Acute Lymphoblastic Leukemia: Symptoms, Diagnosis and Treatment

Leukemia is a group of neoplastic disorders characterized by clonal proliferation of hematopoietic cells in the bone marrow, with abnormal cells spilling into the peripheral blood.

Classifications of Leukemia:

1. Based on Clinical Course:

• Acute Leukemia:
  • Rapid onset and progression.
  • Predominance of immature “blast” cells.
  • Fatal within weeks to months without treatment.
• Chronic Leukemia:
  • Insidious onset, slower progression.
  • Presence of more mature cells alongside blasts.
  • Survival for months to years without treatment.

2. Based on Cell Line Involved:

• Myeloid Lineage: Myelocytic/Granulocytic leukemia.
• Lymphoid Lineage: Lymphocytic leukemia.

Four Main Types:

1. Acute Myeloid Leukemia (AML)
2. Acute Lymphoblastic Leukemia (ALL)
3. Chronic Myeloid Leukemia (CML)
4. Chronic Lymphocytic Leukemia (CLL)

Etiology of Leukemia

Host-Related Risk Factors:

• Genetic syndromes (e.g., Down syndrome, Fanconi anemia)
• Hereditary chromosomal instability
• Immunodeficiency syndromes
• Pre-existing marrow disorders (e.g., MDS, aplastic anemia)

Environmental Risk Factors:

• Exposure to ionizing radiation
• Mutagenic chemicals (e.g., benzene)
• Certain chemotherapeutic agents
• Oncogenic viruses (e.g., HTLV-1, EBV)

Acute Lymphoblastic Leukemia (ALL)

Pathophysiology:

• Uncontrolled proliferation of lymphoid precursor cells (T or B lineage).
• Arrest in differentiation → accumulation of lymphoblasts.
• Bone marrow failure: anemia, thrombocytopenia, neutropenia.
• Extramedullary infiltration: liver, spleen, lymph nodes, CNS, testes.

Epidemiology:

• Most common pediatric cancer.
• Peak age: 2–5 years.
• Slight male predominance.
• Less common in adults; adult prognosis poorer.

Clinical Presentation

Bone Marrow Failure:

• Anemia: Fatigue, pallor, dyspnea.
• Thrombocytopenia: Petechiae, ecchymoses, bleeding.
• Neutropenia: Recurrent infections, fever.

Organ Infiltration:

• Hepatosplenomegaly
• Lymphadenopathy
• Bone pain: Especially in long bones (due to marrow expansion).
• CNS involvement: Headache, vomiting, cranial nerve palsies (in advanced disease).
• Mediastinal mass: More common in T-cell ALL (→ respiratory symptoms, SVC syndrome).
• Testicular enlargement: Occasional in boys due to leukemic infiltration.

Diagnosis of ALL

Initial Laboratory Findings:

• CBC: Variable WBC count, anemia, thrombocytopenia.
• Peripheral blood smear: Presence of lymphoblasts.
• Coagulation profile (to assess for DIC).

Definitive Diagnosis:

• Bone Marrow Aspiration and Biopsy:

  • 20% lymphoblasts (WHO criteria for ALL).

Cytochemical Staining:

• TdT+ (Terminal deoxynucleotidyl transferase): Positive in 90% of cases.
• PAS+ (Periodic acid–Schiff): Characteristic block positivity.
• MPO & Sudan Black B: Negative (differentiates ALL from AML).

Immunophenotyping (Flow Cytometry):

• Determines lineage:
  • B-cell ALL: CD10, CD19, CD22.
  • T-cell ALL: CD2, CD3, CD7.

Cytogenetic and Molecular Studies:

• t(12;21): Favorable prognosis (common in children).
• Philadelphia chromosome (t(9;22)): Poor prognosis (common in adults).
• Other poor prognostic abnormalities: t(4;11), hypodiploidy.

Imaging and Other Tests:

• Chest X-ray: To assess mediastinal mass.
• Lumbar puncture: To assess CNS involvement.
• Testicular ultrasound (in males with testicular signs).

Prognosis and Risk Stratification

Favorable Prognostic Factors:

• Age 1–10 years
• WBC <50,000/μL at diagnosis
• B-cell subtype
• Good initial response to chemotherapy
• Specific genetic translocations (e.g., t(12;21))

Poor Prognostic Indicators:

• Age <1 year or >10 years
• High WBC count (>50,000/μL)
• T-cell ALL or Philadelphia chromosome-positive
• CNS/testicular involvement
• Poor response to induction therapy

Treatment of ALL

Phases of Chemotherapy:

1. Induction: Goal is remission (<5% blasts)
   • Vincristine, corticosteroids, anthracyclines, asparaginase.
2. Consolidation (Intensification):
   • Methotrexate, cytarabine, 6-MP.
3. Maintenance:
   • 6-MP, methotrexate ± vincristine/prednisone.
4. CNS Prophylaxis:
   • Intrathecal methotrexate ± cranial irradiation.

Targeted Therapy:

• Tyrosine kinase inhibitors (e.g., imatinib) for Ph+ ALL.

Hematopoietic Stem Cell Transplant (HSCT):

• Considered in high-risk patients or those with relapsed disease.

Complications

Disease-Related:

• Anemia, infections, bleeding
• CNS involvement
• Tumor lysis syndrome

Treatment-Related:

• Myelosuppression
• Secondary malignancies
• Organ toxicities (hepatotoxicity, neurotoxicity)
• Growth retardation in children

Key Takeaways for Exam:

• ALL is the most common leukemia in children.
• Presents with bone marrow failure, organ infiltration, and high lymphoblast count.
• TdT+ and PAS+ are hallmark features.
• Diagnosis confirmed via bone marrow biopsy.
• Favorable prognosis in children with good risk factors.
• CNS prophylaxis is essential due to risk of leukemic spread to the CNS.

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