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🩸 LEUKEMIA — Full Notes for 2nd Year MBBS

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1. DEFINITION

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2. CLASSIFICATION

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3. CHRONIC MYELOID LEUKEMIA (CML)

Epidemiology

• Adults 25–60 years; peak in 4th–5th decades
• ~4500 new cases/year in USA

Pathogenesis

• Hallmark: Philadelphia chromosome (Ph) — t(9;22)(q34;q11)
• Creates BCR-ABL fusion gene → BCR-ABL fusion protein (210 kDa tyrosine kinase)
• Present in >95% of cases (remainder detected by FISH/PCR)
• Arises from pluripotent HSC (affects granulocytic, erythroid, megakaryocytic, B-cell precursors)
• BCR-ABL constitutively activates RAS signalling → growth factor-independent proliferation
• Differentiation is NOT blocked → early disease = excess mature cells

Peripheral Blood Smear

• Leukocytosis — WBC often >100,000 cells/μL
• Spectrum of maturing granulocytes at all stages (myeloblasts → metamyelocytes → neutrophils)
• Basophilia and eosinophilia (characteristic)
• Thrombocytosis (elevated platelets)
• Low LAP score (Leukocyte Alkaline Phosphatase) — distinguishes from leukemoid reaction

Bone Marrow

• Hypercellular (markedly)
• Increased maturing granulocytic and megakaryocytic precursors
• M:E ratio markedly increased
• Extramedullary haematopoiesis in spleen (red pulp resembles bone marrow) → massive splenomegaly

Clinical Features

• Onset insidious — fatigue, weakness, weight loss
• Dragging sensation in abdomen (splenomegaly)
• Distinguish from leukemoid reaction: CML has low LAP score; leukemoid reaction has high LAP
• Blast crisis: transformation to AML/ALL (acquisition of additional mutations)

Treatment

• Imatinib (Gleevec) — BCR-ABL tyrosine kinase inhibitor; revolutionary treatment

• 80% achieve durable remission

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4. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

Epidemiology

• Most common leukemia of adults in Western world
• Mainly >50 years; males > females
• Less common in Asian populations

Pathogenesis

• Tumour of mature B cells (CD20+, CD5+)
• Increased survival > proliferation — key mechanism
• High BCL-2 (anti-apoptotic) → due to deletion of 13q (loss of miRNAs that negatively regulate BCL-2)
• BTK (Bruton tyrosine kinase) mediates BCR signalling → growth/survival
• CLL/SLL — same disease; CLL = peripheral blood lymphocyte count >5000/μL

Peripheral Blood Smear

• Lymphocytosis — absolute (small, mature-looking lymphocytes)
• Smudge cells (Basket cells) — fragile CLL cells disrupted during smear preparation (pathognomonic)
• Variable larger activated lymphocytes

Bone Marrow / Lymph Node

• Lymph nodes diffusely effaced by sheets of small lymphocytes
• Proliferation centres (foci of larger mitotically active cells) — pathognomonic for CLL/SLL
• Bone marrow, spleen, liver also involved

Immunophenotype

• CD20+, CD5+, surface Ig+ (B-cell marker)
• Only CLL/SLL and mantle cell lymphoma co-express CD5 among B-cell lymphomas

Cytogenetics

• Trisomy 12; deletions of 11q, 13q, 17q
• Chromosomal translocations rare (unlike other B-cell neoplasms)

Clinical Features

• Often asymptomatic initially
• Fatigue, weight loss, anorexia
• Generalised lymphadenopathy + hepatosplenomegaly (50–60%)
• Hypogammaglobulinaemia → bacterial infections
• Autoimmune haemolytic anaemia (warm type), autoimmune thrombocytopenia (~15%)
• WBC can range from mildly elevated to >200,000/μL
• Richter transformation — conversion to aggressive DLBCL (median survival <1 year)

Treatment

• BTK inhibitors (ibrutinib), BCL-2 inhibitors (venetoclax)
• Cure only with haematopoietic stem cell transplant

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5. ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)

Epidemiology

• Most common cancer of children (peak age 3 years)
• ~2500 new cases/year; slightly more in boys
• Hispanic/Latino children have highest incidence
• 85% B-ALL, 15% T-ALL

Pathogenesis

• Neoplasm of immature B (pre-B) or T (pre-T) lymphoblasts
• T-ALL: NOTCH1 mutations (50–70%) — essential for T-cell development
• B-ALL: mutations in PAX5, TCF3, ETV6, RUNX1, BCR-ABL1, KMT2A, PBX1
• Maturation arrest + increased self-renewal → stem cell-like phenotype
• ~90% have chromosomal changes: hyperdiploidy (>50 chr, good prognosis), hypodiploidy (poor)
• Key translocation in B-ALL: t(12;21) ETV6-RUNX1 (25% — most common, good prognosis)
• Ph+ B-ALL [t(9;22)] — worse prognosis

FAB Classification of ALL

Peripheral Blood / Bone Marrow Findings

• Bone marrow replaced by >20% lymphoblasts
• Peripheral blood: lymphoblasts present
• Pancytopenia (anaemia, thrombocytopenia, neutropenia) from marrow replacement
• Lymphoblasts: high N:C ratio, immature chromatin, nuclear irregularity (L2)

Cytochemical Stains

Immunophenotype

• B-ALL: CD19+, CD10 (CALLA)+, CD34+, TdT+, HLA-DR+, PAX5+
• T-ALL: CD7+, CD3+, TdT+, CD34±

Clinical Features

• Symptoms of bone marrow failure: fatigue, fever, bleeding (petechiae, ecchymoses)
• Bone pain (marrow expansion)
• Lymphadenopathy, hepatosplenomegaly
• CNS involvement (headache, vomiting, cranial nerve palsies) — more common than AML
• T-ALL: anterior mediastinal mass (thymus), may cause SVC syndrome
• Testicular involvement — sanctuary site

Prognosis

• B-ALL children: 80–90% cure with chemotherapy (best prognosis of all leukemias)
• Ph+ ALL: poor prognosis (treated with TKI + chemo)

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6. ACUTE MYELOID LEUKEMIA (AML)

Epidemiology

• Most common acute leukemia in adults (median age >60 years)
• ~13,000–20,000 new cases/year in USA

Pathogenesis

1. Transcription factor mutations → block myeloid differentiation
   • t(8;21) → RUNX1::RUNX1T1 — disturbs RUNX1/CBFB transcription factor
   • inv(16) → CBFB::MYH11
   • t(15;17) → PML::RARα (acute promyelocytic leukemia, APL, M3)
2. Tyrosine kinase/RAS signalling mutations → promote proliferation (FLT3, RAS)
3. Epigenome regulators (TET2, DNMT3A, IDH1/2)
4. Tumour suppressor mutations (TP53 — therapy-related AML)

FAB Classification of AML

Peripheral Blood / Bone Marrow Findings

• ≥20% myeloid blasts in bone marrow (WHO criterion) — some cases with <20% if defining genetics present
• Myeloblasts: delicate nuclear chromatin, 2–4 nucleoli, voluminous cytoplasm with azurophilic granules
• Auer rods — needle-like azurophilic granules in cytoplasm; pathognomonic for AML; most numerous in M3 (APL)
• Monoblasts (M4/M5): folded/lobulated nuclei, no Auer rods, NSE+
• Occasional aleukemic leukemia — blasts absent from blood; bone marrow essential

Cytochemical Stains in AML

Clinical Features

• Rapid onset over weeks–months
• Fatigue, fever, spontaneous mucosal/cutaneous bleeding (thrombocytopenia)
• Petechiae, ecchymoses, gingival/urinary tract haemorrhage
• Infections — skin, lungs, urinary tract (opportunists: fungi, Pseudomonas)
• M5: gum hypertrophy (leukemia cutis), skin infiltration
• M3 (APL): severe DIC (disseminated intravascular coagulation) — release of procoagulants
• Myeloid sarcoma (chloroma) — localised soft tissue mass
• CNS spread less common than ALL

Cytogenetics in AML

Treatment

• Standard: 7+3 chemotherapy (cytarabine + anthracycline)
• APL (M3): ATRA (all-trans retinoic acid) + arsenic trioxide → induces differentiation of promyelocytes → excellent outcomes
• ~60% achieve complete remission; only 15–30% disease-free at 5 years overall

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7. FAB CLASSIFICATION SUMMARY — ACUTE LEUKEMIAS

AML — FAB (M0–M7)

ALL — FAB (L1–L3)

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8. COMPARISON TABLE: CML vs CLL vs ALL vs AML

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9. KEY MNEMONICS

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