Acute Lymphoblastic Leukemia (ALL) in Children

Topic Name Introduction Epidemiology Pathogenesis Classification Clinical Presentation Diagnosis Risk Stratification Treatment Prognosis Long-term Follow-up

Acute Lymphoblastic Leukemia in Children

Acute Lymphoblastic Leukemia (ALL) is the most common childhood cancer, accounting for approximately 25% of all pediatric malignancies. It is a hematologic malignancy characterized by the clonal proliferation of immature lymphoid cells in the bone marrow, blood, and other organs.

Key Points:

• Most common cancer in children
• Peaks in incidence between ages 2-5 years
• Arises from B-cell or T-cell precursors
• Rapid onset and progression if untreated
• Highly curable with current treatment protocols
• Requires intensive, prolonged multi-agent chemotherapy

Epidemiology

ALL primarily affects children, with distinct epidemiological features:

• Incidence: 3-4 cases per 100,000 children per year in the United States
• Age: Peak incidence between 2-5 years of age
• Gender: Slightly more common in males (1.2:1 male-to-female ratio)
• Race: Higher incidence in Hispanic and white children compared to Black children
• Geography: Higher incidence in developed countries

Risk Factors:

• Genetic syndromes: Down syndrome, Bloom syndrome, Ataxia-telangiectasia
• Ionizing radiation exposure
• Previous chemotherapy
• High birth weight
• Possible role of infectious exposures (population mixing hypothesis)

Pathogenesis

The pathogenesis of ALL involves genetic alterations that lead to arrested lymphoid differentiation and uncontrolled proliferation:

Key Genetic Abnormalities:

• Chromosomal translocations:
  • t(12;21) ETV6-RUNX1 (TEL-AML1): Most common in B-ALL
  • t(1;19) TCF3-PBX1 (E2A-PBX1)
  • t(9;22) BCR-ABL1 (Philadelphia chromosome)
• Hyperdiploidy (>50 chromosomes): Common in B-ALL, associated with good prognosis
• Hypodiploidy (<44 chromosomes): Associated with poor prognosis
• MLL (KMT2A) gene rearrangements: Common in infant ALL

Molecular Pathways:

• Dysregulation of lymphoid development genes (e.g., PAX5, IKZF1)
• Activation of oncogenic signaling pathways (e.g., RAS, JAK-STAT)
• Cell cycle dysregulation (e.g., CDKN2A/B deletions)

These genetic alterations lead to a block in lymphoid differentiation, increased proliferation, and resistance to apoptosis.

Classification

ALL is classified based on the lineage of the leukemic cells and their specific genetic features:

Immunophenotypic Classification:

1. B-cell ALL (80-85% of cases)
   • Early pre-B ALL
   • Pre-B ALL
   • Mature B-cell ALL (Burkitt leukemia)
2. T-cell ALL (15-20% of cases)
   • Early T-cell precursor ALL (ETP-ALL)
   • Non-ETP T-cell ALL

Genetic Classification (WHO 2016):

• B-ALL with recurrent genetic abnormalities:
  • t(12;21)(p13;q22) ETV6-RUNX1
  • t(9;22)(q34;q11.2) BCR-ABL1
  • t(v;11q23) KMT2A rearranged
  • t(1;19)(q23;p13.3) TCF3-PBX1
  • Hyperdiploidy
  • Hypodiploidy
  • iAMP21 RUNX1 amplified
• B-ALL with Ph-like gene expression profile
• T-ALL

Clinical Presentation

The clinical presentation of ALL can be variable, but common features include:

Symptoms and Signs:

• Bone marrow failure:
  • Fatigue, pallor (anemia)
  • Frequent infections (neutropenia)
  • Easy bruising, petechiae (thrombocytopenia)
• Bone pain, arthralgia
• Lymphadenopathy
• Hepatosplenomegaly
• Fever
• Weight loss, decreased appetite

Less Common Presentations:

• Testicular enlargement
• Cranial nerve palsies
• Mediastinal mass (in T-cell ALL)
• Leukemia cutis

Note: The onset can be acute or subacute, with symptoms developing over days to weeks.

Diagnosis

Diagnosis of ALL involves a combination of clinical assessment, laboratory tests, and bone marrow studies:

Initial Workup:

• Complete blood count (CBC) with differential
• Peripheral blood smear
• Comprehensive metabolic panel
• Coagulation studies
• Uric acid level

Definitive Diagnosis:

• Bone marrow aspiration and biopsy:
  • Morphology: >25% lymphoblasts in bone marrow
  • Flow cytometry: Immunophenotyping
  • Cytogenetics: Karyotype, FISH
  • Molecular studies: PCR, next-generation sequencing

Additional Studies:

• Lumbar puncture: CSF analysis for CNS involvement
• Chest X-ray: To evaluate for mediastinal mass
• Echocardiogram: Baseline cardiac function
• HLA typing: For potential stem cell transplantation

Lymphoblasts in B ALL / LBL.(source)

Risk Stratification

Risk stratification is crucial for tailoring treatment intensity. Factors considered include:

Clinical Factors:

• Age: <1 year and >10 years associated with higher risk
• Initial white blood cell (WBC) count: >50,000/μL associated with higher risk
• CNS involvement
• Testicular involvement

Biological Factors:

• Immunophenotype: T-cell generally higher risk than B-cell
• Cytogenetics:
  • Favorable: ETV6-RUNX1, Hyperdiploidy
  • Unfavorable: BCR-ABL1, MLL rearrangements, Hypodiploidy
• Minimal residual disease (MRD) status: Most important prognostic factor

Risk Groups:

• Standard Risk
• High Risk
• Very High Risk

Note: Specific criteria for risk group assignment may vary between treatment protocols.

Treatment

Treatment of ALL is complex and prolonged, typically lasting 2-3 years. It consists of several phases:

1. Remission Induction (4-6 weeks):

• Goal: Achieve complete remission (<5% blasts in bone marrow)
• Drugs: Vincristine, Corticosteroids, Asparaginase, ± Anthracycline
• CNS prophylaxis: Intrathecal chemotherapy

2. Consolidation/Intensification (6-8 months):

• Goal: Eliminate residual leukemic cells
• High-dose methotrexate, Cytarabine, Cyclophosphamide, others

3. Maintenance (18-30 months):

• Goal: Prevent relapse
• Daily oral mercaptopurine, weekly oral methotrexate
• Periodic vincristine and corticosteroid pulses

Special Considerations:

• Philadelphia chromosome-positive ALL: Addition of tyrosine kinase inhibitors (e.g., imatinib)
• T-cell ALL: More intensive regimens often used
• Infant ALL: Intensified therapy, consideration of stem cell transplantation

Hematopoietic Stem Cell Transplantation (HSCT):

• Considered for very high-risk patients in first remission
• Standard approach for many patients with relapsed ALL

Emerging Therapies:

• Immunotherapy: Blinatumomab, CAR T-cell therapy
• Targeted therapies: Inotuzumab ozogamicin, dasatinib

Prognosis

Prognosis for childhood ALL has improved dramatically over the past decades:

Overall Survival Rates:

• 5-year overall survival: >90% for standard-risk patients
• High-risk and very high-risk patients: 70-80% 5-year survival
• Infant ALL: 50-60% 5-year survival

Prognostic Factors:

• Minimal residual disease (MRD) status: Most important
• Age and initial WBC count
• Cytogenetic and molecular features
• Early response to treatment
• CNS or testicular involvement

Relapse:

• Occurs in 15-20% of patients
• Most common sites: Bone marrow, CNS, testes
• Prognosis for relapsed ALL is guarded, but improving with new therapies

Long-term Follow-up

Survivors of childhood ALL require lifelong monitoring for late effects of therapy:

Potential Late Effects:

• Neurocognitive impairment
• Growth hormone deficiency
• Obesity and metabolic syndrome
• Cardiovascular disease
• Osteonecrosis
• Secondary malignancies
• Infertility

Follow-up Care:

• Regular physical examinations
• Neurocognitive assessments
• Endocrine evaluations
• Cardiovascular screening
• Bone health monitoring
• Cancer surveillance
• Psychosocial support

Specific Monitoring:

• Echocardiograms: For patients who received anthracyclines
• Bone density scans: To assess for osteoporosis
• Thyroid function tests: Particularly for those who received cranial radiation
• Hearing tests: For patients who received platinum-based chemotherapy
• Fertility counseling and hormonal evaluations

Transitioning to Adult Care:

As survivors reach adulthood, a structured transition to adult-focused care is crucial:

• Education about their cancer history and potential late effects
• Development of a personalized long-term follow-up plan
• Connection with adult providers familiar with childhood cancer survivorship
• Encouraging self-advocacy and health management skills

Psychosocial Considerations:

• Educational and vocational support
• Mental health screening and support
• Social reintegration and peer support programs
• Financial counseling related to long-term healthcare needs

The goal of long-term follow-up is not only to monitor for and manage late effects but also to promote overall health and quality of life for ALL survivors.

Acute Lymphoblastic Leukemia in Children

1. What is the most common childhood cancer?
   Acute Lymphoblastic Leukemia (ALL)
2. What is the peak age of incidence for childhood ALL?
   2-5 years old
3. Which chromosome translocation is associated with a poor prognosis in childhood ALL?
   t(9;22) or Philadelphia chromosome
4. What is the initial presenting symptom in most children with ALL?
   Fatigue and pallor
5. Which immunophenotype of ALL has the best prognosis?
   Pre-B cell ALL
6. What is the name of the genetic alteration associated with improved prognosis in ALL?
   ETV6-RUNX1 (TEL-AML1) fusion
7. Which laboratory finding is characteristic of tumor lysis syndrome in ALL?
   Hyperuricemia
8. What is the standard initial treatment for childhood ALL?
   Combination chemotherapy
9. Which central nervous system prophylaxis method has largely replaced cranial radiation in ALL?
   Intrathecal chemotherapy
10. What is the overall cure rate for childhood ALL?
    Approximately 80-90%
11. Which genetic syndrome is associated with an increased risk of developing ALL?
    Down syndrome
12. What is the name of the phase of chemotherapy aimed at eradicating residual leukemic cells?
    Consolidation therapy
13. Which organ is most commonly enlarged on physical examination in ALL?
    Liver (hepatomegaly)
14. What is the definition of complete remission in ALL?
    < 5% blasts in bone marrow
15. Which test is used to detect minimal residual disease in ALL?
    Flow cytometry or PCR
16. What is the most common site of extramedullary involvement in ALL?
    Central nervous system
17. Which chemotherapy drug is associated with osteonecrosis in ALL treatment?
    Dexamethasone
18. What is the name of the ALL subtype with multiple chromosomal gains?
    Hyperdiploid ALL
19. Which tyrosine kinase inhibitor is used in Philadelphia chromosome-positive ALL?
    Imatinib
20. What is the most common late effect of cranial radiation in ALL survivors?
    Neurocognitive deficits
21. Which immunophenotype of ALL has the worst prognosis?
    T-cell ALL
22. What is the name of the phenomenon where leukemic cells infiltrate the testes?
    Testicular sanctuary
23. Which chemotherapy drug requires dose adjustment based on TPMT enzyme activity?
    6-Mercaptopurine
24. What is the typical duration of maintenance therapy in childhood ALL?
    2-3 years
25. Which imaging modality is used to detect CNS involvement in ALL?
    MRI of the brain
26. What is the name of the gene commonly mutated in T-cell ALL?
    NOTCH1
27. Which laboratory finding is associated with tumor lysis syndrome in ALL?
    Hyperphosphatemia
28. What is the name of the ALL subtype with chromosome 11q23 abnormalities?
    MLL-rearranged ALL
29. Which chemotherapy drug is associated with cardiotoxicity in ALL treatment?
    Anthracyclines (e.g., doxorubicin)
30. What is the most common cause of treatment failure in childhood ALL?
    Relapse

Disclaimer

The notes provided on Pediatime are generated from online resources and AI sources and have been carefully checked for accuracy. However, these notes are not intended to replace standard textbooks. They are designed to serve as a quick review and revision tool for medical students and professionals, and to aid in theory exam preparation. For comprehensive learning, please refer to recommended textbooks and guidelines.