Posaconazole for Primary Antifungal Prophylaxis in AML Patients: A Real Life Single Center Experience and a Comparison with the Historical Cohort

Abstract

Backgrounds and aimsPrevention 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 methodsFrom 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 discussionPSZ 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 concentrationReached plasmatic concentration threshold (%)p(univariate)p(multivariate)All Hospitalizations30/47 (64)--SexMale17/23 (74)0.227-Female13/24 (54)Disease StatusActive Disease13/27 (57)0.0140.156Complete Response17/20 (85)MucositisNone or Grade 125/32 (78)0.0080.228Grade >=25/15 (33)Age<=45 years12/21 (57)0.543->45 years18/26 (69)Concomitant PPINo28/36 (78)0.0010.000Yes2/11 (18)Concomitant RanitidineNo26/42 (62)0.640-No4/5 (80)Concomitant Levofloxacine prophylaxisYes27/39 (69)0.1180.042No3/8 (38)Prophylaxis DiscontinuationNever27/36 (75)0.0090.003At least for 2 dd3/11 (27)Infectious ComplicationsNone8/11 (73)0.722-At least one episode22/36 (61)PSZ Assumption withFat snack5/11 (46)0.1530.150Acidic drink25/35 (71)Table 2:Historical comparisonFCZPSZpAll hospitalizations5447-Median age (range)47 (17-72)47 (19-68)0.560Median ANC <500 days (range)18 (12-35)21 (7-30)0.182Infectious complications (%)43/54 (80%)36/47 (77%)0.643Proven or probable IFI (%)16/54 (30%)1/47 (2%)0.000Empirical or targeted antifungal therapy (%)19/54 (36%)5/47 (11%)0.002 DisclosuresNo relevant conflicts of interest to declare.