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Severe graft failure presumably due to phenytoin-induced hypersensitivity syndrome in two patients after bone marrow transplantation

Bone Marrow Transplantation volume 41, pages 833–835 (2008)Cite this article

The use of prophylactic or therapeutic antiepileptic medication is common in patients undergoing bone marrow transplantation (BMT). Here, we report about two siblings who experienced severe graft failure attributed to drug-induced hypersensitivity syndrome (DIHS) after treatment with phenytoin.

Patient 1 is a 9-year-old girl of African descent who underwent allogeneic unmanipulated BMT (cell dose of 3.9 × 108 nucleated cells per kg body weight) from a human leukocyte antigen-matched unrelated donor for homozygous sickle cell anemia. The indication for BMT was based on the history of a life-threatening hepatic sequestration crisis, non-responsiveness to hydroxyurea treatment, and intractable hemolysis caused by alloimmunization against the hemagglutination inhibition antigen, which made transfusion therapy impossible. As the preparative regimen contained busulfan in addition to fludarabine and antithymocyte globuline, the patient received phenytoin for prophylaxis of seizures. We planned to continue this prophylaxis after BMT because of the specific propensity of patients suffering from sickle cell anemia for seizures. Despite adequate serum phenytoin levels, the patient experienced seizures with typical magnetic resonance imaging findings under graft-versus-host-disease (GVHD) prophylaxis with ciclosporin, which was changed to tacrolimus. Hematologic engraftment was complete with >95% donor-derived hematopoiesis after transplantation. Four months after BMT, the patient developed hepatitis with elevated liver enzymes (Table 1) and an increase in cholestasis parameters. Bilirubin remained within the normal range (10 μmol/l). A test for detection of viral pathogens was negative. Because of suspected drug toxicity, tacrolimus and phenytoin doses were reduced and fluconazole prophylaxis was discontinued. One week later, phenytoin was discontinued. Three weeks later, the patient was admitted to the hospital with fever, skin rash, itching and pancytopenia. Clinical and laboratory findings are summarized in Table 1. Chimerism at this point remained at 94% donor hematopoiesis. A bone marrow aspirate showed trilineage aplasia; a skin biopsy revealed interface dermatitis with apoptosis not typical of GVHD. Despite broad-spectrum antimicrobial therapy the patient's condition deteriorated rapidly requiring bilevel positive airway pressure-assisted ventilation and catecholamines for circulatory support. Within hours of administration of 2 mg/kg prednisone (suspecting DIHS), the patient's condition improved substantially. However, despite immunosuppressive treatment and administration of granulocyte–macrophage colony stimulating factor (GM-CSF), her bone marrow graft failed to recover. Therefore, a decision for a second BMT using a different unrelated donor was made. The patient had an uncomplicated second transplant course. Twelve months after the second BMT she is alive and well, although suffering from limited chronic skin GVHD.

Table 1 Clinical and laboratory parameters of the two patients with DIHS at presentation
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  1. Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany

    B Maecker, B Meissner, C Bettoni da Cunha-Riehm, M Sauer, K Welte & K-W Sykora

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  1. B Maecker
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Correspondence to B Maecker.

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Maecker, B., Meissner, B., Bettoni da Cunha-Riehm, C. et al. Severe graft failure presumably due to phenytoin-induced hypersensitivity syndrome in two patients after bone marrow transplantation. Bone Marrow Transplant 41, 833–835 (2008). https://doi.org/10.1038/sj.bmt.1705985

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