Safety and Efficacy of Posaconazole for the Treatment of Invasive Fungal Infections After Failure of One Prior Line of Therapy

Invasive fungal infection (IFI) is a common problem during AML induction or Graft Versus Host Disease (GVHD). Several options are available as first line therapies. However, second line interventions are limited by cumulative toxicities, drug interactions, and potential resistance are often encountered. Posaconazole is a triazole antifungal with broad yeast and mould coverage and possesses a favorable toxicity profile. Prior studies using posaconazole for refractory IFI involved patients with multiple antifungal exposure, thus the efficacy in second line therapy is unclear.

A single arm phase II multicenter study of posaconazole in patients with IFIs who failed or were intolerant to other antifungal therapy. The primary objectives of the study were the safety and efficacy of posaconazole; safety was evaluated in all patients who received at least one dose of study drug; efficacy was assessed in patients who remained on therapy for at least one evaluation after baseline. (Evaluations were performed after 3, 6, 12, 26, 39 and 52 weeks of therapy)

Thirty seven patients with proven (35%), probable (34%) and possible (31%) IFIs were included in the study. Conditions leading to IFI were hematological malignancies (36%), stem cell transplant (27%) solid organ transplant (22%), pulmonary disease (11%) and others (5%). The study population included mainly patients refractory (70%) and/or intolerant (25%) to prior anti-fungal. First line therapy included voriconazole (49%), amphotericin B (24%), fluconazole (14%) and others (11%). Identified pathogens were Aspergillus (50%), Candida (20%) and Zygomycetes (10%) and others (20%). Efficacy could be evaluated in 27 patients. Overall response in proven or probable IFI was 56% including 10% CR and 45% PR. Safety was assessed in all 37 patients and a special attention was given to liver toxicity since it is a common problem in hematological malignancies and transplant patients. More than 40% of patients entered the study with elevated liver enzymes most of whom (70%) received prior azole therapy. Of those, 75% had normalization of their liver enzymes within 12 weeks of posaconazole initiation. Normalization usually occurred during the first month, but some patients experienced transient liver enzyme elevation during the first few weeks of therapy. Common toxicities reported irrespective of causality were: nausea & vomiting (26%), diarrhea (26%), rash (15%), edema (12%) and elevated liver enzymes (9%). No grade 4 toxicities were reported.

Posaconazole was an effective therapy in patients with refractory IFI previously treated with other antifungal therapy. Switching from another azole to posaconazole was also possible even in patients with hepatic dysfunction at study start.

Galarneau:Merck: Employment. Pouliot:Merck Canada: Employment.