What causes a continued decrease in white blood cells (leukopenia)?

Causes of Continued Decrease in White Blood Cells

The most common causes of continued leukopenia include hematologic malignancies (particularly leukemias), medication side effects, infections, and bone marrow suppression from various etiologies. 1

Primary Causes of Leukopenia

Hematologic Malignancies

• Chronic Myeloid Leukemia (CML): Often presents with persistent leukopenia, particularly in advanced phases 2
• Hairy Cell Leukemia: Characterized by pancytopenia including leukopenia 2
• Other hematologic malignancies: Including acute leukemias, lymphomas, and myelodysplastic syndromes 2

Medication-Induced Leukopenia

• Chemotherapeutic agents: Cause myelosuppression as their primary mechanism of action 2
• Tyrosine Kinase Inhibitors (TKIs): Used in CML treatment, can cause persistent leukopenia 2
• Azathioprine: Can cause dose-dependent bone marrow suppression 2
• Antimicrobials: Particularly anti-tuberculosis drugs like rifampicin and isoniazid 3

Infections

• Viral infections: Particularly severe viral infections can cause transient or persistent leukopenia
• Overwhelming bacterial infections: Can cause leukopenia through increased utilization and destruction of white blood cells 4
• COVID-19: Can cause leukopenia, especially in patients with hematologic malignancies 2

Bone Marrow Disorders

• Primary bone marrow failure: Including aplastic anemia
• Infiltrative processes: Metastatic solid tumors infiltrating bone marrow
• Myelofibrosis: Can lead to decreased production of white blood cells

Evaluation Algorithm for Persistent Leukopenia

Step 1: Assess the Severity and Pattern

• Determine the absolute neutrophil count (ANC) - severe if <500/mm³ 2
• Review previous CBC results to establish the pattern (acute vs chronic, fluctuating vs progressive)
• Check if other cell lines are affected (isolated leukopenia vs pancytopenia)

Step 2: Medication Review

• Review all medications, particularly those known to cause leukopenia
• Consider timing relationship between medication initiation and onset of leukopenia
• Assess dose-dependency of medication effect 2

Step 3: Clinical Assessment for Underlying Conditions

• Splenomegaly: Suggests possible hypersplenism or hematologic malignancy 2
• Lymphadenopathy: Suggests possible lymphoma or leukemia
• Constitutional symptoms: Fever, night sweats, weight loss suggest malignancy or infection
• Signs of infection: May indicate infectious cause or consequence of leukopenia

Step 4: Laboratory Investigations

• Complete blood count with differential
• Peripheral blood smear examination 1
• Bone marrow aspiration and biopsy if clinically indicated
• Specific testing based on suspected etiology:
  • BCR-ABL testing for suspected CML 1
  • JAK2, CALR, MPL mutation testing if myeloproliferative disorder suspected 1
  • Viral studies (HIV, hepatitis, EBV, CMV)

Management Considerations

For Medication-Induced Leukopenia

• Consider dose reduction or discontinuation of suspected medication 2
• Monitor white blood cell counts regularly (every 1-2 weeks initially) 2
• For azathioprine-induced leukopenia: dose reduction recommended if lymphocyte count falls below 0.5 × 10⁹/L 2

For Malignancy-Related Leukopenia

• Treatment of the underlying malignancy is the primary approach 2
• For CML with leukopenia: Consider hydroxyurea (25-50 mg/kg/day) followed by appropriate TKI therapy 2
• For severe cases with hyperleukocytosis: Aggressive hydration (2.5-3 L/m²/day) 2

For Infection-Related Leukopenia

• Appropriate antimicrobial therapy for the identified pathogen
• G-CSF may be considered in severe neutropenia with infection 2

For Severe Neutropenia (ANC <500/mm³)

• Immediate broad-spectrum antibiotics if febrile 2
• Consider hospitalization for febrile neutropenia 5
• G-CSF administration may be appropriate in selected cases 2

Monitoring Recommendations

• Regular CBC monitoring (frequency depends on severity and cause)
• For mild leukopenia: Every 1-2 weeks initially, then monthly if stable
• For medication-related leukopenia: Monitor more frequently during dose adjustments
• For severe neutropenia: Consider daily CBC until improvement

Important Caveats

• Isolated lymphopenia is common with azathioprine therapy and may not require dose adjustment unless severe 2
• Leukopenia in CML treatment may represent therapeutic effect rather than adverse effect 2
• Febrile neutropenia is a medical emergency requiring immediate intervention 2
• Persistent unexplained leukopenia warrants bone marrow examination to rule out primary bone marrow disorders 1