Analysis of Efficacy, Safety and Costs of Systemic Antifungal Agents in 159 Consecutive High-Risk Cancer Patients for the Establishment of Standardized Guidelines
Authors: Neubauer Werner , Kleber Martina , Zerweck Alf , Thierry Veronique , Goebel Alexandra , Lubrich Beate , Bertz Hartmut , Engelhardt Monika 
Published: April 2020

Abstract
Introduction: Invasive mycoses (IM) show high morbidity and mortality rates in immunocompromised patients (pts), especially among allogeneic stem cell transplant (allo-SCT) recipients. Efficacy and safety profiles of currently available systemic antifungal drugs (SAD) have been derived from various clinical trials, which, however, do not reflect ‘everyday clinics’ and true SAD efficacy in cancer pts due to tight inclusion and exclusion study criteria. The aim of our analysis is the development of standard operating procedures (SOP) for SAD use also outside clinical trials, leading to less application errors (thereby enhancing treatment safety) and an economically appropriate SAD use.
Methods: Since 11/06, we prospectively analyse the use of SAD on a general hematology ward (n=43) and SCT-unit (n=116) within our department. We assess pt characteristics, organ functions, side effects (SE), potential drug interactions (PDI), treatment outcomes and costs. Data is obtained by daily participation on ward rounds, consultation of ward physicians and review of pts’ medication charts. SAD were given according to EORTC-adapted guidelines, with use of fluconazole as primary prophylaxis in allo-SCT recipients and voriconazole or posaconazole as secondary prophylaxis after aspergillus or zygomycetes infection. Empirical therapy was implemented with liposomal amphotericin, preemptive therapy and therapy of aspergillus infections with voriconazole, caspofungin or liposomal amphotericin B.
Results: So far, data from 159 consecutive pts have been obtained, showing a median age of 57 years (y; range 20–85) and a median Satariano index of 1 (comorbidity index; range 0–4). The underlying malignancies comprised leukemia (n=98), lymphoma (n=41), solid tumors (n=12) and other non-malignant diseases (n=8) with the majority of pts having undergone allo- (n=110) or autologous (n=31) SCT. Subgroup analyses showed that transplant pts were treated more frequently with intravenous (iv) SAD and with two or more consecutively applied SAD, compared with pts on the general hematology ward (Table 1). Transplant pts received SAD earlier with higher pt numbers being treated prophylactically and empirically. Due to often complex co-medication (e.g. antibiotics, immunosuppressive agents), PDI were detected more often among transplant pts. The median duration of SAD use was considerably longer and the median SAD costs exceeded those of the pts treated on the general hematological ward.
Table 1. Use of systemic antifungal drugs (SAD) on a general hematology ward vs. SCT-unit
All patients General hematology ward SCT-unit # pts 159 43 116 Median age (y) 57 62 54 Pts treated with iv SAD (%) 86 (54%) 11 (26%) 75 (65%) Pts treated consecutively with &gt;2 SAD (%) 25 (16%) 1 (2%) 24 (21%) Pts treated prophylactically (%) 119 (75%) 22 (51%) 97 (84%) Pts treated empirically (%) 55 (35%) 12 (28%) 43 (37%) Pts with &gt;1 PDI per SAD (%) 62 (39%) 6 (14%) 56 (48%) Median duration of SAD treatment (d) 30 10 32.5 Median SAD costs per hospital stay (US $) 1325 130 2997
Notable was also the comparison of pts receiving caspofungin vs. liposomal amphotericin B, whereby the echinocandin showed a more favorable safety profile, less SE and PDI (Table 2). Caspofungin was more frequently applied as preemptive and 2-line therapy, whereas liposomal amphotericin B was commonly used as empirical and 1-line therapy.
Table 2. Therapeutical use of caspofungin vs. liposomal amphotericin B
All patients Caspofungin lip. Ampho B # pts 82 21 61 Median age (y) 57 56 57 Pts with &gt;1 SE (%) 12 (15%) 2 (10%) 11 (18%) Pts with &gt;2 PDI (%) 30 (37%) 0 30 (49%) Pts treated empirically (%) 55 (67%) 9 (43%) 46 (75%) Pts treated preemptively (%) 21 (26%) 10 (48%) 11 (18%) Median therapy line 1 2 1
Posaconazole surprisingly showed an unfavorable toxicity profile in our hands and (mainly hepatic) SE in 5/5 pts.
Conclusions: Earlier onset and longer SAD treatment duration lead to substantial costs on our SCT-unit compared to a general hematology ward. PDI emerge much more frequent due to complex co-medication. Caspofungin appears to be more favorably tolerated than liposomal amphotericin B concerning SE as well as PDI. Due to our detection of frequent SE and PDI with SAD, SOPs for their use should help to avoid errors and will impact on pts’ safety. Enrollment of additional pts, especially with induction/consolidation treatment for acute leukemia, is ongoing, which will be presented at the meeting.