Clinical and Pharmacokinetic Evaluation of Prophylactic Micafungin 150mg Daily Against Invasive Fungal Infections in Cord Blood Transplant Recipients
Authors: Asano-Mori Yuki , Ota Hikari , Nishida Aya , Ikebe Taichi , Ishiwata Kazuya , Tsuji Masanori , Yamamoto Hisashi , Uchida Naoyuki , Izutsu Koji , Yoneyama Akiko , Makino Shigeyoshi , Kishino Satoshi , Taniguchi Shuichi 
Published: October 2019

Abstract
Abstract 1961

Objectives:
Invasive fungal infections (IFIs) are considered as important problems especially in the early period after allogeneic cord blood transplantation (CBT), because of the significantly prolonged neutropenia compared to bone marrow or peripheral blood stem cell transplantations. Antifungal prophylaxis should be therefore carefully selected to assure definite effects with less toxicity, without being affected by drug interactions, and patient's compliance and situation. The object of this study was to evaluate antifungal prophylactic efficacy and safety of micafungin (MCFG) at 150mg with monitoring of the plasma concentrations in high-risk CBT recipients.
Patients and Methods: The study was a prospective, one-institution, single-arm trial of MCFG administered during neutropenic phase of CBT. Adult patients aged >= 20 years who were scheduled for CBT were eligible for this study, if they had no history of or symptoms consistent with IFIs. Approval for the study protocol was obtained from the ethical committee of Toranomon Hospital, and written informed consent was obtained from each patient. MCFG at a once daily dose of 150 mg as a 1-h infusion was initiated at the beginning of the transplant-related conditioning regimens. Although the study treatment was principally continued beyond 3 days after engraftment up to a maximum of 50 days after transplantation, it was ceased earlier in cases of the followings; development of proven, probable, or suspected IFIs; development of unacceptable drug toxicity; receipt of a re-transplant; death; withdrawal of study participation by patient' decision; or discontinuation of the study treatment by physician's decision. Trough and peak plasma concentrations of MCFG were measured on the day of transplantation and a week after by using high-performance liquid chromatography. The primary end point was treatment success, which was defined as the absence of proven, probable, or suspected IFIs through the end of therapy and as the absence of proven and probable IFIs through the end of the 50-day period after treatment.

Results:
A total of 73 patients with advanced or high-risk hematologic diseases were enrolled for this study between May, 2010 and June, 2011. The median age was 55 (20–73) years old, and 67 patients who received reduced-intensity conditioning were included. Sixty-four patients achieved engraftment at a median of 18.5 (9–36) days during the study period. The median duration of MCFG administration from transplantation was 33 (2–50) days. No patients discontinued use of the study drug because of an adverse event. In 70 patients who received at least 7 doses of study drug, median trough levels were 3.46 (0.63-7.81) μg/mL on the day of transplantation and 2.88 (0.30-8.25) μg/mL a week after, which were not influenced by body weight, creatinine clearance or serum levels of albumin, bilirubin and hepatobiliary enzymes. Median peak levels of MCFG in the first 10 patients were 12.99 (10.27-18.74) μg/mL and 12.40 (9.46-15.64) μg/mL, respectively, which were fairly constant over time in each individual. The treatment success rate at 50 days after transplantation was 76.7% and the Kaplan-Meier estimate of the treatment success was 75.6%. Seven breakthrough infections occurred at a median of 29 (8–38) days, with a cumulative incidence of 10.0%. There were 4 cases of invasive pulmonary aspergillosis (IPA) and three caused by Candida species recovered from the bloodstream. One probable IPA and two candidemia due to Candida parapsilosis and Candida krusei developed during prophylactic treatment, whereas three probable IPA and one candidemia due to Candida parapsilosis developed during the post-treatment follow-up period. There were 10 patients with suspected IFIs on the basis of abnormality in CT scan, in whom MCFG was switched to a different class of mold-active agents (liposomal amphotericin B in 7 and voriconazole in 3). Nine patients died during the study, one of who died of IPA associated with graft failure at 32 days after transplantation.

Conclusions:
Daily administration of MCFG at 150mg appears to be an effective and generally well-tolerated antifungal prophylaxis during neutropenic phase in high-risk CBT recipients. Prophylactic use of MCFG in the early period after transplantation might also be an appropriate approach to easing concerns about drug interactions and variability of drug concentrations.

Disclosures:
No relevant conflicts of interest to declare.