Antifungal Prophylaxis with Itraconazole in Patients with Acute Leukemia and after Stem Cell Transplantation (SZT): High Plasma Concentrations with a Loading Dose Strategy.

Invasive fungal infection (IFI) is a major complication in the treatment of leukemia. Itraconazole (ITR) is an azole antifungal that has activity against both Candida species and molds. Its prophylactic use in patients at high risk for IFI has been shown to reduce invasive mold infections, but the antifungal efficacy depends on a sufficient plasma concentration early in the course of prophylaxis. We tested a loading dose strategy to reach plasma levels above 500 μg/l by 48 hours.

ITR plasma concentrations from 30 patients (pts) in 51 treatment courses were sampled on day 3, 7 and 11 of prophylaxis which started one day after conclusion of chemotherapy. It consisted of 400 mg oral solution and 400 mg intravenous ITR on day 1+2 and continued with 400 mg oral solution daily until an ANC count > 500/μl, limiting toxicity or the use of empirical antifungal treatment. Plasma concentrations were measured by LC-MS/MS. Two pts received an allogeneic, 4 pts an autologous stem cell graft. Underlying diseases were 43 AML, 4 CML blast crisis, 3 Hodgkin’s disease and 1 Ph+ ALL. In 45 courses chemotherapy was based on Cytarabine plus an anthracycline.

Data from 51 courses were analyzed. Median time of neutropenia (ANC < 500/μl) was 11 days (4–25 days), median time of ITR was 14 days (4–28 days). Median ITR plasma concentrations were 902 μg/l (176–5149) on day 3, 604 μg/l (145–1945) on day 7 and 942 μg/l (191–2987) on day 11. The desirable plasma level of > 500 μg/l after 48 hours of ITR was achieved in 86% of courses and remained above that level in 64% on d 7 and 75% on d 11. No proven or probable IFI could be observed. In 15% of courses empiric antifungal treatment with Amphotericin B and Voriconazole was initiated because of persisting neutropenic fever. Colonization with Candida species was found in 32% of courses. Nausea and vomiting grade 1/2 CTC was observed 39%, diarrhea in 14% of courses.

Sufficient plasma concentrations 48 hours after starting antifungal prophylaxis with ITR can be reached with a loading dose combining oral solution and intravenous formulation. Toxicity is mild with only 10% of patients refusing oral solution. Our strategy suggests a high prophylactic efficacy in terms of preventing IFI in this high-risk group of patients.