Retrospective Analysis of Itraconacole, Voriconazole and Posaconazole As Oral Antifungal Prophylaxis in Pediatric Patients Following Allogeneic Stem Cell Transplantation
Authors: Döring Michaela , Blume Olivia , Haufe Susanne , Hartmann Ulrike , Kimmig Astrid , Schwarze Carl-Philipp , Handgretinger Rupert , Müller Ingo 
Published: October 2019

Abstract
Abstract 3011FN2

Background:
Pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are at high risk of acquiring fungal infections. Post-transplant immune deficiency, additional immunosuppression, viral infection, persistent fever during neutropenia, and GvHD are known risk factors for fungal infections. Antifungal prophylaxis early after allogeneic stem cell transplantation is therefore indicated. Oral antifungal prophylaxis with extended-spectra azoles, e.g. voriconazole or itraconazole, is preferentially used in pediatric patients after allogeneic HSCT, although only few studies have been published on the matter. Due to the absence of controlled studies for oral antimycotic prophylaxis in children after BMT, we retrospectively analyzed patients who received posaconazole based on data in adult patients. Cornely and colleagues published that posaconazole was more effective than fluconazole or itraconazole in the prevention of invasive fungal infections in adult patients undergoing chemotherapy for myelodysplastic syndrome or acute myeloid leukemia. Retrospectively, we assessed the safety, feasibility and initial data of efficacy for itraconazole, voriconazole and posaconazole with regard to pediatric patients and adolescents after high-dose chemotherapy and HSCT.

Patients and Methods:
The study is a single centre, retrospective survey on antimycotic prophylaxis in pediatric patients under eighteen years of age undergoing allogeneic HSCT between January 2004 and June 2011 at the University Children's Hospital Tübingen, Germany. 50 pediatric patients received posaconazole, 50 pediatric patients received voriconazole and 50 pediatric patients received itraconazole after HSCT as oral antifungal prophylaxis. The observation period was defined as the time from the start of oral prophylactic treatment with itraconazole, voriconazole or posaconazole until the end of oral antimycotic prophylaxis, a maximum of 200 days post transplant.

Results:
The median observation period in the itraconazole group (median age 8.5 years) was 109 days (range 20 – 200 days), 105 days (range 18 – 200 days) in the voriconazole group (median age 7.5 years) and 117 days (range 16 – 200 days) in the posaconazole group (median age of 8.5 years), respectively. No incidences of proven or probable invasive mycosis according to EORTC definitions (De Pauw et al., 2008) occurred under itraconazole, voriconazole, and posaconazole during the observation period. Cases of possible fungal infections according to EORTC definitions in the voriconazole group (10%) and itraconazole group (5%) were higher, but still not significantly different from those in the posaconazole group (0%). The percentage of patients with adverse events potentially related to clinical drugs was higher in the voriconazole (17.5%) and itraconazole (15.0%) group than posaconazole (9.8%) group, but not statistically significant. Laboratory investigations were comparable during itraconazole, voriconazole, and posaconazole treatment. Statistical analysis by the Wilcoxon Matched-Pairs Signed Rank Test showed a significant increase beyond the upper normal limit of ALT between baseline before conditioning and maximum during oral antimycotic prophylaxis in all three groups, itraconazole (P = 0.000015), voriconazole (P = 0.0033), posaconazole (P = 0.000013), and a significant increase of AST during itraconazole (P = 0.00023), voriconazole (P = 0.0004), and posaconazole (P = 0.00026) treatment. Significant decreases of potassium (P = 0.000000024) and bicarbonate (P = 0.0026) below the lower limit of the normal range were observed during voriconazole treatment. Moderate elevation of CsA levels were observed during voriconazole and posaconazole treatment, but were also not statistically significant.

Conclusion:
Taken together, itraconazole, voriconazole and posaconazole showed comparable efficacy as antifungal prophylaxis in pediatric patients after allogeneic HSCT. With regard to the clinical tolerability, posaconazole was superior to itraconazole and voriconazole.

Disclosures:
No relevant conflicts of interest to declare.