What are the diagnosis and management approaches for B-cell Acute Lymphoblastic Leukemia (B ALL) in children?

Diagnosis and Management of B-cell Acute Lymphoblastic Leukemia (B-ALL) in Children

Children with B-cell Acute Lymphoblastic Leukemia (B-ALL) should be treated at specialized cancer centers with expertise in ALL management to achieve optimal outcomes, as the complexity of treatment regimens and required supportive care measures necessitate specialized care.1

Diagnosis

Clinical Presentation

• Children with ALL may present with symptoms related to infiltration of blasts in bone marrow, lymphoid system, and extramedullary sites including:
  • Fatigue or lethargy, constitutional symptoms (fever, night sweats, weight loss)
  • Dyspnea, dizziness, infections, easy bruising or bleeding
  • Pain in extremities or joints (may be the only presenting symptom in children)
  • Lymphadenopathy, splenomegaly, and/or hepatomegaly (found in ~20% of patients)
  • Abdominal masses from gastrointestinal involvement (more suggestive of mature B-cell ALL/Burkitt lymphoma) 1

Diagnostic Criteria

• Diagnosis requires demonstration of ≥20% bone marrow lymphoblasts on hematopathology review of bone marrow aspirate and biopsy materials 1
• Peripheral blood may substitute for bone marrow if significant circulating disease is present (≥1,000 circulating lymphoblasts per microliter or ≥20% lymphoblasts) 1

Required Diagnostic Procedures

1. Morphologic assessment:

   • Wright-Giemsa–stained bone marrow aspirate smears
   • Hematoxylin and eosin–stained core biopsy and clot sections 1

2. Comprehensive immunophenotyping:

   • Flow cytometry to determine lineage (B-cell vs T-cell) 1
   • B-ALL constitutes approximately 80% of pediatric ALL cases 1

3. Genetic characterization:

   • Karyotyping of G-banded metaphase chromosomes
   • Interphase fluorescence in situ hybridization (FISH) testing for major recurrent genetic abnormalities
   • Reverse transcriptase-polymerase chain reaction (RT-PCR) testing for BCR::ABL1 in B-ALL 1
   • Assessment of gene fusions and mutations associated with BCR-ABL1–like (Ph-like) ALL if BCR-ABL1 negative 1

4. Baseline characterization of leukemic clone:

   • Flow cytometry or molecular assay to facilitate subsequent minimal residual disease (MRD) analysis 1

5. Lumbar puncture:

   • All patients should have cerebrospinal fluid examination for evidence of CNS involvement 1

Risk Stratification

Favorable Risk Features

• Hyperdiploidy (>50 chromosomes) - present in 25% of pediatric B-ALL cases
• ETV6-RUNX1 subtype (t(12;21) translocation) - present in 25% of pediatric B-ALL cases 1

Unfavorable Risk Features

• Hypodiploidy (<44 chromosomes)
• t(9;22)(q34.1;q11.2), BCR-ABL1 (Philadelphia chromosome)
• KMT2A (MLL) rearrangements
• BCR-ABL1–like (Ph-like) ALL
• Intrachromosomal amplification of chromosome 21 (iAMP21) 1

Response-Based Risk Assessment

• Minimal residual disease (MRD) measurement is essential for risk stratification and treatment planning 1
• MRD assessment during and after induction therapy has strong prognostic significance 1

Management Approach

Treatment Phases

1. Induction therapy:

   • Typically includes vincristine, corticosteroids, and asparaginase with or without anthracycline 1, 2
   • Goal is to achieve complete remission and MRD negativity 2

2. Consolidation therapy:

   • Multi-agent consolidation including high-dose methotrexate 2
   • Response to consolidation is an important prognostic factor 1
   • Followed by interim maintenance and delayed intensification (reinduction) therapy 1

3. Maintenance therapy:

   • Less intensive therapy required for 1-2 years to maintain event-free survival 2
   • 6-mercaptopurine is indicated as part of combination chemotherapy maintenance regimen 3

Special Considerations

Philadelphia Chromosome-Positive (Ph+) B-ALL

• Requires specific treatment approach with tyrosine kinase inhibitors 1
• Periodic quantification of BCR-ABL1 transcript should be performed during follow-up 1

Relapsed/Refractory Disease

• Treatment options include:
  • Clinical trials (preferred)
  • Chemotherapy
  • Blinatumomab (anti-CD19 and anti-CD3 bispecific T-cell engager)
  • Tisagenlecleucel (CAR T-cell therapy)
  • Inotuzumab ozogamicin 1
• Recent evidence shows that adding blinatumomab to combination chemotherapy in newly diagnosed standard-risk B-ALL significantly improves disease-free survival (96.0% vs 87.9% at 3 years) 4

Hematopoietic Stem Cell Transplantation (HSCT)

• Consider for high-risk patients and those with relapsed/refractory disease 1, 5
• Recommended to achieve MRD negativity prior to HSCT 1

Supportive Care

• Adequate hydration and allopurinol before starting steroids or chemotherapy to prevent tumor lysis syndrome 6
• Infection control measures including hand hygiene and isolation precautions 6
• Nutritional support to prevent malnutrition, which can impair immunity and decrease tolerance to chemotherapy 6

Follow-up and Monitoring

• Regular assessment of bone marrow aspirate for suspected relapse 1
• Monitoring for late effects:
  • Echocardiogram for anthracycline-related cardiotoxicity
  • Neuropsychological testing for neurotoxicity
  • Monitoring for obesity and encouraging healthy lifestyle choices 1

Outcomes

• With current treatment regimens, cure rates among children with ALL are approximately 80-90% 2, 7
• Recent studies from India using modified BFM 95 protocol with MRD monitoring reported event-free survival of 79.4% and overall survival of 88.2% 5

Common Pitfalls to Avoid

• Delaying diagnosis due to nonspecific symptoms
• Inadequate genetic characterization leading to suboptimal risk stratification
• Failure to monitor MRD, which is essential for treatment decisions
• Inadequate supportive care during intensive chemotherapy phases
• Insufficient attention to long-term follow-up for late effects of therapy 1