Part I
Overview & Epidemiology
What leukaemia is, the four canonical subtypes, the size of the global burden, the age distributions that explain why ALL is a paediatric disease and CLL an octogenarian one, and the historical arc that turned an unintelligible “weisses Blut” into the most molecularly tractable cancer in medicine.
1. What is Leukaemia?
Leukaemia is a clonal malignancy of haematopoietic cells — the precursor cells of the bone marrow that normally generate the cellular elements of blood (red cells, granulocytes, monocytes, lymphocytes, platelets). The clonal cells expand in marrow, displace normal haematopoiesis, and spill into peripheral blood; the consequent cytopenias — anaemia, neutropenia, thrombocytopenia — explain the cardinal clinical features (pallor, infection, bleeding) and most of the early mortality.
Etymologically the word is Virchow’s. In 1845 he reported a patient with massively elevated leucocytes and dubbed the condition Leukämie (from the Greek leukos = white + haima = blood) — a literal description of the buffy-coat layer in a centrifuged sample. The same year, independently, Edinburgh pathologist John Hughes Bennett described the same disease as “suppuration of the blood.” Virchow’s terminology stuck.
2. The Four Major Types
The classical taxonomy crosses two axes — cell lineage (myeloid vs lymphoid) and tempo (acute vs chronic) — producing four headline diseases:
| Type | Cell of origin | Tempo | Typical age | Annual cases (US) |
|---|---|---|---|---|
| AML | Myeloid blast | Acute | Median 68–70 | ~20,000 |
| ALL | Lymphoid blast (mostly B-cell) | Acute | Bimodal (2–5 yrs; ≥50) | ~6,500 |
| CML | Myeloid (granulocyte) progenitor | Chronic | Median 64 | ~9,000 |
| CLL | Mature B-cell | Chronic | Median 70 | ~21,000 |
Several “orphan” entities sit alongside these four:
- Myelodysplastic syndromes (MDS) — clonal but pre-leukaemic; ~25–30% transform to AML.
- Myeloproliferative neoplasms (MPN) — polycythaemia vera (JAK2-V617F), essential thrombocythaemia, primary myelofibrosis.
- Hairy-cell leukaemia — rare mature B-cell leukaemia driven by BRAF-V600E; exquisitely sensitive to cladribine.
- Adult T-cell leukaemia/lymphoma (ATLL) — HTLV-1-driven mature T-cell disease, mostly southern Japan and the Caribbean.
- Acute promyelocytic leukaemia (APL) — AML M3 with t(15;17) PML-RARA; uniquely curable with ATRA + arsenic, no chemotherapy.
3. Acute vs Chronic — the Operational Divide
Despite the time-based language, the acute / chronic split is fundamentally about differentiation arrest:
Acute leukaemia
Blasts dominate
Maturation is blocked at the blast stage. By definition (WHO 2022), ≥20% blasts in marrow or peripheral blood, or a defining genetic lesion (e.g. PML::RARA, RUNX1::RUNX1T1, CBFB::MYH11) at any blast count. Untreated, acute leukaemias kill in weeks to months from marrow failure.
Chronic leukaemia
Mature cells expand
The clonal cells differentiate, sometimes nearly fully, but proliferate or accumulate inappropriately. CML produces a “left-shifted” granulocyte expansion; CLL accumulates small mature B-cells. Without treatment the natural history is years — CLL median survival historically ~10 yrs; CML 3–5 yrs pre-imatinib.
The clinical implications are stark. Acute leukaemia is a haematological emergency demanding induction chemotherapy within days. Chronic leukaemia is often watched for years before the first dose of any drug.
4. Global Incidence
~470 K
new cases / year worldwide
~310 K
deaths / year worldwide
~2.5%
of all cancers
~57 K
new cases / year USA
~30%
of all paediatric cancers (ALL dominant)
~14/100k
age-standardised incidence (high-income)
Sources: GLOBOCAN 2022 (IARC), SEER program (NCI), GBD 2019 collaborators. Incidence has been slowly rising in absolute numbers (population aging) but age-standardised rates have been roughly stable for AML/CLL and falling for CML since the introduction of imatinib (which converts CML into a chronic, often non-fatal disease and therefore inflates prevalence while reducing mortality).
Five-year survival has transformed in the imatinib and ibrutinib era:
| Type | 5-yr survival 1975 | 5-yr survival current (SEER) |
|---|---|---|
| CML | ~22% | ~71% (much higher in chronic-phase responders) |
| CLL | ~67% | ~88% |
| ALL (children) | ~57% | ~92% |
| ALL (adults) | ~30% | ~45–50% (Ph+ now ≥70%) |
| AML (≤60) | ~6% | ~50% |
| AML (>60) | ~2% | ~10–25% |
5. Age & Sex Distribution
Each leukaemia has a distinctive age profile that reflects its cell of origin and the mutations it depends on:
- ALL — sharp paediatric peak at 2–5 years, accounting for ~25% of all childhood cancer; a smaller second rise in older adults. ETV6-RUNX1-driven B-ALL is the prototypical childhood cancer.
- AML — rises steeply with age; median diagnosis ~68–70 years. AML in <60 yo and AML in ≥60 yo behave almost like different diseases (different mutations, different chemotherapy tolerance, different survival).
- CML — broad distribution, median age ~64 years; rare in childhood; very rare in infancy (where juvenile myelomonocytic leukaemia, JMML, takes its place).
- CLL — the most age-skewed: median diagnosis ~70 years; almost never under 40. Strong familial component.
Sex: most leukaemias have a slight male predominance (M:F ~1.3:1 for AML, ~1.7:1 for CLL), partly attributable to mutational events accumulating on the unprotected single X.
Geographic and ethnic patterns: CLL is rare in East Asia (~1/10 the rate seen in Caucasians) for incompletely understood genetic reasons; ATLL clusters in HTLV-1 endemic areas (southern Japan, Caribbean basin, parts of equatorial Africa).
6. Risk Factors
Most leukaemias are sporadic, but a stereotyped list of exposures and predisposing syndromes recurs:
| Class | Examples | Predisposes to |
|---|---|---|
| Ionising radiation | Hiroshima/Nagasaki survivors; therapeutic radiation | AML, ALL, CML |
| Chemicals | Benzene; formaldehyde; ethylene oxide | AML, MDS |
| Cytotoxic chemo | Alkylators (5–7 yr latency); topoisomerase-II inhibitors (1–3 yr; KMT2A) | Therapy-related AML/MDS (t-AML, t-MDS) |
| Tobacco | Smoking | Modest ↑ AML risk |
| Constitutional | Down syndrome (trisomy 21) | ~20× ↑ ALL; transient myeloproliferative disorder; AML M7 |
| Inherited BMF | Fanconi anaemia, dyskeratosis congenita, severe congenital neutropenia | AML, MDS |
| Germline TP53 | Li-Fraumeni | Hypodiploid ALL, therapy-related AML |
| Germline RUNX1 | Familial platelet disorder w/AML predisposition | AML, MDS |
| Germline DDX41 | Familial MDS/AML | AML, MDS (often older onset) |
| Viruses | HTLV-1 (ATLL); EBV (Burkitt-like) | ATLL; B-ALL with BL features |
| Clonal haematopoiesis | CHIP — DNMT3A, TET2, ASXL1, JAK2 | 10–15× ↑ MDS/AML risk over decades |
7. Clinical Presentation
The presenting features are the predictable consequence of marrow failure plus tissue infiltration:
Anaemia
Fatigue, pallor, exertional dyspnoea, angina in the elderly. Typically normocytic, normochromic; reticulocyte count low.
Neutropenia
Recurrent bacterial infection; oral/perianal ulcers; sepsis; neutropenic fever a haematological emergency.
Thrombocytopenia
Petechiae, mucosal bleeding, epistaxis, intracranial haemorrhage in extreme cases (especially APL with concurrent DIC).
Infiltration
Hepatosplenomegaly, lymphadenopathy (CLL, ALL); gum hypertrophy (AML M4/M5); bone pain; CNS disease (ALL).
Leucostasis
WBC >100×10⁹/L can sludge in pulmonary or cerebral microvasculature: hypoxia, confusion, retinal haemorrhage. AML myeloblasts most dangerous.
Tumour lysis
High proliferative index (Burkitt, T-ALL, blast-phase CML): hyperuricaemia, hyperkalaemia, hyperphosphataemia, acute kidney injury. Allopurinol or rasburicase.
Chronic leukaemias are often incidental findings: a CBC drawn for unrelated reasons shows lymphocytosis (CLL) or leucocytosis with left shift (CML). Many CLL patients are asymptomatic for years.
8. A Brief History
- 1845 — John Hughes Bennett (Edinburgh) and Rudolf Virchow (Berlin) independently describe leukaemia. Virchow coins Leukämie.
- 1856 — Virchow distinguishes “splenic” (CML-like) from “lymphatic” (lymphoid) leukaemias.
- 1877 — Paul Ehrlich’s aniline staining reveals myeloid vs lymphoid morphology.
- 1947 — Sidney Farber achieves transient remission of paediatric ALL with aminopterin (anti-folate) — the dawn of cancer chemotherapy.
- 1948 — 6-mercaptopurine synthesised (Elion & Hitchings).
- 1960 — Peter Nowell & David Hungerford in Philadelphia describe a small abnormal chromosome in CML — the “Philadelphia chromosome.” First specific cancer cytogenetic lesion.
- 1973 — Janet Rowley shows the Ph chromosome is t(9;22), not a deletion.
- 1976 — FAB classification of acute leukaemias.
- 1982–84 — BCR-ABL1 fusion gene cloned (de Klein, Heisterkamp, Groffen, Witte).
- 1988 — Huang & Wang report ATRA-induced remission in APL — differentiation therapy.
- 1996 — STI-571 (later imatinib) shown to inhibit BCR-ABL kinase (Druker, Lydon, Buchdunger).
- 2001 — Imatinib FDA-approved for CML; IRIS trial reports unprecedented response rates.
- 2008 — First whole-genome sequence of an AML (Ley et al., Nature).
- 2014 — Ibrutinib (BTK inhibitor) approved for CLL (RESONATE trial).
- 2016 — Venetoclax (BCL2 inhibitor) approved for del(17p) CLL.
- 2017 — Tisagenlecleucel (CD19 CAR-T) approved for paediatric/young-adult relapsed B-ALL.
- 2017 — Midostaurin approved for FLT3-mutant AML (RATIFY).
- 2018 — Venetoclax + azacitidine reshape elderly AML therapy (VIALE-A).
- 2022 — WHO 5th edition and ICC integrate molecular classification of myeloid and lymphoid neoplasms.