Voriconazole Is Safe and Effective as a Prophylactic Regimen of Invasive Fungal Infections for High Risk Patients after Reduced-Intensity Umbilical Cord Blood Transplantation

Abstract

Invasive fungal infections (IFI) are significant complications after allogeneic hematopoietic stem cell transplantation. We previously reported that 3-year cumulative incidence of IFI was 10.2 % and median onset of IFI was day 20 post reduced-intensity umbilical cord blood transplantation (RI-CBT) under the prophylaxis by fluconazole or micafungin (Biol Bone Marrow Transplant 2007; 13:771). In recent years, voriconazole (VOR) has been employed in IFI prophylactic regimens during bone marrow or peripheral blood stem cell transplantation in several clinical trials and reports, but the safety and efficacy during umbilical cord blood transplantation is unclear. In order to address this issue, we prospectively administered VOR to 46 high risk recipients of RI-CBT for IFI prophylaxis, between August 2007 and May 2008. All of the patients had no prior episode of IFI and were treated in reverse isolation in laminar airflow-equipped rooms. The plasma trough concentration of VOR and serum galactomannan index was obtained once a week. Chest CT scan was performed for persistent fever under the administration of broad antibiotics. Proven and probable IFI were defined according to revised EORTC/MSG criteria. Median age was 58 years old (range, 21–82). Twenty-three were AML, 10 were non-Hodgkin lymphoma, 6 were aplastic anemia, 5 were ALL, 1 was CML, and 1 was multiple myeloma. All patients were at high risk of IFI, except one patient with lymphoma in CR; 22 had high risk underlying diseases, 17 had prior transplantation, and 6 were very severe aplastic anemia. All patients received fludarabine-based preparative regimens. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus & mycophenolate mofetil in 30, tacrolimus alone in 15, and cyclosporine alone in 1. Additional immune suppressive therapy against pre-engfraftment immune reactions (Transplant 2005; 80:34) or GVHD were administered in 35 patients; 19 received corticosteroid (CS), 7 beclomethasone (BDP), 5 CS & BDP, 1 CS & BDP & infliximab, 1 CS & infliximab, 1 CS & BDP & etanercept, and 1 CS & methotrexate. Forty-two patients achieved neutrophil recovery > 500/uL on day 21 post-transplant at medium (range, 11–38). The median length of VOR prophylaxis from transplantation was 85 days (range, 6–422) for patients who survived longer than 100 days. The total number of patient-days on VOR was 4241 days. There were no proven IFI. Two patients developed probable pulmonary aspergillosis during VOR administration (at day 71 and 75; 1-year cumulative incidence 4.3 %.) No breakthrough infections by candida or zygomycetes were detected. VOR was well tolerated, except in 2 patients who discontinued VOR due to abnormal liver test and severe visual disturbance. Two patients developed probable pulmonary aspergillosis after switching from VOR to other antifungals (at day 80 and 263 under the administration of micafungin and itraconazole, respectively). Thus, VOR can be safely administered, and have reduced the incidence of IFI, with no breakthrough infections by candida or zygomycetes, indicating possible superiority of incorporating this drug as an IFI prophylactic regimen in RI-CBT.