Notes · Pathology · 20 October 2026

Acute lymphoblastic leukemia (ALL)

Definition

• Acute lymphoblastic leukemia (ALL) is a malignant clonal proliferation of lymphoid progenitor cells (lymphoblasts) that infiltrates the bone marrow, peripheral blood, and often extramedullary sites.
• The disease is “acute” because the marrow is rapidly replaced by blasts, leading to marrow failure within weeks to months.

Epidemiology

• ALL accounts for ~25% of all adult leukemias and ~80% of childhood leukemias.
• Peak incidence in children is 2–5 years; a second smaller peak occurs in adults aged 50–70 years.
• Male : female ratio ≈ 1.3 : 1.
• In the United States, the age‑adjusted incidence is ≈ 1.7 per 100 000 per year (2023 data).

Aetiology (Risk Factors)

• Genetic predisposition – constitutional syndromes such as Down syndrome, Li‑Fraumeni, neurofibromatosis type 1, and familial ALL.
• Radiation exposure – therapeutic or accidental ionising radiation.
• Chemotherapy‑related – prior exposure to alkylating agents or topoisomerase II inhibitors (e.g., etoposide).
• Infectious agents – limited evidence linking Epstein‑Barr virus or human T‑lymphotropic virus‑1 (HTLV‑1) to specific ALL subtypes.
• Environmental – benzene, pesticides, and parental occupational exposures have been implicated in epidemiologic studies.

Pathophysiology

Clonal Evolution

• A single hematopoietic stem cell acquires genetic lesions that confer a growth advantage, leading to a dominant clone of lymphoblasts.

Key Genetic Lesions (high‑yield)

Molecular Pathways

• Tyrosine‑kinase activation (BCR‑ABL1) → constitutive signaling through RAS/RAF/MEK/ERK and PI3K/AKT pathways, driving proliferation.
• Transcription factor dysregulation (RUNX1, ETV6) → impaired differentiation.
• Cell‑cycle checkpoint loss (CDKN2A/B deletions) → unchecked division.

Immunophenotype (first‑time definitions)

• B‑ALL – expresses CD19, CD22, CD79a; most common subtype (≈ 85%).
• T‑ALL – expresses cytoplasmic CD3, CD7; more common in adolescents and young adults.
• Mature B‑ALL (Burkitt‑type) – surface IgM, CD20, CD10 negative; associated with MYC translocation t(8;14).

Bone‑Marrow Failure Mechanism

• Blast infiltration (> 20 % of nucleated cells) displaces normal hematopoiesis → anemia, neutropenia, thrombocytopenia.

Extramedullary Infiltration

• Central nervous system (CNS) – leukemic cells cross the blood‑brain barrier, often seeding the leptomeninges.
• Testes, spleen, liver, skin – less common but clinically relevant sites of disease.

Clinical Features

Note: In infants, presentation may be subtle, with irritability and failure to thrive.

Investigations

Hematology & Biochemistry

• Complete blood count (CBC) – often shows anemia, thrombocytopenia, and variable leukocyte count (may be low, normal, or high).
• Peripheral smear – presence of circulating blasts (large nuclei, scant cytoplasm, occasional Auer rods in mixed‑phenotype).
• Serum chemistry – elevated uric acid, potassium, phosphate, and lactate dehydrogenase (LDH) suggest high tumor turnover.

Bone‑Marrow Examination (definitive)

• Aspirate & trephine biopsy – ≥ 20 % lymphoblasts confirms diagnosis.
• Immunophenotyping by flow cytometry – determines B‑ vs T‑lineage and guides targeted therapy.

Cytogenetics & Molecular Studies

• Conventional karyotype – detects translocations, hyperdiploidy.
• Fluorescence in situ hybridisation (FISH) – rapid detection of BCR‑ABL1, ETV6‑RUNX1, MLL rearrangements.
• Polymerase chain reaction (PCR) / Next‑generation sequencing (NGS) – quantifies minimal residual disease (MRD) to 10⁻⁴ sensitivity.

Imaging

• Chest X‑ray – baseline before intensive chemotherapy.
• CT/MRI of head – if neurological symptoms.
• Ultrasound abdomen – assesses hepatosplenomegaly.

Lumbar Puncture

• Cerebrospinal fluid (CSF) analysis – cytology and flow cytometry for CNS disease; prophylactic intrathecal therapy is given regardless of initial CSF status.

Management (Current Guidelines – NCCN 2024 & BFM 2023)

General Principles

1. Risk‑adapted therapy – stratify patients into standard‑, intermediate‑, and high‑risk groups based on age, white‑blood‑cell count at presentation, cytogenetics, and MRD status.
2. Multiphase treatment – induction → consolidation (intensification) → maintenance (continuation).

Induction (Remission‑Induction)

• Regimen (B‑ALL):

  • Vincristine 1.5 mg/m² (max 2 mg) IV on days 1, 8, 15, 22.
  • Prednisone 60 mg/m² PO daily days 1‑28 (or dexamethasone 10 mg/m² PO daily).
  • L‑asparaginase (pegylated) 2,500 IU/m² IM or IV on days 1, 8, 15, 22.
  • Anthracycline (Daunorubicin 25 mg/m² IV days 1‑3) – omitted in some pediatric protocols to reduce cardiotoxicity.
  • Intrathecal methotrexate (MTX) 12 mg on days 1, 8, 15 for CNS prophylaxis.

• T‑ALL specific – add cyclophosphamide 1,000 mg/m² IV day 1 and etoposide 100 mg/m² IV days 1‑3.

• Targeted therapy – for Ph⁺ ALL, add a tyrosine‑kinase inhibitor (TKI) such as dasatinib 80 mg PO daily from day 1 (NCCN 2024).

• Goal – achieve morphological remission (≤ 5 % blasts) and MRD < 0.01 % by end of induction.

Consolidation / Intensification

• High‑dose methotrexate (3 g/m² IV over 24 h) with leucovorin rescue.
• Cytarabine 3 g/m² IV every 12 h for 2‑3 doses (especially in high‑risk adult protocols).
• Additional asparaginase cycles.
• Allogeneic stem‑cell transplantation (allo‑SCT) – indicated for high‑risk adult patients (age ≤ 55 y, Ph⁺, MRD‑positive after consolidation) per NCCN 2024.

Maintenance (12–24 months)

• 6‑mercaptopurine (6‑MP) 50 mg/m² PO daily.
• Methotrexate 20 mg/m² PO weekly.
• Prednisone 40 mg/m² PO on weekends (Saturday–Sunday).
• Periodic intrathecal MTX every 3 months.

Supportive Care

• Tumor lysis syndrome (TLS) prophylaxis – allopurinol 300 mg PO daily or rasburicase 0.2 mg/kg IV on day 1 of therapy; vigorous hydration 2–3 L/m²/day.
• Antimicrobial prophylaxis – fluoroquinolone during neutropenia, antifungal (posaconazole) if prolonged neutropenia > 7 days.
• Transfusion support – packed RBCs to keep Hb ≥ 8 g/dL; platelet transfusion to keep > 10 × 10⁹/L (or > 20 × 10⁹/L if bleeding).
• Growth‑factor support – G‑CSF (filgrastim 5 µg/kg/day) may be used after induction to shorten neutropenia.

Emerging & Salvage Options

• Blinatumomab (bispecific T‑cell engager) – FDA‑approved 2022 for MRD‑positive B‑ALL and relapsed/refractory disease.
• Inotuzumab ozogamicin (anti‑CD22 antibody‑drug conjugate) – for relapsed B‑ALL; monitor for veno‑occlusive disease.
• CAR‑T cell therapy (tisagenlecleucel) – indicated for patients ≤ 25 y with refractory B‑ALL; requires bridging chemotherapy and cytokine‑release‑syndrome monitoring.

Complications

High‑Yield Exam Points

• Age peaks: 2–5 y (childhood) and 50–70 y (adult).
• Diagnostic threshold: ≥ 20 % lymphoblasts in marrow.
• Key cytogenetics: t(12;21) – good prognosis; t(9;22) – poor but TKI‑responsive; MLL rearrangements – infant poor prognosis.
• Immunophenotype markers: CD19, CD22, CD79a for B‑ALL; cytoplasmic CD3, CD7 for T‑ALL.
• MRD importance: MRD ≥ 0.01 % after induction → intensify therapy or consider allo‑SCT.
• TLS prophylaxis is mandatory before starting asparaginase‑containing regimens.
• CNS prophylaxis is given to all patients regardless of initial CSF status (intrathecal MTX ± systemic high‑dose MTX).
• Ph⁺ ALL management includes a TKI (imatinib, dasatinib, or ponatinib) combined with chemotherapy; many adult protocols now use a TKI‑only induction followed by early transplant.

Practice questions

1. A 4‑year‑old boy presents with fever, bruising, and a peripheral smear showing 30 % blasts. Cytogenetics reveal t(12;21)(ETV6‑RUNX1). Which of the following statements is most accurate?
A. He requires immediate allogeneic stem‑cell transplantation.
B. His prognosis is favorable with standard chemotherapy.
C. He should be treated with a tyrosine‑kinase inhibitor.
D. He is at high risk for early CNS relapse.

Answer: B — t(12;21) confers a favorable prognosis and standard risk‑adapted chemotherapy is sufficient.

2. Which of the following agents is most specifically associated with pancreatitis in ALL therapy?
A. Vincristine
B. L‑asparaginase
C. Prednisone
D. Methotrexate

Answer: B — Asparaginase can cause pancreatitis, hepatic dysfunction, and coagulopathy.

3. In a 30‑year‑old patient with newly diagnosed Ph⁺ B‑ALL, the NCCN 2024 guideline recommends which of the following as part of induction therapy?
A. High‑dose cytarabine only
B. Dasatinib combined with standard chemotherapy
C. Blinatumomab as single‑agent induction
D. No CNS prophylaxis is required

Answer: B — Dasatinib (a TKI) is added to standard induction chemotherapy for Ph⁺ ALL.

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