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.
Invasive fungal infections (IFIs), mainly caused by Candida and Aspergillus species, often occur in patients who have undergone hematopoietic SCT (HSCT).1,2 Because treatment of an established IFI is difficult, prophylactic treatment with antifungal agents is commonly used in patients who have received immunosuppressants after HSCT. For selecting antifungal agents, safety profile, potential for drug interaction, administration route, frequency and emerging resistance are all important parameters to consider. In the case of children, the route of drug administration is also important: administering long-term oral antifungal agents to small children can be both challenging and unreliable.
Echinocandin has little toxicity for humans, as it targets glucan polymers in the fungal cell wall, and glucans are not components of mammalian cells. Micafungin is a novel antifungal agent of the echinocandin class that inhibits the synthesis of 1,3–β-D-glucan, an essential component of the fungal cell wall.3 Micafungin has excellent in vitro activity against both Candida and Aspergillus species,3 and clinical studies have also shown good activity in the treatment of IFI in patients with febrile neutropenia.4,5
The efficacy and safety of micafungin have been demonstrated for antifungal prophylaxis in patients undergoing HSCT.6,7 There have been few reports describing its prophylactic use exclusively in pediatric patients.6,8 Therefore, we performed a prospective multicenter study to evaluate the safety, feasibility and efficacy of i.v. micafungin in prophylactic antifungal therapy in children and adolescents undergoing allogeneic HSCT (allo-HSCT).
Materials and methods
This study was a prospective, open-labeled, single-arm study conducted in 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 i.v. infusion from the beginning of the transplant-associated conditioning regimen. Patients were to receive micafungin prophylaxis until the earliest of the following: (1) ⩽5 days after engraftment (defined as an ANC of ⩾500 cells/mm3 after nadir), (2) development of proven, probable, possible or suspected IFI, (3) development of grade IV adverse events (AEs), (4) death, (5) withdrawal from study participation (patient’s decision) or (6) discontinuation of study treatment (investigator’s decision). Patients who terminated micafungin treatment due to the above criteria (2)–(6) were considered as premature interruption.
Study procedures were reviewed and approved by the institutional review board at each of the study centers before patient enrollment. All participants provided written informed consent before treatment. To manage the data sets, we used a web-based clinical research management platform (Velos, Fremont, CA, USA). All the analyses performed in this study are based on the Full Analysis Set, which included those patients who satisfied the inclusion/exclusion criteria.
Patients ⩽20 years with hematological and non-hematological disease 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 >5 times the upper limit of normal, (2) bilirubin >2.5 times the upper limit of normal, (3) previous history of allergy or any serious side effect to echinocandin, (4) IFI at the time of enrollment, (5) systemic antifungal therapy within 72 h before administration of the first dose of micafungin or (6) positive pregnancy test.
The primary endpoint was treatment success, which was defined as the absence of proven, probable, possible or suspected IFI during the period of prophylactic therapy and up to 4 weeks after stopping micafungin administration.
Diagnosis of IFI was made by the investigators of each center. Proven, probable or possible IFI was defined as described by EORTC/MSG group criteria.9 Proven fungal infections were defined by a positive culture for fungus in the blood, lung, bronchoalveolar lavage fluid, sinuses, soft tissues or visceral organs in association with symptoms and signs of infection. Patients were deemed to have probable IFI if fungal elements were detected directly or indirectly (galactomannan antigen or serum β–D-glucan) in conjunction with compatible clinical and radiographic findings. Possible IFI was defined if sufficient clinical evidence was consistent with IFI but without mycological support. Patients were classified as having suspected IFI if they were undergoing broad-spectrum antibacterial therapy and had a persistent fever of 38.3 °C or more for >96 h that necessitated the initiation of empirical antifungal therapy.
The secondary endpoints included the time to treatment failure, mortality and drug-related safety. Survival was followed up for 100 days after HSCT. Safety analyses included AEs and results of clinical and laboratory parameters. Patients were monitored daily for their clinical signs and symptoms. Analysis of complete blood counts and chemistry parameters were performed at the study sites at baseline, three times a week while study drugs were administered, and on the final day of therapy. Fungal surveillance cultures were obtained at least once a week throughout the period. Serum galactomannan was uniformly checked at 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 the basis of the Common Terminology Criteria for Adverse Events version 4.0 and rated as possibly, probably or definitely related to treatment with micafungin according to the Naranjo Adverse Drug Reaction probability scale.10
Between April 2010 and December 2011, 162 patients were screened for eligibility and 155 patients were enrolled. Eight patients were excluded during study recruitment due to violation of the patient selection criteria, leaving 147 patients for analysis in this study (Figure 1). Clinical characteristics of the patients are listed in Table 1.
Out of 147 patients, 121 (82.3%) completed the protocol without premature interruption. The median duration of micafungin prophylaxis was 23 days (range, 1–56 days). The reasons for interrupting micafungin treatment included IFI (n=11, 7.5%), investigator’s decision (n=6, 4.1%), protocol violation (switch to oral antifungal agents, n=5, 3.4%), AEs that did not meet the discontinuation criteria (n=2, 1.4%) and early death (n=2, 1.4%). Reasons of premature micafungin interruption by investigators included the following: switch to other antifungal agents due to fever not persisting for >96 h without any evidence of fungal infection (n=3), organ dysfunction that did not meet the discontinuation criteria (n=1), severe GVHD (n=1) and concurrent rash (n=1).
Fifteen patients were removed from the efficacy analysis as a result of the decisions of six investigators, five protocol violations, two AEs, and two early deaths. Of the 132 remaining patients in whom micafungin efficacy could be evaluated, treatment success was achieved in 119 patients (90.2%). Cases of prophylaxis failure are summarized in Table 2. The median duration of micafungin administration was 18 days (range, 10–41 days) in patients who developed IFI. IFIs developed at a median of 13 days (range, 1–42 days) after HSCT. None of the patients developed proven IFI. The numbers of patients with probable, possible and suspected IFI were two (1.5%), two (1.5%), and nine (6.8%), respectively.
In two cases of probable IFI, dense, well-circumscribed lesions with a halo sign in a chest computed tomography were documented in addition to a positive galactomannan result. One of the patients with probable IFI (UPN 2) showed rapidly progressive cheek swelling that led to severe pain and dyspnea along with Pseudomonas aeruginosa septicemia 3 days after HSCT and died after development of generalized tonic–clonic seizure with multiorgan failure.
Possible IFIs were observed in two cases: both showed abnormal chest CT findings with dense, well-circumscribed lesions with a halo sign or a cavity. They did not undergo bronchoalveolar lavage or biopsy to prove the pathogen of the IFI due to their clinical condition. We could not find any mycological support of IFI in the two patients.
Suspected IFIs were observed in nine patients. Among these, two patients (UPN 5 and UPN 6) had a positive result for galactomannan antigen within a week after switching antifungal agents but had no clinical or radiological evidence of IFI. No patients with suspected IFI met the criteria of possible, probable or proven IFI later.
Eleven patients were diagnosed with IFI during prophylactic therapy, and two patients (UPN 4 and UPN 13) were diagnosed with IFI within 4 weeks of completion of micafungin treatment.
Thirty-five micafungin-treated patients (23.8%) experienced 109 AEs that were considered by the investigator to have an association with the study drug (Table 3). Hepatic toxicity (45.0%) was the most frequently found AE, followed by gastrointestinal toxicity (25.7%). All AEs were graded as ‘possible’ in relation to causation by micafungin. One-hundred and one (92.7%) of the AEs were rated as grade I or II. Only six patients (4.1%) experienced eight grade III AEs; three hepatic (transaminase elevation), three gastrointestinal (vomiting), one electrolyte imbalance (hypocalcemia) and one allergic reaction.
Micafungin administration was interrupted because of AEs in only two patients (1.4%), one with grade III allergic reaction and one with grade II hyperbilirubinemia. No drug-to-drug interaction was reported.
Among 147 patients, 5 patients had died by 100 days after allo-HSCT. Three patients (2.0%) died during the course of study: the causes of death were sepsis, multiorgan failure and hemophagocytic lymphohistiocytosis after cord blood infusion. The other two deaths occurred after the study completion and causes of death included disease progression and infection not associated with IFI. None of the deaths occurred until day 100 after allo-HSCT was directly related to the study drug.
The diagnosis of IFI is often delayed or difficult to establish with certainty, which can cause a delay in antifungal treatment and increased mortality in allo-HSCT patients.11,12 Antifungal prophylaxis has therefore been commonly used as a treatment strategy. Fluconazole has been widely used for antifungal prophylaxis. However, fluconazole does not protect patients from invasive aspergillosis and may cause emergence of resistant Candida species, including C. krusei and C. glabrata.13 Moreover, azoles including fluconazole have serious drug-to-drug interactions through the cytochrome P450 3A4 pathway. Furthermore, the oral administration of triazoles is limited by poor absorption of some products, inter-individual variation in metabolism and hepatic toxicity. Liposomal amphotericin B, one of the frequently used antifungal agents during HSCT, causes nephrotoxicity or infusion-related side effects, which eventually led to discontinuation of liposomal amphotericin B in studies in adolescents and adults.14, 15, 16 Therefore, more effective and safe alternative antifungal agents are needed for the prevention of IFI in children and adolescents undergoing HSCT.
In a recent randomized study, micafungin was as effective as itraconazole in preventing IFI in adult patients undergoing HSCT (92.6% vs 94.6%, P=0.48).17 However, the incidence of AEs and events leading to premature discontinuation of the study was 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, randomized phase III trial, micafungin was more efficacious than fluconazole in preventing IFI in a population of 882 patients at a high risk of developing IFI.6 This latter study was conducted in a very heterogeneous population, including pediatric (9.5%) and adult patients (90.5%) receiving auto- or allo-HSCT. The overall success rate was significantly higher for patients in the micafungin arm (80.0%) compared with 73.5% in the fluconazole arm (P=0.03). Fewer micafungin-treated patients discontinued use of the study drug because of AEs (4.2% vs 7.2%, P=0.058).
The efficacy and safety of micafungin for antifungal prophylaxis specifically in pediatric patients during neutropenia after allo-HSCT has not yet been established. There have been a few studies describing its prophylactic use in pediatric patients: however, there has been no prospective study with relatively large patient numbers of the role of micafungin in pediatric patients undergoing allo-HSCT. We therefore planned to evaluate micafungin as a prophylactic antifungal therapy specifically in a pediatric patient population undergoing allo-HSCT.
In a pharmacokinetic study of micafungin for antifungal prophylaxis in febrile neutropenic pediatric patients, micafungin over a dosage range between 0.5 and 4.0 mg/kg/day in 77 febrile neutropenic pediatric patients displayed linear pharmacokinetics and increased clearance as a function of decreasing age.18 Several doses of micafungin are used clinically. In a retrospective study of 40 children, an 80.0% success rate was achieved in patients who received 3 mg/kg micafungin once daily for antifungal prophylaxis after HSCT.8 In a randomized trial in neutropenic pediatric patients undergoing chemotherapy and HSCT, the event-free ratios of IFI of 2 mg/kg/day micafungin and 10 mg/kg/day fosfluconazole were 94.4% and 94.3%, respectively, with no significant difference in AEs.19 Van Burik et al.6 reported that micafungin administered to pediatric HSCT patients (n=39) at a dose of 1 mg/kg/day micafungin achieved a treatment success rate of 69.2%, whereas fluconazole at 8 mg/kg/day achived a treatment success rate of 53.3%.
In our study, treatment success was achieved in ~90% of patients who received 1 mg/kg/day micafungin for antifungal prophylaxis, which was comparable to the results of other antifungal prophylaxis trials.7,20 The treatment efficacy of micafungin in this study was comparable to that of micafungin prophylaxis reported in adult populations.7,17 Furthermore, micafungin showed 100% efficacy for preventing any proven fungal infection, not only during the neutropenic phase but also 4 weeks after stopping micafungin prophylaxis. Our study included only patients who had undergone allo-HSCT, and ~76% of patients received myeloablative conditioning, which is a known risk factor for developing IFI. Our data shows that the efficacy of micafungin is encouraging even in patients at high risk of developing IFI.
The safety of micafungin has been reported in patients with febrile neutropenia and in pediatric patients.11,21 Siebel et al. 18 showed no dose-limiting toxicity for micafungin up to 4 mg/kg/day in febrile neutropenic pediatric patients. Micafungin was well tolerated in our study without any grade IV AEs. Drug-related AEs were observed in 35 patients (23.8%), but only two patients were 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 and ~93% of total AEs were mild and graded as I or II and transient.
Another important observation in our study is that no drug interaction-related adverse effects were reported. The use of micafungin has proven to be safe and well tolerated with few known drug interactions,22 which are important considerations when implementing antifungal prophylaxis in HSCT recipients. The pharmacokinetics of micafungin are not altered by concomitant administration of tacrolimus, mycophenol mofetil, prednisolone or amphotericin B, as micafungin appears to be metabolized primarily through the O-methyl transferase pathway and only minimally through the cytochrome P450 3A pathway.23 All these factors, combined with its efficacy, make micafungin an attractive choice for prophylaxis of IFIs in neutropenic pediatric patients after HSCT.
A prior randomized study of van Burik et al.6 demonstrated the efficacy of echinocandin for prophylaxis in neutropenic host. However, the proportion of pediatric patients was low and they included both allogeneic (51.8%) and autologous (47.8%) HSCT. Therefore, it was not sufficient to draw a confident conclusion regarding pediatric patients who underwent allo-HSCT. Limitations of our study include that this is a non-randomized study. However, we included the largest pediatric population as far as we know and homogenous patient population who had undergone allogeneic HSCT, which makes our study distinctive.
In summary, this is the first prospective study of micafungin use for antifungal prophylaxis after allo-HSCT that has been carried out in a relatively large cohort of pediatric patients under 20 years of age. Our study demonstrated that 1 mg/kg/day of micafungin, up to a maximum of 50 mg/day, is a new option for antifungal prophylaxis in neutropenic pediatric patients receiving allo-HSCT, with promising efficacy without significant AEs. A further randomized comparative prospective study is needed to define clinical guidelines for antifungal prophylaxis in children and adolescents undergoing allo-HSCT.
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This study was coordinated by the Clinical Research Coordination Center, National Cancer Center, Korea, using the web-based clinical research management platform (Velos).
HJP designed the study, collected the data, performed analysis and reviewed the manuscript; MP performed the analysis and wrote the paper; JJS designed the study and reviewed the manuscript; MH collected the data and performed the analysis; BHN performed the anlaysis; KNK, HJI, JWL, N-GC, BC, H-KK, KHY, HHK, HJK, HYS, HSA, YTL, HK, CJL, JOH contributed to data collection.
The authors declare no conflict of interest.
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