Voriconazole Is Safe and Effective as Prophylactic Antifungal Therapy Following Allogeneic Transplantation.
Authors: Martin Thomas , Working Meaghan , O’Malley Ryan , Guglielmo Joe , Fischbach Neal , Damon Lloyd , Navarro Willis , Kaplan Lawry , Jacobs Richard , Andrews John , Linker Charles 
Published: April 2020

Introduction: Despite fluconazole prophylaxis, invasive fungal disease (IFD) following allogeneic transplantation (alloBMT) remains problematic. Voriconazole is a second-generation triazole with activity against yeast and molds. Since FDA approval, voriconazole (VORI) has been used as antifungal prophylaxis in AlloBMT patients at UCSF Med Ctr. The goals of this retrospective study were to evaluate the incidence of IFD and to assess organ toxicity in alloBMT patients receiving VORI.

Patients and Methods: The charts of 72 patients who received VORI as antifungal prophylaxis for alloBMT were reviewed. The mean age was 54 years (range 19–70), including 44 males and 28 females. Thirty-nine patients received reduced-intensity preparative therapy and 31 received myeloablative therapy. Thirty-six patients received stem cells from an HLA-identical relative, and 36 from an HLA-matched unrelated donor. All patients received tacrolimus, methotrexate +/− MMF for GVHD prophylaxis, G-CSF, acyclovir and antibacterial prophylaxis. Voriconazole (4 mg/kg) BID was administered from day −2 through day +100 post-transplant as tolerated. EORTC criteria were utilized to assess for IFD.

Results: Two patients (3%) developed definitive IFD (mucor and aspergillus) and 3 patients (4%) had possible fungal infections. No cases of probable IFD were identified. Both patients with definitive IFD died, one from severe Grade IV GVHD and the other from sepsis and multiorgan failure. The patient with aspergillus had discontinued VORI &gt;1 month prior to IFI due to elevated liver tests (LFT’s). All the patients with possible IFD continued to receive VORI but received additional antimicrobial agents (i.e. caspofugin and antibacterials). One of these patients died from progressive pneumonia. Overall, voriconazole appeared well tolerated. Fifty-four of the 72 patients (75%) received VORI throughout transplant without interruption. Ten patients discontinued voriconazole within 30 days of alloBMT; increased LFT’s (n=7), prolonged QTc (n=2) and suspected new IFD (n=1). Four of the 10 patients were restarted on VORI and continued through day 100. Eight patients discontinued VORI after day 30 but before day 100; 2 planned taper, 1 died, 4 increased LFT’s and 1 for suspected IFD. Two of these patients restarted VORI. No significant cardiac toxicity was noted, despite a QTc of &gt;500 msec in 10 patients. The mean increase in QTc after initiating VORI was 34 msec (n=36). The median bilirubin, alk. phos and AST values post-transplant were 1.3 mg/dL, 134 U/L and 34 U/L, respectively. Eight patients developed severe hyperbilirubinemia (&gt;6 mg/dL); 3 had VOD, 3 had GVHD. The mean peak creatinine was 1.5 mg/dL and four patients required hemodialysis. No severe or unexpected toxicity was noted. In addition, VORI increased serum tacrolimus levels necessitating a 60% reduction in standard tacrolimus dosing. The 100 and 180-day treatment related mortality rates in this study were 8% and 18%, respectively.

Conclusions: In this cohort of 72 patients, VORI appears safe and effective as prophylaxis for alloBMT. A randomized trial comparing VORI to fluconazole as prophylaxis in alloBMT is currently ongoing. Recommendations regarding VORI administration in regards to QTc and LFT’s will be presented.