LAS VEGAS — High-dose liposomal amphotericin B was no more effective than standard doses for the treatment of invasive aspergillosis in a large randomized study, and was associated with significantly more adverse effects, according to Dr. Mark Bresnik.
Invasive fungal infections remain a significant cause of morbidity and mortality in seriously immunocompromised patients, such as those with hematologic malignancies. Conventional amphotericin B deoxycholate has long been used, but is limited in efficacy and has significant toxicity. Three lipid formulations of the drug now are available and they are more easily tolerated.
For one of these, liposomal amphotericin B, the standard dose in invasive fungal infections is 3 mg/kg per day. However, preclinical investigations have suggested that efficacy may increase with higher doses, and preliminary human studies found no significant increase in adverse effects with doses of 10 mg/kg per day, Dr. Bresnik said at a meeting on fungal infections sponsored by Imedex.
To test the hypothesis that higher doses of liposomal amphotericin B might improve outcomes, a prospective, double-blind study was done to compare dosages of 10 mg/kg and 3 mg/kg daily in 201 highly immunocompromised patients.
After the first 2 weeks of therapy, all patients could remain on the standard 3- mg/kg dosage for as long as the investigators deemed appropriate. The trial was conducted at 46 sites in Europe and Australia.
A total of 93% of patients in both groups had hematologic malignancies, and in two-thirds, the disease was uncontrolled. More than 70% were neutropenic at baseline. All the patients had proven or probable invasive aspergillosis, or infection with another filamentous fungus; 95% had invasive pulmonary aspergillosis.
A favorable overall response rate, which included complete plus partial responses, was seen in 50% and 46% of the standard- and high-dose groups, respectively. Survival at 12 weeks in the two groups was 72% and 59%, said Dr. Bresnik, director of medical affairs for Gilead Sciences, the manufacturer of liposomal amphotericin B (Ambisome).
These between-arm differences were not statistically significant, and were comparable with those previously reported for voriconazole, a broad-spectrum triazole agent, compared with conventional amphotericin B (N. Engl. J. Med. 2002;347:408–15).
Median duration of treatment was 15 days in the standard-dose arm and 14 days in the high-dose arm, but treatment duration for some patients in both arms extended upwards of 5 weeks, he said.
No unusual or new safety issues were noted in the study. Discontinuations due to toxicity were significantly more frequent in the high-dose group, at 32%, compared with 20% in the standard-dose group.
“So what the trial has told us is that the appropriate dose is 3 mg/kg per day, but 95% of patients in this trial had invasive pulmonary aspergillosis. What that means is that the data are not yet available to determine whether benefits could be obtained with higher doses in nonpulmonary sites of infection or with non-Aspergillus molds such as zygomycetes,” Dr. Bresnik said.