Cornely, O.A., Maertens, J., Winston, D.J., Perfect, J., Ullmann, A.J., Walsh, T.J., . . . Anqulo-Gonzalez, D. (2007). Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. New England Journal of Medicine, 356, 348–359.

Study patients received  200 mg of posaconazole in an oral suspension three times daily, 400 mg of fluconazole in an oral suspension once daily, or 200 mg of itraconazole in an oral solution twice daily.

Patients who were unable to tolerate the oral study drug could receive IV prophylaxis at the same dose for three days or less per chemotherapy cycle. Patients in either group were permitted to receive amphotericin B or another systemic agent as empirical antifungal therapy for a suspected invasive fungal infection.

Antifungal prophylaxis was administered with each chemotherapy cycle, starting either 24 hours after the last anthracycline dose or, in patients not  receiving an anthracycline-based regimen, on the first day of chemotherapy.

Prophylaxis was continued until recovery from neutropenia and complete remission, until occurrence of an invasive fungal infection, or for up to 12 weeks from randomization, whichever came first. Patients were followed for 100 days after randomization and for 30 days after the last dose of the study drug administered during the last chemotherapy cycle.

• 602 total patients
• Patients aged 13 years or older who had or were anticipated to have neutropenia with an absolute neutrophil count of 500 cells/mcl or lower for seven days or longer resulting from remission-induction chemotherapy for newly diagnosed or the first relapse of acute myelogenous leukemia or myelodysplastic syndrome.
• Exclusion criteria included an invasive fungal infection within the previous 30 days.
   

Eighty-nine centers worldwide.

Prospective, randomized trial.

An independent data review committee of infectious disease experts who were unaware of the treatment assignments reviewed and classified all cases of fungal infection as proven, probable, or possible, according to the consensus criteria of the European Organisation for the Research and Treatment of Cancer and the Mycoses Study Group.

• Incidence of proven or probable invasive fungal infection during the treatment phase.
• Incidence of invasive aspergillosis.
• Incidence of invasive fungal infection within 100 days after randomization and treatment success (versus failure) during the treatment phase. Treatment failure was defined as the occurrence of a proven or probable invasive fungal infection; receipt of an IV study drug for four consecutive days or more, or 10 days in total; receipt of any other systemic antifungal agent for four days or more for suspected invasive fungal infection; the occurrence of an adverse event possibly or probably related to the study treatment, resulting in the discontinuation of treatment; or withdrawal from the study with no additional follow-up.
• Survival was evaluated 100 days after randomization.
   

Proven or probable invasive fungal infections occurred during the treatment phase in 7 of the 304 patients (2%) in the posaconazole group and in 25 of the 298 patients (8%) in the fluconazole or itraconazole group (absolute reduction in the posaconazole group = –6%; 95% confidence interval [CI] [–9.7, –2.5]; p < 0.001).

During the 100-day period after randomization, 14 of 304 patients (5%) in the posaconazole group had a proven or probable fungal infection, as compared with 33 of 298 patients (11%) in the fluconazole or itraconazole group (p = 0.003).

The mean time to invasive fungal infection was 41 (SD = 26) days in the posaconazole group and 25 (SD = 26) days in the fluconazole or itraconazole group.

Kaplan-Meier analysis of the time to invasive fungal infection showed a significant difference in favor of posaconazole (p = 0.003).

The analysis of the time to first use of empirical antifungal therapy during the 100-day period revealed a significant difference in favor of posaconazole over fluconazole or itraconazole (p = 0.02).

Of the 304 patients in the posaconazole group, 49 (16%) died during the study period, as did 67 of 298 patients (22%) in the fluconazole or itraconazole group (p = 0.048); 44 patients (14%) and 64 patients (21%), respectively, died within 100 days.

The relative reduction in mortality at day 100 in the posaconazole group, as compared with the fluconazole or itraconazole group, was 33%.

The analysis of the time to invasive fungal infection or death also showed a significant benefit in favor of posaconazole (p = 0.01).

The incidence of treatment-related adverse events was similar among the treatment groups.

• All 602 patients in the intention-to-treat population were included in the safety evaluation.
• The different dosing schedules of the three study drugs and the logistics of their IV alternatives precluded a double-blind design.