Acute Leukaemias (ALL & AML)
Pathology · Haematology · lean revision notes
Acute Leukaemias (ALL & AML)
Acute leukaemias are clonal malignancies of immature haematopoietic precursors (blasts) that proliferate uncontrollably, replace the marrow, and spill into peripheral blood. They are defined by ≥20% blasts in marrow or blood (WHO) and present acutely with marrow-failure symptoms. This is among the highest-yield haematology areas for NEET PG—cytogenetic-disease pairings, immunophenotyping markers and Auer rods recur every year.
Definition & Core Concept
A leukaemia is "acute" when the dominant cell is a blast (immature, undifferentiated precursor) and the disease is rapidly fatal if untreated (weeks to months). In contrast, chronic leukaemias are dominated by mature/maturing cells and follow an indolent course over years.
The two great divisions:
- Acute Lymphoblastic Leukaemia (ALL) — malignancy of lymphoid blasts (B-cell or T-cell). Peak: children (2–5 yr); commonest childhood malignancy.
- Acute Myeloid Leukaemia (AML) — malignancy of myeloid blasts. Peak: adults, median age ~65 yr; commonest acute leukaemia in adults.
High-yield: Blast cut-off for diagnosing acute leukaemia = ≥20% (WHO 2008 onwards; older FAB used 30%). Certain recurrent cytogenetic abnormalities—t(15;17), t(8;21), inv(16)—are diagnostic of AML regardless of blast count, even if <20%.
Classification
FAB (French-American-British) Classification
The FAB system is morphology-based and remains exam favourite despite WHO supremacy.
| FAB | Name | Key Feature |
|---|---|---|
| M0 | AML, minimally differentiated | No granules; MPO negative on light microscopy, needs immunophenotyping |
| M1 | AML without maturation | Few granules; ≥3% MPO+ blasts |
| M2 | AML with maturation | t(8;21); Auer rods common |
| M3 | Acute Promyelocytic Leukaemia (APL) | t(15;17); faggot cells; DIC; ATRA-responsive |
| M4 | Acute myelomonocytic leukaemia | Myeloid + monocytic; M4Eo with inv(16) |
| M5 | Acute monocytic leukaemia | Gum infiltration, skin involvement; NSE+ |
| M6 | Acute erythroleukaemia (Di Guglielmo) | Dysplastic erythroid precursors; PAS+ |
| M7 | Acute megakaryoblastic leukaemia | Marrow fibrosis (dry tap); ↑in Down syndrome; CD41/CD61+ |
High-yield: M3 (APL) is the medical emergency—presents with DIC and bleeding. M7 is associated with Down syndrome and gives a dry tap due to marrow fibrosis. M5 classically causes gum hypertrophy and CNS/skin (leukaemia cutis) infiltration.
FAB Classification of ALL
| FAB | Morphology | Note |
|---|---|---|
| L1 | Small, uniform blasts, scanty cytoplasm | Commonest in children; best prognosis |
| L2 | Larger, heterogeneous blasts, prominent nucleoli | Commoner in adults |
| L3 | Vacuolated deeply basophilic cytoplasm | Burkitt-type / B-ALL; t(8;14); worst (in old schemes) |
WHO Classification (concept)
WHO supersedes FAB by integrating cytogenetics, molecular markers, and clinical history rather than morphology alone. Major AML groups: AML with recurrent genetic abnormalities, AML with myelodysplasia-related changes, therapy-related AML, and AML-NOS. WHO also reclassified L3 (Burkitt) out of ALL into mature B-cell neoplasms.
Etiology & Risk Factors
Acquired/environmental:
- Ionising radiation (atomic bomb survivors, radiotherapy).
- Benzene exposure → AML.
- Alkylating agents (cyclophosphamide, melphalan) → therapy-related AML, typically with del(5q)/del(7q), latency 5–7 yr.
- Topoisomerase-II inhibitors (etoposide) → AML with 11q23 (MLL/KMT2A) rearrangement, shorter latency 2–3 yr.
Genetic/constitutional:
- Down syndrome (trisomy 21) — ↑ both ALL and AML (especially M7); transient abnormal myelopoiesis in neonates.
- Fanconi anaemia, Bloom syndrome, ataxia-telangiectasia (DNA repair defects).
- Neurofibromatosis-1, Li-Fraumeni, Klinefelter.
High-yield mnemonic — leukaemogenic agents: "BART" = Benzene, Alkylating agents, Radiation, Topoisomerase inhibitors.
Pathophysiology
Leukaemogenesis follows the two-hit model:
- Class I mutations → confer proliferative/survival advantage (e.g. FLT3-ITD, RAS, KIT mutations).
- Class II mutations → block differentiation (e.g. fusion genes from t(15;17) PML-RARA, t(8;21) RUNX1-RUNX1T1).
Together they produce a clone that both divides excessively and fails to mature, accumulating as blasts. Blasts crowd out normal haematopoiesis → pancytopenia (anaemia, neutropenia, thrombocytopenia)—the basis of clinical presentation.
In APL, the PML-RARA fusion blocks retinoic-acid-mediated promyelocyte maturation. ATRA (all-trans retinoic acid) overrides this block pharmacologically, forcing differentiation—a unique "differentiation therapy."
Clinical Features
Symptoms reflect marrow failure plus organ infiltration:
Marrow failure:
- Anaemia → fatigue, pallor, dyspnoea.
- Thrombocytopenia → petechiae, ecchymoses, mucosal bleeding.
- Neutropenia → fever, recurrent infections.
Infiltration / proliferation:
- Bone pain & tenderness (marrow expansion)—prominent in childhood ALL.
- Hepatosplenomegaly, lymphadenopathy (more in ALL).
- CNS involvement (cranial nerve palsies, headache)—ALL > AML; ALL needs prophylactic intrathecal therapy.
- Testicular infiltration—a sanctuary site & relapse source in ALL.
- Gum hypertrophy & skin (leukaemia cutis)—monocytic AML (M4/M5).
- Chloroma / granulocytic sarcoma—solid green-tinged tumour mass (myeloperoxidase pigment), AML, esp. t(8;21).
- Mediastinal mass—T-ALL in adolescent males (thymic origin) ± SVC obstruction.
- Mediastinal/anterior mass + high WBC—think T-ALL.
High-yield: APL (M3) presents with catastrophic bleeding/DIC at diagnosis—the prothrombotic-fibrinolytic granules of promyelocytes trigger consumptive coagulopathy. Start ATRA immediately on clinical suspicion, before genetic confirmation, to reduce early mortality.
Diagnosis & Investigations
Approach — stepwise:
Peripheral smear + CBC → Bone marrow aspiration & biopsy (≥20% blasts) → Cytochemistry → Immunophenotyping (flow cytometry) → Cytogenetics/FISH + molecular (PCR) → integrate for WHO diagnosis and risk-stratify.
Blood & marrow
- CBC: anaemia, thrombocytopenia; WBC variable (may be high, normal, or low—"aleukaemic leukaemia").
- Smear: circulating blasts; Auer rods point to myeloid lineage.
- Marrow: ≥20% blasts; hypercellular (except dry tap in M7).
Cytochemistry (classic discriminator)
| Stain | AML | ALL |
|---|---|---|
| Myeloperoxidase (MPO) | Positive | Negative |
| Sudan Black B | Positive | Negative |
| Non-specific esterase (NSE) | Positive in monocytic (M4/M5) | Negative |
| PAS (block positivity) | Negative (except M6) | Positive (B-ALL) |
| Acid phosphatase | — | Focal positive in T-ALL |
| TdT | Negative | Positive (lymphoblasts) |
High-yield: Auer rods = AML (azurophilic crystalline rods of fused lysosomes/MPO). Bundles of Auer rods = "faggot cells" = APL (M3). MPO is the single best cytochemical marker for AML; TdT and PAS for ALL.
Immunophenotyping (flow cytometry) — high-yield markers
| Marker | Lineage |
|---|---|
| CD33, CD13, CD117, MPO | Myeloid (AML) |
| CD41, CD61, CD42 | Megakaryocytic (M7) |
| CD14, CD64 | Monocytic (M4/M5) |
| CD19, CD20, CD22, CD79a | B-lineage |
| CD10 (CALLA) | Common B-ALL (good prognosis) |
| CD2, CD3, CD5, CD7 | T-lineage (T-ALL) |
| CD34, TdT | Immaturity (both, stem/early) |
High-yield: CD10 = CALLA (common ALL antigen) → marks common B-ALL, the commonest and best-prognosis childhood subtype. CD19 = pan-B; CD33 = myeloid; CD34 = stem/progenitor immaturity marker.
Cytogenetics & Molecular — the exam goldmine
| Abnormality | Disease | Significance |
|---|---|---|
| t(15;17) PML-RARA | APL (M3) | ATRA-responsive; good prognosis |
| t(8;21) RUNX1-RUNX1T1 | AML-M2 | Favourable |
| inv(16)/t(16;16) CBFB-MYH11 | AML-M4Eo | Favourable |
| t(9;22) BCR-ABL (Philadelphia) | CML; Ph+ ALL | Poor in ALL (adults); imatinib-responsive |
| t(12;21) ETV6-RUNX1 | Childhood B-ALL | Best prognosis |
| t(8;14) MYC-IgH | Burkitt / B-ALL (L3) | Aggressive |
| t(1;19) E2A-PBX1 | Pre-B ALL | Intermediate |
| t(4;11) / 11q23 MLL(KMT2A) | Infant ALL, therapy-related AML | Poor |
| FLT3-ITD | AML (normal karyotype) | Poor; midostaurin target |
| NPM1 mutation | AML | Favourable (if FLT3-ITD negative) |
| Hyperdiploidy (>50) | Childhood B-ALL | Good |
| Hypodiploidy (<44) | B-ALL | Poor |
High-yield pairings to memorise cold: APL = t(15;17); Philadelphia = t(9;22) (CML and poor-prognosis adult ALL); best childhood ALL = t(12;21) & hyperdiploidy; infant ALL = t(4;11)/MLL.
Management & Drug of Choice
General phases (ALL)
Induction → Consolidation (intensification) → CNS prophylaxis → Maintenance.
- Induction: vincristine + prednisolone/dexamethasone + anthracycline (daunorubicin) + L-asparaginase → achieve remission.
- CNS prophylaxis: intrathecal methotrexate ± cranial irradiation (CNS is a sanctuary site; essential in ALL).
- Maintenance: prolonged (2–3 yr) oral 6-mercaptopurine + methotrexate.
- Ph+ ALL: add tyrosine kinase inhibitor (imatinib/dasatinib).
AML
- "7+3" regimen: cytarabine (Ara-C) for 7 days + daunorubicin for 3 days → induction → consolidation with high-dose cytarabine. Allogeneic stem cell transplant for high-risk/relapsed disease.
- FLT3-mutated AML: add midostaurin.
APL (M3) — special therapy
- ATRA (all-trans retinoic acid) + Arsenic trioxide (ATO) ± anthracycline. Differentiation therapy; chemo-free ATRA+ATO cures most low-risk APL.
- Aggressively support coagulopathy (FFP, cryoprecipitate, platelets).
High-yield: Drug of choice for APL = ATRA + arsenic trioxide. Watch for differentiation syndrome (retinoic acid syndrome)—fever, weight gain, pulmonary infiltrates, hypotension, effusions; treat with dexamethasone and hold ATRA if severe.
Tumour Lysis Syndrome (TLS)
Rapid blast lysis (esp. high-count ALL/Burkitt) → ↑K⁺, ↑PO₄³⁻, ↑uric acid, ↓Ca²⁺ → arrhythmia, AKI.
- Prophylaxis: hydration + allopurinol (or rasburicase for high risk—recombinant urate oxidase).
High-yield: TLS labs = high potassium, high phosphate, high urate, LOW calcium. Rasburicase is contraindicated in G6PD deficiency (causes haemolysis & methaemoglobinaemia).
Complications
- Pancytopenia complications: severe infection (neutropenic sepsis—medical emergency, start empirical broad-spectrum antibiotics within 1 hr), bleeding.
- DIC — especially APL.
- Tumour lysis syndrome — at presentation or with chemo.
- Leukostasis / hyperleukocytosis (WBC >100×10⁹/L) → CNS & pulmonary microvascular sludging; treat with leukapheresis + hydroxyurea; commoner in AML-M4/M5.
- CNS relapse, testicular relapse (sanctuary sites in ALL).
- Therapy-related: anthracycline cardiotoxicity, secondary malignancy, infertility.
Key Differentials
- Leukaemoid reaction vs AML: leukaemoid reaction has high LAP (leucocyte alkaline phosphatase) score and toxic granulation; CML has low LAP. Leukaemoid is reactive (infection), not clonal.
- Aplastic anaemia — pancytopenia but hypocellular marrow, no blasts.
- Myelodysplastic syndrome (MDS) — dysplasia, <20% blasts; may transform to AML.
- Leukaemoid/infectious mononucleosis — atypical lymphocytes, not blasts.
- ALL vs AML — use MPO/TdT/Auer rods and immunophenotype (see tables).
- Lymphoma with marrow involvement — mature lymphoid cells, nodal mass.
Prognostic Factors (quick)
| Favourable | Unfavourable |
|---|---|
| Child 2–10 yr (ALL) | Age <1 or >10 yr (ALL); elderly (AML) |
| WBC <50×10⁹/L | High WBC, hyperleukocytosis |
| Hyperdiploidy, t(12;21) | Hypodiploidy, t(9;22), t(4;11), FLT3-ITD |
| CD10+ common B-ALL | Pro-B, mature B (Burkitt) at presentation |
| Rapid MRD clearance | Persistent minimal residual disease (MRD) |
High-yield: MRD (minimal residual disease) assessment by flow/PCR after induction is now the strongest independent predictor of relapse in both ALL and AML.
Recently asked / exam angle
- Auer rod identification on smear → answer AML (and faggot cells → APL/M3).
- Cytogenetic-disease matching: t(15;17)→APL; t(9;22)→CML/Ph+ ALL; t(8;21)→M2; inv(16)→M4Eo; t(12;21)→best childhood ALL.
- Marker matching: CD10/CALLA → B-ALL; CD33 → myeloid; CD41/61 → M7; TdT → lymphoblast; MPO → AML.
- Dry tap + Down syndrome → M7 (megakaryoblastic).
- DIC at presentation + promyelocytes → APL, give ATRA + arsenic.
- Gum hypertrophy → monocytic AML (M4/M5).
- MPO = best cytochemical stain to distinguish AML from ALL.
- WHO blast cut-off = 20%; recurrent translocations diagnose AML at any blast %.
- Best-prognosis childhood ALL cytogenetics: t(12;21) & hyperdiploidy; worst: t(4;11)/MLL, hypodiploidy, Ph⁺.
- Rasburicase contraindicated in G6PD deficiency.
- L3 (Burkitt) reclassified by WHO as a mature B-cell neoplasm, not ALL.
Rapid revision
- Acute leukaemia = ≥20% blasts (WHO); ALL = children, AML = adults.
- Auer rods = AML; bundles ("faggot cells") = APL/M3.
- MPO & Sudan Black positive = AML; TdT & PAS positive = ALL.
- t(15;17) PML-RARA = APL, treat with ATRA + arsenic trioxide; beware differentiation syndrome (give dexamethasone) and DIC.
- t(9;22) Philadelphia = CML and poor-prognosis adult Ph⁺ ALL (add imatinib).
- CD10 = CALLA = common B-ALL (best childhood prognosis along with t(12;21)/hyperdiploidy).
- CD33 myeloid, CD19 B-cell, CD41/61 megakaryocytic (M7), CD34 immaturity.
- M7 (megakaryoblastic) → dry tap + Down syndrome; M5 → gum hypertrophy.
- AML induction = "7+3" (cytarabine 7d + daunorubicin 3d); ALL needs intrathecal methotrexate for CNS sanctuary.
- Tumour lysis: ↑K⁺, ↑PO₄, ↑urate, ↓Ca²⁺; prevent with hydration + allopurinol/rasburicase (avoid rasburicase in G6PD deficiency).
- FLT3-ITD = poor AML prognosis (midostaurin); NPM1+/FLT3− = favourable.
- Differentiate from leukaemoid reaction (high LAP) and aplastic anaemia (hypocellular, no blasts); MRD is the key relapse predictor.