Can Mycophenolate Mofetil Cause Agranulocytosis?
Mycophenolate mofetil does not typically cause agranulocytosis, but it commonly causes neutropenia and leukopenia as dose-dependent hematologic toxicities. The FDA label specifically warns about severe neutropenia (ANC < 0.5 × 10³/µL) occurring in up to 2% of renal, 2.8% of cardiac, and 3.6% of hepatic transplant patients receiving MMF 3 g daily, but does not list agranulocytosis as a recognized adverse effect 1.
Hematologic Toxicity Profile
The primary hematologic concern with MMF is neutropenia, not agranulocytosis:
- Leukopenia, anemia, and thrombocytopenia are common hematologic effects reported in 23-45% of transplant patients, though these are generally less severe than true agranulocytosis 2, 3, 1
- Severe neutropenia (ANC < 0.5 × 10³/µL) develops in 2-3.6% of patients and may necessitate dose reduction or switching to alternative immunosuppression 1
- Pure red cell aplasia has been reported as a rare postmarketing adverse event, but agranulocytosis is not mentioned in FDA labeling 1
Clinical Context: MMF as Treatment for Agranulocytosis
Interestingly, MMF has been successfully used to treat agranulocytosis in autoimmune conditions:
- One case report documented successful treatment of refractory agranulocytosis in primary Sjögren's syndrome with MMF, where the patient achieved complete hematologic recovery after two months of therapy 4
- This suggests MMF's mechanism may actually help restore granulocyte production in certain autoimmune-mediated cytopenias 4
Monitoring Requirements to Detect Hematologic Toxicity
Mandatory CBC monitoring is essential to detect neutropenia early:
- Weekly CBC counts for the first month, twice monthly for months 2-3, then monthly through year 1, followed by every 1-3 months indefinitely 5, 6
- If neutropenia develops (ANC < 1.3 × 10³/µL), dosage interruption or reduction should be considered 1
- Development of severe neutropenia may be related to MMF itself, concomitant medications (particularly ganciclovir/valganciclovir), viral infections, or combinations thereof 1, 7
Management of Hematologic Toxicity
When neutropenia occurs, the approach depends on severity:
- Mild to moderate neutropenia often responds to dose reduction without complete discontinuation 7
- Severe cases may require temporary cessation of MMF, with spontaneous recovery typically occurring within days to weeks 7
- Granulocyte colony-stimulating factor (G-CSF) can be administered in persistent cases 7
- Switch to alternative immunosuppression (azathioprine, mTOR inhibitors) if neutropenia is refractory to dose adjustment 5
Important Caveats
Several factors increase the risk of MMF-related neutropenia:
- Concomitant use of other myelosuppressive agents, particularly ganciclovir or valganciclovir for CMV prophylaxis, significantly increases neutropenia risk 1
- Renal impairment leads to accumulation of the glucuronide metabolite (MPAG) at approximately five times normal levels in end-stage renal disease, potentially increasing hematologic toxicity 6
- Viral infections, particularly CMV, can independently cause or exacerbate neutropenia in transplant recipients 1, 8