An EORTC International Multicenter Randomized Trial (EORTC Number 19923) Comparing Two Dosages of Liposomal Amphotericin B for Treatment of Invasive Aspergillosis

Abstract

This is the first completed prospective randomized clinical efficacy trial of antifungals in the treatment of invasive aspergillosis (IA) and the first to compare the clinical efficacy of two dosages of liposomal amphotericin B (L-AmB) for IA in neutropenic patients with cancer or those undergoing bone marrow transplantation. Eighty-seven of 120 patients were eligible and evaluable. Clinical responses were documented for 26 (64%) of 41 patients receiving 1 mg/(kg.d) (L-AmB-1) and 22 (48%) of 46 receiving 4 mg/(kg.d) (L-AmB-4). Radiologic response rates were similar: 24 (58%) of the L-AmB-1 recipients and 24(52%) of the L-AmB-4 recipients. The six-month survival rates were 43% (L-AmB-1) and 37% (L-AmB-4). These differences were not significant. The numbers of deaths directly due to IA at 6 months were similar: 9 (22%) of 41 L-AmB-1 recipients and 9 (20%) of 46 L-AmB-4 recipients. No other variable independently influenced survival, apart from central nervous system IA. L-AmB is effective in treating approximately 50%-60% of patients who have IA. A 1-mg/(kg.d) dosage is as effective as a 4-mg/(kg.d) dosage, and no advantages to use of the higher, more expensive, dosage has been observed.

Diagnosis and treatment of invasive pulmonary aspergillosis in neutropenic patients

“…The recommended dose ranges between 1-3 mg?kg -1 ?day -1 , but can be increased to 6 mg?kg -1 . However, reports of beneficial effects of doses w3 mg?kg -1 are discrepant [85,98,99]. In febrile neutropenia, AmBisome1 in a dose of 3 mg?kg -1 is as effective as cAmB, but is associated with less side-effects, nephrotoxicity, and breakthrough fungal infections [83].…”

Comparative Efficacies, Toxicities, and Tissue Concentrations of Amphotericin B Lipid Formulations in a Murine Pulmonary Aspergillosis Model

“…Even so, infusion-related toxicities and nephrotoxicity limit the optimal use of D-AMB for many patients (10, 47). To reduce these toxicities, the lipid formulations of amphotericin B, i.e., liposomal amphotericin B (L-AMB) (AmBisome) and amphotericin B lipid complex (ABLC) (Abelcet), have been used to treat IA patients (9,19,34,44,46).With the reduced toxicity of the lipid formulations, a number of preclinical studies have been done which show that doses of L-AMB and ABLC ranging from 5 to 15 mg/kg of body weight have improved therapeutic efficacy in different animal models of invasive fungal infection (3, 13-18, 21, 28). These preclinical studies would suggest that improved efficacy might be correlated with increased levels of drug in tissues.…”

“…Even so, infusion-related toxicities and nephrotoxicity limit the optimal use of D-AMB for many patients (10, 47). To reduce these toxicities, the lipid formulations of amphotericin B, i.e., liposomal amphotericin B (L-AMB) (AmBisome) and amphotericin B lipid complex (ABLC) (Abelcet), have been used to treat IA patients (9,19,34,44,46).…”

Formas lipídicas de anfotericina

“…También se ha estudiado la respuesta de pacientes con aspergilosis invasora pulmonar a AmB liposomal en diferentes dosis. En este estudio, los pacientes a los cuales se les administró AmB liposomal en dosis de 1 mg/kg/día respondieron en 64%, mientras que los pacientes que recibieron 4 mg/kg/ día respondieron al tratamiento en 48% 38 . Esto concuerda con los hallazgos en el ensayo clínico con asignación aleatoria AmBiload donde se comparó la respuesta de pacientes con aspergilosis invasora a AmB liposomal en dosis de 10 mg/kg/día y dosis estándar.…”