Safety and efficacy of Fluconazole Plus Inhalational Liposomal Amphotericin B Versus Voriconazole for the Prevention of Invasive Fungal Infections in Children Undergoing Chemotherapy for Acute Leukemia: A Phase III open label Randomized Controlled Trial

Invasive fungal infections (IFI’s) are the leading cause of morbidity and mortality among children undergoing chemotherapy, which is a substantial burden on healthcare systems. While antifungal prophylaxis offers reduction in the incidence of IFI’s, pediatric-specific data are essential to guide optimal treatment strategies. This is critical for children with acute leukemia, who represent the largest cohort at increased risk for IFI’s.

Primary Objective - To compare the efficacy of fluconazole plus inhalational liposomal amphotericin B versus voriconazole in preventing IFI in children undergoing chemotherapy for HR and IR ALL, AML, and relapsed ALL.

Secondary Objective(s) –

To evaluate the safety profiles of fluconazole plus inhalational liposomal amphotericin B and voriconazole

To compare the time to onset IFIs between the two-treatment group

To assess the yield of serial monitoring of serum galactomannan as a biomarker for early detection of IFIs in children undergoing chemotherapy

To evaluate the therapeutic drug monitoring (TDM) levels of voriconazole and to assess their correlation with safety, efficacy, and the prevention of IFIs.

Study Design - Phase III, Open-label, Randomized Controlled Trial (RCT)

 Study Setting - This trial will be conducted at the Division of Pediatric Hematology and Oncology, Department of Medical Oncology/Hematology, at AIIMS Bhubaneswar.

Study Groups - <18 years of age diagnosed with ALL (HR and IR), AML, relapsed ALL

Sample size – A sample size of 118 is required in each group to detect a reduction by 11% in its incidence of fungal infection in fluconazole and inhalational L amphotericin B group. The incidence in voriconazole group is assumed as 16% (incidence of IFI in India as per Gouri et.al.,1 was 13% and as per COG western data was 19%). The alpha error and beta errors assumed are 0.05 and 0.2 respectively with a allocation ratio of 1:1

Inclusion criteria –

Age: ≤ 18 years at the time of enrollment

Diagnosis Criteria:

1. Newly diagnosed HR or IR B ALL and T ALL
2. First or subsequent relapse of ALL
3. Newly diagnosed AML

Organ Function Requirements:

Renal Function:

1. Creatinine clearance ≥ 70 mL/min/1.73 m²

Liver Function:

1. Total bilirubin ≤ 1.5 x ULN for age.
2. SGOT or SGPT ≤ 2.5 x ULN for age.

 Exclusion criteria

7.      Patients with a diagnosis of APML, Down syndrome associated leukemia and JMML

8.      Documented history of IFI 3 months prior to enrollment

9.      Patients already receiving treatment for IFI

10.     Hypersensitivity reaction documented for L amphotericin B or fluconazole or voriconazole

 Details of Control(s) – voriconazole arm

Details of intervention – inhalational L amphotericin B and fluconazole arm

Duration of study – 21 months (January 2025 till September 2026)