Systemic Antifungal Drugs in the Hematology and Oncology Setting: A Real-Life Analysis in Consecutive Leukemia Patients of Patterns of Usage and Associated Problems,

Invasive fungal infections (IFI) show high morbidity and mortality rates in immunocompromised patients (pts). Systemic antifungal drugs (SAD), therefore, play an important role in the supportive care, especially in patients with acute leukemia. Over the last few years, new drugs for the prevention and treatment of IFI have been introduced. Due to the difficult diagnostics of IFI, SAD are broadly used, which represents a substantial burden for public health systems and raises issues about the optimal antifungal regimen as well as drug safety. Apart from their high costs, the use of these drugs is hampered by potential drug interactions and adverse events. We determined the extent of SAD use as well as frequency and clinical relevance of problems related to these drugs in a real-life cohort of leukemia pts at our institution.

Since 2009, we prospectively analyzed SAD usage on two wards within our department. So far, the total antifungal and concomitant medication of 180 consecutive leukemia pts during antifungal prophylaxis and therapy was analyzed in terms of potential drug interactions using the electronic database Micromedex®. Drug-related adverse events were detected by regular participation on ward rounds, consultation of ward physicians and review of patients' medication charts and laboratory values. In particular, the renal and hepatic function during SAD application was closely assessed. SAD were given according to EORTC-adapted guidelines, with use of fluconazole or posaconazole as primary prophylaxis, and voriconazole, liposomal amphotericin B or caspofungin as therapeutic options.

Underlying diseases of the analyzed cohort included AML (n=133), ALL (n=27) and MDS (n=20). Leukemia therapy during analysis predominantly comprised chemotherapy (n=98) and allogeneic hematopoietic stem cell transplantation (n=66). Median SAD costs per analyzed hospital stay in our patient cohort were 2757€ (range: 8–34061€), with 63% of pts inducing costs higher than 1000€. SAD generated 23% of total drug costs in our hematology/oncology department in 2010, thereby ranking second position behind cytostatic agents. Within the analyzed cohort, 83/180 pts received antifungal prophylaxis only, while 97/180 pts received therapeutic regimen involving 1 (n=58), 2 (n=31), 3 (n=6) or 4 (n=2) different SAD in sequence or in combination. Due to drug-related adverse events, SAD application was discontinued or switched to a different drug in 19/180 patients (11%), primarily therapy with voriconazole (7/47, 15%) and liposomal amphotericin B (9/74, 12%). Elevations in creatinine and total bilirubin levels were most frequent during application of liposomal amphotericin B (in 17% and 33% of pts, respectively), while increased levels of alanine transaminase (ALT) were most frequent during use of posaconazole (53% of pts; predominantly CTC grade 1 and 2). Caspofungin was predominantly used in pts with liver predamage, indicated by a median baseline level of total bilirubin of 1.2 mg/dl as compared to ≤ 0.7 mg/dl for all other agents, and showed excellent tolerability. Of note, during the application of SAD, pts received a median number of 25 different concomitant drugs (range 1–54, chemotherapy not included). The proportion of pts exposed to one or more potentially interacting drug combinations involving the respective SAD was: fluconazole 95/102 (93%), caspofungin 16/20 (80%), posaconazole 37/52 (71%), liposomal amphotericin B 52/74 (70%) and voriconazole 33/47 (70%); the number of different potentially interacting drugs for each of these SAD was 17, 4, 9, 6, and 9, respectively. These 45 potentially interacting combinations were rated as moderate (n=27), major (n=17), and contraindicated (n=1) by the drug interaction software. In terms of treatment optimization, therapeutic drug monitoring of posaconazole and voriconazole proved very useful in detecting subtherapeutic levels and showed high inter-pt variability of serum levels.

SAD are used intensively in the hematology and oncology setting and require close monitoring of pts' concomitant medication, clinical parameters and laboratory values. This ongoing project at our institution illustrates the use of these drugs in every day clinics, and valuably contributes to a safe and efficient application of this increasingly important class of drugs in our pts.

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