ALBERT

Description: 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.

Description: Abstract 1308 Pediatric patients undergoing hematopoietic stem cell transplantation (HSCT) are at high risk of acquiring fungal infections. Post-transplant immune deficiency, immunosuppressive medication, viral infections, and acute graft-versus-host disease (GvHD) are known risk factors for fungal infections especially with Aspergillus spp. and Candida spp. Thus, antifungal prophylaxis early after transplantation is indicated, but data for pediatric patients under twelve years of age is scarce. Oral antifungal prophylaxis with extended spectra azoles, e. g. voriconazole or itraconazole, is preferentially used in pediatric patients after allogeneic HSCT, while only few studies have been published. Under either one prophylaxis, break-through invasive fungal infections were still observed in our center. In adults, another broad-spectrum triazole, posaconazole, showed activity against Candida spp., Aspergillus spp., Cryptococcus spp., Zygomycetes, Fusarium spp. Based on these data pediatric BMT patients received oral prophylaxis using posaconazole in our clinic, and we retrospectively assessed the safety, feasibility, and initial data on efficacy. The patient group consisted of sixty pediatric patients (median of age 6.0 years) early after high dose chemotherapy and allogeneic HSCT for hemato-oncological malignancies and inborn errors of metabolism. 31 patients (51.7%) received a T cell-depleted graft. Posaconazole was commenced after discharge from the BMT unit. The observation period was defined as the time from treatment start of posaconazole till the end of oral antimycotic prophylaxis with posaconazole with a maximum of 200 days after transplant. The dosage of posaconazole given on the basis of adult dosage of 200 mg three times per day (tid) and was adapted according to the weight of the pediatric patients accordingly. Twenty-eight of the sixty pediatric patients received 5 mg per kg body weight twice a day (bid) (5 mg/kg BW bid) in an oral suspension, and thirty-two pediatric patients received 4 mg/kg BW tid. Pediatric patients, who received posaconazole 4 mg/kg BW tid had more stable trough levels in the morning (median 377 μg/L, mean 390±137.1 μg/L) in comparison to patients, who received posaconazole 5 mg/kg BW bid (median 134 μg/L, mean 217±187.9 μg/L). Both regimens were well tolerated without severe side effects. There was no decline in white blood cell counts, granulocytes, platelets, the number of CD3 positive T cells, CD4 positive T cells and CD16/56 positive NK cells during treatment with posaconazole. There were no adverse effects on the organ functions of any of the 60 pediatric patients due to the administration of posaconozole. After start of posaconazole we observed an increase in the liver parameters AST (baseline value smaller than 39 U/L) in 3 (5%) out of sixty pediatric patients amount equivalent to 2 × baseline values, in 14 (23.3%) patients amount equivalent 3 × baseline and ALT in 9 (15%) pediatric patients amount equivalent to 2 × baseline, in 14 patients amount equivalent to 3 × baseline of 39 U/L. The increase of liver parameters occurred in 83% of cases within the first fourteen days after start of posaconazole and normalized by day twenty-six after discontinuation of the drug. The analysis of cyclosporine A (CsA) whole blood concentrations was performed in a total of 28 pediatric patients, who were treated with CsA during the observation period with posaconazole. There was a statistically significant, but moderate increase of CsA blood concentrations by 28% on days 2 to 6 (p