What is the management for a patient with macrocytic anemia on Cellcept (Mycophenolate Mofetil) and Plaquenil (Hydroxychloroquine)?

Management of Macrocytic Anemia in a Patient on Cellcept and Plaquenil

This patient requires immediate workup for drug-induced macrocytic anemia with priority evaluation of B12, folate, and bone marrow function, as mycophenolate mofetil (Cellcept) is a known cause of bone marrow suppression and macrocytosis.

Initial Diagnostic Workup

The evaluation must focus on distinguishing between drug-induced toxicity versus underlying autoimmune disease progression 1:

• Complete blood count with peripheral smear to assess for schistocytes, hemolysis, and reticulocyte count 1
• Nutritional deficiencies: B12, folate, copper, ceruloplasmin, vitamin D levels 1
• Hemolysis markers: LDH, haptoglobin, indirect bilirubin, direct antiglobulin test (Coombs) 1
• Bone marrow evaluation: Consider if refractory or if cytopenias worsen, including aspirate and biopsy with cytogenetic analysis 1
• Viral studies: CMV, EBV, parvovirus B19, human herpesvirus 6 1
• Autoimmune serology and paroxysmal nocturnal hemoglobinuria (PNH) screening 1

Critical Drug Considerations

Mycophenolate mofetil is a well-documented cause of bone marrow toxicity manifesting as macrocytic anemia, neutropenia, and thrombocytopenia 1, 2. The MCHC of 30.9 suggests mild hypochromia alongside macrocytosis (MCV 96), which may indicate a mixed picture 3.

Common Pitfalls:

• MMF-induced bone marrow suppression can occur months after initiation (mean 4 months in one series) 2
• Hydroxychloroquine (Plaquenil) rarely causes hematologic toxicity but should not be excluded 1
• The combination of immunosuppressants increases risk of viral reactivation causing cytopenias 1

Management Algorithm

Step 1: Assess Severity and Hemoglobin Level

If hemoglobin is ≥10 g/dL (Grade 1):

• Continue current medications with close monitoring 1
• Weekly CBC until stable 1
• Supplement with folic acid 1 mg daily 1

If hemoglobin is 8-10 g/dL (Grade 2):

• Hold mycophenolate mofetil and strongly consider permanent discontinuation 1
• Initiate prednisone 0.5-1 mg/kg/day if hemolysis is present 1
• Supplement with folic acid 1 mg daily 1

If hemoglobin is <8 g/dL (Grade 3-4):

• Permanently discontinue mycophenolate mofetil 1
• Obtain urgent hematology consultation 1
• Initiate prednisone 1-2 mg/kg/day (oral or IV) 1
• Consider RBC transfusion to maintain hemoglobin 7-8 g/dL in stable patients 1
• If no improvement or worsening on corticosteroids, add rituximab, IVIG, or cyclosporine 1

Step 2: Address Nutritional Deficiencies

All patients should receive empiric folic acid supplementation while awaiting B12 and folate levels 1. If B12 deficiency is confirmed, initiate replacement therapy immediately 1.

Step 3: Alternative Immunosuppression

If MMF must be discontinued due to bone marrow toxicity, consider alternative agents for the underlying autoimmune disease 1:

• Azathioprine 1-2 mg/kg/day (maximum 150 mg/day) - response may take 3-6 months 1
• Cyclosporine A 5 mg/kg/day for 6 days, then 2.5-3 mg/kg/day titrated to levels 100-200 ng/mL 1
• Rituximab 375 mg/m² weekly × 4 doses for severe autoimmune cytopenias 1, 4

Note: Azathioprine may also cause macrocytosis but typically with less severe bone marrow suppression than MMF 3.

Step 4: Monitor Response

• Weekly hemoglobin monitoring until corticosteroid taper is complete 1
• Reassess CBC 1-2 weeks after MMF discontinuation to confirm recovery 2
• If neutropenia develops alongside anemia, consider G-CSF support 2

Special Considerations for Autoimmune Disease Context

Given the underlying autoimmune disease requiring immunosuppression 4, 5:

• Autoimmune hemolytic anemia (AIHA) may coexist with drug toxicity - check direct Coombs test 1, 5
• If AIHA is confirmed, the combination of corticosteroids plus MMF has shown efficacy in pediatric series, but this patient's macrocytosis suggests MMF toxicity predominates 4
• Hydroxychloroquine should generally be continued as it rarely causes significant hematologic toxicity and is beneficial for autoimmune disease control 5

When to Escalate Care

Admit the patient if 1:

• Hemoglobin <8 g/dL with symptoms
• Evidence of hemolysis with rapid decline
• Concurrent thrombocytopenia or neutropenia suggesting severe bone marrow suppression
• Signs of end-organ dysfunction

The key decision point is whether to continue or discontinue mycophenolate mofetil based on anemia severity, with Grade 2 or higher warranting drug cessation and alternative immunosuppression 1.