Azathioprine-Induced Life-Threatening Myelotoxicity in a Patient with Multiple Sclerosis: Are We Utilizing TPMT Activity Testing to Identify Susceptible Individuals?

Background: Immunosuppressive agents, such as AZA, are alternative treatment options in MS patients who are suboptimal responders or intolerant to other disease-modifying agents. AZA, a thioprine drug, is capable of causing life-threatening myelosuppression. Genetic polymorphism of TPMT, an enzyme that catalyzes S-methylation of AZA, causes some individuals to be particularly vulnerable to this side effect of AZA.

Objectives: To report a case of life-threatening myelotoxicity in a multiple sclerosis (MS) patient treated with standard dose of azathioprine (AZA) who later was found to have low thiopurine methyltransferase (TMPT)  activity.

Methods: A 29-year-old woman with relapsing-remitting MS, who had previously failed treatment with glatiramer acetate and Interferon beta 1a, was started on AZA 100 mg/day after a disabling attack. Six weeks after initiation of AZA, she presented with 4 days of severe epistaxis, fatigue and fever. On admission, laboratory studies revealed profound pancytopenia:  White blood count, 800/mm³ with an Absolute Neutrophil Count of 48; Hemoglobin, 4.4mg/dl;  and Platelet count, 4,000/mm³ .

Results: AZA was discontinued and during her 19-day hospital stay, she received multiple transfusions, colony-stimulating factor and was empirically treated with antibacterial, antiviral and antifungal agents. TPMT activity measured  1 month after presentation was 9.1 units/mL. TMPT activity measured 9 months later, to eliminate masking effect of the transfused bloodproducts, was 1.8 units/mL indicative of  homozygous mutant allel with low activity

Conclusions: AZA remains an invaluable treatment option in a select group of MS patients. Both the FDA and the manufacturer recommend genotype testing prior to the use of AZA. A significantly reduced dose, or alternative nonthiopurine immunosuppressant therapy, is recommended for individuals heterozygous/ homozygous for nonfunctional TPMT alleles. Though not consistently reliable, measuring TPMT activity before initiating AZA therapy can help avert potentially life-threatening toxicity and costly hospital admission.