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)
Aetiology
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, URTIsUpper respiratory tract infections)
- 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 other clinical features 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 clinical features 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
- ITPImmune thrombocytopaenia, 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
Key management principles:
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]
- BTKBruton's tyrosine kinase 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)
Definition
CML is classified as a MPNMyeloproliferative neoplasm. However, it is typically considered separately from other MPNsMyeloproliferative neoplasms (i.e. primary myelofibrosis, polycythaemia vera, essential thrombocythaemia), due to its distinct molecular driver.
- CML is associated with the Philadelphia chromosome (BCR-ABL1 fusion gene)
- Other MPNsMyeloproliferative neoplasms are commonly associated with JAK2, CALR, or MPL mutations
MPNs are a group of clonal haematopoietic stem cell disorders characterised by overproduction of mature myeloid lineage cells. The 4 classical myeloproliferative neoplasms are:
- Primary myelofibrosis
- Polycythaemia vera
- Essential thrombocythaemia
- Chronic myeloid leukaemia
MPNs share several features:
- Mutations affecting the JAK-STAT signalling pathway (most commonly JAK2, but also CALR or MPL mutations)
- CML is distinct, driven by the Philadelphia chromosome (BCR-ABL fusion gene)
- Bone marrow hypercellularity
- ↑ Risk of thrombosis (particularly in polycythaemia vera and essential thrombocythaemia)
- Risk of transformation to AML
Epidemiology
Mainly affects older adults, 70% of cases are diagnosed in >65 y/o [Ref]
Aetiology
CML is driven by a specific genetic abnormality: t(9;22), which results in the BCR‑ABL1 fusion gene (Philadelphia chromosome) [Ref]
This chromosomal translocation arises idiopathically 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 asymptomatic and diagnosed incidentally through routine blood tests. [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 are 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 other clinical features 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 clinical features 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