Posaconazole demonstrates efficacy for prophylaxis of fungal infections in certain patients

Two randomized, controlled trials published in the New England Journal of Medicine (NEJM) demonstrate that posaconazole may be considered a first-line option for prophylaxis of fungal infections in patients with severe graft versus host disease (GVHD) after allogeneic hematopoietic stem-cell transplantation as well as in immunosuppressed patients undergoing chemotherapy for acute myelogenous leukemia or the myelodysplastic syndrome.

In the first study, Ullmann et al conducted an international, randomized, double-blind, placebo-controlled trial involving 600 patients aged ≥13 years who had undergone allogeneic hematopoietic stem-cell transplantation and had acute GVHD (grade II to IV), chronic extensive GVHD, or were being treated with intensive immunosuppressive therapy of either high-dose corticosteroids, antithymocyte globulin, or a combination of ≥2 immunosuppressive agents or types of treatment.

Patients were randomized to either posaconazole oral suspension 200 mg 3 times daily plus placebo capsules once daily (n=301) or fluconazole capsules 400 mg once daily plus placebo oral suspension 3 times daily (n=299). The primary end point was the incidence of proven or probable invasive fungal infections starting from randomization through the end of the 16-week treatment period.

The authors stated the reason for posaconazole's demonstrated superiority over fluconazole in preventing invasive aspergillosis as fluconazole's lack of activity against filamentous fungi, which are the major fungal pathogens affecting patients with GVHD.

Posaconazole's demonstrated superior efficacy in preventing invasive aspergillosis infections may help explain why the number of deaths from invasive fungal infections was lower in the posaconazole group compared with the fluconazole group (1% vs 4%, respectively; P=.046). The incidence of treatment-related adverse events was similar between the 2 groups.

In the second trial, conducted by Cornely et al, a total of 602 patients with prolonged neutropenia due to chemotherapy for acute myelogenous leukemia or the myelodysplastic syndrome were randomly assigned to receive posaconazole (n=304) or either fluconazole (n=240) or itraconazole (n=58). The goal of this study was to compare the efficacy and safety of posaconazole with fluconazole and itraconazole when used for prophylaxis in patients with prolonged neutropenia. Prophylaxis was given with each cycle of chemotherapy until recovery from neutropenia and complete remission, until occurrence of an invasive fungal infection, or for ≤12 weeks, whichever came first. As with Ullmann et al, the primary end point was incidence of proven or probable invasive fungal infections during treatment.

The primary end point occurred significantly less often in the posaconazole group compared with the fluconazole or itraconazole group (2% vs 8%, respectively; absolute risk reduction, –6%; 95% CI, –9.7 to –2.5%; P<.001). In addition, fewer patients in the posaconazole group had invasive aspergillosis (1% vs 7%, respectively; P<.001).

Survival was significantly longer in recipients of posaconazole than in recipients of fluconazole or itraconazole (P=.04). As with the Ullmann et al study, it is likely that posaconazole's superior efficacy in preventing fungal infections, specifically invasive aspergillosis, explains this finding.

Serious adverse events possibly or probably related to treatment were reported in 6% of patients in the posaconazole group compared with 2% in the fluconazole or itraconazole group (P=.01).

The authors said that "since the numbers of patients needed to treat to prevent 1 invasive fungal infection or 1 death are low (16 and 14, respectively), the benefit of posaconazole prophylaxis seems to outweigh the risks of toxic effects and selection of resistant organisms, which are inherent in prophylactic drug regimens and to justify the cost."

SOURCES

Ullmann AJ, Lipton JH, Vesole DH, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. New Engl J Med. 2007;356:335–47.

Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. New Eng J Med. 2007;356:348–59.