Rapid Onset Neutropenia After Mycophenolate Mofetil Initiation: 2 Cases

Background Mycophenolate mofetil (MMF) is widely used as an immunosuppressive therapy for autoimmune diseases. Although leukopenia and neutropenia are recognized adverse effects, these typically develop subacutely. To date, rapidly developing cytopenias within days of treatment onset have not been documented. We report 2 cases of neutropenia occurring within 4 days of exposure to MMF, both of which recurred upon re-challenge, suggesting a likely hypersensitivity phenomenon.

Case Report Case 1 involves a 46-year-old man with newly diagnosed idiopathic inflammatory myositis who was treated with MMF 500mg daily along with glucocorticoids and IVIG. Within 3 days he developed neutropenia with neutrophils nadiring at 0.4 × 10^9/L on day 6 after MMF initiation. His neutropenia resolved with cessation of MMF and administration of filgastrin. However, re-challenge with MMF at 250mg daily led to recurrence of neutropenia within 1 day so MMF was permanently discontinued, after which his neutrophil count quickly rebounded. Case 2 involves a 73-year-old woman with a new diagnosis of limited cutaneous systemic sclerosis and scleroderma renal crisis, who was initiated on MMF 500mg twice daily. Within 4 days her neutrophils dropped from 11.1 × 10^9/L to 2.4 × 10^9/L. Accordingly, the MMF was held for a day, after which her neutrophil count normalized, so MMF was re-initiated at a lower dose of 500mg daily. Within 4 days neutropenia had recurred, so MMF was discontinued and the neutropenia resolved within 2 days.

Conclusion Bone marrow suppression is a well-established side-effect of MMF, with leukopenia and neutropenia occurring in as many as 25% of patients.[1] Onset, however, is generally subacute, occurring >100 days after initiation of MMF.[1,2] Prior to our cases, we found no reports of neutropenia or leukopenia developing within a matter of several days of MMF initiation without other obvious causal factors. A complex array of enzymes is responsible for metabolism and defects of any of these can lead to supratherapeutic drug or metabolite levels. Pharmacokinetic studies of MRP2/ABCC2 variants in renal transplant patients have identified both high expressor and low expressor phenotypes that can lead to either sub therapeutic or supratherapeutic MMF levels at standard dosing.[3] However, there is not yet a body of study investigating whether the pharmacokinetic differences seen in MRP2/ABCC2 variants translate into adverse events such as MMF-related neutropenia. The confirmation of such a link would offer a potential target for genetic screening, which could help to prevent hypersensitivity events in patients treated with MMF.

References [1.] Varnell CD. Pediatr Transplant 2017;21:10.1111/petr.13033. [2.] Zafrani L. Am J Transplant 2009;9:1816-25. [3.] Brazeau D. J Clin Pharm 2021;61:1592-605.