Abstract

Supportive care guidelines recommend anti-mold prophylaxis in hematopoietic stem cell transplant (HSCT) recipients deemed high-risk for invasive fungal infection, leading to long-term use of voriconazole following allogeneic HSCT in patients that remain immunocompromised. Voriconazole has been associated with periostitis, exostoses, and fluoride excess in patients following solid organ transplant, HSCT and leukemia therapy. The study aims were: to describe the frequency and clinical presentation of patients presenting with pain and fluoride excess in allogeneic HSCT patients taking voriconazole; to identify when a plasma fluoride concentration was measured with respect to voriconazole initiation and onset of pain; and to describe the outcomes of patients with fluoride excess in the setting of HSCT. A retrospective review was conducted of all adult allogeneic HSCT patients receiving voriconazole at Mayo Clinic in Rochester, Minnesota, between 1/1/09 – 7/31/12. Of 242 patients included, 32 had plasma fluoride measured to explore the etiology of musculoskeletal pain. In 31 patients with fluoride measurement while on voriconazole, 29 (93.5%) had elevated levels. The median plasma fluoride was 11.1 ?mol/L (range, 2.4-24.7). The median duration of voriconazole was 163 days (range, 2-1327). The median time to fluoride measurement was 128 days following voriconazole initiation (range, 28 – 692). At 1 year after the start of voriconazole post-HSCT, 15.3% of patients had developed pain associated with voriconazole use, and 35.7% developed pain while on voriconazole after two years. Of the patients with an elevated fluoride level, 22 discontinued voriconazole; pain resolved or improved in 15, stabilized in 3, and worsened in 4 patients. Ten patients continued voriconazole; pain resolved or improved in 7, was attributable to alternative causes in 2 and undefined in 1. Serum creatinine, estimated glomerular filtration rate, alkaline phosphatase, and voriconazole concentration did not predict for fluoride excess and associated pain. Periostitis due to fluoride excess is a common adverse effect of voriconazole that should be considered in patients presenting with pain and is often reversible following drug discontinuation. Alternative antifungal agents with a lower risk for fluoride excess should be considered in patients receiving voriconazole who develop fluoride excess and pain.

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