Wingard, J. R., Carter, S. L., Walsh, T. J., Kurtzberg, J., Small, T. N., Baden, L. R., . . . Blood and Marrow Transplant Clinical Trials Network. (2010). Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood, 116, 5111–5118.

To evaluate fluconazole versus voriconazole in terms of fungal-free survival (FFS) (i.e., alive and free from proven, probable, or presumptive invasive fungal infection [IFI]) at 180 days posttransplant.

Patients who met the eligibility criteria were randomly assigned to receive voriconazole 200 mg twice daily or fluconazole 400 mg once daily before transplantation.  To maintain the blind, placebo was administered to match the number of doses for the two arms.  Study drugs were continued from days 0 until 100 posttransplantation.  Premature withdrawal of study drug was mandated for the occurrence of documentation of IFI, grade 3 or 4 toxicity, or relapse of underlying disease.

• Six hundred patients were included (295 in the fluconazole arm [55% male, 45% female] and 305 in the voriconazole arm [56% male, 44% female]).
• Median age for both groups was 43 years.
• Two hundred thirty-four (78%) patients had acute myeloid leukemia (AML), 122 (41%) had acute lymphoblastic leukemia, 103 (34%) had chronic myelogenous leukemia, 98 (33%) had myelodysplastic syndrome, and 43 (14%) had non-Hodgkin lymphoma.
• Human leukocyte antigen matched 6/6 encompassed 96% of patients, and the remaining 4% being 5/6 matches.

• Mutli-site  
• Thirty-five centers participated in the Blood and Marrow Transplant Clinical Trials Network.

Patients were undergoing the active treatment phase of care.

This was a randomized, double-blind, multi-center study.

• Routine galactomannan testing on serum samples were collected twice weekly through day 60 and once weekly through day 100.    
• Computed tomography scans were obtained.
• Bronchoalveolar lavage/biopsies were performed.

By 180 days after hematopoietic cell transplant (HCT), 55 patients had developed IFIs (14 proven, 24 probable, and 17 presumptive), and by one year after HCT, 79 patients had developed IFIs (28 proven, 33 probable, and 18 presumptive). Aspergillus was the most frequent pathogen, accounting for 26 (47%) and 38 (48%) IFIs at days 180 and 365, respectively.  Cumulative incident rates of IFIs were 11.2% and 7.3% for fluconazole and voriconazole, respectively, at 180 days and 13.7% and 12.75%, respectively, at 356 days.  At 180 days, there was a trend toward fever and Aspergillus spp. infections in the voriconazole arm, but no difference existed in the rates of other IFIs, including those caused by Zygomycetes. Fungal-free survival rates were similar at 180 days:  75% and 78% for fluconazole versus voriconazole, respectively, and 65% and 64%, respectively, at 365 days. There was no difference in overall survival at 180 days or 365 days between the two groups. Toxicity was similar between the two arms. There were no significant differences in study outcomes between the groups.  Significant predictors of IFIs in both groups were a diagnosis of AML and age >18 and grade 2–4 graft-versus-host disease among those at high risk.

There were no differences in fungal infection-related outcomes between patients receiving fluconazole or voriconazole.

• Enrollment was limited to patients who were not at high risk for early death or relapse.
• Patients who had little or excessive risks for IFI or death were excluded.
• The patient population was selective.

Data indicated that there was no difference in FFS at 6 months between the voriconazole and fluconazole arms in intensive monitoring and early intervention in standard-risk HCT patients.  However, it is unclear if this would be true in patients who are not intensively monitored and/or at higher risk of IFI.  Further studies are needed to optimize outcomes in higher-risk groups.