Incidence of Fluoride Toxicity in Allogeneic Hematopoietic Stem Cell Transplant (HSCT) Patients Taking Voriconazole

Background: Guidelines recommend anti-mold prophylaxis in HSCT patients deemed high-risk for IFI; this has led to long-term use of voriconazole following allogeneic HSCT in patients that remain immunocompromised.  Voriconazole has three fluoride atoms and has been associated with periostitis, exostoses, and fluoride toxicity in patients taking voriconazole following solid organ transplant, HSCT and leukemia therapy.

Objectives:  To describe the incidence of fluoride toxicity in allogeneic HSCT patients taking voriconazole that had a fluoride level measured, identify when a fluoride level was measured due to symptomatic fluoride toxicity in relation to voriconazole initiation, and describe the clinical presentation and outcomes of patients with fluoride toxicity in HSCT patients. 

Methods: Retrospective review of all adult allogeneic HSCT patients at Mayo Clinic Rochester between 1/1/09 – 7/31/12.  Fluoride assays were conducted with an ion selective electrode (normal range 0 – 4 µmol/L).

Results: 292 patients received an allogeneic HSCT between 1/1/09 – 7/31/12.  Patients were excluded if they did not consent to research (n=4), were treated by the pediatric service (n=7), or did not receive voriconazole for more than 7 days (n=38).  The median duration of voriconazole was 167 days (range 7–1321).  Of 243 patients included, 32 presented with musculoskeletal pain and had a fluoride assay.  In 31 patients with fluoride measured while on voriconazole, 29 (93.5%) had elevated fluoride levels; 1 patient had a normal fluoride level measured 1 month after voriconazole discontinuation due to pain. The median fluoride level was 10.5 µmol/L (range 2-24.7).  The median time to measurement of fluoride was 113 days following voriconazole initiation (range 28 – 692).  Of the 29 patients with an elevated fluoride level, pain improved in 17 patients following voriconazole discontinuation; 2 patients did not have improvement after holding voriconazole for 1 week and resumed voriconazole. Four patients had repeat fluoride measurement and subsequently discontinued voriconazole because of pain; pain improved in 2 of those patients, did not improve in 1 patient and 1 patient was not assessed. Six patients continued voriconazole; pain resolved in 4 of those patients, was not assessed in 1 patient and persisted in 1 patient with recurrent leukemia. Eight patients (27.6%) with elevated fluoride levels had an estimated glomerular filtration rate < 50 mL/min.

Conclusions:  Of 243 consecutive allogeneic HSCT patients receiving voriconazole for more than 7 days, the development of musculoskeletal pain in 32 (13.2%) patients led to fluoride assessment; 29 patients (93.5%) with fluoride levels measured while on voriconazole had elevated levels.  Fluoride toxicity is an adverse effect of voriconazole that should be considered in patients presenting with pain and is often reversible following drug discontinuation.