Noxafil Prophylaxis Reduces Fatal Fungal Infections in AML, MDS, and GVHD Pts

March 1, 2007

Two clinical studies with a total of 1,202 patients have found posaconazole (Noxafil) significantly more effective than two other antifungal agents in preventing fatal invasive fungal infections in acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) patients who develop neutropenia as a result of chemotherapy

BOSTON—Two clinical studies with a total of 1,202 patients have found posaconazole (Noxafil) significantly more effective than two other antifungal agents in preventing fatal invasive fungal infections in acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) patients who develop neutropenia as a result of chemotherapy, as well as in patients who develop graft-vs-host disease (GVHD) while receiving immunosuppressive therapy.

Oliver A. Cornely, MD, and his colleagues compared posaconazole to fluconazole (Diflucan) or itraconazole (Sporanox) in patients with AML and MDS. Andrew J. Ullmann, MD, and his fellow researchers compared posaconazole to fluconazole in GVHD patients. Both studies were reported in the New England Journal of Medicine (356:335-347; 358-359, 2007).

"Prophylaxis is a commonly used therapeutic strategy because the diagnosis of fungal infection is often delayed or difficult to establish with certainty, and a delay in antifungal treatment increases mortality," said Dr. Cornely, assistant professor of internal medicine, University of Cologne, Germany. "With posaconazole, we now can help prevent infections caused by the two most common pathogens, Aspergillus and Candida, before they occur."

Dr. Cornely and his colleagues enrolled 602 AML or MDS patients with prolonged neutropenia in a randomized, multicenter trial. They assigned 304 patients to posaconazole 200 mg thrice daily, 240 to fluconazole 400 mg once daily, and 58 to itraconazole 200 mg twice daily, all delivered in oral suspension. The researchers administered the prophylactic drugs with each chemotherapy cycle until patients recovered from neutropenia and achieved complete remission.

In the posaconazole arm, proven or probable invasive fungal infections occurred in 7 patients (2%), compared with 25 (8%) in the fluconazole or itraconazole group, an absolute reduction of 6% (P ≤ .001). Posaconazole demonstrated a significant advantage in reducing invasive aspergillosis infections, which occurred in 2 (1%) patients who received the drug, compared with 20 (7%) in the control arm (P ≤ .001).

Survival also proved significantly higher in the posaconazole group. During the study period, there were 49 deaths (16%) in the posaconazole group and 67 (22%) in the fluconazole or itraconazole arm (P = .048): 21 of the 116 total deaths were related to fungal infections, 5 (2%) in the posaconazole group and 16 (5%) in the control arm (P = .01).

Serious adverse events were significantly higher with posaconazole prophylaxis, occurring in 19 (6%) of the posaconazole-treated patients vs 6 patients (2%) who received either fluconazole or itraconazole, Dr. Cornely said. Gastrointestinal disturbances proved the most common treatment-related problems in both study arms.

GVHD Study

Dr. Ullmann and his colleagues enrolled 600 GVHD patients in an international, randomized, double-blind trial and assigned 301 to receive posaconazole 200 mg three times daily plus placebo capsules once a day and 299 patients to receive fluconazole 400 mg once daily plus placebo thrice daily for a fixed 112-day treatment period.

The researchers found posaconazole to be as effective as fluconazole in preventing all invasive fungal infections, 5.3% vs 9.0%, respectively (P = .07), and superior to fluconazole in preventing proven or probable invasive aspergillosis, 2.3% vs 7.0% (P = .006). The posaconazole-treated patients also had significantly fewer breakthrough invasive fungal infections (2.4% vs 7.6%, P = .004), especially invasive aspergillosis (1.0% vs 5.9%, P = .001). Overall mortality was similar in both groups, but death from invasive fungal infections was significantly lower in the posaconazole arm (1.0% vs 4.0%, P = .046).

The trial showed similar rates of treatment-related adverse events: 36% in the posaconazole arm and 38% in the fluconazole group, and similar rates of serious treatment-related side effects, 13% and 10%, respectively.

"There is an urgent need worldwide for establishing a standard of care for preventing life-threatening fungal infections in high-risk patients," said Dr. Ullmann, attending physician for infectious diseases and hematology/oncology, University Hospital, Johannes Gutenberg University, Mainz, Germany. "Due to an expanding patient population, these infections are being seen more frequently and are a leading cause of death in these seriously ill patients. These studies demonstrate that posaconazole prophylaxis provides effective, well-tolerated preventive therapy."