Acute Lymphocytic Leukemia

Aka: Acute Lymphocytic Leukemia, Acute Lymphoblastic Leukemia, ALL

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II. History

  1. Success story of Twentieth Century Oncology
  2. Previously ALL was 100% fatal in 3 months
  3. Current Chemotherapy regimens hold >50% cure

III. Epidemiology

  1. Disease of children and young adults in 80% of cases
    1. Onset is at under age 20 years old in more than half of patients
    2. Highest Incidence is between ages 2-3 years (most cases occur in age <5 years)
    3. However, 20% of Acute Lymphoblastic Leukemia cases occur in age >50 years old
  2. Most common childhood (25% of cancers diagnosed under age 15 years)
    1. Incidence: 35-40 cases per 1 Million
    2. Annual Incidence: 2900 children and adolescents per year in U.S
  3. Ethnicity
    1. Highest Incidence in hispanic and white children
    2. Lowest rate among black children

IV. Risk Factors

  1. Prenatal Radiation Exposure
  2. Genetic Syndromes
    1. Down Syndrome
    2. Neurofibromatosis
    3. Ataxia Telangiectasia
    4. Shwachman syndrome
    5. Bloom syndrome

V. Symptoms

  1. See Acute Leukemia
  2. Asymptomatic in 6% of children at time of diagnosis
  3. Fever (49 to 57%)
  4. Unintentional Weight Loss (26 to 31%)
  5. Lethargy or Fatigue (45 to 64%)
  6. Pallor (28 to 46%)
  7. Bleeding or Bruising (10 to 43%)
  8. Musculoskeletal pain, esp. leg or back pain (21 to 59%)
  9. Gastrointestinal symptoms from Hepatosplenomegaly
    1. Nausea
    2. Abdominal fullness
    3. Early Satiety

VI. Signs

  1. See Acute Leukemia
  2. Hepatomegaly or Splenomegaly (50% to 75% in children, 20% of adults)
  3. Lymphadenopathy
  4. Testicular involvement may occur
  5. Anterior Mediastinal Mass (T-Cell Variant)
  6. CNS Involvement (Meningeal Irritation, cranial Neuropathy) in 5-8% of adults with Acute Lymphoblastic Leukemia

VII. Labs: Pathology

  1. Immature Lymphoblasts (blast cells)
    1. Round or convoluted nuclei
    2. Express Common ALL Antigen (CALLA) in 60% of cases
    3. Contrast with Acute Myelogenous Leukemia
      1. Smaller blast cells with ALL
      2. No Auer rods in ALL
      3. Contain deoxynucleotidyl transferase in 90% of cases (rare in AML)
  2. Lymphocyte Cell Types
    1. T-Cell Type (20% of cases)
    2. B-Cell Type (5%)
    3. Null Cell Type (15%)
  3. Other findings and diagnostics
    1. Lumbar Puncture for CSF
    2. Philadelphia Chromosome (BCR-ABL1 Fusion Gene) may be present
      1. Primarily seen in CML (90% of cases)
      2. However also present in ALL (2-4% of children, 20-40% of adults)

VIII. Diagnosis

  1. Sources
    1. Peripheral Blood Smear
    2. Bone Marrow Biopsy
  2. Blast cell predominance (both ALL and AML)
    1. However, blast cell absence on Peripheral Smear does not exclude Acute Leukemia
  3. Studies to distinguish between ALL and AML
    1. Lymphoblasts represent >20% of cells in Bone Marrow sample in ALL
    2. Flow cytometry with immunophenotyping
      1. Sorts and counts cells by cell surface markers
    3. Cytogenetic testing
      1. Chromosome evaluation (karyotype or fluorescence in situ hybridization analysis)

IX. Management: Acute

  1. Remission-Induction Chemotherapy
    1. Vincristine
    2. Prednisone
    3. Daunorubicin or L-asparaginase
  2. CNS Prophylaxis (prevents Leukemic Meningitis)
    1. Whole Brain Radiation (18 to 24-Gy)
    2. Intrathecal Methotrexate
  3. Maintenance Chemotherapy for 2-3 years
    1. 6-Mercaptopurine
    2. Methotrexate
  4. Targeted Cancer Therapy (small molecule inhibitors and Biologic Agents, typically in adults)
    1. Tisagenleucel (Kymriah)
      1. FDA approved in under age 25 years
    2. Tyrosine Kinase Inhibitors
      1. Indicated in Philadelphia Chromosome positive ALL

X. Management: Surveillance of survivors treated with Chemotherapy and Radiation

  1. Initial surveillance
    1. Year 1
      1. Monthly Physical Exam and Complete Blood Count (CBC) with differential
      2. Every 2 month Liver Function Tests until normal
      3. Bone Marrow Aspirate or Lumbar Puncture as indicated
      4. Echocardiogram as indicated
    2. Year 2
      1. Every 3 month physical exam (with testicular exam) and Complete Blood Count with differential
    3. Year 3 (and after)
      1. Every 6 to 12 month physical exam (with testicular exam) and Complete Blood Count with differential
  2. Routine periodic exams
    1. Annual physical exam (or more often in first 3 years as above)
    2. Growth Exam (growth chart plotting in children)
    3. Annual Eye Examination
    4. Dental care every 6 months
    5. Cancer screening
      1. Complete skin exam
      2. Testicular exam
  3. Annual lab testing
    1. Complete Blood Count with differential
      1. Obtain for up to 10 years following last treatment
      2. Obtain more often in first three years as listed above
    2. Comprehensive metabolic panel
      1. Includes serum Electrolytes, Serum Creatinine, Blood Urea Nitrogen, Serum Calcium and Liver Function Tests
    3. Serum Phosphorus
    4. Serum Magnesium
    5. Thyroid Stimulating Hormone
    6. Urinalysis
      1. If Hematuria, frequency or urgency
  4. Communicable Disease Testing (one time screening)
    1. Hepatitis C Antibody testing (if treated before 1993)
    2. Hepatitis B Surface Antigen and Hepatitis B Core Antibody (if treated before 1972)
    3. HIV Test (if treated between 1977 and 1986)
  5. Other tests as indicated
    1. Respiratory symptoms
      1. Chest XRay
      2. Pulmonary Function Testing
    2. Hearing changes
      1. Audiometry
    3. Cardiac symptoms (e.g. CHF)
      1. Repeat testing every 3-5 years if pretreatment cardiac testing was abnormal
      2. Echocardiogram
      3. Electrocardiogram (EKG)
        1. Obtain baseline and every 2 to 5 years if anthracycline-based Chemotherapy (daunorubicin, doxorubicin)
  6. Vaccinations
    1. See Hematopoietic Stem Cell Transplant for Vaccination precautions
    2. Do not administer live Vaccinations during Chemotherapy
    3. Maintain age appropriate Vaccinations if not contraindicated
    4. Maintain Covid19 Vaccine, Influenza Vaccine, Pneumococcal Vaccine if not contraindicated

XI. Management: Surveillance of survivors miscellaneous

  1. Treated with cranial or craniospinal radiation
    1. Neuroimaging is indicated for neurologic symptoms
  2. Treated with Hematopoietic Stem Cell Transplantation
    1. See Hematopoietic Stem Cell Transplant for protocol

XII. Prognosis (U.S., 2000 to 2018)

  1. Child: Cure rates approach 90%
    1. Age under 20 years: 87% five year survival
  2. Adults: Cure rates 40 to 50%
    1. Long term survival <30% (increasing with Targeted Cancer Therapy)
    2. Age under 50 years: Five-year survival 75%
    3. Age 50 to 64 years: Five-year survival 30%
    4. Age over 50 years: Five-year survival 15%

XIII. Complications

  1. See Acute Leukemia
  2. Leukemic Meningitis in relapse
    1. Headache and Nausea
    2. Cranial Nerve palsy
    3. Seizures
    4. Altered Level of Consciousness
  3. General Chemotherapy complications
    1. Lymphocytopenia
    2. Immunodeficiency (predominantly T-Cells)
      1. Pneumocystis carinii Pneumonia
    3. Growth retardation (most attain normal growth)
    4. Sterility (most resolves)
    5. Joint osteonecrosis (hips, Shoulders and knees)
      1. Cummulative 20 year Incidence 2.8% in adolescents treated for ALL
  4. Cyclophosphamide related
    1. Bladder Cancer
  5. Anthracycline (doxorubicin or daunorubicin) related
    1. Cardiomyopathy
  6. Cranial Radiotherapy related
    1. CNS tumor
    2. Papillary Thyroid Carcinoma
    3. Acute monocytic Leukemia
    4. Cognitive decline
    5. Osteoporosis
    6. Obesity
    7. Periodontal Disease
    8. Cataracts

XIV. Resources

  1. National Cancer Institute
    1. http://www.cancer.gov/cancertopics/pdq/treatment/childALL/HealthProfessional

XV. References

  1. Clarke (2016) Arch Dis Child 101(10): 894-901 [PubMed]
  2. Davis (2014) Am Fam Physician 89(9): 731-8 [PubMed]
  3. Gbenjo (2023) Am Fam Physician 107(4): 397-405 [PubMed]
  4. Wilbur (2014) Am Fam Physician 91(1):29-36 [PubMed]

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