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Acute Leukaemia – ALL

  • Uncontrolled proliferation of hematopoietic precursor cells with loss of maturation and differentiation
    • The malignant cells (blasts) take over the BM and suppress normal haematopoiesis
  • Auer rods – is characteristic of AML
    • Linear reddish cytoplasmic inclusions, diagnostic of myeloid lineage

Complications

  • Suppression of normal hematopoiesis
    • High risk of infx (granulocytopenia), and hemorrhage (thrombocytopenia)
  • Metabolic complications
    • Hyperuricemia, hyperphosphatemia, hyperkalemia – due to high cell turnover in malignant cells
    • Tumour lysis syndrome with ARF – due to urate crystals depositing in tubules (during chemo)
      • Allopurinol started and urine is alkalised prior to chemo to prevent this
  • Hyperleukocytosis and leukostasis syndrome
    • High blast count increases blood viscosity
    • Leukostasis syndrome (blasts >50,000/Μl) – altered mental status, respiratory failure, CHF
      • MC in AML
      • Leukapheresis (removal of WBCs) used to reduce blast count

Diagnosis

  • CBC and blood smear
  • BM aspirate
  • Cytochemical stains
    • MPO – positive in AML
    • Sudan black B – positive in AML
    • PAS – positive in some ALL
  • Flow cytometry
  • Cytogenetics

Complications of therapy

  • Chemo with cytotoxic agents causes BM aplasis which leads to cytopenias
  • Infections – E.coli, K.pneumoniae, Pseudomonas, S.aureus. Fungal infections. Viral (HSV, VZV, CMV)
  • Hemorrhage – due to thrombocytopenia. Prophylactic platelet transfusion given
  • Other SEs – N, V, alopecia, infertility
  • Cytosine arabinoside – cerebellar dysfunction
  • Anthracyclines (daunorubicin/doxorubicin) – cardiomyopathy
  • Therapy-related AML

1. ACUTE LYMPHOBLASTIC LEUKEMIA

Pathophysiology and Classification

  • Clonal proliferation of immature lymphocyte precursors – can be B or T cell precursors (B = 80% of cases)
  • FAB classification – based only on morphology, doesn’t mention phenotypes; limited prognostic value
  • WHO classification – differentiates based on phenotype (B vs T cell precursors) and cytogenetic anomalies

Epidemiology

  • MC in childhood – 1-5 years of age
  • Increased risk in children with Down syndrome
  • Other predisposing anomalies – Fanconi anaemia, ataxia-telangiectasia

Clinical features

  • CF are related to BM infiltration and suppression of normal hematopoiesis
  • Pallor, fatigue
  • Petechiae and other bleeding signs
  • Fever
  • Bone/joint pain – due to expansion of medullar cavity by malignant cells
  • HSM, lymphadenopathy
  • CNS involvement – leukemic meningitis
    • BBB decreases penetration of chemotherapy into CSF – provides a ‘pharmacological sanctuary’ for the leukemic cells
  • Painless enlargement of testes
  • Precursor T-cell ALL – large mediastinal mass
    • May present as respiratory distress

Diagnosis

  • Anemia, thrombocytopenia
  • Variable WCC – high/normal/low
  • Blasts usually found on smear
    • Except in aleukemic leukemia
  • ↑LDH and UA
  • Bone marrow
    • Monomorphic population of blasts
    • Marked ↓ in normal hematopoietic precursors of all types
    • 50% are PAS+
    • Trephine/BM aspiration biopsy
  • Immunophenotype
    • Precursor B-cell ALL
      • Express CD19
      • CD10 (cALLA)
      • CD34
      • TdT+
    • Precursor T-cell ALL
      • CD2-8
      • TdT+
    • Burkit cell leukemia (Mature B-cell ALL)
      • Presence of Ig (kappa OR lambda)
      • CD 19, 20

Differential diagnosis

  • Reactive lymphocytosis – EBV, CMV
  • ITP – similar CFs (petechiae, bleeding)
  • Aplastic anemia

Treatment

  • 3 phases: remission induction, intensification, continuation
    • Tx usually lasts 2-3 years.
  • Induction – aims to induce remission
    • CTST + vincristine
      • Plus L-asparaginase or anthracycline in children
    • Lasts 4-6 weeks
  • Intensification – higher doses of the drugs in phase 1
    • E.g. methotrexate, high dose L-asparaginase, ara-C
    • Or combo of vincristine, dexamethasone, L-asp, doxorubicin
    • Lasts 6 months
  • Continuation
    • Weekly methotrexate (po/im) and daily 6-MPU (po)
    • Lasts 2 years
  • CNS therapy
    • Intrathecal methotrexate/ara-C
      • Combo with BBB penetrating drugs – dexamethasone
  • Neuropenic regime
    • I.V fluids, abx, antivirals, chlorhexidine

Complications of tx

  • Immediate
    • N, V, alopecia, infection, hemorrhage
  • Long term
    • Avascular necrosis of femoral head due to CTSTs
    • Leukoencephalopathy due to methotrexate
    • Rare – aggressive brain tumours
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