually managed by temporary withdrawal or dose reduction.
    
    
• Chemotherapy-Related Toxicities:
  • Includes myelosuppression, mucositis, and organ toxicities (e.g., hepatotoxicity with PI3K inhibitors).
    
    
• Long-Term Immunosuppression:
  • CLL and its treatment impair both humoral and cellular immunity, predisposing to persistent viral, bacterial, and opportunistic infections.
    
    
    

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