Antifungal Prophylaxis with Oral and Intravenous Itraconazole in Pediatric Stem Cell Tansplantation: A Retrospective Comparison with Fluconazole and Amphotericin B-Preparations in 116 Children.
Authors: Grigull Lorenz , Kuehlke Oliver , Beilken Andreas , Schmid Hansjoerg , Linderkamp Christin , Sauer Martin G. , Rehe Klaus , Welte Karl , Sykora Karl W. 
Published: April 2020

Abstract
Fungal infections (FI) remain a major threat for patients during allogeneic stem cell transplantation (SCT). There is an ongoing controversy regarding the best fungal prophylaxis. The current study was performed to retrospectively compare three different antifungal medications (itraconazole (ITRA), fluconazole (FLU), and amphotericin B (AMB) preparations) during SCT with regard to FI, survival and complications (toxicity, GVHD, engraftment). 116 children (mean age 10.1 years, female n=48, mean body weight (bw) 27.5 kg) transplanted between March 1998 and August 2003 with complete clinical, microbiological and radiological data were included. Four patients receiving a different antifungal medication (combination therapy ± caspofungin) were excluded. The underlying diseases included acute and chronic leukemias (n=71), inborn metabolic or immunological diseases, lymphomas and bone marrow failure syndromes. In 53 children (46%) a matched family donor was available; in 45 patients (39%) a matched unrelated donor was chosen. In the remaining patients alternative donors (haploidentical, mismatch-related or -unrelated, cord-blood) were selected. Forty children received FLU, 23 patients received AMB-preparations, and 53 children received ITRA. ITRA was given intravenously from day +3 after SCT (10mg/kg bw for 3 days as “loading”, afterwards 5mg/kg bw) until oral medication (ITRA solution) became possible. All prophylactic regimen were continued until day +100 after SCT. In AMB patients FLU was administered after discharge. The three groups did not differ with regard to demographic data, underlying diseases or type of transplantation, only the follow-up period was significantly shorter in the ITRA group. We observed three new FI in the FLU/AMB group (fusariosis n=1, aspergillosis n=2) and one new FI in the ITRA group (candidiasis n=1) (p = 0.377). A change of the antimycotic regimen was necessary in 27/40 (68%) of the FLU, in 21% of the ITRA and in 30% of the AMB patients. Toxicity was minimal in the FLU and ITRA groups and only rarely necessitated a change of the prophylaxis. At day +100 after SCT, 10/63 (16%) of the patients in the FLU/AMB group and 4/53 (8%) in the ITRA group had died (p = 0.139). At the end of the study period (12-31-2004) we observed 17/63 (27%) deaths in the FLU/AMB group compared to 6/53 (8%) in the ITRA group (p &lt; 0.029), with a median follow-up of 5.7 years in the AMB, 4.5 years in the FLU and 2.0 years in the ITRA group. In three children the FI was regarded as the cause of death (not in the candidemia-patient), in the remaining patients relapse (n=5), viral infections (n=6), SCT-related toxicity (n=4) and other infection (n=5) were the cause of death without statistical differences between the groups. The incidence of acute and chronic graft versus host disease (GVHD) differed not significantly between the study groups but the time to engraftment (leukocyte count &gt; 1000/μl) lasted significantly longer in the ITRA group (14.8 days vs. 19.3 days, p &lt; 0.000). Our results indicate that ITRA (oral and intravenous) starting on day 3 after SCT is a safe prophylaxis in pediatric SCT, the analysis of FI is hampered by low numbers. The issues of survival (ITRA group performed better than AMB/FLU) and engraftment (ITRA group longer than AMB/FLU) will be addressed by longer follow-up during ongoing studies.