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Efficacy and Safety of Micafungin for the Prophylaxis of Invasive Fungal

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Efficacy and Safety of Micafungin for the Prophylaxis of Invasive Fungal Bone Marrow Transplantation (2014) 49, 1212–1216 © 2014 Macmillan Publishers Limited All rights reserved 0268-3369/14 www.nature.com/bmt ORIGINAL ARTICLE Efficacy and safety of micafungin for the prophylaxis of invasive fungal infection during neutropenia in children and adolescents undergoing allogeneic hematopoietic SCT HJ Park1, M Park2, M Han3, BH Nam3, KN Koh4,HJIm4, JW Lee5, N-G Chung5, B Cho5, H-K Kim5,KHYoo6, HH Koo6, HJ Kang7, HY Shin7, HS Ahn7, YT Lim8, H Kook9,CJLyu10, JO Hah11, JE Park12, YJ Lim13 and JJ Seo4 The objective of this study was to evaluate the efficacy and safety of micafungin for the prevention of invasive fungal infection (IFI) during the neutropenic phase of allogeneic hematopoietic SCT (allo-HSCT) in children and adolescents. This was a prospective, multicenter, open-label, single-arm study. Micafungin was administered i.v. at a dose of 1 mg/kg/day (max 50 mg) from the beginning of conditioning until neutrophil engraftment. Treatment success was defined as the absence of proven, probable, possible or suspected IFI through to 4 weeks after therapy. From April 2010 to December 2011, 155 patients were enrolled from 11 institutions in Korea, and 147 patients were analyzed. Of the 147 patients, 121 (82.3%) completed the protocol without premature interruption. Of the 132 patients in whom micafungin efficacy could be evaluated, treatment success was achieved in 119 patients (90.2%). There was no proven fungal infection in any patient. The number of patients with probable, possible and suspected IFI was two, two and nine, respectively. Thirty-five patients (23.8%) experienced 109 adverse events (AEs) possibly related to micafungin. No patients experienced grade IV AEs. Two patients (1.4%) discontinued micafungin administration due to adverse effects. None of the deaths were related to the study drug. Bone Marrow Transplantation (2014) 49, 1212–1216; doi:10.1038/bmt.2014.136; published online 7 July 2014 INTRODUCTION There have been few reports describing its prophylactic use 6,8 Invasive fungal infections (IFIs), mainly caused by Candida and exclusively in pediatric patients. Therefore, we performed a Aspergillus species, often occur in patients who have undergone prospective multicenter study to evaluate the safety, feasibility fi hematopoietic SCT (HSCT).1,2 Because treatment of an established and ef cacy of i.v. micafungin in prophylactic antifungal therapy in IFI is difficult, prophylactic treatment with antifungal agents is children and adolescents undergoing allogeneic HSCT (allo-HSCT). commonly used in patients who have received immunosuppres- fi sants after HSCT. For selecting antifungal agents, safety pro le, MATERIALS AND METHODS potential for drug interaction, administration route, frequency and emerging resistance are all important parameters to consider. In Study design the case of children, the route of drug administration is also This study was a prospective, open-labeled, single-arm study conducted in important: administering long-term oral antifungal agents to small 11 institutions in Korea (Protocol KSPHO 2010-02; NCT01135589). Patients received 1 mg/kg of micafungin (Mycamine, max 50 mg) once daily as a 1 h children can be both challenging and unreliable. i.v. infusion from the beginning of the transplant-associated conditioning Echinocandin has little toxicity for humans, as it targets glucan regimen. Patients were to receive micafungin prophylaxis until the earliest polymers in the fungal cell wall, and glucans are not components of the following: (1) ⩽ 5 days after engraftment (defined as an ANC of of mammalian cells. Micafungin is a novel antifungal agent of the ⩾ 500 cells/mm3 after nadir), (2) development of proven, probable, possible echinocandin class that inhibits the synthesis of 1,3–β-D-glucan, an or suspected IFI, (3) development of grade IV adverse events (AEs), essential component of the fungal cell wall.3 Micafungin has (4) death, (5) withdrawal from study participation (patient’s decision) or ’ excellent in vitro activity against both Candida and Aspergillus (6) discontinuation of study treatment (investigator s decision). Patients who terminated micafungin treatment due to the above criteria (2)–(6) species,3 and clinical studies have also shown good activity in the 4,5 were considered as premature interruption. treatment of IFI in patients with febrile neutropenia. Study procedures were reviewed and approved by the institutional The efficacy and safety of micafungin have been demonstrated review board at each of the study centers before patient enrollment. for antifungal prophylaxis in patients undergoing HSCT.6,7 All participants provided written informed consent before treatment. 1Center for Pediatric Oncology, National Cancer Center, Goyang-si, Republic of Korea; 2Department of Pediatrics, Chungbuk National University College of Medicine, Cheongju, Republic of Korea; 3Clinical Research Center, National Cancer Center, Goyang-si, Republic of Korea; 4Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea; 5Department of Pediatrics, Seoul St Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea; 6Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 7Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; 8Department of Pediatrics, Pusan National University College of Medicine, Busan, Republic of Korea; 9Department of Pediatrics, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea; 10Department of Pediatrics, Yonsei University, College of Medicine, Seoul, Republic of Korea; 11Department of Pediatrics, Yeungnam University College of Medicine, Daegu, Republic of Korea; 12Department of Pediatrics, Ajou University School of Medicine, Suwon, Republic of Korea and 13Department of Pediatrics, Chungnam National University School of Medicine, Daejon, Republic of Korea. Correspondence: Professor JJ Seo, Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan Collge of Medicine, Songpa-gu, Seoul, Republic of Korea. E-mail:[email protected] Received 31 December 2013; revised 12 May 2014; accepted 18 May 2014; published online 7 July 2014 Micafungin for IFI prophylaxis in children HJ Park et al 1213 To manage the data sets, we used a web-based clinical research RESULTS management platform (Velos, Fremont, CA, USA). All the analyses Between April 2010 and December 2011, 162 patients were performed in this study are based on the Full Analysis Set, which included screened for eligibility and 155 patients were enrolled. Eight those patients who satisfied the inclusion/exclusion criteria. patients were excluded during study recruitment due to violation of the patient selection criteria, leaving 147 patients for analysis in Patients this study (Figure 1). Clinical characteristics of the patients are Patients ⩽ 20 years with hematological and non-hematological disease listed in Table 1. undergoing allo-HSCT were eligible for this study. Patients were excluded if they met one of the following: (1) aspartate transaminase or alanine transaminase levels 45 times the upper limit of normal, (2) bilirubin 42.5 Treatment outcome times the upper limit of normal, (3) previous history of allergy or any Out of 147 patients, 121 (82.3%) completed the protocol without serious side effect to echinocandin, (4) IFI at the time of enrollment, (5) premature interruption. The median duration of micafungin systemic antifungal therapy within 72 h before administration of the first prophylaxis was 23 days (range, 1–56 days). The reasons for dose of micafungin or (6) positive pregnancy test. interrupting micafungin treatment included IFI (n = 11, 7.5%), investigator’s decision (n = 6, 4.1%), protocol violation (switch to Outcome oral antifungal agents, n = 5, 3.4%), AEs that did not meet the The primary endpoint was treatment success, which was defined as the discontinuation criteria (n = 2, 1.4%) and early death (n = 2, 1.4%). absence of proven, probable, possible or suspected IFI during the period of Reasons of premature micafungin interruption by investigators prophylactic therapy and up to 4 weeks after stopping micafungin included the following: switch to other antifungal agents due to administration. fever not persisting for 496 h without any evidence of fungal Diagnosis of IFI was made by the investigators of each center. Proven, fi infection (n = 3), organ dysfunction that did not meet the probable or possible IFI was de ned as described by EORTC/MSG group discontinuation criteria (n = 1), severe GVHD (n = 1) and concurrent criteria.9 Proven fungal infections were defined by a positive culture for fl rash (n =1). fungus in the blood, lung, bronchoalveolar lavage uid, sinuses, soft tissues fi or visceral organs in association with symptoms and signs of infection. Fifteen patients were removed from the ef cacy analysis as a Patients were deemed to have probable IFI if fungal elements were result of the decisions of six investigators, five protocol violations, detected directly or indirectly (galactomannan antigen or serum β–D- two AEs, and two early deaths. Of the 132 remaining patients in glucan) in conjunction with compatible clinical and radiographic findings. whom micafungin efficacy could be evaluated, treatment success Possible IFI was defined if sufficient clinical evidence was consistent
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