Chronic Lymphocytic Leukemia

Aka: Chronic Lymphocytic Leukemia, CLL

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II. Epidemiology

  1. Most common Leukemia in the United States
  2. Older patients
    1. Usually over age 50 years
    2. Age over 65 years old in 70 to 85% of new cases
  3. More common in men
  4. Rare in Asian patients

III. Pathophysiology

  1. Neoplastic accumulation of mature Lymphocytes
    1. Involves Blood and Bone Marrow
    2. May infiltrate Spleen and Lymph Nodes
  2. Clonal B Lymphocyte mass involved in 95% of cases
  3. Chromosomal Abnormality: Trisomy 12

IV. Symptoms

  1. Asymptomatic in 50 to 70% of patients
    1. Leukocytosis often found incidentally on Complete Blood Count (CBC)
  2. Constitutional and generalized symptoms
    1. Weakness
    2. Fatigue
    3. Anorexia
    4. Pruritus
  3. Other presentations
    1. Frequent infections

V. Signs

  1. Fever
  2. Hepatomegaly
  3. Splenomegaly
  4. Lymphadenopathy

VI. Labs

  1. Peripheral Smear
    1. Leukocytosis
    2. Morphologically normal small Leukocytes
      1. HemeoncCllBlood.jpg
  2. Complete Blood Count
    1. Leukocyte count 15,000 to 200,000 (80-90% mature)
      1. Clonal expansion of >5000 B Lymphocytes/mm3
    2. Decreased Platelet Count
    3. Hemoglobin or Hematocrit consistent with Anemia
  3. Electrocardiogram (EKG)
    1. Obtain baseline EKG prior to treatment and as needed

VII. Diagnosis

  1. Leukocytosis or Hyperleukocytosis is present in 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. CLL is often asymptomatic at time of diagnosis
  2. Chronic Lymphocytic Leukemia (CLL) specific findings
    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)

VIII. Differential Diagnosis

  1. B-Cell CLL
    1. Reactive Lymphocytosis
  2. T-Cell CLL
    1. Sezary Syndrome
    2. Adult T-Cell Leukemia
  3. General
    1. Prolymphocytic Leukemia
    2. Lymphosarcoma Cell Leukemia
    3. Hairy Cell Leukemia
    4. Waldenstrom's Macroglobulinemia

IX. Complications

  1. Pancytopenia
  2. Coombs-positive Hemolytic Anemia (20%)
  3. Hypogammaglobulinemia
  4. Opportunistic infection
  5. Richter's Syndrome (evolves into aggressive Lymphoma)
  6. Autoimmune Thrombocytopenia

X. Imaging

  1. Chest XRay
    1. Enlarged mediastinal Lymph Nodes

XI. Management: Treatment

  1. Indications for active management
    1. Active stage disease
    2. Worsening constitutional symptoms
    3. Worsening Lymphocytosis, Thrombocytopenia, Anemia
    4. Worsening Lymphadenopathy, Hepatosplenomegaly
  2. Efficacy of treatment
    1. No regimen effective at eradicating CLL
    2. Goal is to reduce Leukemia cell mass and symptoms
  3. Alkylating Agents (pulsed q3-6 weeks or continuous)
    1. Indications
      1. Hemolytic Anemia and other cytopenia
      2. Disfiguring Lymphadenopathy
      3. Symptomatic organomegaly
      4. Marked systemic symptoms
    2. Agents
      1. Chlorambucil
      2. Cyclophosphamide
  4. Glucocorticoids
    1. Coombs-positive Hemolytic Anemia
    2. Immune Thrombocytopenia
    3. Pancytopenia
    4. "Packed Marrow" Syndrome
  5. Splenectomy indications
    1. Hypersplenism
    2. Refractory Hemolytic Anemia
    3. Thrombocytopenia
  6. Radiation Therapy indications
    1. Localized disease
    2. Palliative end-stage disease therapy (total-body)
  7. Other agents
    1. Small molecule inhibitors (e.g. Venetoclax)
    2. Immunoglobulin transfusion (not proven efficacious)

XII. Management: Surveillance for those under observation only (no treatment)

  1. Indications for observation only (no active treatment)
    1. Anemia absent AND
    2. Thrombocytopenia absent AND
    3. Fewer than 3 Lymph Node regions involved
  2. Repeat history and physical exam every 6 to 12 months (evaluate for progression to active disease)
    1. Periodic constitutional symptom history every 6 to 12 months
      1. Fatigue
      2. Weight loss
      3. Night Sweats
      4. Fever
    2. Periodic exam every 6 to 12 months
      1. Hepatosplenomegaly
      2. Complete skin exam
    3. Periodic Labs every 6 to 12 months
      1. Complete Blood Count (CBC with differential)
      2. Hematology Consultation for Anemia or Thrombocytopenia
  3. Vaccination
    1. Influenza Vaccine yearly
    2. Pneumococcal Vaccine every 5 years
    3. Covid19 Vaccine
    4. Avoid Live Vaccines in patients being monitored without treatment
    5. Routine cancer screening (appropriate for age and gender)

XIII. Management: Surveillance for those who have been treated

  1. Cardiology Consultation for baseline examination
  2. Periodic Echocardiogram (rest and stress)
    1. Frequency depends on risks and Echocardiogram findings

XIV. Course

  1. Indolent nature
  2. Often incidental finding on Complete Blood Count

XV. Staging

  1. Stage A: Lymphocytosis (<3 Lymph Node groups involved)
    1. Median survival: over 10 years
  2. Stage B: Lymphocytosis (>3 Lymph Node groups involved)
    1. Median survival: 5 years
  3. Stage C: Lymphocytosis with Anemia or Thrombocytopenia
    1. Median survival: 2 years

XVI. Prognosis

  1. Age <50 years old: 93% five-year survival
  2. Age 50 to 64 years old: 91% five-year survival
  3. Age >65 years: 80% five-year survival

XVII. References

  1. Davis (2014) Am Fam Physician 89(9): 731-8 [PubMed]
  2. Gbenjo (2023) Am Fam Physician 107(4): 397-405 [PubMed]
  3. Yee (2006) Mayo Clin Proc 81(8): 1105-29 [PubMed]

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