Use of Systemic Antifungal Agents In Patients with Acute Leukemia: a Prospective Analysis Covering Clinical Parameters, Side Effects, Drug Interactions and Costs
Authors: Metzke Barbara , Hieke Stefanie , Neubauer Werner , Bertz Hartmut , Kümmerer Klaus , Jung Manfred , Engelhardt Monika 
Published: October 2019

Abstract
Abstract 2568

Introduction:
Invasive mycoses show high morbidity and mortality rates among immunocompromised patients (pts), and have multiplied the use and costs of systemic antifungal drugs (SAD). Especially pts with induction chemotherapy for acute leukemia and pts after allogeneic stem cell transplantation are at a high risk. This challenges physicians, as various drug-related aspects have to be considered. As side by side comparisons in unselected high-risk pts with different SAD are lacking, we prospectively analysed the frequency, clinical relevance and severity of SAD-related problems in consecutive pre- and acute leukemic pts, a 'typical', rather than highly-selected study cohort, in order to improve the efficacy and safety of SAD treatment.

Methods:
SAD-analysis was performed by daily participation on ward rounds, consultation of ward physicians and review of pts' medication charts and laboratory values. Pt characteristics, side effects (SE), in particular development of renal and hepatic toxicity, potential drug interactions (DI), treatment outcome and costs were assessed. SAD were given according to EORTC-adapted guidelines.

Results:
Currently, data from 100 consecutive pts have been obtained (AML n=71, ALL n=20, MDS n=9), these showing a median age of 59 years (range 19–75). For SAD use and their respective indications, see Table 1. The frequency of 1, 2 or 3–5 SAD regimens/pt was 56, 28 and 16, respectively, with SAD combination therapy rarely being applied (3%). Pts with relapsed leukemia (n=28) vs. with initial leukemia diagnosis (n=72) received more than one subsequent SAD in 64% vs. 36%, respectively. The importance of detailed DI analyses was stressed with a substantial median number of 22 concomitantly administered medications (range 1–50). We identified 47 potentially interacting combinations of SAD and concomitant drugs (Table 1). In total, 88% of pts receiving SAD were affected by at least one DI.
SE leading to a change of SAD occurred in 13%, 10% and 6% of pts receiving lip. amphotericin B, voriconazole and posaconazole, respectively. Fluconazole, which was applied prophylactically and was low dosed in all cases, and caspofungin, showed very favourable safety profiles, necessitating no therapy adaptations. Determining renal function (RF) deterioration by comparing median eGFR values at SAD-initiation vs. after SAD-medication-end revealed a considerable eGFR decrease of 17% for lip. amphotericin B, whereas caspofungin and azole SAD had no major effects on RF. Pts with liver predamage were preferably treated with caspofungin (median baseline bilirubin level of 0.9 mg/dl compared to ≤ 0.7 mg/dl for all other agents), showing excellent tolerability. In 2009, SAD accounted for 20% of our department's inpt drug expenses, including chemotherapeutics. Median SAD costs per analysed hospital stay in our pt cohort were 2813€, with 64% of pts inducing costs higher than 1000€. According to the increased SAD use in pts with relapsed leukemia, costs in this cohort exceeded those of pts with initial diagnosis by 109% (4794€ vs. 2290€). As posaconazole is increasingly used for prophylaxis and treatment of fungal infections, we are currently obtaining serum posaconazole levels using our previously published HPLC method for quantification [Neubauer W. J Chromatogr B 2009] to ensure sufficient protection in these high-risk pts. Data on obtained serum levels will be presented at the meeting.

Conclusion:
This ongoing real-life analysis highlights the high number of aspects related to SAD-treatment in a high-risk pt cohort and the need for close monitoring of pts to avoid negative effects of DI and to reduce the rate of SE. By detecting and analyzing frequent DI, SE as well as pharmacoeconomic aspects, it suggests to valuably contribute to a safe, efficient and economically appropriate use of SAD.

Disclosure:
Metzke: MSD Merck Sharp & Dohme GmbH: Research Funding. Engelhardt:MSD Merck Sharp & Dohme GmbH: Research Funding.