What causes severe leukopenia?

Causes of Severe Leukopenia

Severe leukopenia results from either decreased bone marrow production, increased destruction, or abnormal distribution of white blood cells, with chemotherapy agents being the most common cause, followed by immunosuppressive medications, hematologic malignancies, infections, and autoimmune disorders. 1, 2

Medication-Related Causes

Chemotherapy and Immunosuppressive Agents

• Chemotherapy agents are the most common cause of severe leukopenia through direct bone marrow suppression, affecting myeloid progenitor cell proliferation and maturation 1, 2
• Azathioprine and 6-mercaptopurine cause bone marrow toxicity with leukopenia occurring in approximately 3.2% of patients overall, with severe leukopenia (WBC <2500 cells/mm³) in 5.3% of rheumatoid arthritis patients and 16% of renal transplant recipients 3, 4
• Patients with thiopurine methyltransferase (TPMT) deficiency or NUDT15 deficiency are at dramatically increased risk for severe, life-threatening myelosuppression from azathioprine, as 6-thioguanine accumulates in bone marrow tissue 3, 1, 4
• The combination of azathioprine with xanthine oxidase inhibitors (allopurinol, febuxostat) causes severe leukopenia by blocking drug metabolism pathways, requiring dose reduction to 1/3 to 1/4 of the usual dose 4

Drug Interactions That Exacerbate Leukopenia

• Aminosalicylates (sulfasalazine, mesalamine, olsalazine) inhibit TPMT enzyme activity and increase leukopenia risk when combined with azathioprine 4
• Ribavirin combined with azathioprine induces severe pancytopenia by inhibiting inosine monophosphate dehydrogenase (IMDH), leading to accumulation of the toxic metabolite 6-MTITP 4
• ACE inhibitors combined with azathioprine have been reported to induce severe leukopenia 4
• Co-trimoxazole and other drugs affecting leukocyte production lead to exaggerated leukopenia, especially in transplant recipients 4

Hematologic Malignancy-Related Causes

Bone Marrow Infiltration

• Hematologic malignancies including acute leukemia, chronic leukemia, lymphomas, and myelodysplastic syndromes cause severe leukopenia through bone marrow infiltration with malignant cells, impairing normal blood cell production 1, 2
• Chronic lymphocytic leukemia (CLL) causes cytopenias through both bone marrow infiltration and immune-mediated destruction mechanisms 2, 5
• Lymphoproliferative malignancies result in dysfunctional marrow production of normal immune cells due to malignant cell infiltration 5

Treatment-Related Marrow Failure

• Patients with refractory hematologic malignancies receiving multiple chemotherapy regimens face dramatically increased risk—nearly 90% of heavily pretreated patients experience serious infectious complications requiring hospitalization 5
• Prior treatment with rituximab and fludarabine emerged as specific risk factors for severe cytopenias (OR 1.8,95% CI 1.05-3.3) 5

Infection-Related Causes

• Viral infections, particularly HIV and hepatitis C virus (HCV), cause leukopenia through direct bone marrow suppression 2
• Cytomegalovirus (CMV) infection leads to cytopenias including leukopenia 2
• Bacterial infections, especially severe sepsis, cause leukopenia as a manifestation of overwhelming infection 1
• Leukopenia (WBC <4,000 cells/mm³) from community-acquired pneumonia is consistently associated with excess mortality and increased risk of acute respiratory distress syndrome 2

Autoimmune and Immune-Mediated Causes

• Autoimmune disorders cause immune-mediated destruction of white blood cells, with autoimmune granulocytopenia occurring in conditions like CLL 2, 5
• Immune checkpoint inhibitors induce hematologic immune-related adverse events including leukopenia 2
• Autoimmune cytopenias in CLL may respond to corticosteroids as first-line therapy 2

Bone Marrow Failure Syndromes

• Aplastic anemia causes pancytopenia including severe leukopenia through bone marrow hypocellularity, which can be idiopathic or secondary to drugs, infections, or inherited syndromes 2, 6
• Congenital neutropenia is linked to mutations in genes such as ELANE, HAX1, and SBDS 7
• Myelodysplastic syndromes impair normal blood cell production in the bone marrow 2

Post-Transplant Causes

• Graft failure after allogeneic transplantation results in severe leukopenia with mortality up to 80% 2
• Post-transplant immunosuppression causes leukopenia through multiple mechanisms 2

Nutritional and Metabolic Causes

• Megaloblastosis from vitamin B12 or folate deficiency causes leukopenia through impaired DNA synthesis 8
• Nutritional deficiencies can contribute to bone marrow failure 6

Critical Clinical Pitfalls

• TPMT genotype and enzyme activity cannot explain the majority of leukopenia cases—only 27% of cases in one study were explained by common TPMT variants, so normal TPMT testing does not exclude risk 3
• TPMT enzyme activity measurement is influenced by blood transfusions and drug interactions, making interpretation unreliable in certain clinical contexts 3
• In patients with alcohol abuse history presenting with leukopenia from pneumonia, adverse manifestations of septic shock and ARDS may be delayed or masked, requiring ICU monitoring 2
• EDTA-dependent platelet agglutination can cause pseudo-leukopenia and should be excluded when evaluating cytopenias 2