Nebulized Amphotericin B Lipid Complex in Invasive Pulmonary Aspergillosis in Paediatric Patients With Acute Leukaemia
Condition: Invasive Pulmonary Aspergillosis; Lymphoblastic Leukaemia; Myeloblastic Leukaemia; Lymphoblastic Leukemia; Myeloblastic Leukemia
MeSH terms: Aspergillosis; Pulmonary Aspergillosis; Invasive Pulmonary Aspergillosis; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Leukemia, Myeloid
Study type: Interventional
Phase: Phase 2

Summary: 
      The trial evaluates the overall tolerability of the drug and the efficacy of aerosolised
      amphotericin B as a lipid complex (ABLC) for primary prophylaxis of invasive pulmonary
      aspergillosis (IPA) in pediatric patients with acute leukemia undergoing intensive
      chemotherapy.
    

Detailed description: 
      In recent years the incidence of invasive fungal infection (IFI) especially when caused by
      filamentous fungi has increased in patients with haematological malignancies and there exists
      an international consensus on diagnostic criteria. Despite diagnostic and therapeutic
      progress, invasive aspergillosis remains a major clinical problem of haematological patients,
      given the still high mortality rates and the huge economic cost of hospitalization of
      patients, which is attributable to aspergillosis. In addition to the morbidity and mortality
      rates, these infections interfere with the chemotherapy treatment plan with the risk of
      compromising the outcome of the antileukemic treatment.

      In a few uncontrolled studies inhaled amphotericin B deoxycholate showed some benefit in
      haematological patients, however it was not effective in a large multicenter study with
      neutropenic patients. Based on the outcome of that clinical trial, the use of aerosolised
      amphotericin B deoxycholate in neutropenic patients was abandoned for nearly a decade. During
      this time the use of azole agents as drugs of choice for antifungal prophylaxis in high risk
      patients was consolidated. However, one of the main problems in the use of triazoles with
      activity against filamentous fungi (itraconazole, voriconazole, posaconazole) is drug-drug
      interactions due to their CYP3A4 inhibitory activity. One of the most serious interactions is
      that which occurs with vincristine, used throughout the treatment of acute lymphoblastic
      leukemia, and which has lead to reports of neurotoxicity due to metabolic inhibition.

      ABLC (Abelcet®) belongs to the group of polyenes with antifungal activity against a broad
      spectrum of fungal species, including Aspergillus spp. The active component of ABELCET®,
      amphotericin B, acts by binding to sterols in the cell membrane of susceptible fungi, with a
      resultant change in the permeability of the membrane. Mammalian cell membranes also contain
      sterols, and damage to human cells is believed to occur through the same mechanism of action.

      Abelcet® is recommended for the intravenous treatment of a broad spectrum of systemic fungal
      infections in adult patients. Although it has a pediatric indication, there are numerous
      studies published regarding the safety levels of Abelcet® administered intravenously in
      children and in haematological adults patients which look very promising. In this context,
      the working hypothesis proposed in this project is that the administration of aerosolised
      ABLC for pediatric patients with acute leukemia treated with intensive chemotherapy will be
      an effective alternative as a prophylaxis of pulmonary fungal infections in these patients.

      In the treatment of pediatric patients with haematological malignancies the use of intensive
      chemotherapy is required, which is immunosuppressive and therefore significantly increases
      the risk of IFI, especially filamentous fungi. IPA is associated with high mortality (>50%)
      in those patients, making it imperative to adopt effective, preventive, prophylactic
      measures. Drug interactions occur frequently with triazole antifungal drugs; cases of
      clinically significant interactions with vincristine, an anchor drug in the treatment of the
      majority of pediatric leukemia, are documented. On the other hand, there are promising data
      from previous studies regarding the safety and efficacy of the intravenous ABLC formulation
      (Abelcet®) in the treatment of pediatric patients with fungal infections.

      If the working hypothesis is confirmed, the aerosolised ABLC treatment would be an effective,
      safe and reliable prophylactic option for IPA. It would offer an alternative to the systemic
      administration of antifungal triazoles without affecting the antileukemic treatment in
      pediatric patients with AL.
    

Intervention name(s): AMPHOTERICIN B
Intervention type(s): Drug
Intervention description(s): The study drug will be administered by inhalation, to hospitalised patients or outpatients in the day hospital.
Other intervention name(s): Abelcet® 5 mg/ml
Intervention MeSH terms: Amphotericin B; Liposomal amphotericin B
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Invasive pulmonary aspergillosis; IFI; Leukaemia; Leukemia; Pediatric; Paediatrics; Amphotericin B; Aspergillosis; Pulmonary Aspergillosis; Invasive Aspergillosis; Antifungal agents; Fungal infections; Invasive Fungal Infection