Azathioprine–allopurinol interaction causing myelosuppression

Transplantmedium

A 52-year-old woman with ESRD from ADPKD, hypertension, and gout is admitted with fatigue, headache, fever, and chills 10 months after kidney transplantation. She received basiliximab induction; donor and recipient were both CMV seronegative. Maintenance was tacrolimus, mycophenolate, and prednisone until mycophenolate-induced colitis 6 months post-transplant prompted replacement of mycophenolate with azathioprine. Other medications are amlodipine, omeprazole, allopurinol, and trimethoprim-sulfamethoxazole. Temperature is 37.5°C. Examination is otherwise unremarkable. WBC count 900/µL, absolute neutrophil count 200/µL, absolute lymphocyte count 400/µL, hemoglobin 9.8 g/dL, platelets 115,000/µL; creatinine 0.8 mg/dL (baseline). What is the most likely cause of her pancytopenia?

  1. A.Trimethoprim toxicity
  2. B.Primary CMV infection
  3. C.6-Mercaptopurine toxicityCorrect
  4. D.Post-transplant lymphoproliferative disorder

Explanation

The most likely cause of pancytopenia is 6-mercaptopurine toxicity from the interaction between azathioprine and allopurinol. Azathioprine is a prodrug converted to 6-mercaptopurine, which has three metabolic fates: activation by hypoxanthine-guanine phosphoribosyltransferase to cytotoxic 6-thioguanine nucleotides, methylation by thiopurine methyltransferase, and oxidation by xanthine oxidase to inactive 6-thiouric acid. Allopurinol inhibits xanthine oxidase, blocking a major inactivation pathway and shunting 6-mercaptopurine toward thioguanine nucleotides. The result is profound marrow suppression with neutropenia, anemia, and thrombocytopenia, which can be fatal. This patient with gout was already taking allopurinol when mycophenolate was replaced with azathioprine, and severe neutropenia with fever followed. If the combination is unavoidable, the azathioprine dose must be reduced to 25% to 33% of the usual dose with close blood count monitoring; better options are to switch the urate-lowering agent or avoid azathioprine. Management now includes stopping azathioprine, evaluating and treating neutropenic fever, and considering granulocyte colony-stimulating factor. Testing for TPMT and NUDT15 variants is also useful before reintroducing a thiopurine. Trimethoprim inhibits dihydrofolate reductase and can cause cytopenias, particularly at treatment doses or with folate deficiency. Prophylactic doses rarely cause pancytopenia of this severity, and the timing after the azathioprine switch implicates the purine interaction. Primary CMV infection can cause leukopenia and fever after transplant, but both donor and recipient were CMV seronegative, making primary infection very unlikely without a transfusion or community exposure history. Post-transplant lymphoproliferative disorder can infiltrate the marrow, but it typically presents with lymphadenopathy, extranodal masses, or allograft involvement, usually in EBV-seronegative recipients. Isolated pancytopenia shortly after adding azathioprine to allopurinol is far more consistent with drug toxicity.

Why each option

A.
Prophylactic trimethoprim-sulfamethoxazole rarely causes severe pancytopenia, and the timing after starting azathioprine with allopurinol implicates the thiopurine interaction instead.
B.
Primary CMV infection is very unlikely when both donor and recipient were CMV seronegative, despite leukopenia and fever being typical features.
C.
Correct. Allopurinol inhibits xanthine oxidase, so azathioprine-derived 6-mercaptopurine is shunted toward cytotoxic thioguanine nucleotides, causing profound marrow suppression with neutropenia.
D.
PTLD usually presents with lymphadenopathy, extranodal or allograft masses, and EBV mismatch, not isolated pancytopenia after a new drug combination.

Reference: Venkat Raman G, J Intern Med 1990 (azathioprine and allopurinol: a potentially dangerous combination); KDIGO 2009 Clinical Practice Guideline for the Care of Kidney Transplant Recipients

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