Chronic Leukaemia
Acute vs chronic leukaemia:
- Acute leukaemias (ALL and AML) typically present with rapid onset, and patients are often clinically unwell
- Chronic leukaemias (CLL and CML) usually have an insidious onset and are frequently diagnosed incidentally
Clinical features within subtypes of acute and chronic leukaemia (i.e. ALL vs AML, and CLL vs CML) are largely overlapping.
Also read the Acute Leukaemia article.
Chronic Lymphoblastic Leukaemia (CLL)
Epidemiology
CLL predominantly affects older adults [Ref]
Median age at diagnosis: >70 y/o [Ref]
Aetiology
Advanced age is a well-recognised risk factor. [Ref]
Genetic factors also play a major role in susceptibility, including: [Ref]
- Family history
- Key genetic mutations (e.g. TP53, IGHV, etc.)
Clinical Manifestation
Many patients are asymptomatic and are diagnosed incidentally. [Ref]
If symptomatic, CLL tends to come on and progress gradually: [Ref]
- Lymphadenopathy – hallmark feature
- Painless, generalised lymphadenopathy is very typical
- Splenomegaly
- B symptoms (fever, night sweats, weight loss)
- Features of progressive bone marrow failure
- Anaemia → pallor, exertional dyspnoea, fatigue
- Thrombocytopaenia → easy bruising, unexplained bleeding
- Hypogammaglobulinaemia → frequent infections (e.g. pneumonia, URTIs)
- This occurs because the dysfunctional mature B lymphocytes do NOT make effective immunoglobulins
Richter transformation occurs in ~5-10% of patients. [Ref]
CLL transform into an aggressive high-grade lymphoma, most commonly diffuse large B-cell lymphoma.
It is important to differentiate features suggestive of malignant lymphadenopathy (as seen in Hodgkin lymphoma) from reactive lymphadenopathy.
| Feature | Malignant lymphadenopathy | Reactive lymphadenopathy |
|---|---|---|
| Mobility | Immobile / fixed to surrounding tissue | Mobile |
| Consistency | Hard / firm / rubbery | Soft / rubbery |
| Tenderness | Non-tender | Tender |
Referral Guidelines
The following NICE red flags and referral guidance for leukaemia are presentations, but may also identify chronic leukaemias (though they are generally less useful for this purpose)
| Suspected leukaemia in children and young people (<24 y/o) | If there is unexplained petechiae OR hepatosplenomegaly → refer for immediate specialist assessment (acute admission / referral within a few hours) |
| If there are of leukaemia → offer a very urgent FBC (within 48 hours) | |
| Suspected leukaemia in adults | Consider a very urgent FBC (within 48 hours) in adults with of leukaemia |
Investigation and Diagnosis
As suggested above (in the referral guidelines section), the initial test of choice is a FBC
Laboratory Tests
| Test / investigation | Interpretation / supportive findings |
|---|---|
| FBC | Isolated lymphocytosis is classic
Cytopaenias are often only seen in advanced disease
|
| Peripheral blood smear |
|
CLL is known to cause autoimmune complications: [Ref]
- Warm haemolytic anaemia (IgG-mediated), which presents as:
- Normocytic anaemia
- ↑ Reticulocytes
- Haemolysis markers (↑ unconjugated bilirubin, ↑ LDH, ↓ haptoglobin)
- Confirmatory test: +ve direct Coombs test (IgG +ve)
In CLL, anaemia can occur due to bone marrow failure OR immune dysregulation, where warm IgG antibodies destroy RBCs
- ITP, which presents as:
- Isolated thrombocytopaenia
- Normal coagulation
- Normal haemoglobin
CML vs CLL (FBC findings):
- CML: ↑WCC = ↑ myeloid cells (neutrophils + basophilia + eosinophilia); relatively normal lymphocyte count
- CLL: ↑WCC = ↑ lymphocytes; relatively normal myeloid cell count
Confirmatory Tests
CLL can be diagnosed with peripheral blood flow cytometry showing: [Ref]
- ↑ Monoclonal B lymphocytes (at least 5 x 109/L), and
- Showing B-cell markers (lymphocyte antigens) (e.g. CD19, CD20, CD23 +ve)
Unlike acute leukaemia, where a bone marrow biopsy is typically essential for diagnosis and classification, a bone marrow evaluation is generally not required to diagnose CLL
Management
Most patients do not require specific treatment and are managed with active observation [Ref]
Early intervention in asymptomatic patients has not shown survival benefits. [Ref]
Treatment
Some treatment indications (non-exhaustive): [Ref]
- Bone marrow failure (haemoglobin <10 mg/dL or platelet count <100 x 109/L)
- Massive or symptomatic splenomegaly
- Massive or symptomatic lymphadenopathy
- Significant constitutional symptoms
- Autoimmune complications (autoimmune anaemia or ITP) that do not respond to standard treatment
1st line treatment often involves either of the following (if indicated): [Ref]
- BTK inhibitor (e.g. acalabrutinib, zanubrutinib, ibrutinib)
- 12-month course of venetoclax + obinutuzumab
Before starting any treatment, it is important to establish TP53 status and IGHV mutation status to determine the most effective approach [Ref]
- TP53 mutated → continuous BTK inhibitor preferred
- IGHV mutated → either BTK inhibitor or time-limited venetoclax is appropriate
Prognosis
Key poor prognostic factors: [Ref]
- Presence of TP53 mutation
- ABSENCE of IGHV mutation
- >65 y/o
- Advanced clinical stage
Chronic Myeloblastic Leukaemia (CML)
Epidemiology
Mainly affects older adults, 70% of cases are diagnosed >65 y/o [Ref]
Aetiology
CML is characteristically driven by a specific genetic abnormality: t(9;22) creating the BCR‑ABL1 fusion (Philadelphia chromosome) [Ref]
The origin of such genetic abnormality is idiopathic in most cases
By contrast, most other leukaemias (i.e. ALL, AML, CLL)) do not have one universal pathognomonic lesion but instead show heterogeneous combinations of chromosomal abnormalities and gene mutations along with host factors and environmental risks.
Clinical Manifestation
Most patients are through routine blood tests and are often asymptomatic. [Ref]
If symptomatic
- Often vague constitutional symptoms (e.g. fatigue, weight loss, night sweats, low-grade fever)
- Massive splenomegaly is classic (→ LUQ discomfort / mass, early satiety)
- Features of leukostasis / hyperviscosity (→ headache, blurred vision, priapism)
Key distinguishing features:
- CML classically does NOT present with prominent lymphadenopathy (instead, it is a typical finding in lymphoid malignancies such as CLL and lymphoma)
- Recurrent infections is NOT a feature of CML, due to the intact granulocytes (e.g. neutrophils)
Referral Guidelines
The following NICE red flags and referral guidance for leukaemia are presentations, but may also identify chronic leukaemias (though they are generally less useful for this purpose)
| Suspected leukaemia in children and young people (<24 y/o) | If there is unexplained petechiae OR hepatosplenomegaly → refer for immediate specialist assessment (acute admission / referral within a few hours) |
| If there are of leukaemia → offer a very urgent FBC (within 48 hours) | |
| Suspected leukaemia in adults | Consider a very urgent FBC (within 48 hours) in adults with of leukaemia |
Investigation and Diagnosis
As suggested above (in the referral guidelines section), the initial test of choice is a FBC
Laboratory Tests
| Test / investigation | Interpretation / supportive findings |
|---|---|
| FBC |
|
| Peripheral blood smear |
|
CML vs CLL (FBC findings):
- CML: ↑WCC = ↑ myeloid cells (neutrophils + basophilia + eosinophilia); relatively normal lymphocyte count
- CLL: ↑WCC = ↑ lymphocytes; relatively normal myeloid cell count
Confirmatory Tests
Confirmatory test: identification of Philadelphia chromosome (BCR-ABL1) t(9;22) [Ref]
- This can be detected via cytogenetics (karyotyping), or PCR
- Peripheral blood is often sufficient
- Bone marrow evaluation is not strictly mandatory in every case, but it is commonly done for full baseline assessment
Management
1st line standard treatment: tyrosine kinase inhibitors [Ref]
- Imatinib (1st generation)
- Dasatinib, nilotinib, bosutinib (2nd generation)
The use of tyrosine-kinase inhibitors have transformed the disease into a manageable condition with a near-normal life expectancy for patients who respond well to treatment.
Prognosis
Response to treatment is monitored by quantifying the BCR-ABL1 transcripts (molecular product of the Philadelphia chromosome) [Ref]
- A reduction in BCR-ABL1 transcript levels following tyrosine-kinase inhibitor therapy is a critical prognostic factor