Chronic Lymphocytic Leukaemia
Chronic lymphocytic leukaemia is a low-grade B-cell lymphoproliferative disorder characterized by the progressive accumulation of mature but functionally incompetent lymphocytes in the blood, bone marrow, and lymphoid tissues.
Chronic Lymphocytic Leukaemia (CLL)
Chronic lymphocytic leukaemia (CLL) is a chronic lymphoproliferative disorder characterised by the progressive accumulation of functionally incompetent, monoclonal mature B lymphocytes in the peripheral blood, bone marrow, lymph nodes, and spleen [1][2][3].
Let's break this down from first principles:
- "Chronic" — unlike acute leukaemia, this is NOT about time course per se. The distinguishing factor between chronic and acute leukaemia is the pathological definition: in chronic leukaemia, < 20% of cells in the peripheral blood or bone marrow are blasts; in acute leukaemia, ≥ 20% are blasts [4]. Chronic leukaemias involve maturing/mature cells with slow progression, because maturation is not impaired, but there is uncontrolled proliferation and impaired apoptosis [4].
- "Lymphocytic" — the malignant clone arises from the lymphoid lineage (specifically B cells in >95% of cases; T-cell CLL is exceptionally rare) [2].
- "Leukaemia" — by convention, this term implies primary involvement of blood and bone marrow, distinguishing it from lymphoma which presents as a solid tissue mass [3].
CLL is pathologically equivalent to small lymphocytic lymphoma (SLL) — they are the same disease entity on a spectrum [1][2][3][5]:
- Monoclonal B-cell lymphocytosis (MBL): Clonal B cells in blood only, without cytopenias, lymphadenopathy, or organomegaly (< 5 × 10⁹/L monoclonal B lymphocytes)
- CLL: When there is cytopenia due to bone marrow infiltration and/or ≥ 5 × 10⁹/L monoclonal B lymphocytes in peripheral blood
- SLL: When lymph node, splenic, or other extramedullary involvement predominates with minimal blood involvement
Key Distinction: Chronic vs Acute Leukaemia
Chronic leukaemia can transform into acute leukaemia if left untreated — leukemic cells acquire more mutations over time [4]. This is why CLL can undergo Richter transformation into aggressive lymphoma (most commonly DLBCL).
2. Epidemiology
- 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.
3. Anatomy and Function — Relevant Immunological and Haematological Background
To understand CLL, you must understand where these cells come from and what they normally do.
- Bone marrow: Haematopoietic stem cell → common lymphoid progenitor → pre-B cell → immature B cell (expresses surface IgM)
- 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
- 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)
4. Aetiology and Risk Factors
4.1 Aetiology
The aetiology of CLL is unknown [5], but several factors have been identified:
- CLL is associated with genetic predisposition [5]
- Family history: First-degree relatives of CLL patients have a 2–8× increased risk
- Genome-wide association studies (GWAS) have identified >40 susceptibility loci
- The marked ethnic variation (Western >> Chinese) strongly supports a genetic basis
- CLL arises from progression from monoclonal B-cell lymphocytosis (MBL), which is common in the elderly [5]
- MBL is defined as < 5 × 10⁹/L clonal B cells in peripheral blood without lymphadenopathy, organomegaly, or cytopenias
- MBL progresses to CLL requiring treatment at a rate of ~1–2% per year
- MBL is detectable in ~5–12% of adults > 60 years with normal blood counts
- Unlike many other haematological malignancies, no clear environmental exposure (radiation, benzene, chemotherapy) has been definitively linked to CLL
- No viral aetiology has been established (unlike some lymphomas linked to EBV, HTLV-1, etc.)
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]:
| Cytogenetic Abnormality | Frequency | Prognostic Significance |
|---|---|---|
| del(13q) | ~55% | Favourable (sole abnormality) — most common |
| Trisomy 12 | ~15% | Intermediate |
| del(11q) (ATM gene) | ~25% | Unfavourable — bulky lymphadenopathy |
| del(17p) (TP53 gene) | ~7% at diagnosis, higher at relapse | Very poor — refractory to chemoimmunotherapy |
| Normal karyotype | ~20% | Intermediate |
Why del(17p) Matters
TP53 is the "guardian of the genome." Loss of TP53 (via del(17p) or TP53 mutation) renders cells resistant to DNA-damaging chemotherapy (fludarabine, cyclophosphamide, chlorambucil all work by inducing DNA damage → p53-mediated apoptosis). These patients require novel agents (BTK inhibitors, BCL-2 inhibitors) that work independently of p53.
5. Pathophysiology
Understanding the pathophysiology of CLL explains every single clinical feature. Let me build this from first principles.
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:
-
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]
-
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]
-
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)
| Site of Accumulation | Consequence |
|---|---|
| Peripheral blood | Lymphocytosis (often > 5 × 10⁹/L, sometimes >100 × 10⁹/L) |
| Bone marrow | Infiltration → marrow failure → anaemia, thrombocytopenia, neutropenia |
| Lymph nodes | Lymphadenopathy (painless, generalised) [6] |
| Spleen | Splenomegaly [6] — also contributes to cytopenias via hypersplenism |
| Liver | Hepatomegaly [6] |
CLL is fundamentally a disease of immune failure. The CLL cells themselves are functionally incompetent — they cannot produce effective antibodies. Additionally:
-
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)
-
T-cell dysfunction
- CLL cells suppress normal T-cell function via immune checkpoint interactions
- Contributes to increased risk of opportunistic infections (especially with treatment)
-
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
Why Does CLL Cause AIHA?
CLL B cells produce autoreactive antibodies (warm IgG antibodies directed against red cell antigens). Additionally, the immune dysregulation in CLL disrupts normal T-regulatory cell function, allowing autoreactive clones to escape suppression. The DAT (direct antiglobulin test / Coombs test) will be positive.
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)
6. Classification
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)
6.2 Clinical Staging Systems
Two staging systems are used. Both are purely clinical (no imaging required) and are based on the degree of lymphoid tissue involvement and cytopenias [1][4]:
| Stage | Features | Risk Group | Median Survival |
|---|---|---|---|
| 0 | Lymphocytosis only (blood and marrow) | Low | > 10 years |
| I | Lymphocytosis + lymphadenopathy | Intermediate | ~8 years |
| II | Lymphocytosis + hepato/splenomegaly (± lymphadenopathy) | Intermediate | ~6 years |
| III | Lymphocytosis + anaemia (Hb < 110 g/L) due to BM infiltration | High | ~2–4 years |
| IV | Lymphocytosis + thrombocytopenia (Plt < 100 × 10⁹/L) due to BM infiltration | High | ~2–4 years |
| Stage | Features | Median Survival |
|---|---|---|
| A | < 3 involved lymphoid areas*, no anaemia, no thrombocytopenia | > 10 years |
| B | ≥ 3 involved lymphoid areas*, no anaemia, no thrombocytopenia | ~7 years |
| C | Anaemia (Hb < 100 g/L) and/or thrombocytopenia (Plt < 100 × 10⁹/L) regardless of number of areas | ~2–4 years |
*The 5 lymphoid area sites are: (1) head and neck, (2) axillae, (3) inguinal regions, (4) spleen, (5) liver [1]
Treatment decision for CLL is based on clinical staging and symptoms [4][6]. Early-stage asymptomatic CLL (Rai 0 / Binet A) does NOT require treatment — just watch and wait (W&W) [1][4][6].
7. Clinical Features
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]
7.1 Symptoms
- Asymptomatic presentation is the most common [1]
- Found incidentally when CBC is done for another reason → lymphocytosis
- Why? Because the disease is indolent, and early-stage CLL causes no symptoms. The functionally incompetent B cells silently accumulate.
These reflect the systemic inflammatory cytokine response from the neoplastic clone:
- Fatigue [1][6] — the most common symptom; extreme fatigue defined as ECOG Performance Status ≥ 2 (unable to perform usual activities) [2]
- Mechanism: Cytokine-mediated (TNF-α, IL-1, IL-6 released by CLL cells and the tumour microenvironment), anaemia, and metabolic demands of the tumour
- Weight loss [1][6] — unintentional weight loss ≥ 10% of body weight within the previous 6 months [2]
- Mechanism: Hypermetabolic state from tumour burden and inflammatory cytokines
- Fever [2][6] — > 38°C for ≥ 2 weeks without evidence of infection
- Mechanism: Endogenous pyrogen release (IL-1, IL-6, TNF-α) from tumour cells
- Night sweats [1][6] — without evidence of infection
- Mechanism: Cytokine-driven thermoregulatory dysregulation
B Symptoms in CLL
"B symptoms" (fever, night sweats, weight loss >10%) indicate more advanced/active disease and are one of the indications for treatment initiation. They reflect high tumour burden and systemic inflammatory activation.
- Swollen lymph nodes — patients may notice painless lumps in neck, axillae, or groin
- Mechanism: CLL cells home to lymph nodes via chemokine receptors (CXCR4, CXCR5) and accumulate → progressive nodal enlargement
- Abdominal discomfort/fullness/early satiety — from splenomegaly and/or hepatomegaly
- Mechanism: Massive spleen pushes on stomach; CLL cells infiltrate splenic white pulp → expansion
- Anaemic symptoms [1]: Fatigue, exertional dyspnoea, pallor, dizziness, palpitations
- Mechanism: (1) Bone marrow infiltration by CLL cells displaces normal erythropoiesis; (2) AIHA (warm antibody-mediated destruction); (3) Hypersplenism
- Bleeding symptoms [1]: Easy bruising, petechiae, mucosal bleeding, menorrhagia
- Mechanism: Thrombocytopenia from (1) bone marrow infiltration; (2) immune-mediated destruction (ITP); (3) hypersplenism
- Recurrent infections: Sinopulmonary infections (pneumonia, sinusitis, bronchitis), herpes zoster reactivation
- Mechanism: (1) Hypogammaglobulinaemia from functional B-cell failure; (2) Neutropenia from marrow infiltration; (3) T-cell dysfunction; (4) Treatment-related immunosuppression
- Rapid worsening of systemic symptoms (high fevers, drenching sweats, rapid weight loss)
- Rapidly enlarging lymph nodes (especially one discordant node growing much faster than others)
- New onset of abdominal pain (rapidly enlarging extranodal mass)
7.2 Signs
- Lymphadenopathy [1][6] — the most common physical sign
- Typically painless, symmetrical, generalised (involving cervical, axillary, and inguinal regions)
- Nodes are usually non-tender, firm, rubbery, mobile (not fixed or matted, unless very advanced)
- Mechanism: Homing and accumulation of clonal B cells in lymph nodes
- Bulky lymphadenopathy (>10 cm or rapidly enlarging) may indicate transformation or advanced disease
- Hepatosplenomegaly [1][6]
- Splenomegaly — palpable in ~25–50% at some point; due to CLL infiltration of splenic white pulp
- Hepatomegaly — less common than splenomegaly; due to portal tract infiltration
- Massive splenomegaly can cause:
- Left upper quadrant discomfort
- Early satiety
- Hypersplenism (worsening cytopenias: anaemia, thrombocytopenia, neutropenia out of proportion to marrow disease)
- Pallor (conjunctival, palmar crease)
- Tachycardia, flow murmur (ejection systolic murmur from hyperdynamic circulation)
- Petechiae, purpura, ecchymoses
- Mucosal bleeding (gingival, epistaxis)
- Fever with focal signs depending on infection source
- Skin infections (cellulitis, herpes zoster)
- Jaundice (unconjugated hyperbilirubinaemia from haemolysis)
- Splenomegaly (site of extravascular haemolysis)
- Dark urine (urobilinogen)
- Leukaemia cutis — nodular or papular skin lesions from CLL cell infiltration
- Non-specific skin findings: increased susceptibility to skin infections, exaggerated insect bite reactions (due to immune dysregulation)
| Clinical Feature | Pathophysiological Mechanism |
|---|---|
| Incidental lymphocytosis | Clonal B-cell accumulation in blood |
| Fatigue/weight loss/fever/night sweats | Cytokine-mediated systemic inflammation (TNF-α, IL-1, IL-6) |
| Painless lymphadenopathy | CLL cell homing and accumulation in lymph nodes |
| Splenomegaly | CLL infiltration of splenic white pulp |
| Hepatomegaly | CLL infiltration of hepatic portal tracts |
| Anaemia | BM infiltration + AIHA + hypersplenism |
| Thrombocytopenia/bleeding | BM infiltration + ITP + hypersplenism |
| Recurrent infections | Hypogammaglobulinaemia + neutropenia + T-cell dysfunction |
| Jaundice (haemolytic) | Warm AIHA → extravascular haemolysis |
| Richter transformation signs | Acquisition of additional mutations → DLBCL or HL |
PBS Finding — Pathognomonic
Smear cells (smudge cells) on peripheral blood smear are essentially diagnostic of CLL [4]. These are fragile CLL lymphocytes that get damaged/lysed during the preparation of the blood film. They appear as "squashed" cells with nuclear debris. This is because CLL lymphocytes have abnormally fragile membranes due to cytoskeletal defects.
While full diagnostic workup will be covered in the next section, the following features are so intertwined with clinical presentation that they deserve mention:
- CBC D/C: Leukocytosis with ↑ lymphocytes (often >5 × 10⁹/L; can be >100 × 10⁹/L) ± anaemia ± thrombocytopenia [1]
- PBS: Smear/smudge cells (fragile lymphocytes damaged during slide preparation) — diagnostic [1][4]
- Peripheral blood flow cytometry: CD5+, CD19+, CD20+ (dim), CD23+, sIg+ (dim) [1]
- CD5: Normally a T-cell marker; aberrant expression on B cells is characteristic of CLL (and mantle cell lymphoma — but MCL is CD23−)
- CD19, CD20: B-cell markers (CD20 is dim in CLL, unlike normal B cells — important for anti-CD20 therapy dosing)
- CD23: Positive in CLL, negative in mantle cell lymphoma — key distinguishing feature
- Surface immunoglobulin (sIg): Dim expression (vs. bright in mantle cell lymphoma)
- Bone marrow biopsy: Not required for diagnosis, but useful in monitoring treatment response [1]
CLL vs Mantle Cell Lymphoma — Common Exam Trap
Both CLL and mantle cell lymphoma (MCL) are CD5+ B-cell neoplasms. The key distinguishing features:
| Feature | CLL | MCL |
|---|---|---|
| CD23 | Positive | Negative |
| CD200 | Positive | Negative |
| sIg intensity | Dim | Bright |
| Cyclin D1 | Negative | Positive (t(11;14)) |
| Clinical course | Indolent | Aggressive |
This is a frequently tested distinction.
High Yield Summary
- Definition: CLL = monoclonal proliferation of functionally incompetent mature B cells accumulating in blood, BM, and lymphoid tissues. Pathologically equivalent to SLL.
- Epidemiology: Most common leukaemia in Western adults; uncommon in Chinese. Median age 70. NEVER in children. M > F.
- Aetiology: Unknown; genetic predisposition; arises from MBL. Key cytogenetics: del(13q) most common/good prognosis; del(17p)/TP53 = poor prognosis.
- Pathophysiology: Impaired apoptosis (BCL-2 overexpression) > uncontrolled proliferation. BCR signalling via BTK and PI3K drives survival. Immune dysfunction → hypogammaglobulinaemia, autoimmunity (AIHA, ITP).
- Classification: Rai (0–IV) and Binet (A–C) staging — purely clinical. 5 lymphoid sites: H&N, axillae, inguinal, spleen, liver.
- Clinical features: Most common = asymptomatic/incidental lymphocytosis. Constitutional (B) symptoms. Painless generalised lymphadenopathy, hepatosplenomegaly. Cytopenias (BM failure). Recurrent infections. Risk of Richter transformation (→ DLBCL).
- Smear/smudge cells on PBS are pathognomonic. Flow cytometry: CD5+, CD19+, CD20 dim, CD23+, sIg dim.
- Treatment: Watch & wait for early stage. FCR for young/fit. Chlorambucil for old/frail. Novel agents: ibrutinib/acalabrutinib (BTK inhibitors), venetoclax (BCL-2 inhibitor), idelalisib (PI3K inhibitor).
Active Recall - Chronic Lymphocytic Leukaemia (Definition, Epidemiology, Pathophysiology, Clinical Features)
[1] Senior notes: Maksim Medicine Notes.pdf (Haematology section, p.177) [2] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Chronic Lymphocytic Leukemia section, p.1409–1411) [3] Senior notes: Ryan Ho Fundamentals.pdf (Lymphoid neoplasm classification, p.400) [4] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (CLL sections, p.2, 24–25) [5] Senior notes: Ryan Ho Haemtology.pdf (CLL section, p.66) [6] Lecture slides: GC 060. High white cell count.pdf (CLL slides, p.33–34) [7] Past papers: 2024 Fourth Summative MCQ.pdf [8] Past papers: 2022 Fourth Summative MCQ.pdf
Differential Diagnosis of Chronic Lymphocytic Leukaemia (CLL)
When a patient — typically elderly — presents with persistent lymphocytosis (±lymphadenopathy, ±splenomegaly, ±cytopenias), the clinical challenge is to distinguish CLL from the many other causes of lymphocytosis, lymphadenopathy, and cytopenias. The differential diagnosis is best organised by thinking about what CLL actually looks like and then asking: "What else could mimic this picture?"
CLL presents with three cardinal features that each generate their own differential:
- Persistent mature lymphocytosis → What else causes lymphocytosis?
- Generalised lymphadenopathy → What else causes generalised lymphadenopathy?
- Cytopenias (anaemia, thrombocytopenia) → Could these be from another cause (e.g., AIHA from another aetiology)?
The most important clinical task is to separate reactive (benign) lymphocytosis from clonal (malignant) lymphoproliferative disorders, and then within the malignant category, to distinguish CLL from other chronic lymphoproliferative diseases that can look very similar.
These are non-clonal, polyclonal expansions of lymphocytes — usually self-limiting, typically < 3 months duration, and often accompanied by atypical lymphocyte morphology on the blood film [5][9].
Infectious causes of lymphocytosis should NOT sustain ≥ 3 months and should be non-clonal. Morphology typically shows atypical lymphocytes with abundant cytoplasm and sparse collections of azurophilic granules [5].
| Reactive Cause | Key Distinguishing Features from CLL |
|---|---|
| Infectious mononucleosis (EBV) | Young patient, pharyngitis, fever, atypical lymphocytes (NOT smudge cells), heterophile antibody +ve, self-limiting |
| CMV infection | Similar to EBV but heterophile −ve; atypical lymphocytes; CMV IgM/PCR +ve |
| Acute viral hepatitis | Hepatitis serology +ve; transaminases markedly elevated; lymphocytosis transient |
| HIV seroconversion | Risk factors present; atypical lymphocytes; HIV Ag/Ab +ve |
| Pertussis (Bordetella pertussis) | Paroxysmal cough; can cause very high lymphocyte counts in children/young adults; mature small lymphocytes (can mimic CLL morphologically) but non-clonal |
| Toxoplasmosis | Exposure to cats/raw meat; atypical lymphocytes; Toxoplasma IgM +ve |
| Other infections | TB (disseminated), brucellosis, rickettsial infections |
| Drug reactions / hypersensitivity | Temporal association with drug (e.g., phenytoin, carbamazepine — DRESS syndrome); atypical lymphocytes; eosinophilia may coexist |
| Stress lymphocytosis | Transient, minutes to hours after acute physiological stress (trauma, MI, status epilepticus); resolves rapidly |
Atypical Lymphocytes vs Smudge Cells vs Blasts — Don't Confuse Them
Atypical lymphocytes (activated lymphocytes) in reactive conditions have abundant pale blue cytoplasm that moulds around red cells — they are NOT neoplastic and NOT blasts [9][10].
Smudge/smear cells are fragile CLL lymphocytes mechanically disrupted during slide preparation — they are the hallmark of CLL [1][4].
Blasts in ALL can mimic atypical lymphocytes if you don't look at the blood film carefully [10] — blasts have fine chromatin, prominent nucleoli, and high N:C ratio, whereas atypical lymphocytes have condensed chromatin and abundant cytoplasm.
How to clinically separate reactive from clonal lymphocytosis:
- Duration: Reactive typically < 3 months; CLL persists ≥ 3 months
- Morphology: Reactive → atypical lymphocytes; CLL → small mature lymphocytes with smudge cells
- Flow cytometry: Reactive → polyclonal (mixed kappa/lambda light chains); CLL → monoclonal (light chain restriction) with CD5+, CD19+, CD20 dim, CD23+ [1][5]
- Clinical context: Reactive → younger patients, acute infection symptoms; CLL → elderly, insidious
2. Other Chronic Lymphoproliferative Disorders (Clonal/Malignant)
This is the most critical differential category. Once you have confirmed clonal lymphocytosis, you must distinguish CLL from other mature B-cell (and rarely T-cell) neoplasms that can present with lymphocytosis ± lymphadenopathy [5].
CD5 expression on a B cell → differential is CLL or mantle cell lymphoma [11]
| Feature | CLL / SLL | Mantle Cell Lymphoma (MCL) |
|---|---|---|
| Age | Elderly (median 70) | Middle-aged to elderly (median 65) |
| CD5 | + | + |
| CD23 | Positive | Negative |
| CD200 | Positive | Negative |
| sIg | Dim | Bright |
| Cyclin D1 | Negative | Positive — due to t(11;14) |
| SOX11 | Negative | Positive |
| Morphology | Small mature lymphocytes, smudge cells | Slightly irregular/cleaved nuclei |
| Clinical course | Very indolent | Aggressive (median survival 3–5 years) |
| GI involvement | Rare | Common (lymphomatous polyposis) |
CLL vs MCL — The Must-Know Distinction
Both are CD5+ B-cell neoplasms. The single best discriminator is CD23: positive in CLL, negative in MCL. Additionally, MCL is cyclin D1+ due to the pathognomonic t(11;14)(q13;q32) translocation, and has bright surface Ig (CLL has dim sIg). This distinction is critical because MCL is far more aggressive and requires different treatment [5][11].
| Condition | Key Distinguishing Features from CLL |
|---|---|
| Prolymphocytic leukaemia (PLL) | Morphologically distinct from CLL cells [5] — prolymphocytes are larger with prominent central nucleolus, abundant cytoplasm; >55% prolymphocytes in blood; CD5 variable, FMC7+; much more aggressive |
| Hairy cell leukaemia (HCL) | Pancytopenia (NOT lymphocytosis), splenomegaly (often massive) WITHOUT lymphadenopathy; "hairy" cytoplasmic projections on PBS; very strong CD20 expression [11]; CD25+, CD103+, CD123+, Annexin A1+; BRAF V600E mutation |
| Lymphoplasmacytic lymphoma (LPL / Waldenström macroglobulinaemia) | Lymphomatous counterpart to... [5] — presents with IgM paraprotein, hyperviscosity symptoms; MYD88 L265P mutation; lymphoplasmacytic morphology on BM; no CD5 expression |
| Splenic marginal zone lymphoma (SMZL) | Splenomegaly prominent with circulating villous lymphocytes; CD5−, CD23−; no specific cytogenetic marker |
| Follicular lymphoma (FL) — leukaemic phase | Cleaved ("buttock") cells on PBS; CD10+, BCL6+, BCL2+; t(14;18); CD5−, CD23− |
| Condition | Key Distinguishing Features |
|---|---|
| T-cell prolymphocytic leukaemia (T-PLL) | CD4+ (usually), markedly elevated WCC, skin infiltration, serous effusions; aggressive |
| Large granular lymphocyte (LGL) leukaemia | Indolent; associated with neutropenia, anaemia, rheumatoid arthritis; CD3+, CD8+, CD57+; large granular lymphocytes on PBS |
| Adult T-cell leukaemia/lymphoma (ATLL) | Associated with HTLV-1; hypercalcaemia, skin lesions, "flower cells" on PBS; endemic in Japan, Caribbean |
| Sézary syndrome | Erythroderma (generalised red skin), circulating Sézary cells (cerebriform nuclei); CD4+; leukaemic phase of mycosis fungoides |
When lymphadenopathy is the dominant feature, the differential broadens beyond haematological malignancy [10]:
Differential diagnosis of generalised lymphadenopathy: (1) Neoplastic — leukaemias, lymphomas/LPD; (2) Infective — viral (EBV, CMV), bacterial, mycobacterial, parasitic, dimorphic fungi; (3) Autoimmune; (4) Drugs [10]
| Category | Examples | How to Distinguish from CLL |
|---|---|---|
| Lymphomas | DLBCL, Hodgkin lymphoma, FL, MZL | LN biopsy with histology and immunohistochemistry is definitive; no persistent lymphocytosis with smudge cells in most lymphomas |
| Infections | EBV, CMV, HIV, TB, toxoplasmosis, dimorphic fungi (Talaromyces marneffei — important in HK) | Acute onset, fever, specific serology/PCR; atypical lymphocytes (not smudge cells); self-limiting |
| Autoimmune | SLE, rheumatoid arthritis, sarcoidosis | Other systemic features (rash, arthritis, serositis); ANA, anti-dsDNA; reactive lymphadenopathy on biopsy |
| Drug reactions | Phenytoin, carbamazepine (pseudolymphoma) | Temporal drug relationship; resolves on drug withdrawal |
| Metastatic carcinoma | Any solid organ malignancy | Hard, fixed nodes; primary tumour usually identifiable; biopsy shows carcinoma cells |
If a patient presents with anaemia or thrombocytopenia and CLL is being considered, you must also think about:
- AIHA from other causes (other lymphoproliferative disorders, autoimmune diseases, drugs, idiopathic) — CLL-associated AIHA is warm-antibody type; DAT positive [12]
- ITP from other causes — primary ITP, drug-induced, other autoimmune diseases
- Myelodysplastic syndrome (MDS) — cytopenias with dysplastic morphology, in elderly; no lymphocytosis
- Bone marrow failure — aplastic anaemia (pancytopenia, hypocellular marrow, no lymphocytosis)
The following algorithm shows the clinical thought process when evaluating a patient with suspected CLL:
| Feature | CLL | MCL | HCL | PLL | Reactive |
|---|---|---|---|---|---|
| Age | Elderly | Middle-aged+ | Middle-aged M | Elderly | Any age |
| WCC | ↑↑ lymphocytes | ↑ lymphocytes | Pancytopenia | ↑↑↑ lymphocytes | ↑ lymphocytes (transient) |
| PBS | Smudge cells | Irregular nuclei | Hairy projections | Large cells, nucleolus | Atypical lymphocytes |
| CD5 | + | + | − | Variable | N/A |
| CD23 | + | − | − | − | N/A |
| CD20 | Dim | Moderate | Very strong [11] | Bright | N/A |
| sIg | Dim | Bright | Bright | Bright | Polyclonal |
| Specific marker | — | Cyclin D1, t(11;14) | BRAF V600E | — | — |
| Course | Indolent | Aggressive | Indolent (responds well to Tx) | Aggressive | Self-limiting |
High Yield: The 3 Questions That Clinch the CLL Diagnosis Over Mimics
- Is the lymphocytosis persistent (≥ 3 months) and monoclonal? → Rules out reactive causes
- Is the immunophenotype CD5+, CD23+, CD20 dim, sIg dim? → Confirms CLL over MCL (CD23−), HCL (CD20 bright), and other LPDs
- Are there smudge cells on PBS? → Classic for CLL (fragile lymphocyte membranes)
If all three are present in an elderly patient, the diagnosis is virtually certain without bone marrow biopsy.
Hong Kong Exam Relevance
In Hong Kong, CLL is uncommon in Chinese populations. When an exam question presents lymphocytosis in an elderly Chinese patient, also consider:
- Extranodal NK/T cell lymphoma (nasal type) — more common in East Asia; EBV-associated [9]
- T-cell LGL leukaemia — presents with neutropenia, not lymphocytosis per se
- Splenic marginal zone lymphoma — presents with splenomegaly and villous lymphocytes
However, CLL still occurs and is very testable because of its classic presentation and immunophenotype.
Active Recall - Differential Diagnosis of CLL
References
[1] Senior notes: Maksim Medicine Notes.pdf (Haematology, p.177) [4] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (CLL sections, p.24–25) [5] Senior notes: Ryan Ho Haemtology.pdf (CLL section, p.67) [9] Senior notes: Block A - Generalised Lymphadenopathy_ Differential diagnosis and principle of management.pdf (p.3, 25–26) [10] Senior notes: Block A - Generalised Lymphadenopathy_ Differential diagnosis and principle of management.pdf (DDx of generalised lymphadenopathy, p.2) [11] Lecture slides: Laboratory Diagnostic Investigations Seminar_Flow cytometry in haematology.pdf (CD5 on B cell, p.23; CD20 intensity, p.25; ZAP70, p.44) [12] Senior notes: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (AIHA diagnosis and treatment, p.3, 6)
Diagnostic Criteria, Diagnostic Algorithm, and Investigations for CLL
1. Diagnostic Criteria
The diagnosis of CLL is fundamentally a peripheral blood diagnosis — unlike most other haematological malignancies, you do NOT need a bone marrow biopsy to make the diagnosis. This is a key concept to understand from first principles: CLL cells circulate freely in the blood, so you can catch them, count them, and phenotype them directly from a simple blood draw.
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].
MBL vs CLL — The Threshold Distinction
Patients with absolute lymphocyte count < 5 × 10⁹/L and no evidence of other disease manifestation such as enlarged lymph node are diagnosed with monoclonal B-cell lymphocytosis rather than CLL, even if they have cytopenias [2]. MBL progresses to CLL requiring treatment at ~1–2% per year.
CLL and SLL are the same disease entity with different clinical presentations. The diagnostic distinction is:
| CLL | SLL | |
|---|---|---|
| Primary site | Blood and bone marrow | Lymph nodes/extranodal tissue |
| Peripheral B-lymphocyte count | ≥ 5 × 10⁹/L | < 5 × 10⁹/L |
| Tissue involvement | May or may not be present | Required (biopsy-proven) |
| Diagnosis by | Peripheral blood flow cytometry | Lymph node biopsy |
The workup for any suspected haematological malignancy follows the 5 steps to diagnosis of haematological malignancy (MCICM) [3][15]:
MCICM = Morphology, Cytochemistry, Immunophenotyping, Cytogenetics, Molecular genetics [3][15]
| Step | What It Means | Application in CLL |
|---|---|---|
| M — Morphology | PBS (number, morphology, blasts), BM aspirate and trephine [15] | PBS: smudge cells, mature small lymphocytes; BM: not required for dx |
| C — Cytochemistry | MPO/Sudan black B for myeloid, no marker for lymphoid [15] | Not useful in CLL (lymphoid lineage has no good cytochemical marker) |
| I — Immunophenotyping | Flow cytometry (peripheral blood, marrow aspirate), IHC (trephine only) for cell surface marker expression [15] | Flow cytometry on peripheral blood is the KEY diagnostic tool |
| C — Cytogenetics | Karyotyping, FISH for chromosomal abnormalities [15] | FISH for del(13q), del(11q), del(17p), trisomy 12 — prognostic |
| M — Molecular genetics | PCR, sequencing for genetic mutations [15] | IGHV mutation status, TP53 mutation, NGS panels — prognostic |
For CLL specifically, the most important steps are M (morphology — PBS) and I (immunophenotyping — flow cytometry). The cytogenetics and molecular genetics are primarily for prognostication and treatment selection, not for diagnosis per se.
3. Investigations — Detailed Breakdown
CBC D/C: leukocytosis with ↑ lymphocytes ± anaemia ± thrombocytopenia [1]
| Parameter | Expected Finding in CLL | Pathophysiological Explanation |
|---|---|---|
| WBC | Elevated (often 20–200 × 10⁹/L, can exceed 100) | Clonal B-cell accumulation in blood |
| Differential count | Lymphocytosis [4] — absolute lymphocyte count ≥ 5 × 10⁹/L | Monoclonal mature B cells predominate |
| Haemoglobin | Normal or ↓ | (1) BM infiltration → reduced erythropoiesis; (2) AIHA; (3) Hypersplenism |
| MCV | Usually normocytic (unless concurrent B12/folate deficiency or AIHA with reticulocytosis → macrocytic) | CLL itself does not alter MCV |
| Platelets | Normal or ↓ | (1) BM infiltration; (2) ITP; (3) Hypersplenism |
| Reticulocyte count | ↑ if AIHA present; normal/↓ if BM failure | AIHA → compensatory reticulocytosis; BM failure → inadequate response |
| Neutrophil count | May be ↓ in advanced disease | BM infiltration + treatment-related |
Risk of Leukostasis
WBC count can be as high as > 100, risk of leukostasis if WBC > 250 [5]. Leukostasis is a medical emergency with microvascular occlusion causing respiratory distress and neurological symptoms. However, leukostasis is much less common in CLL than in acute leukaemias because CLL cells are small and deformable (unlike large, rigid blasts).
PBS (diagnostic): smear cells / smudge cells (fragile lymphocytes damaged during slide preparation) [1][4]
Detailed PBS findings in CLL [13]:
| Finding | Description | Significance |
|---|---|---|
| Smear / smudge cells | Fragile CLL lymphocytes mechanically disrupted when spread on glass slide [4][5] | Virtually pathognomonic for CLL |
| Small-to-medium sized lymphocytes | High N:C ratio, round nuclei, condensed chromatin (mature), no nucleoli, smooth cytoplasmic border [13] | Confirms "mature" lymphoid phenotype (not blasts) |
| Prolymphocytes | Larger cells with prominent nucleolus; if > 55%, reclassify as prolymphocytic leukaemia | Small numbers acceptable in CLL; if increasing, suggests transformation |
| Genuine thrombocytopenia with no clumps | Occasional giant platelets [13] | Rules out pseudothrombocytopenia (EDTA artifact) |
| Little polychromasia, no spherocytes, no rouleaux [13] | If spherocytes present → suspect concurrent AIHA | Rouleaux would suggest myeloma or chronic inflammation instead |
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]
| Marker | Expected in CLL | Explanation |
|---|---|---|
| CD19 | Positive | Pan-B-cell marker — confirms B-cell lineage |
| CD20 | Positive but DIM (weak expression) | B-cell marker; dim expression distinguishes CLL from other B-LPDs where CD20 is bright (e.g., MCL, HCL) |
| CD5 | Positive | CD5 expression on a B cell → CLL or mantle cell lymphoma [11] — aberrant T-cell marker on B cells |
| CD23 | Positive | Key differentiator: CLL is CD23+; MCL is CD23− |
| CD200 | Positive | Helps distinguish from MCL (CD200−); not always tested |
| sIg (SmIg) | Dim (extremely low levels) | Monoclonal — either κ or λ but not both (light chain restriction proves clonality) [2] |
| FMC7 | Negative | Negative in CLL; positive in MCL and PLL |
| CD22 | Weak expression [11] | Another marker that is characteristically dim in CLL |
| CD79b | Weak/negative | Dim in CLL; bright in MCL |
How Flow Cytometry Works — First Principles
Flow cytometry passes cells in a single-file stream through a laser beam. Fluorescent antibodies attached to the cells' surface markers emit light when hit by the laser. The machine detects which antibodies stuck (i.e., which markers are present) and how brightly they fluoresce (i.e., the intensity/density of marker expression).
Flow cytometry is superior to immunohistochemistry due to ability to detect two or more markers simultaneously, rapid turnaround time, greater quantitative capacity and higher sensitivity for certain markers [14].
This is why CLL can be diagnosed from peripheral blood — you don't need tissue. The cells are already circulating.
Matutes/Moreau Scoring System (CLL Immunophenotypic Score)
A scoring system used to confirm CLL immunophenotype:
| Feature | Score 1 | Score 0 |
|---|---|---|
| sIg | Weak | Strong |
| CD5 | Positive | Negative |
| CD23 | Positive | Negative |
| FMC7 | Negative | Positive |
| CD79b | Weak/Negative | Strong |
- Score 4–5: Classic CLL
- Score 3: Atypical CLL (consider other LPDs)
- Score 0–2: NOT CLL (investigate for other LPDs)
3.4 Prognostic / Risk Stratification Investigations
These investigations are NOT needed for diagnosis but are essential for treatment decision-making and prognostication.
Cytogenetics: for specific chromosomal aberrations, eg. del(17p), del(11q) [5]
FISH (fluorescence in situ hybridisation) is preferred over conventional karyotyping because CLL cells have a low mitotic index (they don't divide much — remember, the problem is impaired apoptosis, not rampant proliferation), making it hard to catch them in metaphase for karyotyping.
| Abnormality | Frequency | Prognostic Impact | Clinical Relevance |
|---|---|---|---|
| del(13q14) | ~55% | Favourable (sole abnormality) | Most common; targets miR-15a/16-1 (negative regulators of BCL-2) |
| Trisomy 12 | ~15% | Intermediate | Often associated with atypical morphology |
| del(11q22-23) | ~25% | Unfavourable | Targets ATM gene (DNA damage response); bulky lymphadenopathy |
| del(17p13) | ~7% at dx | Very unfavourable | Targets TP53; resistant to chemoimmunotherapy; mandates novel agents |
| Normal | ~20% | Intermediate | — |
| Test | What It Shows | Clinical Significance |
|---|---|---|
| IGHV mutation status | Mutated vs unmutated immunoglobulin heavy chain variable region | Mutated → better prognosis (median survival > 20 years); unmutated → worse prognosis |
| TP53 mutation | Point mutations in TP53 (can occur WITHOUT del(17p)) | Same poor prognosis as del(17p); must test both FISH and sequencing |
| NOTCH1, SF3B1, BIRC3 mutations | Recurrent somatic mutations found by NGS | Adverse prognostic markers; NOTCH1 mutation a/w Richter transformation |
| ZAP70 expression | ZAP70-positive CLL has worse prognosis [11] | Surrogate marker for IGHV unmutated status; tested by flow cytometry |
| CD38 expression | High CD38 → worse prognosis | Another flow cytometry prognostic marker |
| β2-microglobulin | High LDH and β2-microglobulin in ~60% [5] | Reflects tumour burden; independent prognostic marker |
Use of the abnormal immunophenotype for minimal residual disease monitoring after treatment [11] — after treatment, flow cytometry can detect residual CLL cells at very low levels (< 1 in 10,000 leukocytes = MRD-negative). MRD negativity is increasingly used as a treatment endpoint, especially with venetoclax-based regimens.
Hypogammaglobulinaemia is present in ~25% at diagnosis, increasing over time [2][5]:
- ↓ IgG, IgA and IgM [2]
- Why? CLL cells are functionally incompetent and suppress normal B-cell function → reduced antibody production
- Clinical significance: increased susceptibility to infections; may require IVIg replacement if recurrent severe infections
Rarely, CLL can produce a monoclonal paraprotein (in up to 5%) [5] — this is important to distinguish from Waldenström macroglobulinaemia or myeloma.
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
- 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
| Investigation | Purpose | Expected Findings |
|---|---|---|
| LDH | Tumour burden / haemolysis screen | ↑ in CLL; markedly ↑ suggests Richter transformation or AIHA |
| Haptoglobin, unconjugated bilirubin, reticulocyte count | Screen for AIHA | ↓ haptoglobin, ↑ unconjugated bilirubin, ↑ reticulocytes = haemolysis [12] |
| Direct antiglobulin test (DAT / Coombs) | Confirm immune-mediated haemolysis | Positive (IgG ± C3d) in warm AIHA [12] |
| CT scan (neck, chest, abdomen, pelvis) | Assess lymphadenopathy, organomegaly | Generalised lymphadenopathy, hepatosplenomegaly; useful for treatment planning |
| PET-CT | Suspected Richter transformation | Discordantly high SUV uptake in one node (SUV > 5) suggests transformation |
| Hepatitis B serology (HBsAg, anti-HBc, anti-HBs) | Pre-treatment screening | Rituximab (anti-CD20) can reactivate occult hepatitis B [16] — HBV prophylaxis with entecavir if HBsAg+ or anti-HBc+ |
| Uric acid, potassium, phosphate, calcium, creatinine | Tumour lysis syndrome risk assessment | Usually low risk in CLL (indolent), but important with venetoclax initiation |
Pre-Treatment HBV Screening Is Mandatory in Hong Kong
Anti-CD20 (rituximab) and anti-CD52 (alemtuzumab) can reactivate occult hepatitis B [16]. Given Hong Kong's high HBV carrier rate (~7–8% of the population), this is critically important. HBV reactivation can be FATAL — one of the earliest reported cases was a patient who recovered from lymphoma but died from fulminant liver failure 11 months after stopping rituximab [16]. Always check HBsAg, anti-HBc, and anti-HBs before initiating anti-CD20 therapy.
| Investigation | Diagnostic vs Prognostic | Key Finding in CLL |
|---|---|---|
| CBC D/C | Diagnostic | Lymphocytosis ≥ 5 × 10⁹/L |
| PBS | Diagnostic | Smudge cells, mature small lymphocytes |
| Flow cytometry | Diagnostic (definitive) | CD5+, CD19+, CD20 dim, CD23+, sIg dim, light chain restriction |
| FISH | Prognostic | del(13q) good; del(17p) poor |
| IGHV mutation | Prognostic | Mutated = good; unmutated = poor |
| TP53 mutation/del(17p) | Prognostic + treatment selection | Mandates novel agents over chemoimmunotherapy |
| ZAP70 | Prognostic | Positive = worse prognosis |
| β2-microglobulin | Prognostic | Higher = higher tumour burden |
| BM biopsy | NOT required for dx | Useful for treatment response, unexplained cytopenias |
| DAT (Coombs) | Complication screen | Positive → AIHA |
| Serum Ig | Complication screen | Hypogammaglobulinaemia → infection risk |
High Yield: The CLL Diagnosis in 3 Steps
- CBC: Persistent lymphocytosis (≥ 5 × 10⁹/L B lymphocytes)
- PBS: Smudge cells + mature small lymphocytes with condensed chromatin
- Flow cytometry: CD5+, CD19+, CD20 dim, CD23+, sIg dim with light chain restriction
BM biopsy is NOT required for diagnosis [1][2][5]. This is one of the few haematological malignancies diagnosed entirely from peripheral blood.
Active Recall - Diagnosis and Investigations of CLL
References
[1] Senior notes: Maksim Medicine Notes.pdf (Haematology, p.177) [2] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (CLL Diagnosis section, p.1411–1413) [3] Senior notes: Ryan Ho Fundamentals.pdf (Lymphoid neoplasm classification, p.400) [4] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (CLL, p.24) [5] Senior notes: Ryan Ho Haemtology.pdf (CLL section, p.67) [6] Lecture slides: GC 060. High white cell count.pdf (CLL slides, p.33–34) [11] Lecture slides: Laboratory Diagnostic Investigations Seminar_Flow cytometry in haematology.pdf (CD5 on B cell, p.23; CD20/CD22 intensity, p.25; ZAP70/MRD, p.44) [12] Senior notes: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (AIHA diagnosis, p.6) [13] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (CLL PBS findings, p.8) [14] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (Flow cytometry and immunophenotyping, p.764) [15] Senior notes: Ryan Ho Fundamentals.pdf (MCICM framework, p.390–391) [16] Senior notes: Block A - I am a hepatitis B carrier.pdf (Rituximab and HBV reactivation, p.68)
Management of Chronic Lymphocytic Leukaemia (CLL)
1. Fundamental Principles of CLL Management
Before diving into specifics, there are several overarching principles that distinguish CLL management from virtually every other leukaemia. Understanding why these principles exist is essential.
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
Why Watch and Wait? — The Logic
Avoid early treatment → may shorten the life expectancy if instituted early for indolent disease [5]. The rationale: (1) Treatment toxicity may cause more harm than the disease itself in early stages. (2) Older chemotherapies are not curative. (3) Many patients, especially Rai 0/Binet A, may never need treatment in their lifetime. (4) There is no proven overall survival benefit from early treatment with chemoimmunotherapy.
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.
Not every CLL patient needs treatment. The iwCLL guidelines define specific indications [1]:
Indications of treatment [1]:
- Advanced stage: Rai stage III/IV (i.e., anaemia or thrombocytopenia from marrow failure)
- Symptomatic: Severe B symptoms, bulky lymphadenopathy/splenomegaly
- Active disease progression: Lymphocytosis ≥ 50% increase over 2 months or lymphocyte doubling time ≤ 6 months
- Disease-related complications: Refractory AIHA/ITP, recurrent infections, Richter's transformation
Let me explain each from first principles:
| Indication | Why This Mandates Treatment |
|---|---|
| Rai III/IV (Hb < 110, Plt < 100) | Cytopenias mean the bone marrow is failing due to CLL infiltration → without treatment, progressive marrow failure → fatal bleeding/infection |
| Severe B symptoms | Fever, drenching sweats, > 10% weight loss → indicate high tumour burden and systemic inflammatory state → quality of life severely impaired |
| Bulky lymphadenopathy/splenomegaly | Causing compressive symptoms; indicates high tumour burden |
| Rapidly progressive lymphocytosis | ≥ 50% increase in 2 months or doubling time ≤ 6 months → disease is accelerating → will soon cause marrow failure or organ compromise |
| Refractory AIHA/ITP | Autoimmune cytopenias not responding to steroids/standard therapy → the underlying CLL must be treated |
| Recurrent infections | Reflects severe immune dysfunction from CLL → treating CLL may improve immune function |
| Richter's transformation | Transformation to aggressive lymphoma (DLBCL) → requires urgent treatment as DLBCL regimen |
What Is NOT an Indication for Treatment
An absolute lymphocyte count of 100 × 10⁹/L alone is NOT an indication for treatment if the patient is asymptomatic, has no cytopenias, and the count is stable. High lymphocyte count ≠ treatment indication. It is the rate of rise and consequences that matter.
4. Treatment Modalities in Detail
Early stage CLL → No treatment, W&W (watch and wait) [4][6]
No treatment in early stages [6]
| Aspect | Detail |
|---|---|
| Who qualifies | Rai 0 / Binet A [1] (and often Rai I–II / Binet B if asymptomatic and stable) |
| What it involves | Regular clinical review every 3–6 months: CBC D/C, physical examination for lymphadenopathy/organomegaly, symptom assessment |
| How long | Indefinitely, until treatment indication develops — some patients NEVER need treatment |
| Why not treat early | No overall survival benefit from early treatment with chemoimmunotherapy; treatment toxicity may cause net harm |
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)
4.2 Chemoimmunotherapy (CIT) — Traditional Approach
Young and fit: chemotherapy based with fludarabine, cyclophosphamide, rituximab [4][6]
FCR Regimen — the historical "gold standard" for fit CLL patients without del(17p)/TP53 mutation:
| Drug | Class | Mechanism | Why Used in CLL |
|---|---|---|---|
| Fludarabine (flud-ARA-been) | Purine analogue (nucleoside analogue) | Incorporates into DNA → inhibits DNA synthesis and repair → induces apoptosis via p53-dependent pathway | Highly active against CLL cells; achieves deep remissions |
| Cyclophosphamide (sigh-clo-FOSS-fa-mide) | Alkylating agent | Cross-links DNA strands → prevents replication → cell death | Synergistic with fludarabine; broadens cytotoxicity |
| Rituximab (rit-UX-i-mab) | Anti-CD20 monoclonal antibody | Binds CD20 on B cells → complement-dependent cytotoxicity (CDC) + antibody-dependent cellular cytotoxicity (ADCC) → B-cell depletion | CD20 is expressed (albeit dimly) on CLL cells |
Key toxicities of FCR:
- Myelosuppression → neutropenia, infection risk (particularly prolonged T-cell depletion from fludarabine → risk of PJP, CMV, herpes)
- Secondary malignancies (MDS/AML) from alkylating agent
- Infusion reactions with rituximab (first dose)
- Rituximab can reactivate occult hepatitis B [16] — must screen HBV serology pre-treatment
Why Is FCR p53-Dependent?
Both fludarabine and cyclophosphamide work by damaging DNA. For this DNA damage to kill the cell, the cell needs a functional p53 pathway to trigger apoptosis. CLL cells with del(17p) or TP53 mutations have lost p53 function → they survive DNA damage → FCR is ineffective. This is why del(17p)/TP53 patients must receive p53-independent agents (BTK inhibitors, BCL-2 inhibitors).
Important note on current practice (2025–2026): In current guidelines, BTK inhibitors (ibrutinib/acalabrutinib) or venetoclax-based regimens are increasingly used as first-line therapy even in young/fit patients, gradually displacing FCR. However, FCR remains relevant for IGHV-mutated CLL without del(17p)/TP53 mutation, where it can achieve long-term MRD-negative remissions (potentially "functional cure" in a subset).
| Drug | Class | Mechanism | Why Used |
|---|---|---|---|
| Chlorambucil (klor-AM-byoo-sil) | Alkylating agent | Cross-links DNA → cell death | Well-tolerated oral agent; minimal toxicity; suitable for elderly/frail patients |
4.3 Novel Targeted Agents — The Modern Era
New small molecules targeting specific signal pathways [4][6]:
These agents represent a paradigm shift in CLL management. They target the specific pathogenic pathways that drive CLL cell survival (see pathophysiology section). They work independently of p53, making them effective in del(17p)/TP53-mutated disease.
BTK = Bruton's Tyrosine Kinase ("Bruton" was the physician who described X-linked agammaglobulinaemia, where BTK is mutated → no B cells → no antibodies)
BTK is a crucial kinase in the B-cell receptor (BCR) signalling pathway. In CLL, constitutive BCR signalling drives cell survival and proliferation.
| Drug | Generation | Key Features |
|---|---|---|
| Ibrutinib | 1st generation | First-in-class; irreversibly inhibits BTK; highly effective across all risk groups including del(17p); now regarded as a standard option for both young and old patients [5] |
| Acalabrutinib | 2nd generation | More selective BTK inhibitor; fewer off-target effects (less atrial fibrillation, less bleeding) than ibrutinib |
| Zanubrutinib | 2nd generation | Another selective BTK inhibitor; increasingly used |
Mechanism: BTK inhibitors block BCR signalling → CLL cells lose survival signals → apoptosis. They also disrupt chemokine receptor signalling → CLL cells are expelled from the protective lymph node microenvironment into the blood → transient lymphocytosis at treatment initiation (this is expected and NOT a sign of treatment failure).
Key side effects of ibrutinib:
- ↑ susceptibility to bleeding [5] — ibrutinib inhibits collagen receptor signalling in platelets (off-target effect on Tec-family kinases); must hold ibrutinib before surgery
- Atrial fibrillation (~5–15%) — off-target cardiac kinase inhibition
- Hypertension
- Infections (pneumonia, opportunistic)
- Arthralgia
- 2nd-generation agents (acalabrutinib, zanubrutinib) have reduced rates of AF and bleeding
Duration: BTK inhibitors are given continuously (daily oral) until disease progression or intolerable toxicity. They are NOT time-limited (unlike venetoclax-based regimens).
BCL-2 = B-Cell Lymphoma 2 — the master anti-apoptotic protein that CLL cells overexpress to resist programmed cell death.
| Drug | Mechanism | Key Features |
|---|---|---|
| Venetoclax (ven-EH-toh-klax) | BH3-mimetic → occupies the BH3-binding groove on BCL-2 → displaces pro-apoptotic proteins (BAX, BAK) → triggers mitochondrial outer membrane permeabilisation → cytochrome c release → caspase activation → apoptosis | Directly targets the core survival mechanism of CLL; p53-independent; achieves deep MRD-negative remissions |
Key clinical considerations:
- Usually combined with obinutuzumab (anti-CD20) as first-line → fixed-duration treatment (12 months) → MRD-driven endpoint
- Tumour lysis syndrome (TLS) is the main concern — venetoclax is so effective at killing CLL cells that rapid cell death can release potassium, phosphate, uric acid, and nucleic acids → hyperuricaemia, hyperkalaemia, hyperphosphataemia, hypocalcaemia, acute kidney injury
- Requires dose ramp-up over 5 weeks (20mg → 50mg → 100mg → 200mg → 400mg)
- Risk stratification based on tumour burden (lymphocyte count, LN size)
- Prophylaxis: aggressive hydration, allopurinol, monitoring of electrolytes
- High-risk patients: hospitalisation for first dose escalation, rasburicase if needed
Advantage over BTK inhibitors: Venetoclax-based regimens are time-limited (typically 12–24 months), after which treatment stops if MRD-negative. BTK inhibitors are continuous.
| Drug | Mechanism | Key Features |
|---|---|---|
| Idelalisib (eye-DEL-a-lis-ib) | Inhibits PI3Kδ (phosphoinositide 3-kinase delta) → blocks downstream AKT/mTOR signalling → reduces CLL cell survival and proliferation | Generally less used in HK due to side effect profile [4] — hepatotoxicity, colitis, pneumonitis, opportunistic infections (PJP, CMV) |
- Usually combined with rituximab
- Reserved for relapsed/refractory disease
- Requires PJP prophylaxis (co-trimoxazole) and CMV monitoring
| Drug | Features |
|---|---|
| Rituximab | 1st-generation anti-CD20; chimeric (mouse/human); used in FCR |
| Obinutuzumab | 2nd-generation anti-CD20; glycoengineered for enhanced ADCC; superior to rituximab in CLL; used with chlorambucil or venetoclax |
| Ofatumumab | Fully human anti-CD20; binds a different CD20 epitope; used in refractory CLL |
HBV Reactivation Risk with Anti-CD20 Agents in Hong Kong
Anti-CD20 (rituximab) and anti-CD52 (alemtuzumab) can reactivate occult hepatitis B [16]. This is potentially dangerous and fatal [16]. In Hong Kong's high-prevalence setting, ALWAYS screen HBsAg, anti-HBc, anti-HBs before any anti-CD20 therapy. If positive, start antiviral prophylaxis (entecavir/tenofovir) and continue for ≥ 12 months after last dose.
- 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]
| Supportive Measure | Indication | Detail |
|---|---|---|
| Blood products | Symptomatic anaemia, thrombocytopenic bleeding | Packed RBC transfusion, platelet transfusion |
| Leukapheresis | Leukostasis (WBC > 250 × 10⁹/L with symptoms) | Emergency removal of excess WBCs; bridge to definitive therapy |
| IVIg replacement | Hypogammaglobulinaemia with recurrent severe infections | Monthly IVIg infusions to maintain IgG > 5 g/L |
| Infection prophylaxis | Treatment-related immunosuppression | PJP prophylaxis (co-trimoxazole) with fludarabine/idelalisib; aciclovir for herpes prophylaxis; HBV prophylaxis with anti-CD20 agents |
| Vaccination | Infection prevention | Pneumococcal, influenza, COVID-19 vaccines (note: response may be blunted due to CLL immune dysfunction; avoid live vaccines) |
| AIHA management | CLL-associated warm AIHA | Corticosteroids first-line; if refractory → treat underlying CLL; rituximab; splenectomy in refractory cases [12] |
| G-CSF | Febrile neutropenia / prolonged neutropenia | Granulocyte colony-stimulating factor to support neutrophil recovery |
| TLS prophylaxis | Venetoclax initiation | Allopurinol, hydration, electrolyte monitoring, dose ramp-up |
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.
| Clinical Scenario | Treatment |
|---|---|
| Early-stage asymptomatic (Rai 0 / Binet A) | W&W — No treatment [4][6] |
| Symptomatic/advanced, no del(17p)/TP53 mutation, young and fit | FCR [4][6] or BTK inhibitor ± anti-CD20 or venetoclax + obinutuzumab |
| Symptomatic/advanced, no del(17p)/TP53 mutation, old and frail | Chlorambucil [4][6] ± obinutuzumab, or BTK inhibitor, or venetoclax + obinutuzumab |
| Symptomatic/advanced, del(17p)/TP53 mutation (any fitness) | BTK inhibitor (ibrutinib/acalabrutinib/zanubrutinib) or venetoclax-based regimen — NOT FCR |
| Relapsed/refractory | Switch class: if failed CIT → BTK inhibitor or venetoclax; if failed BTK inhibitor → venetoclax (or vice versa); idelalisib + rituximab; allo-HSCT in select patients |
| Richter transformation | R-CHOP; consider allo-HSCT; clinical trials |
High Yield: The GC Lecture Treatment Summary
Treatment of CLL [6]:
- W&W
- Young and fit: chemotherapy based with fludarabine, cyclophosphamide, rituximab
- Old and frail: chlorambucil
- New small molecules targeting specific signal pathways:
- Ibrutinib, Acalabrutinib (BTK inhibitor)
- Idelalisib (PI3K inhibitor)
- Venetoclax (BCL2 inhibitor)
This is the highest-yield slide for the in-house exam. Know this cold.
| Agent | Key Contraindications / Cautions |
|---|---|
| FCR | Del(17p)/TP53 mutation (ineffective); severe renal impairment (fludarabine dose adjustment); active HBV without prophylaxis |
| Chlorambucil | Few absolute contraindications; caution in severe BM failure |
| Ibrutinib | Concomitant strong CYP3A4 inhibitors; caution with anticoagulants (bleeding risk); patients at high risk of atrial fibrillation |
| Venetoclax | Must use dose ramp-up (TLS risk); avoid strong CYP3A4 inhibitors during ramp-up; high tumour burden without adequate TLS prophylaxis |
| Idelalisib | History of hepatotoxicity, colitis, pneumonitis; generally less used in HK due to side effect profile [4] |
| Rituximab/obinutuzumab | Active HBV; severe infusion reactions; prior severe mucocutaneous reactions |
| Allo-HSCT | Age > 65–70 (relative); significant comorbidities; no suitable donor |
Active Recall - Management of CLL
References
[1] Senior notes: Maksim Medicine Notes.pdf (Haematology, p.177) [4] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (CLL treatment, p.25) [5] Senior notes: Ryan Ho Haemtology.pdf (CLL management, p.68) [6] Lecture slides: GC 060. High white cell count.pdf (CLL treatment, p.34) [12] Senior notes: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (AIHA treatment, p.6) [16] Senior notes: Block A - I am a hepatitis B carrier.pdf (Rituximab and HBV reactivation, p.68)
Complications of Chronic Lymphocytic Leukaemia (CLL)
CLL complications arise from three fundamental problems: (1) the disease itself (tumour burden, immune dysfunction, autoimmunity), (2) disease transformation (Richter), and (3) treatment-related toxicity. Understanding each complication's pathophysiology makes them logical rather than a list to memorise.
1. Infectious Complications — The Leading Cause of Morbidity and Mortality
Infection is the number one cause of death in CLL patients — accounting for ~30–50% of all deaths. This reflects the profound, multi-layered immune dysfunction intrinsic to CLL.
| Immune Defect | Mechanism | Clinical Consequence |
|---|---|---|
| Hypogammaglobulinaemia | CLL cells are functionally incompetent B cells that cannot produce effective antibodies; they also suppress normal B-cell function | Hypogammaglobulinaemia (~25%) [5] — ↓ IgG, IgA, IgM → recurrent sinopulmonary infections with encapsulated organisms (S. pneumoniae, H. influenzae) |
| T-cell dysfunction | CLL cells express immune checkpoint ligands (PD-L1) and produce immunosuppressive cytokines (IL-10, TGF-β) → suppress CD4+ and CD8+ T-cell function | Increased risk of opportunistic infections: herpes zoster reactivation, CMV, PJP |
| Neutropenia | (1) BM infiltration by CLL cells; (2) Treatment-related (chemotherapy, BTK inhibitors) | Risk of bacterial infections (Gram-negatives, Staphylococcus), fungal infections (Aspergillus, Candida) |
| Complement deficiency | Reduced complement activity (consumed or inadequately produced) | Impaired opsonisation and bacterial killing |
| Treatment-related immunosuppression | Fludarabine → prolonged CD4+ T-cell depletion (months to years); rituximab → B-cell depletion and HBV reactivation; idelalisib → PJP and CMV | Treatment deepens already impaired immunity |
| Phase | Major Pathogens | Prophylaxis |
|---|---|---|
| Untreated CLL | Encapsulated bacteria (S. pneumoniae, H. influenzae); Herpes zoster | Pneumococcal + influenza vaccination; IVIg if recurrent severe infections with IgG < 5 g/L |
| During/after fludarabine | PJP, CMV, herpes simplex/zoster, Listeria, Nocardia | Co-trimoxazole (PJP prophylaxis); aciclovir (herpes); CMV monitoring |
| During/after rituximab/obinutuzumab | HBV reactivation [16], PJP, CMV | Anti-CD20 → rituximab can reactivate occult hepatitis B; anti-CD52 → alemtuzumab can also do so [16] — HBV prophylaxis with entecavir/tenofovir; can also reactivate CMV, Parvovirus B19, Adenovirus, PCP/PJP [16] |
| During idelalisib | PJP (high risk), CMV reactivation, colitis (C. difficile) | Mandatory PJP prophylaxis; CMV PCR monitoring |
| During BTK inhibitors | Pneumonia, upper respiratory infections, invasive fungal infections (esp. aspergillosis with ibrutinib) | Risk stratified; no mandatory prophylaxis but clinical vigilance |
HBV Reactivation — A Hong Kong Priority
Rituximab can reactivate occult hepatitis B. This can be FATAL [16]. Given Hong Kong's ~7–8% HBV carrier rate, this is not a theoretical risk. The first reported case was over two decades ago — reactivation of occult hepatitis B in a patient who was anti-HBs positive, treated with rituximab for lymphoma [16]. Always screen and prophylax.
2. Autoimmune Complications
Autoimmune cytopenias are a hallmark complication of CLL, occurring in ~5–10% of patients. They arise because the dysregulated CLL immune environment allows autoreactive clones to escape suppression.
- 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
Autoimmune Cytopenias vs Disease-Related Cytopenias — An Important Distinction
Anaemia in CLL can be due to BM infiltration OR AIHA. Thrombocytopenia can be due to BM infiltration OR ITP. The treatment is different:
- BM infiltration → treat the CLL
- Autoimmune → corticosteroids first; if refractory, then treat CLL
To distinguish: check reticulocyte count, DAT, haemolysis markers, and BM biopsy if needed.
3. Richter Transformation — The Most Feared Complication
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.
- 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)
As CLL infiltrates the bone marrow, it physically displaces normal haematopoietic precursors. This leads to:
| Cytopenia | Consequence | Clinical Relevance |
|---|---|---|
| Anaemia | Fatigue, exertional dyspnoea, angina in elderly | Rai Stage III; treatment indication |
| Thrombocytopenia | Bleeding — petechiae, purpura, mucosal bleeding | Rai Stage IV; treatment indication |
| Neutropenia | Recurrent bacterial infections, febrile neutropenia | Often worsened by treatment |
Hypersplenism (from CLL-infiltrated spleen sequestering blood cells) contributes to all three cytopenias. Splenectomy is an option for refractory ITP or AIHA or to decrease transfusion requirements, but carries its own risks — life-threatening infection from encapsulated bacteria (overwhelming post-splenectomy infection, OPSI) [17].
- Hypogammaglobulinaemia is present in ~25% at diagnosis, rising to ~60% over time [5]
- Usually all three Ig classes are reduced (IgG, IgA, IgM) [5]
- Clinically: recurrent sinopulmonary infections, recurrent UTIs, skin infections
- Management: monthly IVIg infusions if IgG < 5 g/L with recurrent severe infections
- Vaccination responses are blunted → still recommended but may be less effective (especially after anti-CD20 therapy which depletes the remaining normal B cells)
CLL patients have a significantly increased risk of developing second cancers. This is due to:
- Immune surveillance failure — the dysfunctional immune system cannot adequately detect and eliminate early malignant cells
- Treatment-related mutagenesis — alkylating agents (cyclophosphamide, chlorambucil) and purine analogues (fludarabine) can cause DNA damage in normal cells → secondary MDS/AML
- Shared genetic susceptibility — genetic factors predisposing to CLL may also predispose to other cancers
| Second Malignancy | Approximate Risk |
|---|---|
| Skin cancers (SCC, BCC, melanoma) | 2–3× increased; most common second malignancy |
| Treatment-related MDS/AML | ~2–5% after fludarabine-based regimens; typically occurs 3–7 years after treatment |
| Solid organ tumours (lung, breast, GI) | Modestly increased |
| Other lymphoproliferative disorders | Occasionally |
Paraneoplastic pemphigus (PNP) is a rare but recognised paraneoplastic complication of CLL [18]. CLL is listed among the lymphoproliferative diseases associated with PNP [18], alongside non-Hodgkin lymphoma, Castleman disease, thymoma, and Waldenström macroglobulinaemia. PNP presents with severe painful mucosal erosions (oral, conjunctival, genital) and polymorphic skin lesions. Bronchiolitis obliterans (BOS) is a feared pulmonary complication of PNP with very poor prognosis [18].
- WBC count can be as high as > 100, risk of leukostasis if WBC > 250 [5]
- Leukostasis = microvascular occlusion by excessive leukaemic cells
- Much less common in CLL than in acute leukaemias because CLL cells are small and deformable (unlike large, rigid blasts)
- When it occurs: respiratory distress (pulmonary leukostasis), altered consciousness/visual changes (CNS leukostasis)
- Emergency management: leukapheresis for leukostasis [1] + initiate CLL-directed therapy urgently
| Treatment | Key Complications |
|---|---|
| FCR | Myelosuppression (severe neutropenia), prolonged T-cell depletion (→ opportunistic infections), secondary MDS/AML, tumour lysis syndrome, infusion reactions |
| Chlorambucil | Myelosuppression (usually mild), secondary MDS/AML (long-term), nausea |
| Ibrutinib | Bleeding (off-target platelet kinase inhibition), atrial fibrillation, hypertension, infections (invasive aspergillosis), arthralgia, diarrhoea |
| Acalabrutinib/Zanubrutinib | Similar to ibrutinib but less atrial fibrillation and bleeding; headache more common with acalabrutinib |
| Venetoclax | Tumour lysis syndrome (main acute concern — requires dose ramp-up, hydration, monitoring), neutropenia, infections |
| Idelalisib | Hepatotoxicity (transaminitis), autoimmune colitis, pneumonitis, PJP and CMV reactivation [16]; generally less used in HK due to side effect profile [4] |
| Rituximab/Obinutuzumab | Infusion reactions (especially first dose with obinutuzumab), HBV reactivation [16], progressive multifocal leukoencephalopathy (PML — rare but devastating JC virus reactivation), neutropenia |
| Allo-HSCT | Graft-versus-host disease (acute and chronic), graft failure, veno-occlusive disease, infections, organ toxicity, secondary malignancies [19] |
| Category | Specific Complications |
|---|---|
| Infections | Recurrent sinopulmonary (encapsulated bacteria); opportunistic (PJP, CMV, herpes zoster); HBV reactivation with anti-CD20 |
| Autoimmune | AIHA (most common), ITP, PRCA, autoimmune neutropenia |
| Transformation | Richter transformation → DLBCL (most common) or HL [4][6] |
| Marrow failure | Progressive anaemia, thrombocytopenia, neutropenia |
| Hypogammaglobulinaemia | Secondary immunodeficiency, recurrent infections |
| Second malignancies | Skin cancers, treatment-related MDS/AML, solid tumours |
| Paraneoplastic | Paraneoplastic pemphigus (rare) |
| Leukostasis | Rare in CLL (WBC > 250); respiratory and neurological compromise |
| Treatment-related | TLS (venetoclax), AF/bleeding (ibrutinib), hepatotoxicity/colitis (idelalisib), HBV reactivation (rituximab), secondary MDS/AML (alkylators) |
High Yield Summary — CLL Complications
The three must-know complications for exams:
- Richter transformation — CLL transforms to aggressive DLBCL; sudden clinical deterioration, rapidly enlarging LN, ↑↑ LDH; poor prognosis [4][6]
- Autoimmune cytopenias — AIHA (warm type, DAT positive) and ITP; distinguish from BM failure; refractory cases are an indication for CLL treatment [1]
- Infections — the leading cause of death; from hypogammaglobulinaemia + neutropenia + T-cell dysfunction; worsened by treatment; HBV reactivation with rituximab is a Hong Kong exam favourite [16]
Active Recall - Complications of CLL
References
[1] Senior notes: Maksim Medicine Notes.pdf (Haematology, p.177) [4] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (CLL complications, p.24) [5] Senior notes: Ryan Ho Haemtology.pdf (CLL findings and complications, p.67–68) [6] Lecture slides: GC 060. High white cell count.pdf (CLL — Richter transformation, p.33) [12] Senior notes: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (AIHA diagnosis and treatment, p.6) [16] Senior notes: Block A - I am a hepatitis B carrier.pdf (Rituximab and HBV reactivation, p.68) [17] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf (Splenectomy indications and complications, p.19) [18] Lecture slides: Derm General Clerkship 2026 Part2.pdf (Paraneoplastic pemphigus, p.28) [19] Senior notes: Ryan Ho Haemtology.pdf (HSCT complications, p.156)
High Yield Summary
- Definition: CLL = monoclonal proliferation of functionally incompetent mature B cells accumulating in blood, BM, and lymphoid tissues. Pathologically equivalent to SLL.
- Epidemiology: Most common leukaemia in Western adults; uncommon in Chinese. Median age 70. NEVER in children. M > F.
- Aetiology: Unknown; genetic predisposition; arises from MBL. Key cytogenetics: del(13q) most common/good prognosis; del(17p)/TP53 = poor prognosis.
- Pathophysiology: Impaired apoptosis (BCL-2 overexpression) > uncontrolled proliferation. BCR signalling via BTK and PI3K drives survival. Immune dysfunction → hypogammaglobulinaemia, autoimmunity (AIHA, ITP).
- Classification: Rai (0–IV) and Binet (A–C) staging — purely clinical. 5 lymphoid sites: H&N, axillae, inguinal, spleen, liver.
- Clinical features: Most common = asymptomatic/incidental lymphocytosis. Constitutional (B) symptoms. Painless generalised lymphadenopathy, hepatosplenomegaly. Cytopenias (BM failure). Recurrent infections. Risk of Richter transformation (→ DLBCL).
- Smear/smudge cells on PBS are pathognomonic. Flow cytometry: CD5+, CD19+, CD20 dim, CD23+, sIg dim.
- Treatment: Watch & wait for early stage. FCR for young/fit. Chlorambucil for old/frail. Novel agents: ibrutinib/acalabrutinib (BTK inhibitors), venetoclax (BCL-2 inhibitor), idelalisib (PI3K inhibitor).
High Yield Summary — CLL Complications
The three must-know complications for exams:
- Richter transformation — CLL transforms to aggressive DLBCL; sudden clinical deterioration, rapidly enlarging LN, ↑↑ LDH; poor prognosis [4][6]
- Autoimmune cytopenias — AIHA (warm type, DAT positive) and ITP; distinguish from BM failure; refractory cases are an indication for CLL treatment [1]
- Infections — the leading cause of death; from hypogammaglobulinaemia + neutropenia + T-cell dysfunction; worsened by treatment; HBV reactivation with rituximab is a Hong Kong exam favourite [16]
Acute Lymphoid Leukaemia
Acute lymphoid leukaemia is a malignant clonal proliferation of lymphoid precursor cells (lymphoblasts) in the bone marrow, leading to impaired normal haematopoiesis and infiltration of various organs.
Chronic Myeloid Leukemia
Chronic myeloid leukemia is a myeloproliferative neoplasm characterized by the uncontrolled proliferation of mature and maturing granulocytes, driven by the BCR-ABL1 fusion gene resulting from the Philadelphia chromosome translocation t(9;22).