Comparable Efficacy and Safety with Voriconazole or Posaconazole as Primary Antifungal Prophylaxis in Acute Myeloid Leukemia (AML) Patients Receiving Induction Chemotherapy.

Patients with prolonged neutropenia are at significant risk for invasive fungal infections (IFI's). The incidence of proven or probable IFI's range from 5-24% in patients treated with AML. Furthermore, the mortality rate in this high-risk population has been reported to be as high as 86% for invasive pulmonary aspergillosis. Given the high mortality rate associated with IFI's and our inability to reliably diagnose active cases, prophylactic therapy has emerged as the preferred approach in this high risk patient population. Recently, Cornely et al. conducted a large, prospective randomized trial evaluating prophylactic posaconazole vs. fluconazole or itraconazole in AML/MDS patients receiving induction chemotherapy. Posaconazole (P) was found to be superior to the standard azoles with respect to the incidence of proven or probable IFI's and demonstrated an overall survival benefit. Given these findings, our institution adopted P as primary antifungal (AF) prophylaxis in this setting. Previously our standard prophylactic approach was voriconazole (V) which has a similar spectrum of activity and is available in an oral and IV formulation in contrast to P which is only available orally. There does not appear to be any comparative published literature to date between these two extended-spectrum azoles in the prophylactic setting. We report herein on the efficacy and safety of voriconazole and posaconazole as primary AF prophylaxis between January 2005 and June 2008.

Patients > 18 yo receiving AML/MDS induction chemotherapy without documentation of IFI were included in this retrospective analysis. The voriconazole group received 400mg PO BID × 1 day, then 200mg PO BID. The posaconazole group received 200 mg PO TID with meals. Therapy was initiated on the first day of chemotherapy or 24 hrs post anthracycline and continued until neutrophil recovery, initiation of empiric AF therapy, occurrence of proven/probable IFI, or adverse event (AE) requiring discontinuation of therapy. Proven/probable IFI was defined in accordance with the EORTC/MSG criteria.

195 patients were evaluable (N=129 V; N=66 P). Baseline characteristics were similar between the two groups with respect to age, sex, diagnosis, cytogenetics, disease status, days of neutropenia, and utilization of growth factors. Median time on prophylaxis was 16 (range: 4-44) and 14 (range: 3-69) days, respectively for P and V. Nine pts (7%; 95% CI (3-13%)) developed proven/probable IFI (6 non-albicans candida, 2 fusarium, 1 zygo) in the V group versus four (6%; 95% CI (2-15%)) IFIs ( 2 trichosporon, 1 fusarium, 1 scedosporium) in the P group. Median time of prophylactic therapy to diagnosis of IFI was 29 days for P vs 25 days for V, respectively. Eight pts (6%) discontinued V therapy because of AE's (4 hallucinations, 1 rash, 2 LFT elevation, 1 torsades) vs five pts (7.5%) for P (3 LFT elevation, 1 vomiting, 1 rash).

In the present analysis, we report the comparable efficacy and safety of voriconazole and posaconazole as primary AF prophylaxis in high risk AML/MDS patients receiving induction chemotherapy. There were no differences in the incidence of proven/probable IFI's, time to IFI, time to empiric AF therapy, or AE's requiring discontinuation of therapy.

Wetzstein:Pfizer Pharmaceuticals: Honoraria; Schering-Plough Pharmaceuticals: Honoraria. Off Label Use: Voriconazole as primary antifungal prophylaxis therapy in AML patients receiving induction chemotherapy.