Voriconazole for Secondary Prophylaxis of Invasive Fungal Infection in Allogeneic Stem Cell Transplant Recipients: Results of the VOSIFI Study. on Behalf of the VOSIFI Study Group and the Infectious Diseases Working Party of the European Bone and Marrow Transplantation Group.
Authors: Cordonnier Catherine , Einsele Hermann , Rovira Montserrat , Maertens Johan , Olavarria Eduardo , Faucher Catherine , Cornely Oliver A , De La Camara Rafael , Heussel Claus-Peter , Pineau Marc , Ljungman Per T. 
Published: April 2020

Background: Despite adequate treatment and favorable initial outcome, the risk of recurrence of a previous invasive fungal infection (IFI) or acquisition of a new one is a major obstacle to the success of stem cell transplantation (SCT). The rate of IFI relapse is estimated to be 30 to 50%. Secondary prophylaxis could increase survival and reduce the burden of fungal infections to these patients.

Methods: A prospective open multicenter trial was performed to evaluate the efficacy of voriconazole (VORI) (4mg/kg/12h IV or 200mg/12h oral) as secondary prophylaxis in allogeneic SCT patients with previous proven or probable IFI (2002 EORTC/MSG consensus criteria). Adult patients (Age &gt; 18 y) were eligible if the prior IFI had occurred within the 12 months prior to SCT. Exclusion criteria were prior resistance to VORI, prior history of zygomycosis, or active IFI at time of transplant. VORI was started within 3 days before transplant and planned for 100 days. Prophylaxis could be prolonged up to 150 days in case of persistent graft-versus-host disease (GVHD) and ongoing immunosuppression on day 100. All patients were followed until 12 months post-transplant, or until death, whichever occurred first. The primary endpoint was the rate of proven and probable IFI between the start of VORI prophylaxis and the 12 month follow-up. Diagnosis of prior IFI, diagnosis of IFI occurring during the study, and cause of deaths, were assessed by a Data Review Committee including an independent radiologist.

Results: 45 patients from 17 EBMT centers were included from Feb 2005 to March 2007. The mean age was 48 y (22–72). Forty-one had acute leukemia, and 24 were in first complete remission. Previous IFI included proven (n= 6) or probable (n=26) aspergillosis, proven candidiasis (n=5), and others (n=8). The mean time from diagnosis of the previous IFI to SCT was 151 days. Twenty four patients were transplanted from a family donor (HLA-id: 18; mismatched: 5; twin: 1), and 21 from an unrelated donor. The graft was bone marrow (n=6), peripheral blood stem cells (n=38) or cord blood (n=1). The conditioning regimen was myeloablative in 27 and non myeloablative in 18 patients. The median follow-up was 360 days (range 5–469). Twenty-six (58%) patients experienced at least one episode of GVHD. Three cases of IFI were recorded after transplant: one C. albicans candidemia, one S prolificans fungemia and one zygomycosis, at day 3, 16, and 66 after transplant, respectively (incidence: 7%). Two of these 3 IFI were relapses of a previous IFI. The median duration of the VORI prophylaxis was 94 days (5–180). Eleven patients (24%) died between 96 and 326 days post-transplant (median: 136 days) from scedosporiosis (n=1), leukemia relapse (n=4), respiratory failure or pneumopathy of unknown origin (n=3), GVHD (2), or sepsis (n=1).

Conclusion: Voriconazole appears to be an efficient drug for secondary prophylaxis of proven and probable IFI after allogeneic SCT, with few adverse events. Considering an expected rate of IFI occurrence or recurrence after transplant of around 30%, the observed rate of 7%, and only one death from IFI in this high-risk adult population are promising.