Efficacy and Safety of Micafungin for the Prophylaxis of Invasive Fungal

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 with was achieved in 119 patients (90.2%). Cases of prophylaxis failure IFI but without mycological support. Patients were classified as having are summarized in Table 2. The median duration of micafungin suspected IFI if they were undergoing broad-spectrum antibacterial administration was 18 days (range, 10–41 days) in patients who ℃ 4 therapy and had a persistent fever of 38.3 or more for 96 h that developed IFI. IFIs developed at a median of 13 days (range, necessitated the initiation of empirical antifungal therapy. – The secondary endpoints included the time to treatment failure, 1 42 days) after HSCT. None of the patients developed proven IFI. mortality and drug-related safety. Survival was followed up for 100 days The numbers of patients with probable, possible and suspected IFI after HSCT. Safety analyses included AEs and results of clinical and were two (1.5%), two (1.5%), and nine (6.8%), respectively. laboratory parameters. Patients were monitored daily for their clinical signs In two cases of probable IFI, dense, well-circumscribed lesions and symptoms. Analysis of complete blood counts and chemistry with a halo sign in a chest computed tomography were parameters were performed at the study sites at baseline, three times a documented in addition to a positive galactomannan result. One week while study drugs were administered, and on the final day of of the patients with probable IFI (UPN 2) showed rapidly therapy. Fungal surveillance cultures were obtained at least once a week progressive cheek swelling that led to severe pain and dyspnea throughout the period. Serum galactomannan was uniformly checked at ⩾ along with Pseudomonas aeruginosa septicemia 3 days after HSCT least once a week during the study and values 0.5 on at least two – separate occasions were considered to be positive. AEs were graded on and died after development of generalized tonic clonic seizure the basis of the Common Terminology Criteria for Adverse Events with multiorgan failure. version 4.0 and rated as possibly, probably or definitely related to Possible IFIs were observed in two cases: both showed treatment with micafungin according to the Naranjo Adverse Drug abnormal chest CT findings with dense, well-circumscribed lesions Reaction probability scale.10 with a halo sign or a cavity. They did not undergo bronchoalveolar

Enrolled in this study (n=155) Violation of patient selection criteria (n=8)

Analyzed in this study (n=147) Premature interruption (n=15) ;Investigator’s decision (n=6) Protocol violation (n=5) Adverse events (n=2) Included in efficacy Early death (n=2) analysis (n=132)

Completion of study Premature interruption without premature due to IFI (n=11) interruption (n=121)

Treatment success IFI (n=2) (n=119)

Figure 1. Flow diagram of the study.

© 2014 Macmillan Publishers Limited Bone Marrow Transplantation (2014) 1212 – 1216 Micafungin for IFI prophylaxis in children HJ Park et al 1214 association with the study drug (Table 3). Hepatic toxicity Table 1. Demographic and clinical characteristics of patients (45.0%) was the most frequently found AE, followed by gastro- ‘ ’ Characteristics N = 147 (%) intestinal toxicity (25.7%). All AEs were graded as possible in relation to causation by micafungin. One-hundred and one Gender (92.7%) of the AEs were rated as grade I or II. Only six patients Male: female 86 (58.5):61 (41.5) (4.1%) experienced eight grade III AEs; three hepatic (transaminase elevation), three gastrointestinal (vomiting), one electrolyte Age, years – imbalance (hypocalcemia) and one allergic reaction. Median (range) 9.7 (0.4 19.8) Micafungin administration was interrupted because of AEs in Age o16 130 Age ⩾ 16 17 only two patients (1.4%), one with grade III allergic reaction and one with grade II hyperbilirubinemia. No drug-to-drug interaction Weight (kg) was reported. Median (range) 31 (6–82) Mortality Underlying disease ALL 39 (26.5) Among 147 patients, 5 patients had died by 100 days after allo- AML 41 (27.9) HSCT. Three patients (2.0%) died during the course of study: the SAA 29 (19.7) causes of death were sepsis, multiorgan failure and hemophago- CML 2 (1.4) cytic lymphohistiocytosis after cord blood infusion. The other two Lymphoma 4 (2.7) deaths occurred after the study completion and causes of death Myelodysplastic syndrome 6 (4.1) included disease progression and infection not associated with IFI. Others 26 (17.7) None of the deaths occurred until day 100 after allo-HSCT was Stem cell source directly related to the study drug. BM 18 (12.2) Peripheral blood 121(82.3) DISCUSSION Cord blood 8 (5.4) The diagnosis of IFI is often delayed or difficult to establish with HLA match certainty, which can cause a delay in antifungal treatment and Match 85 (57.8) increased mortality in allo-HSCT patients.11,12 Antifungal prophy- Mismatch 62 (42.2) laxis has therefore been commonly used as a treatment strategy. Fluconazole has been widely used for antifungal prophylaxis. Conditioning regimen fl Myeloablative 111 (75.6) However, uconazole does not protect patients from invasive TBI based 38 (25.9) aspergillosis and may cause emergence of resistant Candida 13 BU based 73 (49.7) species, including C. krusei and C. glabrata. Moreover, azoles Reduced intensity 35 (23.8) including fluconazole have serious drug-to-drug interactions NA 1 (1.0) through the cytochrome P450 3A4 pathway. Furthermore, the oral administration of triazoles is limited by poor absorption of Engraftment some products, inter-individual variation in metabolism and Yes 143 (97.3) hepatic toxicity. Liposomal amphotericin B, one of the frequently No 4 (2.7) used antifungal agents during HSCT, causes nephrotoxicity or Acute GVHD infusion-related side effects, which eventually led to discontinua- Yes 61 (41.5) tion of liposomal amphotericin B in studies in adolescents and – Grade I–II 44 (29.9) adults.14 16 Therefore, more effective and safe alternative anti- Grade III–IV 17 (11.6) fungal agents are needed for the prevention of IFI in children and No 86 (58.5) adolescents undergoing HSCT. In a recent randomized study, micafungin was as effective as CMV reactivation itraconazole in preventing IFI in adult patients undergoing HSCT Yes 31 (21.1) 17 No 116 (78.9) (92.6% vs 94.6%, P = 0.48). However, the incidence of AEs and events leading to premature discontinuation of the study was Abbreviation: NA = not available. significantly higher with itraconazole (26.5% vs 8% in micafungin, P = 0.00). In comparison with itraconazole, treatment tolerance was much better with micafungin. In a prospective, double-blind, lavage or biopsy to prove the pathogen of the IFI due to their randomized phase III trial, micafungin was more efficacious than fi fluconazole in preventing IFI in a population of 882 patients at a clinical condition. We could not nd any mycological support of IFI 6 in the two patients. high risk of developing IFI. This latter study was conducted in a Suspected IFIs were observed in nine patients. Among these, two very heterogeneous population, including pediatric (9.5%) and patients (UPN 5 and UPN 6) had a positive result for galactomannan adult patients (90.5%) receiving auto- or allo-HSCT. The overall fi antigen within a week after switching antifungal agents but had no success rate was signi cantly higher for patients in the micafungin fl clinical or radiological evidence of IFI. No patients with suspected IFI arm (80.0%) compared with 73.5% in the uconazole arm met the criteria of possible, probable or proven IFI later. (P = 0.03). Fewer micafungin-treated patients discontinued use of Eleven patients were diagnosed with IFI during prophylactic the study drug because of AEs (4.2% vs 7.2%, P = 0.058). The efficacy and safety of micafungin for antifungal prophylaxis therapy, and two patients (UPN 4 and UPN 13) were diagnosed specifically in pediatric patients during neutropenia after allo- with IFI within 4 weeks of completion of micafungin treatment. HSCT has not yet been established. There have been a few studies describing its prophylactic use in pediatric patients: however, Adverse events there has been no prospective study with relatively large patient Thirty-five micafungin-treated patients (23.8%) experienced 109 numbers of the role of micafungin in pediatric patients under- AEs that were considered by the investigator to have an going allo-HSCT. We therefore planned to evaluate micafungin as

Table 2. Cases of treatment failure

IFI UPN Diagnosis Age (years) Duration of Time from IFI during Outcome at day Notes micafungin HSCT to micafungin 100 after HSCT administration developing IFI administration (days) (days)

Probable 1 AML 8.0 41 32 Yes Alive Galactomannan antigen (+) 2 AML 18.3 14 2 Yes Death (day 4) Galactomannan antigen (+) Possible 3 ALL 11.4 17 8 Yes Alive 4 ALL 18.2 29 42 No Alive Suspected 5 JMML 1.7 18 9 Yes Alive Galactomannan antigen (+) 6 AML 4.5 25 15 Yes Alive Galactomannan antigen (+) 7 SAA 11.8 14 8 Yes Alive 8 HLH 1.0 17 8 Yes Alive 9 HLH 1.8 16 7 Yes Alive 10 SAA 12.9 15 9 Yes Alive 11 ALL 17.2 26 35 No Alive 12 SAA 12.8 10 1 Yes Alive 13 ALL 15.5 19 10 Yes Alive Abbreviations: HLH = hemophagocytic lymphohistiocytosis; HSCT = hematopoietic SCT; IFI = invasive fungal infection; JMML = juvenile myelomonocytic leukemia; UPN = unique patient number.

over a dosage range between 0.5 and 4.0 mg/kg/day in 77 febrile Table 3. Drug-related AEs neutropenic pediatric patients displayed linear pharmacokinetics 18 AEs Grade I Grade II Grade III and increased clearance as a function of decreasing age. Several doses of micafungin are used clinically. In a retrospective study of Hematologic 40 children, an 80.0% success rate was achieved in patients who Anemia 1 0 0 received 3 mg/kg micafungin once daily for antifungal prophylaxis Platelet count decreased 1 0 0 after HSCT.8 In a randomized trial in neutropenic pediatric patients Febrile neutropenia 0 0 0 undergoing chemotherapy and HSCT, the event-free ratios of IFI of 2 mg/kg/day micafungin and 10 mg/kg/day fosfluconazole were Gastrointestinal 94.4% and 94.3%, respectively, with no significant difference in Abdominal pain 2 0 0 19 6 Nausea 2 8 0 AEs. Van Burik et al. reported that micafungin administered to Vomiting 1 3 3 pediatric HSCT patients (n = 39) at a dose of 1 mg/kg/day Diarrhea 6 2 0 micafungin achieved a treatment success rate of 69.2%, whereas Constipation 1 0 0 fluconazole at 8 mg/kg/day achived a treatment success rate of 53.3%. Hepatic In our study, treatment success was achieved in ~ 90% of ALP increased 4 1 0 patients who received 1 mg/kg/day micafungin for antifungal ALT increased 13 7 1 prophylaxis, which was comparable to the results of other AST increased 13 2 2 7,20 Bilirubin increased 3 3 0 antifungal prophylaxis trials. The treatment efficacy of micafungin in this study was comparable to that of micafungin Electrolyte imbalance prophylaxis reported in adult populations.7,17 Furthermore, Hypocalcemia 0 0 1 micafungin showed 100% efficacy for preventing any proven Hypokalemia 3 0 0 fungal infection, not only during the neutropenic phase but also Hypomagnesemia 7 0 0 4 weeks after stopping micafungin prophylaxis. Our study Hyponatremia 3 0 0 included only patients who had undergone allo-HSCT, and Circulatory ~ 76% of patients received myeloablative conditioning, which is Hypertention 0 1 0 a known risk factor for developing IFI. Our data shows that the Allergic reaction 4 1 1 efficacy of micafungin is encouraging even in patients at high risk Fever 1 1 0 of developing IFI. The safety of micafungin has been reported in patients with Others febrile neutropenia and in pediatric patients.11,21 Siebel et al. 18 Back pain 1 0 0 showed no dose-limiting toxicity for micafungin up to 4 mg/kg/ Hyperglycemia 2 3 0 day in febrile neutropenic pediatric patients. Micafungin was well Total 68 33 8 tolerated in our study without any grade IV AEs. Drug-related AEs Abbreviations: AEs = adverse events; ALP = alkaline phosphatase; were observed in 35 patients (23.8%), but only two patients were ALT = alanine aminotransferase; AST = aspartate aminotransferase. withdrawn due to AEs (one patient with an allergic reaction and one with elevated total bilirubin). The most common AE associated with micafungin was hepatotoxicity (45.0%). All AEs were graded as ‘possible’ in relation to causation by micafungin a prophylactic antifungal therapy specifically in a pediatric patient and ~ 93% of total AEs were mild and graded as I or II and population undergoing allo-HSCT. transient. In a pharmacokinetic study of micafungin for antifungal Another important observation in our study is that no drug prophylaxis in febrile neutropenic pediatric patients, micafungin interaction-related adverse effects were reported. The use of

© 2014 Macmillan Publishers Limited Bone Marrow Transplantation (2014) 1212 – 1216 Micafungin for IFI prophylaxis in children HJ Park et al 1216 micafungin has proven to be safe and well tolerated with few 5 Kuse ER, Chetchotisakd P, da Cunha CA, Ruhnke M, Barrios C, Raghunadharao D known drug interactions,22 which are important considerations et al. Micafungin versus liposomal amphotericin B for candidaemia and invasive when implementing antifungal prophylaxis in HSCT recipients. candidosis: a phase III randomised double-blind trial. Lancet 2007; 369: The pharmacokinetics of micafungin are not altered by con- 1519–1527. 6 van Burik JA, Ratanatharathorn V, Stepan DE, Miller CB, Lipton JH, Vesole DH et al. comitant administration of tacrolimus, mycophenol mofetil, fl prednisolone or amphotericin B, as micafungin appears to be Micafungin versus uconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplan- metabolized primarily through the O-methyl transferase pathway 39 – 23 tation. Clin Infect Dis 2004; :1407 1416. and only minimally through the cytochrome P450 3A pathway. 7 Hashino S, Morita L, Takahata M, Onozawa M, Nakagawa M, Kawamura T et al. All these factors, combined with its efficacy, make micafungin an Administration of micafungin as prophylactic antifungal therapy in patients attractive choice for prophylaxis of IFIs in neutropenic pediatric undergoing allogeneic stem cell transplantation. Int J Hematol 2008; 87:91–97. patients after HSCT. 8 Kusuki S, Hashii Y, Yoshida H, Takizawa S, Sato E, Tokimasa S et al. Antifungal A prior randomized study of van Burik et al.6 demonstrated the prophylaxis with micafungin in patients treated for childhood cancer. Pediatr efficacy of echinocandin for prophylaxis in neutropenic host. Blood Cancer 2009; 53:605–609. However, the proportion of pediatric patients was low and they 9 De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T et al. fi included both allogeneic (51.8%) and autologous (47.8%) HSCT. Revised de nitions of invasive fungal disease from the European Organization for fi fi Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group Therefore, it was not suf cient to draw a con dent conclusion and the National Institute of Allergy and Infectious Diseases Mycoses Study Group regarding pediatric patients who underwent allo-HSCT. Limita- (EORTC/MSG) Consensus Group. Clin Infect Dis 2008; 46: 1813–1821. tions of our study include that this is a non-randomized study. 10 Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA et al. A method for However, we included the largest pediatric population as far as we estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; know and homogenous patient population who had undergone 30:239–245. allogeneic HSCT, which makes our study distinctive. 11 Maertens J, Theunissen K, Verhoef G, Verschakelen J, Lagrou K, Verbeken E et al. In summary, this is the first prospective study of micafungin use Galactomannan and computed tomography-based preemptive antifungal ther- for antifungal prophylaxis after allo-HSCT that has been carried apy in neutropenic patients at high risk for invasive fungal infection: a prospective 41 – out in a relatively large cohort of pediatric patients under 20 years feasibility study. Clin Infect Dis 2005; : 1242 1250. 12 Garey KW, Rege M, Pai MP, Mingo DE, Suda KJ, Turpin RS et al. Time to initiation of of age. Our study demonstrated that 1 mg/kg/day of micafungin, fluconazole therapy impacts mortality in patients with candidemia: a multi- up to a maximum of 50 mg/day, is a new option for antifungal institutional study. Clin Infect Dis 2006; 43:25–31. prophylaxis in neutropenic pediatric patients receiving allo-HSCT, 13 Hachem R, Hanna H, Kontoyiannis D, Jiang Y, Raad I. The changing epidemiology with promising efficacy without significant AEs. A further of invasive candidiasis: Candida glabrata and Candida krusei as the leading causes randomized comparative prospective study is needed to define of candidemia in hematologic malignancy. Cancer 2008; 112: 2493–2499. clinical guidelines for antifungal prophylaxis in children and 14 Kolve H, Ahlke E, Fegeler W, Ritter J, Jurgens H, Groll AH. Safety, tolerance and adolescents undergoing allo-HSCT. outcome of treatment with liposomal amphotericin B in paediatric patients with cancer or undergoing haematopoietic stem cell transplantation. J Antimicrob Chemother 2009; 64:383–387. CONFLICT OF INTEREST 15 Roden MM, Nelson LD, Knudsen TA, Jarosinski PF, Starling JM, Shiflett SE et al. Triad of acute infusion-related reactions associated with liposomal amphotericin The authors declare no conflict of interest. B: analysis of clinical and epidemiological characteristics. Clin Infect Dis 2003; 36: 1213–1220. ACKNOWLEDGEMENTS 16 Walsh TJ, Finberg RW, Arndt C, Hiemenz J, Schwartz C, Bodensteiner D et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever This study was coordinated by the Clinical Research Coordination Center, National and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Cancer Center, Korea, using the web-based clinical research management platform Study Group. N Engl J Med 1999; 340: 764–771. (Velos). 17 Huang X, Chen H, Han M, Zou P, Wu D, Lai Y et al. Multicenter, randomized, open-label study comparing the efficacy and safety of micafungin versus itraconazole for prophylaxis of invasive fungal infections in patients undergoing AUTHOR CONTRIBUTIONS hematopoietic stem cell transplant. Biol Blood Marrow Transplant 2012; 18: – HJP designed the study, collected the data, performed analysis and reviewed 1509 1516. the manuscript; MP performed the analysis and wrote the paper; JJS designed 18 Seibel NL, Schwartz C, Arrieta A, Flynn P, Shad A, Albano E et al. Safety, tolerability, and pharmacokinetics of Micafungin (FK463) in febrile neutropenic pediatric the study and reviewed the manuscript; MH collected the data and performed patients. Antimicrob Agents Chemother 2005; 49:3317–3324. the analysis; BHN performed the anlaysis; KNK, HJI, JWL, N-GC, BC, H-KK, KHY, 19 Sawada A, Sakata N, Higuchi B, Takeshita Y, Ishihara T, Sakata A et al. 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