What is acute lymphoblastic leukemia (ALL)?

Acute Lymphoblastic Leukemia (ALL)

Acute Lymphoblastic Leukemia (ALL) is a heterogeneous hematologic disease characterized by the proliferation and accumulation of immature lymphoid cells in the bone marrow, peripheral blood, and other organs, requiring prompt treatment at specialized cancer centers to optimize survival outcomes. 1

Definition and Epidemiology

• ALL represents a malignancy of lymphoid progenitor cells that affects both bone marrow and extramedullary sites 2
• Incidence rate is 1.8 per 100,000 individuals per year in the US, with approximately 6,550 new cases and 1,330 deaths estimated in 2024 1
• Age distribution:
  • Median age at diagnosis: 17 years
  • 53.5% of patients diagnosed at <20 years of age
  • 29.6% at ≥45 years of age
  • 13.7% at ≥65 years of age 1
• ALL represents 75-80% of acute leukemias in children but only 20% of leukemias in adults 1

Pathophysiology and Classification

ALL is biologically heterogeneous, characterized by different cytogenetic subtypes:

• B-cell ALL subtypes:

  • Hyperdiploidy (>50 chromosomes): 25% of pediatric cases, 7% of adult cases (favorable prognosis) 1
  • TEL-AML1 (ETV6-RUNX1) fusion gene: 22% of pediatric cases, 2% of adult cases (favorable prognosis) 1
  • Philadelphia chromosome (Ph-positive, BCR-ABL1): 3% of pediatric cases, 25% of adult cases (poor prognosis historically, improved with targeted therapies) 1

• T-cell ALL: Often associated with clinical high-risk features including older age, high WBC, and extramedullary disease 3

Diagnosis

Diagnosis of ALL requires:

1. Demonstration of >20% bone marrow lymphoblasts on hematopathology review 1
2. Comprehensive diagnostic workup:
   • Morphologic assessment of Wright-Giemsa-stained bone marrow aspirate smears
   • H&E stained core biopsy sections
   • Flow cytometric immunophenotyping to identify cell lineage and specific markers 1
3. Genetic testing:
   • Karyotyping of G-banded metaphase chromosomes
   • Fluorescence in situ hybridization (FISH)
   • RT-PCR testing for fusion genes (e.g., BCR-ABL1) 1

Prognostic Factors

Key factors affecting prognosis include:

• Age: Children (1-9 years) have better outcomes than adults and infants (<1 year) 3
• White Blood Cell (WBC) count: WBC<50,000 indicates standard risk; WBC>50,000 defines high-risk disease 3
• Cytogenetic subtypes: Favorable (hyperdiploidy, TEL-AML1) vs. unfavorable (Ph-positive) 1
• Minimal Residual Disease (MRD): Critical prognostic factor; MRD negativity defined as <1 × 10^-4 (<0.01%) 1
• Immunophenotype: T-cell phenotype often associated with higher risk features 3

Treatment Approach

ALL treatment is complex and intensive, requiring a multiphase approach:

1. Induction therapy: Based on vincristine, corticosteroids, and anthracyclines 1, 4
2. Consolidation: Often includes high-dose systemic methotrexate 3
3. Maintenance/Continuation therapy: Extended treatment over 2-3 years 2
4. CNS prophylaxis: Critical component using intrathecal chemotherapy with or without cranial radiation 3

Different treatment regimens are used based on risk stratification:

• Pediatric-inspired protocols
• CALGB regimen
• Hyper-CVAD regimen (developed at MD Anderson Cancer Center) 1

Novel Therapies

Recent advances have improved outcomes:

• Targeted therapies for Ph+ ALL: BCR::ABL1 tyrosine kinase inhibitors have dramatically improved 5-year survival rates to 80+% 2
• Immunotherapies:
  • Blinatumomab (bispecific anti-CD3/CD19 monoclonal antibody) for relapsed B-cell ALL 1
  • Inotuzumab ozogamicin 2
  • Tisagenlecleucel (CAR T-cell therapy): 3-year relapse-free survival of 52% in relapsed/refractory ALL 1

Outcome Disparities

Significant outcome differences exist between age groups:

• Children: 80-90% long-term survival 2
• Adults: 40-50% long-term survival 2
• Adolescents and Young Adults (AYAs): 60-70% 5-7 year event-free survival 1
• Elderly patients (≥60 years): Poorer outcomes due to treatment intolerance and high-risk disease features 2

Clinical Pitfalls and Considerations

• Treatment location: Patients should be treated at specialized cancer centers with expertise in ALL management 1
• MRD assessment: Should be performed upon completion of initial induction therapy; persistent MRD positivity indicates higher risk of relapse 1
• Elderly patients: Represent a challenging population due to poor chemotherapy tolerance; novel approaches using immunotherapies instead of intensive chemotherapy have improved outcomes 2
• Relapsed disease: Second complete remission rates range from 68-72% with bortezomib-containing regimens; 5-year progression-free survival after relapse is approximately 56-72%, depending on MRD status 1