Leukaemia — ALL, AML, CLL, CML
Medicine · Haematology · lean revision notes
Leukaemia — ALL, AML, CLL, CML
Leukaemias are clonal neoplastic proliferations of haematopoietic stem/progenitor cells that flood the marrow and blood. For NEET PG the gold lies in the cytogenetics, immunophenotype and the named morphology — match the marker to the leukaemia and you bank the marks. This note locks down the four big players plus their drugs of choice.
Definition & broad classification
Leukaemia = malignant clonal expansion of leucocyte precursors arising in bone marrow, spilling into peripheral blood. Split first by lineage (myeloid vs lymphoid) and by tempo (acute = immature blasts, rapidly fatal if untreated; chronic = relatively mature cells, indolent).
| Axis | Acute | Chronic |
|---|---|---|
| Myeloid | AML | CML |
| Lymphoid | ALL | CLL |
- Acute → ≥20% blasts in marrow/blood (WHO cut-off); presents over days–weeks with marrow failure (anaemia, bleeding, infection).
- Chronic → mature-appearing cells, presents over months–years, often incidental on routine CBC.
High-yield: ALL is the commonest childhood malignancy (peak 2–5 yr). AML is the commonest acute leukaemia in adults. CLL is the commonest leukaemia overall in the West / commonest in the elderly. CML is the classic myeloproliferative neoplasm with the Philadelphia chromosome.
Acute Myeloid Leukaemia (AML)
Pathophysiology & classification
Clonal proliferation of myeloblasts. The older FAB classification (M0–M7) is still examined; WHO now classifies by recurrent genetic abnormalities.
| FAB | Name | Hallmark |
|---|---|---|
| M0 | Minimally differentiated | MPO negative on light microscopy, markers needed |
| M1 | Without maturation | — |
| M2 | With maturation | t(8;21) RUNX1-RUNX1T1 (good prognosis) |
| M3 | Acute promyelocytic (APML) | t(15;17) PML-RARA, faggot cells, DIC |
| M4 | Myelomonocytic | — |
| M4Eo | + abnormal eosinophils | inv(16) CBFB-MYH11 (good prognosis) |
| M5 | Monocytic | gum infiltration, raised lysozyme |
| M6 | Erythroleukaemia | — |
| M7 | Megakaryoblastic | associated with Down syndrome; marrow fibrosis (dry tap) |
Clinical features
Marrow failure (fatigue, infections, bleeding). Gum hypertrophy & skin infiltration → monocytic (M4/M5). DIC → APML (M3). Chloroma/granulocytic sarcoma (greenish soft-tissue mass) and leukaemia cutis may occur.
Diagnosis
- Peripheral smear / marrow: myeloblasts with Auer rods (azurophilic crystalline rods = fused primary granules; pathognomonic of myeloid lineage). Bundles of Auer rods = faggot cells (APML).
- Cytochemistry: Myeloperoxidase (MPO) positive, Sudan Black B positive; non-specific esterase positive in monocytic types.
- Immunophenotype: CD13, CD33, CD117 (c-kit), CD34, HLA-DR. APML is characteristically HLA-DR negative & CD34 negative.
- Cytogenetics define prognosis and therapy.
High-yield: Auer rods = myeloid (AML), never seen in ALL. MPO positivity confirms myeloid lineage.
Management & drug of choice
- Standard AML induction = "7+3" → cytarabine (Ara-C) ×7 days + an anthracycline (daunorubicin/idarubicin) ×3 days, then consolidation; allogeneic stem cell transplant in high-risk.
- APML (M3) is a haematological emergency but the most curable AML: drug of choice = ATRA (all-trans retinoic acid) + arsenic trioxide. ATRA forces terminal differentiation of promyelocytes.
High-yield: APML t(15;17) → ATRA (differentiation therapy). Watch for differentiation (retinoic acid) syndrome — fever, fluid overload, pulmonary infiltrates, hypotension → treat with dexamethasone.
Good-prognosis cytogenetics flow: t(8;21) → inv(16) → t(15;17) are the favourable trio. FLT3-ITD, complex karyotype, monosomy 5/7 = poor prognosis. NPM1 mutation (without FLT3-ITD) = favourable.
Acute Lymphoblastic Leukaemia (ALL)
Pathophysiology
Clonal proliferation of lymphoblasts (B or T lineage). B-ALL is far more common; T-ALL classically presents in adolescent boys with a mediastinal (thymic) mass ± SVC obstruction.
Clinical features
Marrow failure plus organ infiltration: hepatosplenomegaly, lymphadenopathy, bone pain (children limping/refusing to walk), CNS involvement (cranial nerve palsies, meningism) and testicular relapse — both CNS and testis are pharmacological sanctuary sites.
Diagnosis
- Smear/marrow: small-to-medium blasts, scant cytoplasm, no Auer rods.
- Cytochemistry: PAS positive (block positivity), MPO negative; TdT positive (terminal deoxynucleotidyl transferase — a nuclear marker of lymphoblasts).
- Immunophenotype: CD10 (CALLA), CD19, CD79a, CD20, TdT for B-ALL; CD2, CD3, CD7 for T-ALL.
| Feature | AML | ALL |
|---|---|---|
| Age | Adults | Children (peak 2–5 yr) |
| Auer rods | Present | Absent |
| MPO / Sudan Black | Positive | Negative |
| PAS | Usually negative | Positive (block) |
| TdT | Negative | Positive |
| Key markers | CD13, CD33, CD117 | CD10, CD19, TdT |
| Best prognosis cytogen. | t(15;17), t(8;21), inv(16) | hyperdiploidy, t(12;21) |
| Worst cytogen. | FLT3-ITD, monosomy 5/7 | t(9;22) Ph+, MLL/KMT2A t(4;11), hypodiploidy |
High-yield: ALL prognosis — good: hyperdiploidy (>50 chromosomes), t(12;21) ETV6-RUNX1; bad: t(9;22) Philadelphia, t(4;11) (infants, MLL/KMT2A), hypodiploidy, age <1 or >10 yr, WBC >50,000, CNS disease.
Management & drug of choice
Phased: induction → CNS prophylaxis → consolidation → maintenance (total ≈ 2–3 yr).
- Induction backbone = vincristine + prednisolone/dexamethasone + L-asparaginase + an anthracycline.
- CNS prophylaxis = intrathecal methotrexate (± cranial radiotherapy) — mandatory because the CNS is a sanctuary site.
- Maintenance = 6-mercaptopurine + methotrexate.
- Ph+ ALL → add a tyrosine kinase inhibitor (imatinib/dasatinib).
High-yield: Childhood ALL is highly curable (~90% in standard-risk). L-asparaginase depletes asparagine that leukaemic cells cannot synthesise; toxicities = pancreatitis, thrombosis, hypofibrinogenaemia, hypersensitivity.
Chronic Myeloid Leukaemia (CML)
Pathophysiology — the Philadelphia story
CML is a myeloproliferative neoplasm driven by the Philadelphia chromosome = t(9;22)(q34;q11) → BCR-ABL1 fusion gene → constitutively active tyrosine kinase (p210) driving granulocyte proliferation.
Phases & clinical features
Three phases: chronic → accelerated → blast crisis (transformation to acute leukaemia — ~70% myeloid, ~30% lymphoid).
- Chronic phase: massive splenomegaly (commonest sign), fatigue, weight loss, hypermetabolic symptoms, gout, priapism.
- Marked leucocytosis with a "left shift" — the whole granulocytic series, basophilia and eosinophilia.
Diagnosis
- Smear: very high WBC, full spectrum of granulocyte maturation, basophilia (key clue).
- Leucocyte alkaline phosphatase (LAP/NAP score) is LOW in CML (helps distinguish from a leukaemoid reaction, where LAP is high).
- Confirmatory: BCR-ABL1 by FISH / RT-PCR (also used for monitoring minimal residual disease), cytogenetics for Ph chromosome.
| Distinguishing | CML | Leukaemoid reaction |
|---|---|---|
| LAP score | Low | High |
| Basophilia | Present | Absent |
| Philadelphia / BCR-ABL | Present | Absent |
| Splenomegaly | Massive | Usually mild/absent |
High-yield: Low LAP score + basophilia + massive splenomegaly + Philadelphia chromosome = CML. A leukaemoid reaction (reactive, e.g. severe sepsis) has a high LAP score.
Management & drug of choice
- Drug of choice = imatinib (a BCR-ABL tyrosine kinase inhibitor) — first targeted therapy, transformed CML into a chronic manageable disease.
- 2nd-generation TKIs: dasatinib, nilotinib, bosutinib; ponatinib for the resistant T315I gatekeeper mutation.
- Monitor response by serial BCR-ABL transcript levels (RT-PCR).
High-yield: Imatinib = first-line CML. Resistance via T315I mutation → use ponatinib. Allogeneic transplant reserved for TKI failure/blast crisis.
Chronic Lymphocytic Leukaemia (CLL)
Pathophysiology
Clonal accumulation of mature but functionally incompetent B-lymphocytes. Essentially the same disease as small lymphocytic lymphoma (SLL) — CLL when blood/marrow predominant, SLL when nodal.
Clinical features
Often asymptomatic / incidental lymphocytosis in the elderly. Painless lymphadenopathy, hepatosplenomegaly, recurrent infections (hypogammaglobulinaemia), and autoimmune haemolytic anaemia / ITP (warm AIHA, positive direct Coombs).
Diagnosis
- Smear: abundant mature small lymphocytes and smudge / smear cells (Gumprecht shadows) — fragile cells crushed on the slide.
- Immunophenotype: CD5 + CD19 + CD23 positive, weak surface immunoglobulin; CD5 co-expression (a T-cell marker) on B cells is the giveaway.
- Diagnostic threshold: clonal B-lymphocytosis ≥5 × 10⁹/L.
High-yield: CLL = CD5+ B cell + smudge cells. (Mantle cell lymphoma is also CD5+ but CD23 negative and carries t(11;14) cyclin D1 — a favourite distractor.)
Staging
Rai (US) and Binet (Europe) systems.
| Rai stage | Findings |
|---|---|
| 0 | Lymphocytosis only |
| I | + Lymphadenopathy |
| II | + Hepato/splenomegaly |
| III | + Anaemia (Hb <11) |
| IV | + Thrombocytopenia (<100,000) |
Management & complications
- Watch and wait if asymptomatic (early stage) — treatment does not improve survival in early indolent disease.
- Treat for symptomatic/advanced disease: BTK inhibitors (ibrutinib, acalabrutinib) and BCL-2 inhibitor venetoclax are now first-line; older chemo-immunotherapy = FCR (fludarabine + cyclophosphamide + rituximab).
- Richter transformation = aggressive change to diffuse large B-cell lymphoma (DLBCL) — sudden nodal enlargement, B symptoms, rising LDH; poor prognosis. del(17p)/TP53 predicts poor response to chemo.
High-yield: Richter transformation = CLL → DLBCL. Suspect with rapid nodal growth + systemic symptoms + soaring LDH.
Putting the markers together (one-glance map)
| Leukaemia | Signature genetics | Signature morphology/marker | Drug of choice |
|---|---|---|---|
| AML (general) | t(8;21), inv(16) good | Auer rods, MPO+ | 7+3 (cytarabine + anthracycline) |
| APML (M3) | t(15;17) PML-RARA | faggot cells, DIC, HLA-DR− | ATRA + arsenic trioxide |
| ALL | hyperdiploidy/t(12;21) good; t(9;22) bad | TdT+, PAS+, CD10/CD19 | Vincristine+steroid+asparaginase; IT methotrexate for CNS |
| CML | t(9;22) Philadelphia, BCR-ABL | low LAP, basophilia | Imatinib |
| CLL | del(13q) common; del(17p) bad | CD5+ B cell, smudge cells | Ibrutinib / venetoclax |
Tumour lysis & supportive care
Massive cell turnover (esp. high-count ALL/Burkitt, AML induction) → tumour lysis syndrome (TLS): ↑K⁺, ↑PO₄, ↑uric acid, ↓Ca²⁺, acute kidney injury.
- Prophylaxis: aggressive hydration + allopurinol; for high risk give rasburicase (recombinant urate oxidase — degrades uric acid).
High-yield: TLS tetrad = hyperkalaemia, hyperphosphataemia, hyperuricaemia, hypocalcaemia. Rasburicase for high-risk; avoid in G6PD deficiency (causes haemolysis).
Key differentials
- Leukaemoid reaction vs CML → LAP score (high vs low), BCR-ABL.
- Leukoerythroblastic blood picture (nucleated RBCs + immature myeloid) → marrow infiltration / myelofibrosis.
- Aplastic anaemia → pancytopenia but hypocellular marrow, no blasts (vs acute leukaemia which has a hypercellular blastic marrow).
- Infectious mononucleosis / pertussis → reactive lymphocytosis vs CLL (polyclonal vs clonal CD5+).
- Mantle cell lymphoma (CD5+, CD23−, cyclin D1) vs CLL (CD5+, CD23+).
Mnemonics
- AML cytogenetics that are "good": "8, 16, 17 are great" → t(8;21), inv(16), t(15;17).
- CLL markers: "5–19–23" → CD5, CD19, CD23.
- Auer rods are AML (both start with the same vowel sound) — never ALL.
- ALL maintenance: "MTX & 6-MP keep ALL at bay."
Recently asked / exam angle
- Match-the-translocation MCQs are perennial: t(9;22) → CML; t(15;17) → APML; t(8;21) → AML-M2; t(12;21) → good-prognosis ALL; t(11;14) → mantle cell (distractor for CLL).
- "Most curable AML" / "differentiation therapy" → APML with ATRA; recall retinoic acid syndrome treated with dexamethasone.
- "Low LAP score" image-based stems → CML; "smudge cells" → CLL; "Auer rods/faggot cells" → AML/APML.
- T315I mutation → ponatinib appears in pharmacology cross-questions.
- Richter transformation (CLL→DLBCL) and CLL CD5 positivity are repeat favourites.
- TdT positivity as the marker distinguishing ALL from AML; MPO for AML.
- Down syndrome associations: transient myeloproliferative disorder and AML-M7 (megakaryoblastic), plus increased ALL risk.
- Drug-toxicity matches: L-asparaginase → pancreatitis/thrombosis; cytarabine → cerebellar toxicity & conjunctivitis; vincristine → peripheral neuropathy; anthracyclines → cardiomyopathy.
Rapid revision
- Acute = ≥20% blasts; AML in adults, ALL in children (commonest childhood cancer).
- Auer rods + MPO positive = AML; TdT + PAS positive = ALL.
- APML = t(15;17), DIC, treat with ATRA + arsenic trioxide; beware retinoic acid syndrome (give dexamethasone).
- Favourable AML genetics: t(8;21), inv(16), t(15;17), NPM1; poor: FLT3-ITD, monosomy 5/7.
- AML induction = 7+3 (cytarabine 7 days + anthracycline 3 days).
- ALL good prognosis: hyperdiploidy, t(12;21); bad: t(9;22) Ph+, t(4;11), hypodiploidy, WBC >50k, age <1 or >10.
- ALL needs intrathecal methotrexate (CNS/testis = sanctuary sites); maintenance = 6-MP + MTX.
- CML = Philadelphia t(9;22) BCR-ABL, basophilia, massive splenomegaly, LOW LAP; DOC imatinib, T315I → ponatinib.
- Leukaemoid reaction = high LAP (opposite of CML).
- CLL = elderly, CD5+/CD19+/CD23+ B cells, smudge cells; complications = AIHA, hypogammaglobulinaemia, Richter (→DLBCL).
- CLL staging = Rai & Binet; early disease = watch and wait; advanced = ibrutinib/venetoclax.
- Tumour lysis = ↑K, ↑PO₄, ↑urate, ↓Ca; prevent with hydration + allopurinol, rasburicase for high risk (not in G6PD deficiency).