Prophylactic Use of Voriconazole for Invasive Fungal Infection in Children and Adolescents with Acute Myeloid Leukemia
Authors: Sano Hirozumi , Kobayashi Ryoji , Hori Daiki , Kishimoto Kenji , Suzuki Daisuke , Yasuda Kazue , Kobayashi Kunihiko 
Published: October 2019

Abstract
Background
Invasive fungal infection (IFI) is a critical complication in the management of hematologic and malignant diseases. Patients with acute myeloid leukemia (AML) have been shown to be at high risk of IFI. Prophylactic therapy using antifungal agents is important for these patients because the timely and accurate diagnosis of IFI during the course of chemotherapy remains difficult. This study compared voriconazole (VRCZ) at a dose of 5 mg/kg/day versus 10 mg/kg/day for the prevention of IFI.
Methods
Between October 2005 and June 2011, 17 children and adolescents (9 boys and 8 girls, ages ranged from 0 to 20 years, with a median age of 7 years) undergoing chemotherapy for AML were prophylactically administered 5 mg/kg/day oral VRCZ starting at the beginning of chemotherapy. On the other hand, 22 patients (10 boys and 12 girls, ages ranged from 0 to 19 years, with a median age of 10 years) undergoing chemotherapy for AML were prophylactically administered 10 mg/kg/day oral VRCZ between July 2011 and December 2014. For prompt intervention against fungal infection, patients' blood samples were assayed for serum C-reactive protein by ELISA at least twice a week. When fever continued despite the administration of broad-spectrum antibiotics and/or a high level of C-reactive protein persisted, computed tomography (CT) of the chest and abdomen was performed and thoroughly inspected. In these patients, the detection of serum b-D glucan and Aspergillus galactomannan antigen was also carried out. IFI was defined and classified according to the standardized definitions from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Disease Mycosis study group (EORTC/MSG) consensus group. We compared the incidence of proven, probable or possible IFI during treatment between the 5 mg/kg/day and 10 mg/kg/day groups. The primary endpoint was freedom from IFI or death (fungal-free survival; FFS) at 180 days after the initiation of chemotherapy.
Results
Despite the prophylactic use of VRCZ, 8 patients developed IFI (proven 1, probable 3, possible 4). Of these 8 patients, 4 belonged to the 5 mg/kg/day group and 4 to the 10 mg/kg/day group. FFS rates at 180 days after the initiation of chemotherapy were similar between the 5 mg/kg/day and 10 mg/kg/day groups (70.9% vs. 73.8%, P =0.582). The trough concentration levels of VRCZ in the 10 mg/kg/day group ranged from <0.09 to 2.17 mg/ml, with a median concentration of 0.27 mg/ml, and patients within the targeted trough concentration level (1 to 4 mg/ml) constituted only 18.8% of all evaluable patients, whereas the trough concentration levels of VRCZ of all patients in the 5 mg/kg/day group were below the limit of sensitivity (<0.09 mg/ml). In both groups, there were no cases forced to discontinue VRCZ due to adverse effects. No patients exhibited visual disturbances as an adverse effect of VRCZ.
Conclusion
Six-month FFS did not differ in children and adolescents with AML given prophylactic VRCZ at a dose of 5 mg/kg/day or 10 mg/kg/day. It is known to be more difficult to raise the concentration of VRCZ to the targeted concentration in children than in adults. Lower concentration levels of VRCZ might have served as a cause of the poor improvement in IFI prophylaxis despite an increased dosage. IFI prophylaxis using therapeutic drug monitoring of VRCZ might be able to improve FFS in patients with AML.

Disclosures
No relevant conflicts of interest to declare.