Micafungin, a Novel Antifungal Agent, as Empirical Therapy in Acute Leukemia Patients with Febrile Neutropenia

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1 ORIGINAL ARTICLE Micafungin, a Novel Antifungal Agent, as Empirical Therapy in Acute Leukemia Patients with Febrile Neutropenia Masamitsu Yanada 1,2, Hitoshi Kiyoi 2, Makoto Murata 1, Momoko Suzuki 1, Masanori Iwai 2, Toshiya Yokozawa 1, Hisashi Baba 2, Nobuhiko Emi 1 and Tomoki Naoe 1 Abstract Objective Invasive fungal infection is a major cause of morbidity and mortality in patients with febrile neutropenia unresponsive to antibacterial treatment. Empirical antifungal therapy with amphotericin B has been the standard of care for these patients; however, there remains a need for less toxic alternative drugs. Patients and Methods We conducted a prospective study to evaluate the efficacy and safety of micafungin (MCFG), a novel antifungal agent of the echinocandin class, in an empirical therapy setting for patients with febrile neutropenia. Results A total of 31 patients with acute leukemia who developed febrile neutropenia were enrolled in the study. Among them, 18 patients fulfilling the protocol-defined criteria, including 10 with persistent fever and 8 with recurrent fever, received MCFG empirically. Underlying diseases consisted of acute myeloid leukemia (n=15) and acute lymphoblastic leukemia (n=3). The median duration of neutropenia and drug administration was 22 and 9.5 days, respectively. Treatment success, defined as defervescence during the neutropenic period, absence of breakthrough fungal infections, and requiring no replacement of antifungal drugs, was achieved in 14 patients (78%). None of the patients required discontinuation or dose reduction due to adverse events except for one patient with severe hypokalemia. Conclusions Although the studied patients were limited in number, our results indicate that MCFG is an encouraging agent for empirical antifungal therapy in patients with febrile neutropenia, and deserves further investigation in large-scale studies. Key words: fungal infection, micafungin, empirical therapy, febrile neutropenia, prospective study (DOI: /internalmedicine ) Introduction Invasive fungal infection (IFI) is a major cause of morbidity and mortality in patients with prolonged neutropenia after intensive chemotherapy. Difficulty in early diagnosis causes a treatment delay, which makes the prognosis extremely poor. These situations have led to the empirical use of antifungal agents in febrile neutropenic patients unresponsive to broad-spectrum antibacterial treatment (1-14). For this indication, amphotericin B (AMPH-B) has been the drug of choice; however, its use is associated with several serious adverse effects, including nephrotoxicity, electrolyte imbalance, and infusion-related reactions. In this regard, there is a need for less toxic alternative drugs for empirical antifungal therapy. Micafungin (MCFG: formerly FK463) is a novel antifungal agent of the echinocandin class, which inhibits the synthesis of β-d-glucan, an essential component of the fungal cell walls (15). This agent has been demonstrated to have an excellent in vitro activity against both Candida and Aspergillus (15-17), and preliminary clinical studies have also Department of Hematology, Nagoya University Graduate School of Medicine, Nagoya and Department of Infectious Diseases, Nagoya University Graduate School of Medicine, Nagoya Received for publication July 19, 2005; Accepted for publication November 25, 2005 Correspondence to Masamitsu Yanada, Department of Hematology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showaku, Nagoya

2 Table1. PatientCharacteristics Figure1. DesignoftheStudy.Patientsdevelopingfebrile neutropeniareceivedantibacterialtreatmentimmediatelyafterenrolment.micafunginwasaddedforthoseremaining neutropenicandhavingpersistentorrecurrentfeverafterat least5daysofantibacterialtherapy,andalsoforthosewhose bloodcultureswerepositiveforfungiorthosewhohadan elevationofserum β-d-glucanbeforeday5. were allowed to participate, but FLCZ had to be discontinued at the time when administration of MCFG was started. shown good activity in vivo (15, 18). Moreover, the absence of targeted enzymes in humans may possibly contribute to less toxicity. For these reasons, we considered it to be a potential alternative to AMPH-B, and conducted a prospective study to evaluate the efficacy and safety of MCFG in an empirical therapy setting for patients with febrile neutropenia. Study design Patients and Methods This was a prospective non-randomized study conducted in a single center. The major objective of this study was to evaluate efficacy and feasibility of empirical therapy with MCFG for patients with febrile neutropenia unresponsive to antibacterial agents. The primary endpoint was the rate of treatment success, which is defied below. After written informed consent was obtained, patients who developed febrile neutropenia were treated according to the protocol as presented in Fig. 1. Recruitment of 30 patients was planned in order to determine the validity of conducting a subsequent multicenter study. The protocol was reviewed and approved by the Institutional Review Board. Patients Adult patients with acute leukemia who developed febrile neutropenia were eligible if they had serum bilirubin and creatinine levels less than 1.5 times the upper limit of normal. Patients were excluded if they met any of the following criteria; allergy to the study drug; HIV seropositivity; pregnant or lactating woman; or receiving systemic antibacterial therapy within 72 hours before registration. Patients receiving antifungal prophylaxis with oral fluconazole (FLCZ) Treatment After enrollment, antibacterial treatment was initiated immediately. The selection of the initial antibacterial drugs was based on the Guidelines of the Infectious Diseases Society of America (12), and changes were made as required. MCFG was added for patients remaining neutropenic and having persistent or recurrent fever after at least 5 days of antibacterial therapy, as were those whose blood cultures were positive for fungi or those who had an elevation of serum β-d-glucan before day 5. MCFG was administered intravenously over 1 hour at a daily dose of 50 to 150 mg per day, which was determined on the basis of the results of the study testing MCFG for the treatment of documented fungal infection (18). Initial patients in our study were treated with 50 mg. After confirming its safety profile in the first 3 patients, the starting dose could be increased within the above limits according to the attending physicians discretion. It was also permitted to increase the dose up to 300 mg per day during the course if the response was thought to be inadequate. Therapy was continued until both defervescence and absolute neutrophil count above 500/μL for more than 2 successive days were achieved. When patients remained afebrile and absolute neutrophil count was between 100/μL and 500/μL for more than 5 successive days, therapy was discontinued if they had a stable condition, no signs and symptoms of infection, and no severe mucositis. Clinical and laboratory evaluation Patients were monitored daily for clinical signs and symptoms. Complete blood cell counts and chemistry parameters were performed at least 3 times a week. Surveillance cultures were obtained from throat, urine and stool once a week. Blood cultures were drawn before therapy in all patients, on days 3 and 5 if febrile, and thereafter if clinically 260

3 Table2. DetailsofPatientsReceivingEmpiricalMicafungin Table3. TreatmentSchedulesandOutcomes indicated. Serum β-d-glucan was tested before treatment. Chest radiography was taken on day 1 in all patients, on day 5 if febrile, and at any occasion if clinically indicated. Definitions Neutropenia was defined as an absolute neutrophil count of less than 500/μL, or a count of 500/μL to 1,000/μL, which was expected to fall below 500/μL within 48 hours due to preceding chemotherapy. Fever was defined as an axillary temperature of 38.0 or greater on one occasion or of 37.5 to 37.9 lasting for more than 1 hour, unless it was associated with the administration of blood products, underlying disease, or other pyogenic causes. Defervescence was defined as 3 successive days with axillary temperature below Patients were evaluated for response if they had received MCFG for more than 3 days. They were observed for 14 days after completion of the study drug or until death. For efficacy assessment, we used modifications of published criteria (11). Treatment success was defined as defervescence during the neutropenic period, and cure for baseline IFIs, if present. Failure was defined as the presence of any of the following conditions: development of breakthrough fungal infections; discontinuation of MCFG due to serious adverse events or lack of efficacy; addition of other antifungal drugs; and death from any cause during study period. IFIs were defined according to the European Organization for Research and Treatment of Cancer/National Institute of Allergy and Infectious Diseases (EORTC/NIAID) criteria (19). Adverse events were graded based on the National Cancer Institute Common Toxicity Criteria version 2.0. Patients Results Between May 2003 and September 2004, a total of 31 patients were enrolled. Patient characteristics are listed in Table 1. Among them, 18 patients received MCFG empirically after fulfilling the protocol-defined criteria. The following analyses were restricted to the 18 patients. Details about these patients are summarized in Table 2. Underlying diseases consisted of acute myeloid leukemia (n=15) and acute 261

4 lymphoblastic leukemia (n=3). No case had a past history of IFIs. All patients were isolated in a room equipped with a laminar air flow system, and had a central venous catheter (CVC). The median duration of neutropenia was 22 days (range: 11 to 30 days). For the duration of this study, our policy about antifungal prophylaxis changed in the direction of withholding. Four patients in earlier periods received FLCZ prophylaxis, while those in later periods did not. Baseline fungal infections defined by the EORTC/NIAID criteria were absent for all patients before starting MCFG. Treatment and efficacy MCFG was given to 10 patients for persisting fever and 8 patients for recurrent fever. Table 3 shows the treatment schedules and outcomes. Initial dose was 50 mg for 5 patients enrolled in the earlier period, and 100 mg for 12 patients. One case was treated at a dose of 150 mg due to large physical size. While 4 patients had their dosage increased, there was no case requiring dose reduction. The median duration of administration was 9.5 days (range: 6 to 16 days). Treatment success was achieved in 14 patients (78%) with the median duration from starting MCFG to defervescence of 3 days (range: 1 to 6 days). There were seven successful cases with persistent fever, including one who became afebrile within 3 days after change of antibacterial agents. None of the patients fulfilled the microbiological or clinical criteria for IFIs, discontinued the drug due to lack of efficacy, or died during the study period. Although positive results of β-d-glucan were obtained in two cases, the values declined immediately after initiating MCFG. None were positive for Aspergillus antigen tests. Treatment failure was observed in 4, including 2 cases requiring dose escalation of MCFG (Table 3). MCFG was switched to AMPH-B in one patient because of severe hypokalemia. The other 3 cases failed to achieve defervescence before neutrophil recovery. Among them, one was later identified as having a CVC-related infection by Streptococcus epidermidis. Another case was also suspected of having a CVC-related infection clinically, because fever was reduced promptly after removal of CVC, although no pathogens were identified by blood and catheter cultures. In the remaining patient, Candida albicans had colonized multiple sites before starting MCFG, but was resolved after administering MCFG. However, fever persisted by the time of neutrophil recovery, and the cause of the fever remained unknown. Among 14 patients with treatment success, four had developed bacterial sepsis on the day of entry, but blood cultures were all negative on the day when MCFG was initiated. Although two patients had colonization of Candida albicans at multiple sites before starting MCFG, it was resolved after treatment. Toxicity Grade 3 toxicity developed in 4 patients, including GPT elevation in 2 cases and hypokalemia in 2 cases. Grade 2 toxicity occurred in 2 patients, including GPT elevation and skin rash. All of them were successfully managed by supportive therapy without withdrawing MCFG. One case (UPN 30) experienced grade 4 hypokalemia which was progressive despite replenishment. After 7 days of administration, MCFG was switched to AMPH-B, and hypokalemia subsequently improved. Discussion The beneficial role of AMPH-B for patients with persistent or recurrent febrile neutropenia was demonstrated in 2 randomized controlled trials in the 1980s (1, 2), and empirical therapy with the agent has become the standard of care. Its use is, however, hampered by a high incidence of adverse effects such as nephrotoxicity and infusion-related reactions. Therefore, less toxic alternative drugs are needed. Recently, lipid formulations of AMPH-B have been investigated, and have been shown to be equivalent to conventional AMPH-B in efficacy with less toxicity (4, 5, 7, 8, 13). But its routine use is limited due to high acquisition cost. The azole antifungal agents are considered to be less toxic than AMPH-B, and several studies showed that FLCZ or itraconazole (ITCZ) were equally effective as compared to AMPH-B (3, 6, 9, 10). Nevertheless, one of the major concerns about the use of FLCZ is ascribed to its lack of activity against Aspergillus species and some non-albicans Candida species, i.e., C. krusei and C. glabrata. An increasing prevalence of such resistant strains has been reported, primarily due to the widespread use of prophylactic FLCZ (20-22). The use of oral ITCZ is also limited because of the wide variety of bioavailability of the capsule form, and the adverse gastrointestinal effects of the oral solution. Under such conditions, novel antifungal agents have been developed and studied in recent years, such as intravenous ITCZ, voriconazole and caspofungin (10, 11, 14). MCFG, similar to caspofungin, is an echinocandin agent, which targets the fungal cell walls. The in vitro and in vivo studies have shown that it has a broad spectrum and strong activity with fewer adverse effects (15-18). To our knowledge, this is the first report on MCFG as empirical antifungal therapy in patients with febrile neutropenia. Although the number of patients was limited, the percentage of patients who responded to treatment reached 78%. Considering that the response rates reported in previous studies of other antifungal agents range from 26 to 75% (1-11, 13, 14), our results are encouraging. High activity against Candida species and Aspergillus species is an advantage of this drug, where as weak or no activity against other fungi, including Cryptococcus neoformans, Fusarium species, Trichosporon species and Mucor species, should be kept in mind in clinical use (15). It is also notable that none of the patients except one case required discontinuation or dose reduction of the drug due to adverse events. The reason for discontinuation of MCFG in the single case was severe hypokalemia. Although the mechanism is unknown, the causal relation was probable because hypokalemia of the patient improved after switching 262

5 MCFG to AMPH-B. Additionally, 2 cases developed grade 3 hypokalemia, suggesting that attention should be paid to the serum potassium concentration during MCFG treatment. Previous studies reported that patients treated empirically with AMPH-B frequently experienced nephrotoxicity (7 to 38%), or discontinued treatment due to adverse events (18 to 49%) (3, 6, 7, 9, 10, 13). From those findings and the present study, MCFG seems to have a much more favorable safety profile. The small sample size is the major limitation of this study, although these results have prompted us to conduct a large-scale multicenter study. Another problem lies with diagnostic uncertainty of fungal infections, as is often the case of studies dealing with empirical antifungal therapy. In order to solve this problem, the EORTC/NIAID criteria have been recently proposed (19). Because most published studies did not employ the criteria, we could not make a comparison with historical data, but assessment on the basis of applicable definitions will be strongly required for the future. Optimal dosing for patients with febrile neutropenia is also a problem to be resolved. When we started this study, information regarding this point was so scarce that the lower dose was chosen in the earlier period, and dose increase was allowed after confirming safety. This issue should be clarified in future studies. In summary, although the studied patients were limited in number, our results indicate that MCFG is a promising agent for empirical antifungal therapy in patients with acute leukemia who have developed persistent or recurrent febrile neutropenia, and it deserves further investigation in largescale studies. The authors would like to thank Drs. Akihiro Abe, Tetsuya Nishida, Junji Hiraga, and Toshihiro Iwasaki for their contributiontothistrial. References 1. 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