Safety and Feasibility of Posaconazole as Oral Antifungal Prophylaxis In Pediatric Patients Under 12 Years of Age Following Allogeneic Stem Cell Transplantation.

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<0.01) after start of posaconazole in a total of 16 (57.14%) pediatric patients. Adverse events potentially related to posaconazole were observed in six (10.0%) out of the sixty patients and included itching in one case (1.7%), nausea in two cases (3.3%), vomiting in one case (1.7%), and reduced appetite in two cases (3.3%).

No incidence of proven or probable invasive mycosis was recorded during the observation period. Taken together, posaconazole prophylaxis was safe and well tolerated in a cohort of sixty children under the age of 12 years following HSCT.