• CLL is the most common leukaemia in adults in the Western world ^[1][2][5][6]
• Much less common in Chinese / East Asian populations ^[1][2][5][6] — this is a crucial point for Hong Kong exams. The incidence in Hong Kong is significantly lower than in Western countries.
• The reason for this ethnic disparity is not fully understood but is believed to be largely genetic rather than environmental, as ethnic Chinese living in Western countries still have lower rates.

• Disease primarily of the older adults ^[2][5]
• Median age at diagnosis ≈ 70 years ^[2][5]
• NEVER occurs in childhood — this is a classic exam pearl ^[2]
• Male > Female (ratio approximately 1.3–1.7:1) ^[5]
• The incidence increases steeply with age — roughly 30 per 100,000 in those aged > 80 years in Western populations.

Given the low incidence of CLL in Hong Kong's Chinese population, when CLL does present, it often presents at a later stage or is found incidentally. Other chronic lymphoproliferative disorders (e.g., marginal zone lymphoma, extranodal NK/T cell lymphoma) are relatively more prevalent in Hong Kong.

1. Bone marrow: Haematopoietic stem cell → common lymphoid progenitor → pre-B cell → immature B cell (expresses surface IgM)
2. Peripheral lymphoid organs: Immature B cell migrates to lymph nodes/spleen → encounters antigen in germinal centres → undergoes somatic hypermutation and class-switch recombination → becomes memory B cell or plasma cell
3. Key anatomical sites: Bone marrow, lymph nodes, spleen (white pulp), liver, peripheral blood

CLL cells are derived from post-germinal centre lymphocytes (exact cell origin debated) ^[3]:

• They express surface markers of mature B cells (CD19+, CD20+ dim, surface immunoglobulin/sIg+ dim)
• They aberrantly co-express CD5 (normally a T-cell marker — this is a key diagnostic feature) and CD23
• Two subtypes based on immunoglobulin heavy chain variable region (IGHV) mutational status:
  • IGHV mutated (~60%): Cells have passed through the germinal centre → better prognosis
  • IGHV unmutated (~40%): Cells may have bypassed the germinal centre or are pre-germinal centre → worse prognosis

Mature B cells normally produce antibodies, participate in antigen presentation, and contribute to immunological memory. In CLL, these cells are functionally incompetent — they cannot mount effective immune responses, leading to hypogammaglobulinaemia and increased susceptibility to infection (a major cause of morbidity and mortality).

• Lymph nodes: CLL cells infiltrate and expand the paracortical and interfollicular areas, causing painless lymphadenopathy
• Spleen: CLL cells accumulate in the white pulp → splenomegaly
• Liver: Portal tract infiltration → hepatomegaly
• Bone marrow: Diffuse or nodular infiltration → cytopenias (anaemia, thrombocytopenia, neutropenia)

These are not "causes" per se but are acquired somatic mutations found in CLL cells that drive disease behaviour. They are important for prognostication ^[1]:

CLL consists of clonal B cells arrested in some stage between pre-B and mature B cells with arrested apoptotic mechanisms → accumulation in blood and lymphoid tissues ^[5].

The key pathogenic mechanisms are:

1. Impaired apoptosis (NOT primarily increased proliferation)

   • CLL cells have a very low proliferative rate (unlike acute leukaemias)
   • The problem is that they don't die — they have defective apoptotic pathways
   • BCL-2 overexpression is central: BCL-2 ("B-Cell Lymphoma 2") is an anti-apoptotic protein. CLL cells overexpress BCL-2 → resist programmed cell death → progressive accumulation
   • This is why venetoclax (BCL-2 inhibitor) is so effective — it directly targets this mechanism ^[6][4]

2. Uncontrolled proliferation (modest but persistent)

   • B-cell receptor (BCR) signalling is constitutively active in CLL cells
   • BCR signals through Bruton's tyrosine kinase (BTK) → downstream activation of NF-κB, PI3K/AKT, and MAPK pathways → promotes survival and proliferation
   • This is why ibrutinib/acalabrutinib (BTK inhibitors) and idelalisib (PI3K inhibitor) work ^[6][4]

3. Microenvironment dependence

   • CLL cells in isolation (in blood) undergo apoptosis quickly
   • They depend on signals from the tumour microenvironment (lymph nodes, bone marrow) including:
     • Nurse-like cells, T cells, stromal cells
     • Cytokines (BAFF, APRIL, IL-4, IL-21)
     • Chemokine receptors (CXCR4, CXCR5) that home cells to lymphoid tissues
   • BTK inhibitors disrupt this microenvironmental homing → CLL cells spill into blood (causing transient lymphocytosis at treatment initiation — don't panic, this is expected)

CLL is fundamentally a disease of immune failure. The CLL cells themselves are functionally incompetent — they cannot produce effective antibodies. Additionally:

1. Hypogammaglobulinaemia (in ~25% at diagnosis, increasing to ~60% over time)

   • Due to functional B-cell deficiency and suppression of normal B cells
   • Results in recurrent sinopulmonary infections (encapsulated organisms: Streptococcus pneumoniae, Haemophilus influenzae)

2. T-cell dysfunction

   • CLL cells suppress normal T-cell function via immune checkpoint interactions
   • Contributes to increased risk of opportunistic infections (especially with treatment)

3. Autoimmune phenomena — very characteristic of CLL:

   • Autoimmune haemolytic anaemia (AIHA) — most common autoimmune complication (~5–10%)
   • Immune thrombocytopenia (ITP) ^[2]
   • Pure red cell aplasia (PRCA) — rare
   • Autoimmune neutropenia — rare
   • Mechanism: Dysregulated immune surveillance by CLL cells leads to loss of self-tolerance

CLL may transform to aggressive large cell lymphoma — this is called Richter transformation ^[1][4][6]:

• Most commonly transforms into diffuse large B-cell lymphoma (DLBCL) (~90%)
• Less commonly into Hodgkin lymphoma (~10%)
• Occurs in ~2–10% of CLL patients
• Suspect when there is sudden clinical deterioration: rapidly enlarging lymph nodes, rising LDH, new B symptoms, discordant PET avidity
• Prognosis is very poor (median survival ~6–12 months)
• Requires treatment as per DLBCL (R-CHOP or similar)

CLL/SLL is classified under mature B-cell neoplasms in the WHO classification of haematolymphoid tumours.

As noted above ^[3]:

• CLL and SLL are the same disease entity — CLL when the leukaemic phase predominates, SLL when the tissue phase predominates
• Both share the same immunophenotype: CD5+, CD19+, CD20+(dim), CD23+, sIg+(dim)

CLL is very indolent in nature ^[5]. Most patients are asymptomatic at diagnosis — the disease is often an incidental finding of lymphocytosis on a routine blood test ^[1][4][6].

The classic presentation of CLL: an older patient (> 60 years) with an incidental finding of lymphocytosis, along with constitutional symptoms: fatigue, weight loss, lymphadenopathy, hepatosplenomegaly ^[4][6]

Diagnosis of CLL requires BOTH of the following ^[2]:

Criterion 1: Absolute B-lymphocyte count in peripheral blood ≥ 5 × 10⁹/L with a preponderant population of morphologically mature-appearing small lymphocytes ^[2]

Criterion 2: Evidence of clonality of circulating B lymphocytes by flow cytometry of peripheral blood with majority of population expressing the following pattern of monoclonal B-cell markers ^[2]:

• Expression of B-cell associated antigens (CD19, CD20, CD23)
• Expression of T-cell associated antigen (CD5)
• Extremely low levels of surface membrane immunoglobulin (SmIg) and either κ or λ but not both light chains

Let me explain each criterion from first principles:

Why ≥ 5 × 10⁹/L? This threshold separates CLL from its precursor condition, monoclonal B-cell lymphocytosis (MBL). Below this count, even with the right immunophenotype, the disease burden is insufficient to be called leukaemia — the patient has MBL and may never progress ^[2][5].

Why "mature-appearing small lymphocytes"? This distinguishes CLL from acute lymphoblastic leukaemia (which has blasts — immature cells with fine chromatin and nucleoli). CLL cells have condensed chromatin and no nucleoli — they look "mature" ^[13].

Why light chain restriction (κ OR λ, not both)? Normal B cells are polyclonal — a mixture of κ- and λ-expressing cells. A monoclonal population expresses only one type, proving they are all derived from a single neoplastic clone. This is the hallmark of clonality ^[2][5][14].

CLL and SLL are the same disease entity with different clinical presentations. The diagnostic distinction is:

CBC D/C: leukocytosis with ↑ lymphocytes ± anaemia ± thrombocytopenia ^[1]

PBS (diagnostic): smear cells / smudge cells (fragile lymphocytes damaged during slide preparation) ^[1][4]

Detailed PBS findings in CLL ^[13]:

Why are smudge cells formed? CLL lymphocytes have abnormal cytoskeletal structure (reduced vimentin intermediate filaments) → fragile cell membranes → they burst easily when the blood film is prepared by dragging the spreader slide across. This mechanical vulnerability is essentially unique to CLL cells among haematological malignancies.

This is the single most important investigation for CLL diagnosis. It is performed on peripheral blood (no need for BM).

PB flow cytometry: CD5+, CD19+, CD20+, CD23+, sIg+ ^[1]

Flow cytometry in CLL shows monoclonal Ig expression, reduced cellular surface Ig and CD5+, CD19+, CD20+, CD23+ expression ^[5]

Matutes/Moreau Scoring System (CLL Immunophenotypic Score)

A scoring system used to confirm CLL immunophenotype:

• Score 4–5: Classic CLL
• Score 3: Atypical CLL (consider other LPDs)
• Score 0–2: NOT CLL (investigate for other LPDs)

BM biopsy: NOT required for diagnosis of CLL, but useful in monitoring treatment response ^[1][2][5]

When performed, findings include:

• Normal or hypercellularity ^[2]
• Presence of lymphocytes for > 30% of all nucleated cells with increased percentage of mature-appearing lymphocytes ^[2]
• Pattern of infiltration informs prognosis ^[5]:
  • Diffuse pattern → associated with progressive course
  • Non-diffuse (interstitial, nodular) → associated with more indolent course ^[5]

When would you actually do a BM biopsy in CLL?

• Unexplained cytopenias (to distinguish BM infiltration from autoimmune destruction or other causes)
• Before treatment (baseline assessment) in some protocols
• To assess treatment response / MRD
• To evaluate for Richter transformation if clinically suspected

LN biopsy ^[1]: Not routinely required for CLL diagnosis if the blood picture is classic.

Indications for LN biopsy:

• Suspected Richter transformation (rapidly enlarging discordant node)
• SLL presentation (tissue-based disease without significant circulating lymphocytes)
• Diagnostic uncertainty

Histological findings ^[2][5]:

• Diffusely effaced nodal architecture with occasional residual naked germinal centres ^[2]
• Infiltrate is composed of mature-appearing, small lymphocytes with a mixture of prolymphocytes and paraimmunoblasts ^[2]
• Pseudofollicle formation (proliferation centres) ^[5] — these are pale areas within the diffuse infiltrate containing prolymphocytes and paraimmunoblasts; their presence is a hallmark of CLL/SLL on tissue biopsy

CLL is different to ALL, AML and CML → we don't treat all cases ^[4]

This is a critical concept. In acute leukaemias, you must treat urgently or the patient dies within weeks. In CML, early TKI therapy dramatically improves outcomes. But in CLL:

• The disease is very indolent in nature ^[5] — many patients live for decades without needing treatment
• Historically, this was because we did not use to have good treatments ^[4] — older chemotherapies (e.g., chlorambucil) could not cure CLL, and early treatment with these agents did NOT improve survival. Trials showed that treating early-stage CLL with alkylating agents actually shortened life expectancy compared to observation ^[5]
• Therefore, the standard of care evolved to watch and wait (W&W) for early-stage asymptomatic disease
• This may change in the next 10 years ^[4] as newer targeted agents (BTK inhibitors, BCL-2 inhibitors) become available — there are ongoing trials exploring whether early intervention with these agents improves outcomes

Treatment decision based on clinical staging and symptoms ^[4][6]

The treatment decision of CLL is dependent on clinical staging and symptoms — mainly clinical, effect on marrow (anaemia, thrombocytopenia), effect on lymph nodes, effect on liver and spleen ^[4]

CLL is predominantly a disease of the elderly (median age 70). Many patients have significant comorbidities. Treatment must be tailored to the patient's fitness level — there is no point giving intensive chemoimmunotherapy to a frail 85-year-old.

Del(17p)/TP53 mutation predicts resistance to chemoimmunotherapy. These patients MUST receive novel targeted agents.

Early stage CLL → No treatment, W&W (watch and wait) ^[4][6]

No treatment in early stages ^[6]

What to monitor during W&W:

• Lymphocyte doubling time (calculate from serial CBC)
• Development of cytopenias (Hb drop, platelet drop)
• New/progressive lymphadenopathy or organomegaly
• New B symptoms
• Signs of AIHA or ITP (DAT, reticulocytes)
• Signs of Richter transformation (rapidly enlarging node, rising LDH, fevers)

• The only potentially curative option for CLL
• Provides a graft-versus-leukaemia (GVL) effect — donor immune cells recognize and kill residual CLL cells
• However, very high procedural morbidity and mortality (transplant-related mortality ~15–25%)
• Reserved for very select young patients with ultra-high-risk disease (del(17p)/TP53 mutation) who have failed or are refractory to novel agents
• Rarely used now because BTK inhibitors and venetoclax have dramatically improved outcomes for high-risk patients

Supportive care: blood products, leukapheresis for leukostasis ^[1]

When CLL transforms to DLBCL (Richter transformation):

• Treat as de novo DLBCL: R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone)
• Consider allo-HSCT in eligible patients who achieve remission
• Prognosis is poor (median OS ~6–12 months)
• Emerging: anti-PD-1 checkpoint inhibitors, BTK inhibitors, CAR-T cell therapy in clinical trials

Local RT in localised SLL (Ann-Arbor stage I) ^[5]

If SLL presents as a localised mass (Ann-Arbor Stage I), involved-field radiotherapy alone may be sufficient, analogous to management of other indolent lymphomas.

• Most common autoimmune complication of CLL
• Usually warm-type (IgG-mediated extravascular haemolysis)
• DAT (direct antiglobulin test / Coombs test) positive — typically IgG ± C3d ^[12]
• Clinically: worsening anaemia disproportionate to disease burden, jaundice, reticulocytosis, ↑ LDH, ↓ haptoglobin, ↑ unconjugated bilirubin, spherocytes on PBS ^[12]
• Why does CLL cause AIHA? CLL disrupts normal immune tolerance through multiple mechanisms: (1) CLL-derived autoreactive antibodies; (2) loss of T-regulatory cell suppressive function; (3) aberrant antigen presentation by CLL cells
• Management ^[12]: (1) Corticosteroids first-line; (2) Treat underlying CLL if refractory; (3) Rituximab; (4) Splenectomy in refractory cases ^[17]

• Second most common autoimmune complication
• Mechanism: Anti-platelet autoantibodies → platelet destruction in spleen
• Must distinguish from thrombocytopenia due to BM infiltration (the latter = Rai IV staging and mandates CLL treatment; the former may respond to steroids/IVIg alone)
• Refractory AIHA/ITP is an indication for CLL treatment ^[1]

• Both rare (< 1% each)
• PRCA: Selective absence of erythroid precursors in BM; very low reticulocyte count; antibodies against erythroid precursors or erythropoietin
• Autoimmune neutropenia: Anti-neutrophil antibodies

Richter transformation is the development of an aggressive high-grade lymphoma in the setting of pre-existing CLL/SLL. Named after Maurice Richter who described it in 1928.

• Most commonly DLBCL (~90%) ^[4][5]
• Hodgkin lymphoma (~5–10%) ^[5]
• Possible histological transformation into prolymphocytic leukaemia (2%), Hodgkin lymphoma (0.5–2%), multiple myeloma (0.1%) ^[5]

• Occurs in ~2–10% of CLL patients over the disease course (incidence ~0.5–1% per year)
• Risk factors: unmutated IGHV, del(17p)/TP53 mutation, NOTCH1 mutation, bulky lymphadenopathy, prior treatment with multiple lines of therapy
• The transformation represents acquisition of additional genetic hits (e.g., TP53 mutation, MYC translocations, CDKN2A deletion) that convert the indolent clone into an aggressive one

• Rapidly enlarging lymph nodes — especially one discordant node growing much faster than others
• Sudden onset of severe B symptoms — high fevers, drenching night sweats, rapid weight loss
• Markedly elevated LDH — disproportionate to the degree of CLL
• New extranodal disease (skin, CNS, GI tract)
• Rising β2-microglobulin
• Hypercalcaemia (rare, but can occur with aggressive lymphoma)

• PET-CT: Discordantly high FDG uptake in one or more nodes (SUV max > 5 suggests transformation)
• Excisional lymph node biopsy of the most metabolically active node — this is essential. Core needle biopsy may miss the transformation due to sampling error.
• Histology shows DLBCL architecture with large transformed cells

• Very poor — median overall survival ~6–12 months
• Worse if the DLBCL is clonally related to the original CLL (majority); slightly better if clonally unrelated (a true de novo DLBCL arising coincidentally)

• R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) — as for de novo DLBCL
• Consider allo-HSCT for eligible patients who achieve remission
• Emerging therapies: checkpoint inhibitors (anti-PD-1), BTK inhibitors, venetoclax combinations, CAR-T cell therapy (targeting CD19)