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 Chronic Leukaemia article.
Acute Lymphoblastic Leukaemia (ALL)
Epidemiology
ALL is the most common childhood cancer [Ref]
- Bimodal distribution: peak incidence at 5 y/o and 50 y/o (less important)
- Median age of diagnosis: 14 y/o
For exam purposes (ONLY):
- Leukaemia in children is almost always ALL
- Leukaemia in adults is almost never ALL
Aetiology
There is often no specific cause for the development of ALL [Ref]
Key risk factors: [Ref]
- Inherited genetic syndromes
- Down syndrome – significantly increases the risk of both AML (500x risk <5 y/o) and ALL (20x risk) [Ref]
- Li-Fraumeni syndrome
A rare autosomal dominant condition caused by a mutation in the TP53 gene
It significantly increases the risk of developing various cancers at a young age, including breast cancer, sarcomas (bone/soft tissue), brain tumors, and adrenocortical cancer
- Ataxia telangiectasia
- Certain germline variants are linked to rare familial cases
Clinical Manifestation
Clinical features of ALL can be categorised by the underlying pathophysiology: [Ref]
| Underlying pathophysiology | Clinical manifestation |
|---|---|
| Local filtration → bone marrow failure → cytopenia |
|
| Extramedullary organ infiltration |
|
| Constitutional symptoms |
|
Referral Guidelines
The following NICE red flags and referral guidance for leukaemia are particularly important in suspected acute leukaemia, where early recognition and urgent investigation are critical (esp. in children).
| 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 It would be unnecessary to memorise this list, but the list NICE provided is as following:
|
|
| Suspected leukaemia in adults | Consider a very urgent FBC (within 48 hours) in adults with clinical features It would be unnecessary to memorise this list, but the list NICE provided is as following:
|
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 |
|
Confirmatory Test
Gold standard for diagnosis: bone marrow evaluation (often a bone marrow aspirate)
| Morphological assessment | >20% of bone marrow lymphoblasts is diagnostic |
| Immunophenotyping | ALL expresses lymphoid antigens:
MPO is -ve in ALL, helping distinguish it from AML (which is MPO +ve, and TdT -ve) |
| Genetic studies | Significant genetic markers
1) ETV6-RUNX1 fusion gene: t(12;21)
2) Philadelphia chromosome (BCR-ABL1 oncogene): t(9;22)
|
A lumbar puncture should be performed in all patients with ALL to check for CNS involvement (for meningeal infiltration and the presence of blasts in the CSF)
Although CNS involvement at diagnosis is relatively uncommon (5-8%), it is important to identify it immediately
- CNS +ve disease require more intensified treatment
- Standard systemic chemotherapy does NOT penetrate the BBB / CNS effectively
- Without testing and prophylaxis, ALL relapses rates in the CNS can reach 75%
Management
Standard management for ALL patients: [Ref]
| Systemic chemotherapy | Chemotherapy in ALL is made up of a multi-phase protocol, that usually takes 2.5-3 years
There is no single standard chemotherapy regimen to learn. |
| CNS prophylaxis | Intrathecal chemotherapy Typically using methotrexate, cytarabine, and hydrocortisone (triple intrathecal therapy), or methotrexate alone
|
Conditional management: [Ref]
| CNS disease at diagnosis | These patients require:
|
| Targeted therapy | Tyrosine kinase inhibitors (e.g. ponatinib, imatinib) are used for those with Philadelphia chromosome +ve |
Stem cell transplantation (allogeneic primarily) is generally considered in relapsed or high-risk ALL when standard chemotherapy alone is insufficient.
It is used more frequently in adults, as many children with ALL can be cured with chemotherapy alone.
Prognosis
Children have very favourable outcomes [Ref]
- Cure rates of ~80–90%
- 5-year overall survival >90%
Outcomes in adults are poorer and more variable: [Ref]
- Survival declines with increasing age (e.g. ~20–30% in patients >60 years)
- Depends on genetic subtype (e.g. Philadelphia chromosome +ve is associated with worse outcomes)
Acute Myeloid Leukaemia (AML)
Epidemiology
AML is the most common acute leukaemia in adults [Ref]
- Median age at diagnosis: 68 y/o
- >2/3 cases are diagnosed in >55 y/o
Aetiology
There is often no specific cause for the development of AML. [Ref]
Key risk factors: [Ref]
- Pre-existing haematological disorders (most common)
- Myelodysplastic syndrome
Characteristed by ineffective haematopoiesis and dysplasic maturation
Resulting in cytopaenias, despite a hypercellular bone marrow
– most significant - CMLChronic myeloid leukaemia
- Myeloproliferative neoplasms
Characteristed by excess proliferation of 1 or more myeloid cell lineages, leading to elevated blood counts
The classic 4 include:
- Chronic myeloid leukaemia
- Essential thrombocytosis
- Polycythaemia vera
- Primary myelofibrosis
- Myelodysplastic syndrome
- Previous exposure to cytotoxic agents / radiotherapy
- Exposure to benzene, petrochemicals (e.g. occupational or environmental exposure)
- Down syndrome
- Specifically increases the risk of developing acute megakaryoblastic leukaemia before 5 y/o
- Significantly increases the risk of both AML (500x risk) and ALL (20x risk) [Ref]
Clinical Manifestation
Clinical features of AML can be categorised by the underlying pathophysiology: [Ref]
| Underlying pathophysiology | Clinical manifestation |
|---|---|
| Local filtration → bone marrow failure → cytopenia |
|
| Extramedullary organ infiltration |
|
| Constitutional symptoms |
|
AML can also present as oncological emergencies: [Ref]
- DICDisseminated intravascular coagulation and subsequent intracranial haemorrhage – classically seen in acute pro-myelocytic leukaemia (APL)
- Significant leukocytosis → leukostasis
Symptomatic microvascular obstruction due to markedly elevated circulating leukemic blasts
→ respiratory distress, headache/confusion, visual disturbance, stroke-like symptoms
Referral Guidelines
The following NICE red flags and referral guidance for leukaemia are particularly important in suspected acute leukaemia, where early recognition and urgent investigation are critical (esp. in children).
| 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 It would be unnecessary to memorise this list, but the list NICE provided is as following:
|
|
| Suspected leukaemia in adults | Consider a very urgent FBC (within 48 hours) in adults with clinical features It would be unnecessary to memorise this list, but the list NICE provided is as following:
|
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 |
Acute promyelocytic leukaemia (APL) can cause DICDisseminated intravascular coagulation, which present as ↑ PT, ↑ APTT, ↓ fibrinogen, ↑ D-dimer |
| Peripheral blood smear |
|
Confirmatory Test
Gold standard for diagnosis: bone marrow evaluation (often a bone marrow aspirate) [Ref]
| Morphological assessment | >20% of bone marrow myeloblasts is diagnostic |
| Immunophenotyping | AML expresses myeloid antigens:
TdT is -ve in AML, helping distinguish it from ALL (which is TdT +ve, and MPO -ve) |
| Genetic studies | Most significant genetic marker: t(15;17) → PML-RARA
|
Management
| Acute promyelocytic leukaemia (APL) – confirmed by the presence of PML-RARA | Urgent treatment with:
|
| Standard AML |
|
Allogenic haematopoietic stem cell transplantation is a curative consolidation approach, that is used in:
- Adverse risk patients (recommended once patient is in remission)
- High risk of relapse (>35%)
- Relapse / refractory disease
It is used more commonly in AML than ALL.
Prognosis
Age is one of the most critical prognostic factor in AML [Ref]
- Survival rates drop significantly as age increases
- 62% 5-year survival rate in <50 y/o
- 9.4% 5-year survival rate in >65 y/o
Presence of the PML:RARA fusion transcript (hallmark of acute promyelocytic leukaemia) is considered a favourable-risk leukaemia [Ref]
- >90% cure rate with targeted therapy (all-trans retinoic acid and arsenic trioxide)
- Despite excellent long-term prognosis, acute promyelocytic leukaemia is notorious for presenting as an oncological emergency