Prophylaxis of Invasive Pulmonary Aspergillosis with Nebulized Lipid Complex Amphotericin B Is Feasible, Well Tolerated and Safe in Children with Acute Leukemia. Results of a Phase II Open Trial

BACKGROUND: Acute leukemia is the most frequent cancer in childhood. The use of dose-intensive chemotherapy regimens has significantly increased the overall survival of acute leukemia during the last years. As a result of more dose-intensive myelosuppressive and immunosuppressive therapies there is a higher risk of systemic fungal infections. Invasive pulmonary aspergillosis (IPA) represents a significant source of morbidity and mortality (>50%), and therefore measures that effectively prevent IPA are needed. Prophylaxis of IPA with anti-mold azoles is effective, but has adverse systemic effects and important drug interactions with some chemotherapeutic agents (i.e. vincristine). Currently there is no optimal prophylaxis for IPA in pediatric patients so new strategies are needed. Because IPA originates from the inhalation of conidia, a prophylactic approach is the topical administration of antifungals inside the lungs. Aerosolized lipid formulations of amphotericin B could prevent IPA and avoid systemic adverse events and drug interactions. There are no published studies reporting feasibility and safety of inhaled lipidic amphotericins in the pediatric population.

PATIENTS AND METHODS: The safety, feasibility and tolerance of nebulized lipid complex amphotericin B (ABCL) was evaluated in a phase II open label single arm trial on the use in pediatric patients (3 to 18 year-old) with acute leukemia during intensive chemotherapy. Nebulized therapy was administered by a PARI eFlow®rapid nebulizer system twice weekly, at 50 mg the first week and then 25 mg during intensive chemotherapy until recovery of neutropenia (3 consecutive absolute neutrophil count (ANC) ≥1x10⁹/L or one ANC ≥1.5x10⁹/L). Treatment was resumed during neutropenic episodes following subsequent chemotherapy cycles. Serum galactomannan assay was performed twice weekly during neutropenia. High-resolution chest computed tomography was done when there was a clinical suspicion of IPA. Fluconazole was allowed but antifungal drugs with anti-mold activity were not permitted. The trial is registered at www.clinicaltrials.gov as NCT01615809.

RESULTS: Thirty-two patients were included, 19 were male (59.4%), median age was of 5.5 years (range 3-16). Twenty-nine patients were diagnosed with acute lymphoblastic leukemia (ALL), 3 with acute myeloid leukemia. Among the patients with ALL, 24 had a de novo ALL and 5 a relapsed ALL. A total of 389 administrations of nebulized ABCL were performed, with a median per patient of 13 (range 1-19). All patients tolerated the drug and no patient had to discontinue it due to intolerance or an adverse event. No patient presented a severe adverse event in relation to ABCL. Five patients suffered from mild adverse events (cough, eye discomfort). Nine patients were withdrawn from the study, 2 were referred to another institution to undergo bone marrow transplantation and 7 due to systemic administration of an antifungal agent with anti-mold activity. Three of these patients developed a possible or probable IPA. There were no other cases of IPA.

CONCLUSIONS: Prophylactic nebulizations with ABCL were well tolerated, safe and feasible in children aged 3-18 years diagnosed with acute leukemia. There is a need to perform further studies with a higher number of patients to evaluate the efficacy of this approach.