What are the manifestations and treatment options for Acute Lymphoblastic Leukemia (ALL)?

Manifestations of Acute Lymphoblastic Leukemia

Patients with ALL develop symptoms from blast infiltration of bone marrow, lymphoid tissues, and extramedullary sites, presenting most commonly with fatigue, constitutional symptoms, bleeding/bruising, infections, and bone/joint pain, particularly in children. 1

Clinical Presentation

Hematologic and Constitutional Symptoms

• Fatigue or lethargy from anemia due to bone marrow infiltration 1
• Constitutional symptoms including fevers, night sweats, and weight loss 1
• Easy bruising or bleeding from thrombocytopenia 1
• Recurrent infections from neutropenia and immune dysfunction 1

Musculoskeletal Manifestations

• Bone and joint pain, which may be the only presenting symptom in children 1
• Pain in extremities is particularly common in pediatric presentations 1

Organ-Specific Findings

• Lymphadenopathy on physical examination 1
• Splenomegaly and/or hepatomegaly present in approximately 20% of patients 1
• Mediastinal mass from thymic involvement, particularly in T-cell ALL 1

Neurologic Manifestations

• Chin numbness or facial palsy from cranial nerve involvement or CNS infiltration 1
• Dyspnea and dizziness from severe anemia 1

Less Common Presentations

• Abdominal masses from gastrointestinal involvement suggest mature B-cell ALL (Burkitt lymphoma) rather than typical ALL 1
• Rare presentations include acute hepatocellular injury and acute kidney injury, though these are atypical 2

Diagnostic Criteria

Bone Marrow Requirements

• ≥20% bone marrow lymphoblasts on hematopathology review of aspirate and biopsy is required for diagnosis 1, 3
• Treatment protocols often use ≥25% marrow blasts to define leukemia 1
• Diagnosis should be avoided when <20% marrow blasts are present, as there is no evidence that delaying treatment in this scenario adversely affects outcomes 1

Alternative Diagnostic Criteria

• Peripheral blood may substitute for bone marrow when bone marrow aspiration is precluded by hyperleukocytosis (≥100,000 leukocytes/μL) or mediastinal mass 1
• Requires ≥1,000 circulating lymphoblasts/μL or ≥20% lymphoblasts in peripheral blood 1

Lymphoblastic Lymphoma Distinction

• When disease is restricted to a mass lesion (nodal or extranodal) with <20% marrow lymphoblasts, the diagnosis is lymphoblastic lymphoma (LL) rather than ALL 1
• LL is morphologically, genetically, and immunophenotypically indistinguishable from ALL and requires ALL-like treatment regimens 1

Essential Diagnostic Workup

Hematopathology Evaluation

• Morphologic assessment using Wright-Giemsa-stained bone marrow aspirate smears and H&E-stained core biopsy sections 1, 3
• Cell count of at least 500 nucleated cells in bone marrow smears containing spicules 3

Immunophenotyping

• Comprehensive flow cytometric immunophenotyping to determine cell lineage (B-cell vs T-cell) 1, 3
• B-cell markers: CD19, CD79a, CD10 for B-cell precursor ALL 3
• T-cell markers: CD3 for T-cell ALL 3

Cytogenetic and Molecular Studies

• Karyotyping of G-banded metaphase chromosomes (conventional cytogenetics) 1, 3
• Fluorescence in situ hybridization (FISH) with probes for major recurrent genetic abnormalities 1, 3
• RT-PCR testing for fusion genes (e.g., BCR-ABL for Philadelphia chromosome) 1, 3

Risk Stratification Markers

• Favorable risk: Hyperdiploidy, t(12;21)(p13;q22): TEL-AML1 3
• Unfavorable risk: Hypodiploidy 3, 4, t(v;11q23): MLL/KMT2A rearrangements 3, 4, t(9;22)(q34;q11.2): BCR-ABL (Philadelphia chromosome) 3
• Elevated WBC count: ≥30×10⁹/L for B-cell lineage or ≥100×10⁹/L for T-cell lineage indicates poor prognosis 4

Treatment Approach

General Principles

All patients should be treated at specialized cancer centers with expertise in ALL management given the complexity of treatment regimens and required supportive care 1

Standard Induction Therapy

• Four-drug induction regimen (BFM backbone) includes: 4
  • Vincristine 4, 5
  • Anthracycline (daunorubicin or doxorubicin) 4
  • Corticosteroid (prednisone or dexamethasone) 4
  • L-asparaginase/pegaspargase 4
• Standard-risk pediatric patients may receive 3-drug induction without anthracyclines 4
• AYA patients may receive cyclophosphamide added to the 4-drug regimen 4

Corticosteroid Selection Considerations

• Dexamethasone reduces CNS relapse risk and improves event-free survival compared to prednisone 4
• However, dexamethasone increases risks of induction mortality, neuropsychiatric events, and myopathy 4
• No conclusive overall survival advantage has been demonstrated for dexamethasone over prednisone 4

CNS Prophylaxis

• Antimetabolites (methotrexate, cytarabine, mercaptopurine) are included for CNS prophylaxis 4
• Vincristine does not cross the blood-brain barrier adequately; additional agents are required if CNS leukemia is diagnosed 5

Age-Specific Modifications

• Treatment intensity is reduced for patients ≥65 years or those with substantial comorbidities 4
• Chronologic age alone is a poor surrogate for determining fitness for therapy 4
• Pediatric patients have 5-year OS rates of 89%, while AYA patients have 61% 1
• Infants <1 year have particularly poor outcomes with 6-year OS of 58.2% 1

Modern Therapeutic Advances

• Philadelphia chromosome-positive ALL: Combination of BCR-ABL tyrosine kinase inhibitors with chemotherapy or blinatumomab achieves 5-year survival >80% 6
• Novel immunotherapies: Inotuzumab ozogamicin and blinatumomab are being incorporated into regimens to improve measurable residual disease negativity 6
• CAR T-cell therapy is being investigated in clinical trials, particularly for older patients 6

Critical Pitfalls to Avoid

Diagnostic Errors

• Do not diagnose ALL with <20% marrow blasts unless specific recurrent cytogenetic abnormalities are present 1
• Ensure complete cytogenetic and molecular characterization before initiating therapy, as this determines risk stratification and treatment intensity 1, 3

Treatment Complications

• Monitor for tumor lysis syndrome with adequate hydration and allopurinol before starting steroids or chemotherapy 7
• Acute uric acid nephropathy can occur; monitor serum uric acid levels frequently during the first 3-4 weeks of treatment 5
• Neurotoxicity is dose-limiting for vincristine; clinical evaluation is necessary to detect need for dosage modification 5

Drug Interactions

• Avoid strong CYP3A inhibitors (e.g., itraconazole) with vincristine, as they cause earlier onset and increased severity of neuromuscular side effects 5
• Monitor phenytoin levels closely, as vincristine-containing regimens reduce anticonvulsant blood levels and increase seizure activity 5
• Avoid P-glycoprotein inhibitors or inducers with vincristine 5

Infection Prevention

• Implement febrile neutropenia protocols based on local bacterial sensitivity 7
• Trimethoprim-sulfamethoxazole prophylaxis prevents Pneumocystis jiroveci pneumonia 7
• Hand hygiene and isolation from infectious patients are critical cost-effective measures 7