Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan

Correspondence to: Dr H Gondo, Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan

A 38-year-old Japanese woman with severe aplastic anemia received an allogeneic bone marrow transplant from her serologically HLA-identical father. Cyclosporine and methotrexate were administered to prevent graft-versus-host disease (GVHD). However, grade III acute GVHD developed on day 44, which was successfully treated with methylprednisolone and tacrolimus. Fluconazole therapy was started for oral candidiasis on day 112, but she complained of headache soon after. In addition to glycosuria and increased serum creatinine levels, Pelger-Huët anomaly of granulocytes was found in her blood, which disappeared after discontinuation of tacrolimus. Transient occurrence of Pelger-Huët cells may be associated with tacrolimus toxicity due to drug interaction with fluconazole. Bone Marrow Transplantation (2000) 26, 1255-1257.

Pelger-Huët anomaly; tacrolimus; fluconazole; bone marrow transplantation

The Pelger-Huët anomaly of granulocytes is characterized by poor segmentation and excessive clumping of the nuclear chromatin. There are three forms of the Pelger-Huët anomaly: a benign hereditary disorder, an acquired anomaly and a drug-induced anomaly. Acquired Pelger-Huët cells have been described in association with myelodysplastic syndrome (MDS), leukemia, multiple myeloma and various infections such as HIV infection, malaria, influenza and acute enteritis.¹ Drugs, including colchicine, sulphonamides, taxoid and fludarabine, have also been reported to induce the Pelger-Huët anomaly.^2,3,4 We describe a patient who showed transient occurrence of Pelger-Huët cells in association with concomitant tacrolimus and fluconazole therapy after allogeneic bone marrow transplantation (BMT).

Case report

A 38-year-old Japanese woman with a 9-year history of severe aplastic anemia that did not respond to corticosteroids, antithymocyte globulin, cyclosporine or growth factor therapy was referred to our hospital for BMT. She received total body irradiation 3.6 Gy and cyclophosphamide 200 mg/kg followed by infusion of unmodified bone marrow cells (3 ´ 10⁸/kg) from her father, who was HLA-A, -B, -DR serologically identical and ABO blood type matched. HLA-DRB1 loci of the recipient and donor were also confirmed identical at the DNA level. Cyclosporine and methotrexate were administered for prevention of GVHD according to the protocol described previously.⁵

Engraftment was prompt with granulocytes of >500/l on day 18 and the last platelet transfusion on day 22. A skin eruption developed in the anterior chest on day 44, which later extended to the abdomen and extremities. She complained of abdominal pain and diarrhea. Histological examination of skin and gut demonstrated findings consistent with those of GVHD. She was diagnosed with grade III acute GVHD. Cyclosporine was changed to tacrolimus and methylprednisolone was instituted: this was effective in the treatment of the acute GVHD, although positive cytomegalovirus antigenemia was observed transiently. She was discharged to outpatient care on day 88. Fluconazole 200 mg was started for the treatment of oral candidiasis on day 112. However, she began to complain of headache and thirst 1 month later. Her blood pressure was normal. The granulocytes in a stained blood smear, taken during treatment with tacrolimus and fluconazole, had monolobed or bilobed nuclei showing the characteristics of the Pelger-Huët anomaly; 43% of WBC were Pelger-Huët cells (Figure 1). Marrow examination revealed no abnormal leukemic cells or dysplastic changes except the Pelger-Huët anomaly. Cytogenetics were 46, XY normal; the karyotype of the donor. Laboratory examinations at the same time demonstrated anemia, glycosuria, hyperglycemia and increased serum creatinine levels, suggesting toxicity from tacrolimus, although the blood trough concentration of tacrolimus was 15.1 ng/ml (Figure 2). Tacrolimus, but not fluconazole, was discontinued on day 163, because the clinical findings did not improve despite reduction of the dose of tacrolimus. Symptoms and laboratory data improved rapidly over the next few weeks, including disappearance of the Pelger-Huët cells, along with a decrease in the blood concentration of tacrolimus.

Discussion

Reversible Pelger-Huët anomaly occurred in a patient with aplastic anemia following allogeneic BMT. Our patient complained of headache and thirst soon after fluconazole administration. Glycosuria, hyperglycemia and increased serum creatinine levels, in addition to Pelger-Huët cells, were found at that time, suggesting tacrolimus toxicity due to drug interaction with fluconazole. Such toxicity was not observed during treatment with either tacrolimus or fluconazole alone.

Tacrolimus is almost completely metabolized in the liver and is catalyzed by cytochrome p-450.⁶ Drugs which inhibit cytochrome p-450 enzymes may affect the metabolism of tacrolimus, with resultant changes in its blood levels. Fluconazole has inhibitory effects on the cytochrome p-450 enzyme system, and drug interactions between tacrolimus and fluconazole have been reported.⁷ Mañez et al⁷ demonstrated that tacrolimus trough concentrations increased 1.4- to 3.1-fold in patients receiving 100 mg/day to 200 mg/day of fluconazole.

Blood levels of tacrolimus have been shown to correlate with toxicity.⁸ However, adverse effects of tacrolimus are not only found at high concentrations, as nephrotoxicity and impared glucose tolerance have been reported during tacrolimus therapy despite tacrolimus levels being within the therapeutic range.^9,10 The Pelger-Huët anomaly in the present study seemed to be associated with tacrolimus toxicity, even though the tacrolimus blood trough concentration was within the therapeutic range.

An acquired Pelger-Huët anomaly has been described in association with drugs.^2,3,4 A direct toxic effect or hypersensitivity is thought to be a cause of the Pelger-Huët anomaly, although the precise mechanism of poor segmentation is unclear. A contribution of profound T cell suppression to this dysplastic change is suggested.⁴ Loss of immune surveillance in tacrolimus therapy may be related to this effect, because tacrolimus inhibits IL-2 gene transcription, exocytosis and programmed cell death.⁵

The clinically important findings of the present study include distinguishing the reversible Pelger-Huët anomaly from the development of MDS or acute leukemia, because the occurrence of Pelger-Huët cells has been described in such diseases. Although MDS or acute leukemia occur extremely infrequently after allogeneic BMT,¹¹ long-term survivors of aplastic anemia are at high risk for MDS or acute leukemia, showing a 10-year cumulative incidence rate of 9.6% for MDS and 6.6% for acute leukemia after immunosuppressive therapy.¹² Fortunately, the Pelger-Huët anomaly in our patient was reversible and cytogenetic abnormalities or blastic cell proliferation suggesting development of MDS or acute leukemia were not observed in her marrow.

Reversible Pelger-Huët anomaly of granulocytes may occur in association with concomitant tacrolimus and fluconazole therapy and should be differentiated from MDS or acute leukemia following allogeneic BMT.

Acknowledgements

This work was supported in part by the Grant-in-Aid for Cancer Research (7-3) from the Ministry of Health and Welfare.

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Figure 1 Acquired Pelger-Huët anomaly of granulocytes in the peripheral blood during treatment with tacrolimus and fluconazole after BMT, showing bilobed nucleus.

Figure 2 Clinical course. FK506, tacrolimus; Hb, hemoglobin; Plt, platelet; Cr, creatinine; Glu, glucose.