Posaconazole for Primary Antifungal Prophylaxis in AML Patients: A Real Life Single Center Experience and a Comparison with the Historical Cohort
Authors: Minetto Paola , Guolo Fabio , Mikulska Malgorzata , Pastori Giordana , Giannoni Livia , Furfaro Elisa , Miletich Franca , Del Bono Valerio , Ballerini Filippo , Clavio Marino , Miglino Maurizio , Lemoli Roberto , Viscoli Claudio , Gobbi Marco 
Published: October 2019

Abstract
Backgrounds and aims
Prevention and prompt treatment of invasive fungal infections (IFI) in acute myeloid leukemia (AML) patients can improve overall survival not only by reducing infection-related mortality but also allowing to comply induction regimens on time.
The aim of the study was to estimate efficacy and feasibility of primary antifungal prophylaxis with posaconazole (PSZ) in patients affected by acute myeloid leukemia receiving front-line chemotherapy and to optimize our clinical practice.
Materials and methods
From January 2013 to May 2014, 28 AML patients undergoing intensive chemotherapy and potentially eligible for bone marrow transplantation in our institute received PSZ prophylaxis for IFI. All patients received a fludarabine, cytarabine and idarubicin containing regimen as first line treatment. We performed a retrospective analysis to evaluate the efficacy and feasibility of PSZ prophylaxis; to detect factors affecting drug exposure we analyzed each period of hospitalization as a single independent event.
PSZ was given at the standard dose of 200 mg for 3 times/day, concurrently with a fat snack or with at least 100 ml of an acidic drink.
Because of unpredictable absorption rates PSZ serum levels (TDM) were assessed routinely according to a validated high-performance liquid chromato-graphic (HPLC) method as described.
A comparison with an historical cohort with similar features who had received fluconazole (FLC) prophylaxis was made. The use of empirical or targeted antifungal therapies and the incidence of IFI were compared.
Results and discussion
PSZ showed a good tolerability profile with no serious adverse events clearly related to prophylaxis occurring.
A median number of 2 TDM for each period of hospitalization was performed (range 2-5). The achievement of a plasmatic PSZ concentration > 0,7 mcg/mL is considered optimal for prophylaxis efficacy; in 30/47 (64%) episodes of hospitalization and treatment, with at least two TDM, the threshold PSZ serum concentration was reached, with stable plasmatic levels. Median PSZ plasmatic value at first assessment was 0.89 mcg/mL (range 0.1-3.3).
Table 1 summarizes patients features and factors that might affect PSZ plasma concentrations. The strongest negative factors affecting PSZ absorption are the discontinuation of prophylaxis and the concomitant assumption of proton pump inhibitors since their negative impact is shown both in univariate and multivariate analysis.
No proven IFI were observed in our cohort with only one probable IFI occurring in a patient with refractory disease who did not reach adequate serum PSZ concentration.
Table 2 summarizes the comparison with our historical cohort. The risk of experiencing IFI (proven or probable) during AML treatment is significantly higher in the FLC cohort (HR: 9.488, CI: 1,404 - 64,122). Moreover, the use of targeted or empirical antifungal therapies had been significantly higher in FLC cohort (HR: 2.7, CI: 1,212 - 6,050).
Our clinical experience confirms the utility and cost-effectiveness of primary prophylaxis with PSZ in AML patients receiving intensive treatment.
Table 1: Factors affecting PSZ serum concentration Reached plasmatic concentration threshold (%) p(univariate) p(multivariate) All Hospitalizations 30/47 (64) - - Sex Male 17/23 (74) 0.227 - Female 13/24 (54) Disease Status Active Disease 13/27 (57) 0.014 0.156 Complete Response 17/20 (85) Mucositis None or Grade 1 25/32 (78) 0.008 0.228 Grade >=2 5/15 (33) Age <=45 years 12/21 (57) 0.543 - >45 years 18/26 (69) Concomitant PPI No 28/36 (78) 0.001 0.000 Yes 2/11 (18) Concomitant Ranitidine No 26/42 (62) 0.640 - No 4/5 (80) Concomitant Levofloxacine prophylaxis Yes 27/39 (69) 0.118 0.042 No 3/8 (38) Prophylaxis Discontinuation Never 27/36 (75) 0.009 0.003 At least for 2 dd 3/11 (27) Infectious Complications None 8/11 (73) 0.722 - At least one episode 22/36 (61) PSZ Assumption with Fat snack 5/11 (46) 0.153 0.150 Acidic drink 25/35 (71)
Table 2: Historical comparison FCZ PSZ p All hospitalizations 54 47 - Median age (range) 47 (17-72) 47 (19-68) 0.560 Median ANC <500 days (range) 18 (12-35) 21 (7-30) 0.182 Infectious complications (%) 43/54 (80%) 36/47 (77%) 0.643 Proven or probable IFI (%) 16/54 (30%) 1/47 (2%) 0.000 Empirical or targeted antifungal therapy (%) 19/54 (36%) 5/47 (11%) 0.002

Disclosures
No relevant conflicts of interest to declare.