What are the causes of pancytopenia in the absence of blast cells, specifically considering drug-induced or immune-related factors?

Causes of Pancytopenia Without Blast Cells: Drug-Induced and Immune Etiologies

When pancytopenia presents without blast cells on peripheral blood film, drug-induced and immune-mediated causes must be systematically evaluated alongside other reversible etiologies, as these mechanisms account for a substantial proportion of cases and require distinct therapeutic approaches. 1

Drug-Induced Pancytopenia

Chemotherapy and Immunosuppressive Agents

• Chemotherapy agents cause pancytopenia through direct bone marrow suppression and mucosal barrier disruption, representing one of the most common iatrogenic causes. 1
• Methotrexate can cause pancytopenia even with low-dose weekly therapy, particularly in patients with impaired renal function, medication errors, or concomitant sulfonamide-based medications, typically occurring 4-6 weeks after dose increases. 1
• Azathioprine and 6-mercaptopurine cause bone marrow toxicity with severe leukopenia occurring in 5.3% of rheumatoid arthritis patients and 16% of renal transplant recipients, with profound leucopenia developing suddenly and unpredictably between blood tests in around 3% of patients. 2
• Patients with thiopurine methyltransferase (TPMT) deficiency or NUDT15 deficiency face dramatically increased risk for severe, life-threatening myelosuppression, though normal TPMT testing does not exclude risk as only 27% of leukopenia cases are explained by common TPMT variants. 2

Immune Checkpoint Inhibitors

• Immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-L1 agents) cause immune-related hematological toxicity in less than 5% of patients, but carry significant mortality risk. 1
• Persistent post-treatment cytopenias or progressive cytopenias should be evaluated for autoimmune causes with peripheral smear, reticulocyte count, and assessment for hemolysis. 3
• In immunotherapy-treated patients, maintain a low threshold for bone marrow examination to rule out marrow infiltration, secondary myelodysplastic syndromes, or aplastic anemia. 1

Other Drug-Induced Causes

• Oxaliplatin can induce drug-dependent antibodies against platelets, red blood cells, and white blood cells, causing acute pancytopenia within hours of infusion. 4
• Various prescription and non-prescription drugs, including environmental toxins, can cause pancytopenia through idiosyncratic reactions. 2

Immune-Mediated Pancytopenia

Autoimmune Mechanisms

• Autoimmune cytopenias arise from antibody-mediated destruction or dysfunction of blood cells, with corticosteroids as first-line therapy for warm antibody-mediated disease. 1
• Complete blood count should be monitored at treatment initiation, at intervals during therapy, and periodically in long-term survivors to detect immune-related adverse events. 3
• Autoimmune workup, including ANA and anti-dsDNA, should be performed if systemic symptoms suggest autoimmune disease. 1
• Systemic lupus erythematosus represents an important reversible cause of pancytopenia, accounting for a notable proportion of cases in cross-sectional studies. 5

Hemophagocytic Syndromes

• Hemophagocytic lymphohistiocytosis presents with pancytopenia, fever, hepatosplenomegaly, hypertriglyceridemia, hypofibrinogenemia, and elevated ferritin, requiring prompt immunosuppressive treatment. 1
• Bone marrow examination may reveal hemophagocytosis in cases of immune dysregulation. 1

Chronic Lymphocytic Leukemia-Associated Autoimmunity

• Autoimmune mechanisms can cause cytopenias in chronic lymphocytic leukemia, with autoimmune hemolytic anemia and immune thrombocytopenia being more common than autoimmune granulocytopenia. 2
• Autoimmune cytopenias not responding to conventional autoimmune-oriented therapy are indications for CLL treatment. 2

Diagnostic Algorithm for Drug-Induced and Immune Causes

Initial Evaluation

• Obtain detailed medication history including all prescription drugs, over-the-counter medications, herbal supplements, and timing of recent dose changes. 1
• Perform peripheral blood smear examination to exclude pseudothrombocytopenia (EDTA-dependent platelet agglutination) and identify morphological abnormalities. 1, 2
• Measure reticulocyte count to differentiate between production defects and peripheral destruction. 1

Specific Testing

• HIV and HCV testing is recommended in all adult patients with pancytopenia, as viral infections represent important reversible causes. 1
• Consider drug-dependent antibody testing when temporal relationship exists between drug exposure and cytopenia onset, particularly with oxaliplatin, immune checkpoint inhibitors, or other high-risk medications. 4
• Perform autoimmune serologies (ANA, anti-dsDNA) when clinical features suggest systemic autoimmune disease. 1

Bone Marrow Examination Indications

• Bone marrow examination is indicated in patients over 60 years, those with systemic symptoms or abnormal physical findings, and cases where diagnosis remains unclear after initial testing. 1
• In immunotherapy-treated patients, bone marrow biopsy helps exclude marrow infiltration, secondary myelodysplastic syndromes, or aplastic anemia. 1
• Bone marrow aspiration was conclusive in all cases in a prospective study of 104 pancytopenic patients. 6

Management Approach

Drug-Induced Pancytopenia

• Discontinue the offending agent immediately when drug-induced pancytopenia is suspected, as hematologic recovery typically occurs after drug withdrawal. 4
• Consider dose reduction rather than complete discontinuation for essential medications like azathioprine, with close monitoring. 2
• Provide supportive care including transfusions for symptomatic anemia or severe thrombocytopenia. 1

Immune-Mediated Pancytopenia

• Initiate corticosteroids as first-line therapy for autoimmune cytopenia with warm antibodies, with typical response occurring within days. 1, 7
• Immunosuppressive therapy is recommended for non-severe aplastic anemia cases with immune-mediated mechanisms. 1
• For hemophagocytic lymphohistiocytosis, prompt immunosuppressive treatment is essential given high mortality risk. 1

Critical Pitfalls to Avoid

• Do not assume normal TPMT testing excludes risk of thiopurine-induced pancytopenia, as only 27% of cases are explained by common TPMT variants. 2
• TPMT enzyme activity measurement is unreliable after blood transfusions and with certain drug interactions. 2
• Profound leucopenia can develop suddenly and unpredictably between blood tests in patients on thiopurines, occurring in around 3% of patients, necessitating frequent monitoring. 2
• EDTA-dependent platelet agglutination can cause pseudo-thrombocytopenia and must be excluded when evaluating cytopenias. 2
• In immunotherapy patients, hematologic immune-related adverse events are rare but carry significant mortality risk, requiring high clinical suspicion. 3, 1

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