Background and Rationale: Voriconazole is a second generation azole antifungal agent used for both treatment and prophylaxis of fungal pathogens. Because of its broad spectrum of activity, voriconazole is being used in many centers as prophylaxis for pts at high risk for developing fungal infections, and as treatment for pts with proven or probable fungal infection. Our purpose was to examine the incidence and nature of serious side effects of voriconazole use in the setting of stem cell transplantation. Methods: We reviewed the charts of 45 pts who had undergone either autologous or allogeneic transplantation at Emory University and had received voriconazole, as antifungal treatment (20 pts) or prophylaxis (25 pts). Transplant types for the 45 pts included: matched related donor (20pts), matched unrelated donor (16 pts), autologous (6 pts), mismatched family donor (1 pt), and umbilical cord blood (1 pt). 21 pts (47%) underwent TBI based conditioning, and 12 (27%) underwent Busulfan based conditioning, and the remaining 12 patients (27%) underwent Melphalan, Fludarabine or Cyclophosphamide based conditioning prior to transplantation. Among allogeneic transplant pts, 36 (80%) were on cyclosporine or tacrolimus, and 12 pts (27%) were also receiving MMF. Results: Of the 45 pts treated with voriconazole, 15 ( 33%) required discontinuation of voriconazole. Reasons for discontinuation included elevated LFTs(N=11), encephalopathy (N=2), multiorgan failure prohibiting the use of IV voriconazole (N=1), and toxic tacrolimus levels (N=1). Among the pts with elevated LFTs, median ALT/AST values were 135/159 mg/L (range 21-804/57-662) with a median total bilirubin of 3.6mg/dl (range 1.4-20.3). Among the 11 pts with the elevation of LFTs, 9 had improvement with cessation of voriconazole; the remaining 2 pts died of MOF. Two pts with improved LFTs were re-challenged with voriconazole and had recurrent elevation in LFTs. Both pts with encephalopathy improved with discontinuation of voriconazole. Of the 36 pts who received either cyclosporine or tacrolimus, 14 (39%) developed elevated blood levels of immunosuppressive agents necessitating dose adjustment, and 8 pts (22%) had toxicity related to the immunosuppressive agent. Factors associated with increased likelihood of voriconazole related toxicity included allogeneic transplantation (p= 0.021), use of cyclosporine or tacrolimus (p= 0.004) or MMF (p= 0.001). Conclusions: Use of voriconazole in the post-transplant setting may be associated with elevated LFTs and encephalopathy, necessitating discontinuation in approximately 1/3 of pts. Patients receiving allogeneic transplants, particularly those on cyclosporine, tacrolimus or MMF, appear to be at highest risk for voriconazole-related toxicities. Anticipation of pharmacokinetic interactions with tacrolimus and cyclosporine is also critical when allogeneic transplant pts are placed on voriconazole. Identification of other risk factors for toxicity and adverse events will be an important goal for future studies.
Full conference title:
American Society of Hematology 45th Annual Meeting
- ASH 45th (2003)