II. Definitions

  1. Leukemia
    1. Malignant hematologic disorder involving hematopoietic stem cells
    2. Proliferation of primitive or atypical myeloid or lymphoid cells within the blood or Bone Marrow
    3. Cellular type and differentiation determines whether Leukemia is diagnosed as acute or chronic

III. Epidemiology

  1. Incidence
    1. Annual Incidence: 14 per 100,000 people per year (U.S. 2015 to 2019)
    2. Lifetime Incidence: 1 in 70 people
  2. Higher Incidence in men
  3. Age distribution
    1. All Ages
      1. Acute Myelogenous Leukemia (AML)
    2. Young
      1. Acute Lymphocytic Leukemia (ALL)
    3. Elderly
      1. Chronic Lymphocytic Leukemia
      2. Hairy Cell Leukemia

V. Pathophysiology

  1. Malignant neoplasm of hematopoietic origin
  2. Origins
    1. Myeloid (Bone Marrow)
    2. Lymphoid
  3. Acute (Proliferating cell fails to mature past blast)
    1. AML: Immature clonal myeloid Cells (Myeloblast)
    2. ALL: Immature clonal lymphoid Cells (Lymphoblast)

VI. Risk Factors

  1. Idiopathic
  2. Demographics and habitus
    1. White
    2. Male
    3. Obesity (also decreases survival)
  3. Viral Infections
    1. Human T-Cell Leukemia Virus (HTLV-1)
    2. Hepatitis C VIrus Infection (risk of CLL)
  4. History of Hematologic Malignancy
    1. Myelodysplastic Syndrome is associated with secondary Leukemia in 30% of cases (esp. AML)
  5. Congenital syndrome (risk of childhood ALL, AML)
    1. Down Syndrome
    2. Neurofibromatosis
    3. Bloom's Syndrome
    4. Klinefelter Syndrome
    5. Fanconi Syndrome
    6. Wiscott-Aldrich Syndrome
  6. Environmental Factors
    1. Ionizing Radiation exposure (risk of CML, AML, ALL)
      1. Atomic bomb survivors
      2. Medical radiation workers prior to 1950
      3. Medical radiation patients
      4. CT-associated Radiation Exposure
        1. Cummulative radiation exposure (esp. children)
    2. Chemical exposure (risk of AML)
      1. Aromatic Hydrocarbons (e.g. Benzene)
        1. Manufacturing of paints, plastics, Pesticides
        2. Petroleum (and vehicle exhaust), Tobacco smoke or coal combustion
      2. Alkylating Agents
      3. Chemotherapeutic Drugs
    3. Other toxin exposures
      1. Agent Orange (risk of CLL)
      2. Hair dye is NOT considered a risk for Leukemia
        1. Towle (2017) Cancer Med 6(10): 2471-86 [PubMed]

VII. Findings: Signs and Symptoms

VIII. Labs: Initial

  1. Complete Blood Count (CBC) with differential
    1. Background
      1. CBC with differential is the most important first-line test in evaluation of possible Leukemia
      2. Use the differential to evaluate and treat underlying suspected causes
        1. See Leukocytosis and Leukopenia for differential diagnosis
        2. Repeat CBC with differential at long enough interval for abnormalities to resolve
        3. Obtain Peripheral Smear if CBC with differential remains abnormal on repeat testing (see below)
    2. Acute Leukemia
      1. Leukocytosis or Leukopenia
      2. Anemia
      3. Thrombocytopenia
    3. Chronic Leukemias
      1. Leukocytosis >20,000/mm3 in most cases (often >100,000/mm3)
  2. Other initial lab tests
    1. Coagulation studies
      1. ProTime (INR)
      2. Partial Thromboplastin Time (PTT)
    2. Comprehensive metabolic panel
      1. Serum Electrolytes
      2. Renal Function tests including Serum Creatinine
      3. Liver Function Tests
  3. Patient febrile or otherwise ill appearing
    1. Urinalysis
    2. Urine Culture
    3. Blood Culture
    4. Chest XRay
  4. Tumor Lysis Syndrome (Leukemia patients undergoing treatment)
    1. Serum Uric Acid
    2. Serum Phosphorus
    3. Serum Lactate Dehydrogenase

IX. Labs: Peripheral Smear

  1. Whole blood specimen exam under light microscopy
  2. Peripheral Blood Smear indications
    1. Persistent Leukocytosis despite management of suspected cause
    2. Hyperleukocytosis (White Blood Cell Count >100,000/mm3)
    3. Anemia
    4. Thrombocytopenia or Thrombocytosis
    5. Hepatomegaly, Splenomegaly or Lymphadenopathy
    6. Unexplained constitutional symptoms
  3. Findings suggestive of Leukemia on Peripheral Smear
    1. Marked increase in normal appearing Lymphocytes
      1. Consider Chronic Lymphocytic Leukemia (CLL)
      2. Obtain flow cytometry immunophenotyping of peripheral blood
        1. Monoclonal B Lymphocytes >5000/mm3 confirms CLL
    2. Elevated number of hematopoetic precursor cells
      1. Lymphoblasts >20%
        1. Consider Acute Lymphoblastic Leukemia or ALL (see below)
      2. Myeloblasts >20%
        1. Consider Acute Myelogenous Leukemia or AML (see below)
      3. Blast cell numbers low, but prominent Basophilia or Eosinophilia
        1. Consider Chronic Myelogenous Leukemia or CML (see below)
  4. Findings suggestive of Non-Malignant Causes on Peripheral Smear
    1. Elevated Neutrophils
      1. See Neutrophilia for differential diagnosis and approach
      2. Consider underlying infection, Asplenia or Splenic Sequestration, inflammatory conditions
    2. Elevated Lymphocytes
      1. See Lymphocytosis for differential diagnosis and approach
      2. Consider Viral Infections, Pertussis, Tuberculosis, Asplenia or Splenic Sequestration
    3. Atypical lymphocytes
      1. See Atypical lymphocytes
      2. Consider underlying viral infectious causes (e.g. EBV, CMV, HIV Infection, COVID-19)

X. Labs: Advanced Studies

  1. Peripheral Blood Smear
    1. See indications and interpretation above
    2. Identifies Auer Rods (AML), Smudge Cells (CLL), Blast Cells (Acute Leukemia)
  2. Bone Marrow Biopsy
    1. Hematopoetic cell line analysis via Bone Marrow Aspirate
    2. Typically performed on Consultation with hematology oncology Consultation
    3. Identifies Blast Cells (Acute Leukemia)
    4. Offers prognostic information in CLL
  3. Cytogenetic Tests
    1. Chromosome exam via karyotyping or Fluorescence in situ hybridization (FISH)
    2. Identifies Philadelphia Chromosome (CML), Leukemia subtype markers, treatment guidance and prognosis (esp. CLL)
  4. Flow cytometry with immunophenotyping
    1. Peripheral or Bone Marrow Cell Sorting and Counting (via cell surface markers)
    2. Identifies lymphoid clonal cells (CLL), Leukemia subtype markers
  5. Molecular Tests (next generation sequencing)
    1. DNA mutations (via PCR)
    2. Identifies Philadelphia Chromosome (BCR-ABL1 Fusion Gene)
    3. Identifies subtype markers for diagnosis, treatment and prognosis

XI. Diagnosis

  1. Studies
    1. Peripheral Blood Smear
      1. See indications and interpretation above
    2. Bone Marrow Biopsy
      1. Typically performed on Consultation with hematology oncology Consultation
  2. Acute Leukemia findings
    1. General (both ALL and AML)
      1. Blast cell predominance
        1. However, blast cell absence on Peripheral Smear does not exclude Acute Leukemia
      2. Immunophenotyping (flow cytometry, cytogenetic testing) distinguishes between AML and ALL
    2. Acute Lymphoblastic Leukemia (ALL)
      1. Lymphoblasts represent >20% of cells in Bone Marrow sample
      2. Philadelphia Chromosome (BCR-ABL1 Fusion Gene) may be present
        1. Primarily seen in CML (90% of cases), but also present in ALL in 2-4% of children, 20-40% of adults
      3. Also obtain Lumbar Puncture for CSF
    3. Acute Myelogenous Leukemia (AML)
      1. Myeloblasts represent >20% of cells in Bone Marrow or peripheral blood sample
      2. Auer rods on Peripheral Smear (not often found)
      3. Also obtain Lumbar Puncture for AML patients if undergoing intrathecal therapy
  3. Chronic Leukemia Findings
    1. Leukocytosis or Hyperleukocytosis (both CLL and CML)
      1. White Blood Cell Count is >20,000/mm3 in most cases, and often >100,000/mm3 (Hyperleukocytosis)
      2. Contrast with normal white cell counts or Leukopenia associated with Acute Leukemias
      3. Often asymptomatic (esp. CLL)
      4. May be associated with Anemia, Thrombocytopenia or Thrombocytosis, Hepatosplenomegaly, Lymphadenopathy
    2. Chronic Lymphocytic Leukemia (CLL)
      1. Significant increase of normal appearing Lymphocytes (>50% of cells)
      2. Peripheral blood for clonal expansion of B Lymphocytes >5000/mm3, and confirmed by flow cytometry
      3. Bone Marrow Biopsy is not needed for diagnosis (but defines extent of marrow involvement related to prognosis)
    3. Chronic Myelogenous Leukemia (CML)
      1. Peripheral Smear with few blast cells and increased Basophils and Eosinophils
      2. Philadelphia Chromosome (BCR-ABL1 Fusion Gene) on peripheral blood or Bone Marrow testing
        1. Found in >90% of CML patients
        2. Also seen in some ALL patients (see above)

XII. Evaluation: Elevated White Cell Count Evaluation

  1. Step 0: Leukocytosis (White Blood Cell Count >11,000/mm3)
    1. Confirmed with a second Complete Blood Count with differential
    2. No other obvious cause for Leukocytosis (e.g. infection, Corticosteroids)
  2. Step 1: Consider secondary causes based on white cell count differential
    1. Monocyte predominance (monocytosis)
      1. Consider chronic infection (e.g. Tuberculosis, parasitic infectikon)
      2. Consider Connective Tissue Disease (e.g. Sarcoidosis, Inflammatory Bowel Disease)
    2. Eosinophil predominance (Eosinophilia)
      1. Consider allergic condition (e.g. Allergic Rhinitis, atopy, Asthma)
      2. Consider Parasite infection
      3. Consider Collagen vascular disease
        1. Examples: Rheumatoid Arthritis, Systemic Lupus Erythematosus, Sarcoidosis, Addison's Disease
      4. Consider medication causes (e.g. Methotrexate, Sulfonamides, Nitrofurantoin)
    3. Neutrophil predominance (Neutrophilia)
      1. Consider infection or inflammation
      2. Consider medication causes (e.g. Corticosteroids, Lithium, beta Agonists)
      3. Consider aspenia or Splenic Sequestration
    4. Lymphocyte predominance (Lymphocytosis)
      1. Consider infections (e.g. EBV, CMV, Pertussis, Tuberculosis)
      2. Consider Asplenia or Splenic Sequestration
    5. Basophil predominance (Basophilia, rare)
      1. Consider Asplenia
      2. Consider Hypothyroidism
      3. Consider chronic inflammation (e.g. Inflammatory Bowel Disease, Chronic Sinusitis, Asthma)
  3. Step 2: Indications to proceed with Peripheral Smear
    1. Leukocytosis without other secondary cause (or despite treatment)
    2. White Blood Cell Count >20,000/mm3
    3. Associated Anemia, Thrombocytopenia or Thrombocytosis
    4. Hepatomegaly, Splenomegaly or Lymphadenopathy
    5. Unexplained constitutional symptoms (e.g. fever, Fatigue or weight loss)
  4. Step 3: Based on Peripheral Smear interpretation
    1. Findings suggestive of benign cause
      1. Increased normal appearing Neutrophils
        1. Evaluate for causes of Neutrophil predominance (see above)
      2. Increased normal appearing Lymphocytes
        1. Evaluate for causes of Lymphocyte predominance (see above)
      3. Atypical lymphocytes
        1. Consider EBV, CMV or HIV
    2. Findings suggestive of Leukemia
      1. Increased blast cells
        1. Possible Acute Leukemia
        2. Test preipheral blood or Bone Marrow for immunophenotyping
      2. Few blast cells and increased Basophils and Eosinophils
        1. Possible Chronic Myelogenous Leukemia
        2. Test peripheral blood or Bone Marrow for Philadelphia Chromosome testing
      3. Significant increase of normal appearing Lymphocytes (>50% of cells)
        1. Possible Chronic Lymphocytic Leukemia
        2. Test peripheral blood for clonal expansion of B Lymphocytes >5000/mm3

XIII. Management

  1. Hematology-Oncology Referral
  2. Acute management is dependent on specific Leukemia type
    1. See Acute Myelogenous Leukemia (AML)
    2. See Acute Lymphocytic Leukemia (ALL)
    3. See Chronic Myelogenous Leukemia (CML)
    4. See Chronic Lymphocytic Leukemia (CLL)
  3. Post-cancer management
    1. See specific Leukemia
    2. See Cancer Survivor Care

XIV. Complications: Leukemia Treatment

  1. Specific treatment complications vary per agent used
    1. See Targeted Cancer Therapy
    2. See Hematopoietic Stem Cell Transplant
    3. See Cancer Survivor Care
    4. Anthrocycline-based Chemotherapy (Daunorubicin, Doxorubicin) are associated with Cardiomyopathy
      1. Obtain Echocardiogram 12 months after treatment
  2. Tumor Lysis Syndrome
  3. Immunosuppression
    1. Neutropenic Fever
  4. Transfusion Associated Graft Versus Host Disease (TAGVHD)
    1. Associated with See Hematopoietic Stem Cell Transplant
  5. Osteonecrosis of the hips, knees, Shoulders
    1. Affects children, up to 13 years after treatment
  6. Secondary Malignancy
    1. Children
      1. Breast Cancer
      2. Thyroid Cancer
      3. Meningioma
      4. Basal Cell Carcinoma
    2. Adults
      1. Aggressive Lymphoma (in CLL, 2 to 6 years after diagnosis)
  7. Other complications
    1. Infertility
    2. Metabolic Syndrome
    3. Hypogonadism
  8. Hypothyroidism

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