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Caspofungin Treatment for Pulmonary Invasive Fungal Disease in Hematology Patients: A Retrospective Study in a Clinical Practice Setting in China
Clinical Therapeutics/Volume ], Number ], 2017
Caspofungin Treatment for Pulmonary Invasive Fungal Disease in Hematology Patients: A Retrospective Study in a Clinical Practice Setting in China Xiaohui Zhang, Phd1; Jiong Hu, MD2; Yu Hu, MD3; He Huang, MD4; Jie Jin, MD4; Juan Li, MD5; Qifa Liu, MD6; Zonghong Shao, MD7; Jianxiang Wang, MD8; Quanshun Wang, MD9; Depei Wu, MD10; and Xiaojun Huang, Phd1 1
Department of Hematology, Peking University People’s Hospital, Beijing, China; 2Department of Hematology, Ruijin Hospital Shanghai Jiao Tong University School of Medicine, Shanghai, China; 3 Department of Hematology, Union Hospital Tong ji Medical College, Huazhong University of Science and Technology, Wuhan, China; 4Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, China; 5Department of Hematology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; 6Department of Hematology, Nanfang Hospital, Guangzhou, China; 7 Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China; 8Department of Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China; 9Department of Hematology, Chinese PLA General Hospital, Beijing, China; and 10Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China ABSTRACT Purpose: Invasive fungal disease (IFD) is a serious complication in patients with hematologic malignancies. Caspofungin is the first approved inhibitor of fungal β-1,3-glucan synthesis. The aim of the present study was to evaluate the effectiveness of caspofungin in the treatment of IFD in patients with hematologic malignancies. Methods: In this retrospective study, data from the electronic medical records of 1118 inpatients who were admitted to 10 hospitals in China between 2013 and 2014 were analyzed. Inclusion criteria were hematologic disorder and IFD diagnosed during the hospitalization, based on clinical manifestations or evidence of pulmonary invasion, as well as caspofungin treatment for at least 7 days. The primary end point was the favorable response rate at the end of caspofungin as initial therapy for proven/probable/ possible pulmonary IFD. The secondary end point was the survival rate after the completion of the caspofungin treatments. Findings: A total of 704 patients were included, of whom 122 had IFD classified as probable/possible and
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582 had unclassified IFD. The most frequent hematologic diseases were acute myeloid leukemia (42.8%), followed by acute lymphatic leukemia (18.8%), nonHodgkin lymphoma (8.8%), aplastic anemia (7.1%), and others (22.5%). The rates of favorable caspofungin response were 57.2% in all patients, 58.2% in the probable/possible IFD group, and 57.0% in the unclassified IFD group. Caspofungin as initial monotherapy led to a favorable response rate of 62.2% in the probable/possible IFD group. Uni- and multivariate analyses revealed that not recovering from neutropenia during antifungal treatment, and advanced age, were significant factors for unfavorable outcomes. The overall IFD-related mortality rate was 4.1%. Implications: The results of our study show that caspofungin treatment of IFD in hematology patients was reasonable, with an overall rate of favorable Accepted for publication July 10, 2017. http://dx.doi.org/10.1016/j.clinthera.2017.07.013 0149-2918/$ - see front matter & 2017 Elsevier HS Journals, Inc. All rights reserved.
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Clinical Therapeutics response of 57.2% with each caspofungin treatment strategy. (Clin Ther. 2017;]:]]]–]]]) & 2017 Elsevier HS Journals, Inc. All rights reserved. Key words: caspofungin, echinocandin hematological disorders, invasive fungal infection, lymphatic leukemia.
INTRODUCTION Invasive fungal disease (IFD) is a major complication in patients with hematologic malignancies. The majority of patients in whom IFD develops acute myeloid leukemia cases or recipients of allogeneic hemopoietic stem cell transplantation,1 with mortality rates of 13.5% to 28.6%.2,3 IFD is mainly caused by Candida and Aspergillus spp.4 Improvements in early diagnosis and timely initiation of antifungal treatment play a crucial role in the outcome, because the mortality rates are highly associated with delayed medication.5–7 Amphotericin B (AmB) formulations have been standard therapy for decades, but they have limited usefulness due to wellknown nephrotoxicity and infusion-related toxicity (deoxycholate AmB).8–10 Lipid formulations of AmB have been proved to be less toxic, although they are not more effective than conventional AmB.11 However, in 2002 voriconazole was shown to be more efficacious than AmB in the treatment of proven/ probable aspergillosis in 277 patients with 86.6% lung infections and mixed immunocompromising conditions.12 Thus, voriconazole became the first-line therapy for invasive pulmonary aspergillosis, which is reflected in the 2016 guideline from the Infectious Diseases Society of America, which stated that AmB deoxycholate and its lipid derivatives might be considered as alternative medications for invasive pulmonary aspergillosis when voriconazole cannot be administered, or in resource-limited settings when no other agent is available. Lipid formulations of AmB should be the treatment of choice when azoles are contraindicated or not well-tolerated.13–15 Caspofungin is an echinocandin that disrupts fungal cell wall integrity by inhibiting fungal 1,3-β-glucan synthase.16 It has been associated with fewer infusionrelated adverse events, is not nephrotoxic, and has not been associated with major drug-to-drug interactions involving cytochrome P450, as are triazole agents with anti-Aspergillus activity.17 Therefore, caspofungin
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administered as monotherapy or in combination therapy can be considered as an alternative choice in patients who are unable to tolerate azole medications. Caspofungin is the first fungal (1→3)-β-D-glucan synthesis inhibitor approved by the US Food and Drug Administration that has activity against Candida and Aspergillus spp and has been shown to be a reasonable primary treatment of candidemia18 and other forms of invasive candidiasis,19 as well as salvage therapy for invasive Aspergillosis infection.20 In addition, it is recommended as empirical therapy for presumed fungal infections in febrile neutropenic patients.21 Caspofungin has been approved in China for about 10 years, but there is a lack of data from clinical practice on caspofungin treatment outcomes in patients in hospitals in China. In the present investigation, through a multicenter, observational, retrospective study of data from 10 hospitals, we analyzed the curative effectiveness of caspofungin in hematology patients with pulmonary IFD in China, focusing on caspofungin as the initial monotherapy or combination therapy and evaluating its usability in patients unable to tolerate azole medications.
PATIENTS AND METHODS This study was conducted according to the International Conference on Harmonisation guideline on Good Clinical Practice and the Declaration of Helsinki (2004). The protocol was approved by the ethics committees at the 10 participating study centers. Written informed consent was obtained from all of the patients before their participation in the study. The aim of this multicenter, observational, retrospective analysis was to estimate the curative effects of caspofungin in hematology patients with pulmonary IFD.
Inclusion Criteria In this study, data from the electronic medical records of 1118 inpatients between 2013 and 2014 who were admitted into 10 hospitals during a predefined period due to hematologic disorders were analyzed. Inclusion criteria for patients in the present study were: (1) age ≥16 years and at least 1 diagnostic criterion (hematologic malignancy [eg, acute leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma], aplastic anemia, or history of hematopoietic stem cell transplantation) during
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X. Zhang et al. hospitalization; (2) a diagnosis of IFD, based on Chinese clinical guidelines; (3) a diagnosis of at least 1 clinical sign and symptom of pulmonary involvement (new infiltrates or specific signs indicating fungal infection on CT imaging [eg, dense, well-circumscribed lesions with or without a halo sign, aircrescent sign, cavity], symptoms of lower respiratory tract infection [eg, cough, chest pain, hemoptysis, dyspnea], or a physical finding of pleural rub or pleural effusion); and (4) treatment with caspofungin, including monotherapy and combination therapy, for at least 7 days after having been diagnosed with an IFD.
indirect tests of fungal antigens (galactomannan test), β-D-glucan (G-test), and cryptococci, or Histoplasma capsulatum obtained from various samples. Depending on how many of the factors could be confirmed, patients' IFD was classified as proven or probable/possible.
Unclassified IFD Cases that did not meet the EORTC/MSG criteria but that had nonspecific imaging changes, were only antigen positive, or had only microbiologic evidence without clinical symptoms were classified as unclassified IFD.
Exclusion Criteria Patients who participated in any clinical trial involving antifungal therapy during the hospitalization who or received caspofungin monotherapy for antifungal prophylaxis were excluded.
IFD Diagnosis The diagnostic evidence of an IFD was collected according to the criteria from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG; 2008), including host, clinical, and microbiologic factors.22 According to a patient's medical history and EORTC/MSG 2008 criteria, cases were classified as proven, probable, or possible mold IFDs.
Proven or Probable/Possible IFD The host factors for IFD diagnosis included a recent history of neutropenia (neutropenic status at the time of antifungal therapy initiation/admission), prolonged use of corticosteroid, treatment with other recognized T-cell immunosuppressants (AIDS/HIV infection, immunosuppressive medication), and congenital severe immunodeficiency. Clinical factors for IFD diagnosis included symptoms of lower respiratory tract infection (cough, chest pain, hemoptysis, and/or dyspnea), physical findings (pleural rub, pleural effusion), and radiology findings (new infiltrates; dense, well-circumscribed lesions with or without a halo sign; air crescent sign; cavity on CT imaging). Microbiologic testing included cytology, direct microscopic examination, fungi culture and other
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Outcomes Assessment For outcomes analyses, treatments were classified as monotherapy or combination therapy, and as initial therapy, in which caspofungin was the first medication administered, or noninitial therapy, in which caspofungin was added to another medication or another medication was exchanged with caspofungin. The medications used in caspofungin combination therapies were voriconazole (38%), amB or amB liposome (14%), itraconazole (16%), fluconazole (5%), and micafungin (1%). Treatment response was classified as complete response, partial response, stable disease, or failure. Complete response was defined as the resolution of all attributable symptoms and signs of pulmonary infection and radiologic abnormalities; partial response was defined as a substantial reduction in attributable symptoms and signs of pulmonary infection and radiologic abnormalities (450%); stable disease was defined as minimal or no reduction in attributable symptoms and signs of pulmonary infection and radiologic abnormalities; and failure was defined as worsening of pretreatment signs and symptoms of pulmonary infection or radiologic abnormalities. Favorable response rate was a composite of complete and partial responses, and unfavorable response rate comprised stable disease, failures, and mortality from any cause. Treatment response was evaluated at the end of caspofungin treatment (at least 7 days). The primary end point of this study was the favorable response rate at the end of caspofungin as the initial therapy for proven and probable/possible pulmonary IFD. A secondary end point was the survival rate after the completion of caspofungin treatment.
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Clinical Therapeutics
Statistical Analysis All statistical analyses were performed with SAS software version 9.2 (SAS Institute Inc, Cary, North Carolina). The primary and secondary end points of this study were descriptive analyses (ie, frequency, percentages, or 95% CIs). Treatment response was evaluated by descriptive analysis according to the different subgroup factors (IFD type, response type). A multivariate model was established following a univariate analysis of factors having a P value of o0.05 or with significant clinical meaning (eg, duration of therapy) defined as influencing treatment response using a logistic regression model. P values of o0.05 were considered to be statistically significant.
RESULTS Baseline Demographic and Clinical Characteristics of the Patients Data from 1118 patients who received caspofungin were reviewed, and a total of 414 patients were excluded from the final analysis, as shown in the Figure. Data from 704 patients were included. There were more female 278 (39.5%) than male (60.5%) patients, and the mean age of all patients was 46.0 (16.2) years. Comorbidities were present in 306 of the patients (43.5%). The most frequent hematologic diseases were acute myeloid leukemia (42.8%), acute lymphatic leukemia (18.8%), and non-Hodgkin lymphoma (8.8%). The main reasons for Total patients from 10 hospitals
(N = 1118)
Excluded because of lacking inclusion criteria (N = 227)
hospitalization were chemotherapy in 246 patients (34.9%) and hematopoietic stem cell transplantation in 87 patients (12.4%). Among the 704 patients, 122 probable/possible IFD cases were diagnosed during hospitalization according to EORGC/MSG criteria, without any proven cases. There were no statistically significant differences between the subgroups with classified and unclassified cases with regard to basic characteristics (Table I). In these 122 patients, specific abnormal radiology imaging led to 25 probable and 97 possible IFD cases during hospitalization (Table I). Nonspecific radiologic findings were, however, also abnormal in 8 of the probable cases (32.0%) and in 27 of the possible IFD cases (27.8%). Of the unclassified IFD cases, 539 (92.6%) presented with nonspecific abnormal radiology images (data not shown).
Caspofungin Treatment Pattern In the present study, most of the patients received caspofungin monotherapy (321/704 [45.6%]) as initial treatment versus combination caspofungin therapy (76/704 [10.8%]). For noninitial caspofungin treatments, monotherapies were the majority (167 vs 140) (Table II). Prophylaxis with antifungal drugs other than caspofungin was provided in 120 of the 704 patients (17.1%), with the most frequently prescribed prophylactic agents being itraconazole (45 [37.5%]), fluconazole (35 [29.2%]) and voriconazole (25 [21.0%]), followed by micafungin (11 [9.2%]) and amB (4 [3.3%]). Most of this prophylactic medication was applied before caspofungin was used as the initial monotherapy (58 [48.3%]) or initial combination therapy (22 [18.3%]), as well as before caspofungin as noninitial combination therapy (22 [18.3%]) followed by caspofungin as noninitial monotherapy (18 [15.0%]) (data not shown).
891 patients
Excluded because of incompletely recorded data (N = 10) 881 patients
Excluded because of prematurely discontinued CAS therapies (N = 177) Enrolled 704 patients
Probable/possible IFD cases (N = 122)
Unclassified IFD cases (N = 582)
Figure. Flow chart of the study. CAS ¼ caspofungin; IFD ¼ invasive fungal disease.
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Caspofungin Treatment Duration in IFD Patients in the Total Group Including Probable/Possible Cases Caspofungin initial monotherapy or combination therapy was applied for mean durations of 18.1 (13.6) and 23.6 (13.3) days, respectively, whereas caspofungin as noninitial monotherapy or combination therapy was applied for mean durations of 16.7 (15.1) and 20.4 (14.6) days. The most common antifungal drugs administered before caspofungin therapy were voriconazole (50%–460%) and itraconazole (20%–30%) alone or in combination with amB or micafungin as
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X. Zhang et al.
Table I. Demography and baseline characteristics of the study patients. Variable Age, mean (SD), y Sex, no. (%) Female Male BMI, mean (SD), kg/m2 IFD diagnostic status, no. (%) Possible Probable Proven Comorbidities, no. (%) Cardiovascular disease Endocrine disease Liver disease Respiratory disease Renal disease Hematologic disease Acute myeloid leukemia Acute lymphatic leukemia Non-Hodgkin lymphoma Myelodysplastic syndrome Aplastic anemia Mild Moderate Severe Malignant melanoma Chronic myeloid leukemia Acute promyelocytic leukemia Chronic lymphatic leukemia Hodgkin disease Other Malignancy intervention, no. (%) HSCT Chemotherapy Other therapy Neutropenic status, no. (%) ANC (before therapy) o500 cells/mm3 Duration ≤7 d Duration 47 d 500–1000 cells/mm3 41000 cells/mm3 Isolated organisms Candida sp
All Patients (N ¼ 704) Classified (n ¼ 122) Unclassified (n ¼ 582) 46.0 (16.2)
45.9 (15.4)
46.1 (16.4)
278 (39.5) 426 (60.5) 62.9 (11.4)
52 (42.6) 70 (57.4) 24.7 (33.5)
226 (38.8) 356 (61.2) 18.9 (14.6)
– – –
97 (79.5) 25 (20.5) 0
– – –
(15.2) (8.4) (9.2) (6.0) (4.7)
15 (12.3) 9 (7.4) 14 (11.5) 6 (4.9) 7 (5.7)
92 (15.8) 61 (10.5) 55 (9.5) 37 (6.4) 27 (4.6)
301 (42.8) 132 (18.8) 62 (8.8) 55 (7.8) 50 (7.1) 15 (2.1) 4 (0.6) 31 (4.4) 47 (6.7) 17 (2.4) 15 (2.1) 3 (0.4) 2 (0.3) 20 (2.8)
57 25 15 3 8 2 2 4 8 1 3
(46.7) (20.5) (12.3) (2.5) (6.6) (1.6) (1.6) (3.3) (6.6) (0.8) (2.5) 0 1 (0.8) 1 (0.8)
244 (41.9) 107 (18.4) 47 (8.1) 52 (8.9) 42 (7.2) 13 (2.2) 2 (0.3) 27 (4.6) 39 (6.7) 16 (2.7) 12 (2.1) 3 (0.5) 1 (0.2) 19 (3.3)
87 (12.4) 246 (34.9) 371 (52.7)
10 (8.2) 52 (42.6) 60 (49.1)
77 (13.2) 194 (33.3) 311 (53.4)
107 59 65 42 33
P 0.942 0.436
0.064 –
0.326 0.298 0.494 0.546 0.607 0.165
0.086
0.006 264 (37.5) 130 (18.5) 134 (19.0) 70 (9.9) 366 (52.0)
61 (50.4) 35 (28.7) 26 (21.3) 8 (6.6) 52 (43.0)
203 (35.1) 95 (16.3) 108 (18.6) 62 (10.7) 314 (54.2)
–
11 (9.0)
–
– (continued)
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Clinical Therapeutics
Table I. (continued). Variable
All Patients (N ¼ 704) Classified (n ¼ 122) Unclassified (n ¼ 582) – –
Aspergillus sp Other
1 (0.8) 0
P
– –
ANC, absolute neutrophil count; BMI, body mass index; HSCT, hematopoietic stem cell transplantation; IFD ¼ invasive fungal disease.
monotherapies for 13.3 (12.6) days and as combination therapies for 11.9 (11.8) days (Table II). The primary reason for adding/switching to caspofungin was poor efficacy of other antifungal agents in 60% to 80% of cases, with different treatment patterns and adverse events/intolerability in 15% to 30% of cases.
Treatment Outcomes Favorable Treatment Response Rates in IFD Patients The favorable response rates with caspofungin as initial and noninitial monotherapy and combination therapy are shown in Table III. There was no
significant difference between probable/possible cases compared with unclassified IFD cases (58.2% vs 57.0%; P ¼ 0.90).
Factors Influencing Caspofungin Treatment Response–on Univariate and Multivariate Analyses The univariate analyses revealed that age had a negative influence on favorable response, whereas a greater age was seen as less favorable. An absolute neutrophil count (ANC) of o500 cells/mm3 resolved within or after 7 days and an ANC of 41000 cells/mm3 were associated with a greater likelihood of favorable
Table II. Caspofungin treatment duration in all included invasive fungal disease (IFD) cases and in probable/ possible cases. Data are given as mean (SD) duration (in days).
Patients All patients (N ¼ 704)
Probable/possible IFD cases (n ¼ 122)
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Caspofungin Therapy Type
Type of Medication
Initial (n ¼ 397) Monotherapy (n ¼ 321) Combination (n ¼ 76) Noninitial Monotherapy (n ¼ 307) (n ¼167) Combination (n ¼ 140) Initial (n ¼ 54) Monotherapy (n ¼ 45) Combination (n ¼ 9) Noninitial Monotherapy (n ¼ 68) (n ¼ 36) Combination (n ¼ 32)
Duration of Caspofungin Medication
Duration of Antifungals Before Caspofungin
18.1 (13.6) 23.6 (13.3) 16.7 (15.1)
13.3 (12.6)
20.4 (14.6)
11.9 (11.8)
16.1 (8.9) 26.9 (9.9) 16.5 (9.2)
13.7 (13.3)
23.4 (19.7)
9.3 (8.9)
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Table III. Favorable outcomes for probable/possible as well as unclassified cases of invasive fungal disease (IFD) in this study. Caspofungin as Initial Therapy Parameter All patients Monotherapy Combination therapy Probable/possible IFD Monotherapy Combination therapy Unclassified IFD Monotherapy Combination therapy
n 397 321 76 54 45 9 343 276 67
Favorable Response 229 190 39 31 28 3 198 162 36
(57.7) (59.2) (51.3) (57.4) (62.2) (33.3) (57.7) (58.7) (53.7)
response compared with an ANC of o500 cells/mm3 and not recovered during the study period. Caspofungin as noninitial combination therapy had a negative influence on favorable response compared with caspofungin as noninitial monotherapy (Table IV). The multivariate analysis revealed similar results, with age as a negative factor for achieving a favorable response, and non-recovery of ANC o1000 cells/mm3 during the study period was a highly significant negative factor for treatment response. Caspofungin as noninitial combination therapy had a negative influence on favorable response compared with caspofungin as noninitial monotherapy (P o 0.001). For caspofungin as initial combination therapy compared with caspofungin as noninitial monotherapy, the negative influence on favorable response failed to reach significance (P ¼ 0.05) (Table V). The overall survival rates after continuously using caspofungin for at least 7 days were 95.1% in the probable/possible cases (n ¼ 122) and 90.6% in all patients (N ¼ 704). The rates of mortality related to IFD were 2.5% in the probable/possible cases and 4.1% among all included patients (Table VI).
DISCUSSION This study of data from 10 hospitals in China included 704 patients with hematologic diseases prescribed caspofungin for at least 7 days for pulmonary IFD treatment. A total of 122 cases (17.3%) were diagnosed as probable/possible pulmonary IFD according to the
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Caspofungin as Noninitial Therapy n 307 167 140 68 36 32 239 131 108
Favorable Response 174 107 67 40 25 15 134 82 52
(56.7) (64.1) (47.9) (58.8) (69.4) (46.9) (56.1) (62.6) (48.1)
n 704 488 216 122 81 41 582 407 175
Total Favorable Response 403 297 106 71 53 18 332 244 88
(57.2) (60.9) (49.1) (58.2) (65.4) (43.9) (57.0) (60.0) (50.3)
EORTC/MSG criteria, whereas 582 were unclassified IFD cases. These data are in accordance with a previous report in which only 21.5% of onco-hematology patients treated with antifungal medication were classified as having proven/probable/possible IFD.4 Also, in another previous study that included 170 patients with chemotherapy-induced neutropenia or allogeneic stem cell recipients, more than half could not be classified as proven/probable/possible, whereas CT scans revealed pulmonary infiltrates in 62%, which was also an indicator for mortality. The investigators concluded that CT is more appropriate for diagnosing early fungal infections, given that more than half of the radiologic signs could not be matched by mycologic findings,23 which was also the case in our study, with only 9.8% of 122 classified patients being diagnosed using mycologic evidence. There were more female than male patients, and the mean age of all patients was 46.0 (16.2) years. In our study, the most frequent hematologic disease was acute myeloid leukemia (42.8%), which is in accordance with a previous study.1 The primary reasons for switching to caspofungin therapy in our study was poor efficacy of other antifungals in 60% to 80% of cases, and adverse events/intolerability in 15% to 30% of patients. In addition, noninitial combination therapy showed inferior outcomes compared with noninitial monotherapy, which might have been due to the severity of IFD, given that the use of combination therapies indicate a higher likelihood of severe disease.
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Clinical Therapeutics Table IV. Factors influencing a favorable response: univariate analysis (N ¼ 704). Variable
Coeff.
OR (95% CI)
P
Age Sex Hematologic disease (vs AML and MDS) All Other ANC status (vs o500 cells/mm3, ≤7d) o500 cells/mm3, 47 d ≥500 cells/mm3 ANC o1000 duration (vs not resolved) ≤7d 47 d 41000 cells/mm3 Caspofungin: type and use (vs noninitial monotherapy) Noninitial combination therapy Initial monotherapy Initial combination therapy Caspofungin therapy duration (≥14 d vs o14 d) Previous prophylaxis therapy status (yes vs no) Hematologic patients* (other vs HSCT)
–0.01 0.214
0.99 (0.98– 1.00) 1.24 (0.91–1.68)
0.05 0.17
0.12 0.34
1.13 (0.76–1.69) 1.41 (1.00–1.99)
0.55 0.05
–0.25 –0.08
0.78 (0.46–1.31) 0.93 (0.62–1.38)
0.35 0.71
0.95 0.64 0.66
2.57 (1.42–4.53) 1.89 (1.15–3.14) 1.92 (1.25–2.96)
o0.001 0.01 o0.001
–0.68 –0.22 –0.54 0.04 –0.24 0.11
0.51 0.80 0.58 1.05 0.79 1.12
o0.001 0.26 0.05 0.78 0.27 0.57
(0.32–0.81) (0.54–1.18) (0.34–1.01) (0.77–1.41) (0.52–1.20) (0.77–1.63)
MDS ¼ myelodysplastic syndrome. ANC ¼ absolute neutrophil count; AML ¼ acute myeloid leukemia; Coeff. ¼ coefficient, OR ¼ odds ratio. ⁎ Hematopoietic stem cell transplantation (HSCT): including HSCT, post-HSCT, and post-HSCT graft-versus-host disease.
The mean duration of caspofungin application as initial monotherapy was 16.1 days, which is somewhat longer than the 13 days24 and 14 days17 reported in comparable previous studies, but shorter than the 27 days reported by Viscoli et al.25 The favorable response rate with caspofungin treatment in hematology patients with IFD classified as probable or possible according to the EORTC/MSG criteria after initial monotherapy was 62.2% (28/45) in our study. This rate is similar to the 69% with monotherapy and 67% with combination therapies reported by Egerer et al in a recent study of pulmonary aspergillosis treatments of mainly patients with hematologic malignancy.26 However, our rate is somewhat higher than the 56.4% reported in an assessment of caspofungin in mainly patients with invasive pulmonary aspergillosis in clinical practice.27 Glasmacher et al28 reported similar findings (66%) with caspofungin monotherapies for IFD, but they included 118 patients in whom only 21 of the 35
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proven cases were pulmonary IFD and 19% of all cases comprised malignancies other than hematologic disease. The overall favorable response rate was 57.2%, which is higher than that from another study which compared caspofungin with liposomal AmB for empirical antifungal monotherapies in a cohort of 94.2% hematologic cancer cases, with overall favorable response rates of 33.9% and 33.7% with caspofungin and liposomal AmB medications, respectively, whereas successful treatment of baseline fungal infections was achieved in 51.9% of the caspofungin group versus 25.9% of the liposomal AmB group, but the investigators included only patients with persistent fever and neutropenia.24 Other studies noted favorable response rates with first-line caspofungin monotherapy for IFD of 42%29 and 33%,25 but the investigators included only patients with hematologic disease who received HSTCs. With regard to other antifungal therapies, a comparison of voriconazole
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X. Zhang et al. Table V. Factors influencing a favorable response: multivariate analysis (N ¼ 704). Variable
Coeff.
OR (95% CI)
P
Intercept Age Hematologic disease (vs AML and MDS) All Other ANC o1000 duration (vs not resolved) ≤7d 47 d 41000 cells/mm3 Caspofungin: type and use (vs noninitial monotherapy) Noninitial combination therapy Initial monotherapy Initial combination therapy Caspofungin therapy duration (≥14 d vs o14 d)
0.50 –0.01
– 0.99 (0.98–1.00)
0.17 0.02
–0.08 0.30
0.92 (0.60–1.41) 1.35 (0.93–1.95)
0.71 0.11
1.00 0.55 0.59
2.72 (1.44–5.13) 1.73 (1.04–2.89) 1.81 (1.16–2.81)
o0.001 0.04 0.01
–0.75 –0.21 –0.57 0.10
0.47 (0.29–0.76) 0.81 (0.54–1.21) 0.57 (0.32–1.00) 1.10 (0.80–1.52)
o0.001 0.31 0.05 0.54
MDS ¼ myelodysplastic syndrome. AML ¼ acute myeloid leukemia; ANC ¼ absolute neutrophil count; Coeff. ¼ coefficient; OR ¼ odds ratio.
and AmB treatments of mainly patients with hematological disease (84%) and patients with pulmonary IFD (87%) revealed that 52.8% of the patients in the initial voriconazole group and 31.6% in the initial AmB monotherapy group achieved a favorable response.12 The overall favorable response rate in patients with unclassified IFD in our study was 57.0%, which was not significantly different from that in the probable/
Table VI. Summary of overall survival. Parameter Overall survival (censored) Death Related to IFD Not related to IFD
Probable/Possible Cases (n ¼ 122)
All Patients (N ¼ 704)
116 (95.1)
640 (90.9)
6 (4.9) 3 (2.5)
64 (9.1) 29 (4.1)
3 (2.5)
35 (5.0)
IFD ¼ invasive fungal disease.
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possible cases. This finding indicates that, in a large percentage of patients with hematologic disease, IFD was not diagnosed by the EORTC/MSG criteria. The finding also underlines the importance of timely empirical medication, which was reflected in the relatively low overall rate of IFD-related mortality of 4.1% in our study. The mortality can be favorably compared to the 13.5% to 28.6%2,3 rates documented in previous reports, given that a 46-day delay in initiating treatment after diagnosis has been found to result in a 2-fold increase in mortality rate.7 The major factor for a favorable response to caspofungin treatment was recovery of neutropenia, which is in agreement with findings from previous studies.25,30–34 Prolonged neutropenia has been suggested to serve as a powerful indicator of the need for initiating empiric antifungal therapy in high-risk patients.35 Advanced age is another risk factor for unfavorable IFD treatment outcomes, which has also been noted in previous studies.3,31,36
CONCLUSIONS Our retrospective study of data from 10 hospitals in China revealed that the favorable caspofungin response rates with IFD treatment of hematology
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Clinical Therapeutics patients were 58.2% in 122 probable/possible cases and 57.0% in 582 unclassified cases. Caspofungin as initial monotherapy led to a favorable response rate of 62.2% in the probable/possible cases. Univariate and multivariate analyses revealed that none recovering neutropenia and advanced age were significant factors for unfavorable outcomes, with an IFD-related overall mortality rate of 4.1%. Caspofungin might be considered as more efficacious option than AmB for IFD treatment in refractory disease or intolerance in hematology patients.
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ACKNOWLEDGMENTS We thank the Peking University People's Hospital; Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Union Hospital, Tongji Medical College, Huazhong University of Science and Technology; The First Affiliated Hospital, Zhejiang University; The Affiliated Hospital, Sun Yat-sen University; Nanfang Hospital; Tianjin Medical University General Hospital; Institute of Hematology and Blood Diseases Hospital; Chinese Academy of Medical Sciences and Peking Union Medical College; Chinese PLA General Hospital; and The First Affiliated Hospital, Soochow University, for their participation in this study. Xiaohui Zhang, Xiaojun Huang contributed to study concept and design. Xiaohui Zhang, Jiong Hu, Yu Hu, He Huang, Jie Jin, Juan Li, Qifa Liu, Zonghong Shao, Jianxiang Wang, Quanshun Wang, Depei Wu, Xiaojun Huang contributed to acquisition of data. Xiaohui Zhang, Jiong Hu, Yu Hu contributed to analysis and interpretation of data. Xiaohui Zhang contributed to drafting of the manuscript. Xiaojun Huang contributed to critical revision of the manuscript for important intellectual content. Xiaojun Huang contributed to study supervision.
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CONFLICTS OF INTEREST This study was supported by Merck Sharp & Dohme (China) Ltd. The authors have indicated that they have no other conflicts of interest with regard to the content of this article.
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REFERENCES 1. Caira M, Girmenia C, Fadda RM, et al. Invasive fungal infections in patients with acute myeloid leukemia and in
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those submitted to allogeneic hemopoietic stem cell transplant: who is at highest risk? Eur J Haematol. 2008;81:242–243. Hahn-Ast C, Glasmacher A, Muckter S, et al. Overall survival and fungal infection-related mortality in patients with invasive fungal infection and neutropenia after myelosuppressive chemotherapy in a tertiary care centre from 1995 to 2006. J Antimicrob Chemother. 2010;65:761–768. Song AX, Huang Y, Yang DL, et al. [Risk factors and prognosis of invasive fungal infections in patients with hematological diseases]. Zhonghua Xue Ye Xue Za Zhi. 2011;32:507–511. des Champs-Bro B, Leroy-Cotteau A, Mazingue F, et al. Invasive fungal infections: epidemiology and analysis of antifungal prescriptions in onco-haematology. J Clin Pharm Ther. 2011;36:152–160. Denning DW. Early diagnosis of invasive aspergillosis. Lancet. 2000;355:423–424. Barnes RA. Early diagnosis of fungal infection in immunocompromised patients. J Antimicrob Chemother. 2008;61 (Suppl 1):i3–i6. Chamilos G, Lewis RE, Kontoyiannis DP. Delaying amphotericin B-based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis. Clin Infect Dis. 2008;47:503–509. Wingard JR, Kubilis P, Lee L, et al. Clinical significance of nephrotoxicity in patients treated with amphotericin B for suspected or proven aspergillosis. Clin Infect Dis. 1999;29:1402–1407. Bates DW, Su L, Yu DT, et al. Mortality and costs of acute renal failure associated with amphotericin B therapy. Clin Infect Dis. 2001;32:686–693. Arning M, Kliche KO, Heer-Sonderhoff AH, et al. Infusionrelated toxicity of three different amphotericin B formulations and its relation to cytokine plasma levels. Mycoses. 1995;38:459–465. Hamill RJ. Amphotericin B formulations: a comparative review of efficacy and toxicity. Drugs. 2013;73:919–934. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347:408–415. Patterson TF, Thompson GR, 3rd, Denning DW, et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63:e1–e60. Geist MJ, Egerer G, Burhenne J, et al. Induction of voriconazole metabolism by rifampin in a patient with acute myeloid leukemia: importance of interdisciplinary communication to prevent treatment errors with complex medications. Antimicrob Agents Chemother. 2007;51:3455– 3456. Kim SH, Yim DS, Choi SM, et al. Voriconazole-related severe adverse events: clinical application of therapeutic
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drug monitoring in Korean patients. Int J Infect Dis. 2011;15:e753–e758. Letscher-Bru V, Herbrecht R. Caspofungin: the first representative of a new antifungal class. J Antimicrob Chemother. 2003;51:513–521. Jarque I, Tormo M, Bello JL, et al. Caspofungin for the treatment of invasive fungal disease in hematological patients (ProCAS Study). Med Mycol. 2013;51:150–154. Mora-Duarte J, Betts R, Rotstein C, et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med. 2002;347:2020–2029. Cornely OA, Lasso M, Betts R, et al. Caspofungin for the treatment of less common forms of invasive candidiasis. J Antimicrob Chemother. 2007;60:363– 369. Maertens J, Raad I, Petrikkos G, et al. Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy. Clin Infect Dis. 2004;39:1563–1571. Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48:503–535. De Pauw B, Walsh TJ, Donnelly JP, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis. 2008;46:1813–1821. Rieger H, Lustig D, Barlow S, et al. Applicability of the EORTC/MSG criteria for IFD in clinical practice. Ann Hematol. 2015;94:847–855. Walsh TJ, Teppler H, Donowitz GR, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with
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persistent fever and neutropenia. N Engl J Med. 2004;351:1391–1402. Viscoli C, Herbrecht R, Akan H, et al. An EORTC Phase II study of caspofungin as first-line therapy of invasive aspergillosis in haematological patients. J Antimicrob Chemother. 2009;64:1274–1281. Egerer G, Reichert D, Pletz MW, et al. Caspofungin for treatment of invasive aspergillosis in Germany: results of a pre-planned subanalysis of an international registry. Eur J Med Res. 2012;17:7. Maertens J, Egerer G, Shin WS, et al. Caspofungin use in daily clinical practice for treatment of invasive aspergillosis: results of a prospective observational registry. BMC Infect Dis. 2010;10:182. Glasmacher A, Cornely OA, Orlopp K, et al. Caspofungin treatment in severely ill, immunocompromised patients: a case-documentation study of 118 patients. J Antimicrob Chemother. 2006;57:127–134. Herbrecht R, Maertens J, Baila L, et al. Caspofungin first-line therapy for invasive aspergillosis in allogeneic hematopoietic stem cell transplant patients: an European Organisation for Research and Treatment of Cancer study. Bone Marrow Transplant. 2010;45:1227– 1233. Sun Y, Huang H, Chen J, et al. Invasive fungal infection in patients
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receiving chemotherapy for hematological malignancy: a multicenter, prospective, observational study in China. Tumour Biol. 2015;36:757– 767. Akan H, Antia VP, Kouba M, et al. Preventing invasive fungal disease in patients with haematological malignancies and the recipients of haematopoietic stem cell transplantation: practical aspects. J Antimicrob Chemother. 2013;68(Suppl 3): iii5–iii16. Post MJ, Lass-Floerl C, Gastl G, et al. Invasive fungal infections in allogeneic and autologous stem cell transplant recipients: a single-center study of 166 transplanted patients. Transpl Infect Dis. 2007;9:189–195. Montagna MT, De Giglio O, Napoli C, et al. Invasive fungal infections in patients with hematologic malignancies (aurora project): lights and shadows during 18-months surveillance. Int J Mol Sci. 2012;13:774–787. Segal BH. Aspergillosis. N Engl J Med. 2009;360:1870–1884. Groll AH, Tragiannidis A. Recent advances in antifungal prevention and treatment. Semin Hematol. 2009;46:212–229. Pagano L, Akova M, Dimopoulos G, et al. Risk assessment and prognostic factors for mould-related diseases in immunocompromised patients. J Antimicrob Chemother. 2011;66(Suppl 1):i5–i14.
Address correspondence to: Xiaojun Huang, Department of Hematology, Peking University People's Hospital, No 11 Xizhimen South Street, Beijing 100044, China. E-mail: [email protected]
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Caspofungin Treatment for Pulmonary Invasive Fungal Disease in Hematology Patients: A Retrospective Study in a Clinical Practice Setting in China Xiaohui Zhang, Phd1; Jiong Hu, MD2; Yu Hu, MD3; He Huang, MD4; Jie Jin, MD4; Juan Li, MD5; Qifa Liu, MD6; Zonghong Shao, MD7; Jianxiang Wang, MD8; Quanshun Wang, MD9; Depei Wu, MD10; and Xiaojun Huang, Phd1 1
Department of Hematology, Peking University People’s Hospital, Beijing, China; 2Department of Hematology, Ruijin Hospital Shanghai Jiao Tong University School of Medicine, Shanghai, China; 3 Department of Hematology, Union Hospital Tong ji Medical College, Huazhong University of Science and Technology, Wuhan, China; 4Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, China; 5Department of Hematology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; 6Department of Hematology, Nanfang Hospital, Guangzhou, China; 7 Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China; 8Department of Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China; 9Department of Hematology, Chinese PLA General Hospital, Beijing, China; and 10Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China ABSTRACT Purpose: Invasive fungal disease (IFD) is a serious complication in patients with hematologic malignancies. Caspofungin is the first approved inhibitor of fungal β-1,3-glucan synthesis. The aim of the present study was to evaluate the effectiveness of caspofungin in the treatment of IFD in patients with hematologic malignancies. Methods: In this retrospective study, data from the electronic medical records of 1118 inpatients who were admitted to 10 hospitals in China between 2013 and 2014 were analyzed. Inclusion criteria were hematologic disorder and IFD diagnosed during the hospitalization, based on clinical manifestations or evidence of pulmonary invasion, as well as caspofungin treatment for at least 7 days. The primary end point was the favorable response rate at the end of caspofungin as initial therapy for proven/probable/ possible pulmonary IFD. The secondary end point was the survival rate after the completion of the caspofungin treatments. Findings: A total of 704 patients were included, of whom 122 had IFD classified as probable/possible and
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582 had unclassified IFD. The most frequent hematologic diseases were acute myeloid leukemia (42.8%), followed by acute lymphatic leukemia (18.8%), nonHodgkin lymphoma (8.8%), aplastic anemia (7.1%), and others (22.5%). The rates of favorable caspofungin response were 57.2% in all patients, 58.2% in the probable/possible IFD group, and 57.0% in the unclassified IFD group. Caspofungin as initial monotherapy led to a favorable response rate of 62.2% in the probable/possible IFD group. Uni- and multivariate analyses revealed that not recovering from neutropenia during antifungal treatment, and advanced age, were significant factors for unfavorable outcomes. The overall IFD-related mortality rate was 4.1%. Implications: The results of our study show that caspofungin treatment of IFD in hematology patients was reasonable, with an overall rate of favorable Accepted for publication July 10, 2017. http://dx.doi.org/10.1016/j.clinthera.2017.07.013 0149-2918/$ - see front matter & 2017 Elsevier HS Journals, Inc. All rights reserved.
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Clinical Therapeutics response of 57.2% with each caspofungin treatment strategy. (Clin Ther. 2017;]:]]]–]]]) & 2017 Elsevier HS Journals, Inc. All rights reserved. Key words: caspofungin, echinocandin hematological disorders, invasive fungal infection, lymphatic leukemia.
INTRODUCTION Invasive fungal disease (IFD) is a major complication in patients with hematologic malignancies. The majority of patients in whom IFD develops acute myeloid leukemia cases or recipients of allogeneic hemopoietic stem cell transplantation,1 with mortality rates of 13.5% to 28.6%.2,3 IFD is mainly caused by Candida and Aspergillus spp.4 Improvements in early diagnosis and timely initiation of antifungal treatment play a crucial role in the outcome, because the mortality rates are highly associated with delayed medication.5–7 Amphotericin B (AmB) formulations have been standard therapy for decades, but they have limited usefulness due to wellknown nephrotoxicity and infusion-related toxicity (deoxycholate AmB).8–10 Lipid formulations of AmB have been proved to be less toxic, although they are not more effective than conventional AmB.11 However, in 2002 voriconazole was shown to be more efficacious than AmB in the treatment of proven/ probable aspergillosis in 277 patients with 86.6% lung infections and mixed immunocompromising conditions.12 Thus, voriconazole became the first-line therapy for invasive pulmonary aspergillosis, which is reflected in the 2016 guideline from the Infectious Diseases Society of America, which stated that AmB deoxycholate and its lipid derivatives might be considered as alternative medications for invasive pulmonary aspergillosis when voriconazole cannot be administered, or in resource-limited settings when no other agent is available. Lipid formulations of AmB should be the treatment of choice when azoles are contraindicated or not well-tolerated.13–15 Caspofungin is an echinocandin that disrupts fungal cell wall integrity by inhibiting fungal 1,3-β-glucan synthase.16 It has been associated with fewer infusionrelated adverse events, is not nephrotoxic, and has not been associated with major drug-to-drug interactions involving cytochrome P450, as are triazole agents with anti-Aspergillus activity.17 Therefore, caspofungin
2
administered as monotherapy or in combination therapy can be considered as an alternative choice in patients who are unable to tolerate azole medications. Caspofungin is the first fungal (1→3)-β-D-glucan synthesis inhibitor approved by the US Food and Drug Administration that has activity against Candida and Aspergillus spp and has been shown to be a reasonable primary treatment of candidemia18 and other forms of invasive candidiasis,19 as well as salvage therapy for invasive Aspergillosis infection.20 In addition, it is recommended as empirical therapy for presumed fungal infections in febrile neutropenic patients.21 Caspofungin has been approved in China for about 10 years, but there is a lack of data from clinical practice on caspofungin treatment outcomes in patients in hospitals in China. In the present investigation, through a multicenter, observational, retrospective study of data from 10 hospitals, we analyzed the curative effectiveness of caspofungin in hematology patients with pulmonary IFD in China, focusing on caspofungin as the initial monotherapy or combination therapy and evaluating its usability in patients unable to tolerate azole medications.
PATIENTS AND METHODS This study was conducted according to the International Conference on Harmonisation guideline on Good Clinical Practice and the Declaration of Helsinki (2004). The protocol was approved by the ethics committees at the 10 participating study centers. Written informed consent was obtained from all of the patients before their participation in the study. The aim of this multicenter, observational, retrospective analysis was to estimate the curative effects of caspofungin in hematology patients with pulmonary IFD.
Inclusion Criteria In this study, data from the electronic medical records of 1118 inpatients between 2013 and 2014 who were admitted into 10 hospitals during a predefined period due to hematologic disorders were analyzed. Inclusion criteria for patients in the present study were: (1) age ≥16 years and at least 1 diagnostic criterion (hematologic malignancy [eg, acute leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma], aplastic anemia, or history of hematopoietic stem cell transplantation) during
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X. Zhang et al. hospitalization; (2) a diagnosis of IFD, based on Chinese clinical guidelines; (3) a diagnosis of at least 1 clinical sign and symptom of pulmonary involvement (new infiltrates or specific signs indicating fungal infection on CT imaging [eg, dense, well-circumscribed lesions with or without a halo sign, aircrescent sign, cavity], symptoms of lower respiratory tract infection [eg, cough, chest pain, hemoptysis, dyspnea], or a physical finding of pleural rub or pleural effusion); and (4) treatment with caspofungin, including monotherapy and combination therapy, for at least 7 days after having been diagnosed with an IFD.
indirect tests of fungal antigens (galactomannan test), β-D-glucan (G-test), and cryptococci, or Histoplasma capsulatum obtained from various samples. Depending on how many of the factors could be confirmed, patients' IFD was classified as proven or probable/possible.
Unclassified IFD Cases that did not meet the EORTC/MSG criteria but that had nonspecific imaging changes, were only antigen positive, or had only microbiologic evidence without clinical symptoms were classified as unclassified IFD.
Exclusion Criteria Patients who participated in any clinical trial involving antifungal therapy during the hospitalization who or received caspofungin monotherapy for antifungal prophylaxis were excluded.
IFD Diagnosis The diagnostic evidence of an IFD was collected according to the criteria from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG; 2008), including host, clinical, and microbiologic factors.22 According to a patient's medical history and EORTC/MSG 2008 criteria, cases were classified as proven, probable, or possible mold IFDs.
Proven or Probable/Possible IFD The host factors for IFD diagnosis included a recent history of neutropenia (neutropenic status at the time of antifungal therapy initiation/admission), prolonged use of corticosteroid, treatment with other recognized T-cell immunosuppressants (AIDS/HIV infection, immunosuppressive medication), and congenital severe immunodeficiency. Clinical factors for IFD diagnosis included symptoms of lower respiratory tract infection (cough, chest pain, hemoptysis, and/or dyspnea), physical findings (pleural rub, pleural effusion), and radiology findings (new infiltrates; dense, well-circumscribed lesions with or without a halo sign; air crescent sign; cavity on CT imaging). Microbiologic testing included cytology, direct microscopic examination, fungi culture and other
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Outcomes Assessment For outcomes analyses, treatments were classified as monotherapy or combination therapy, and as initial therapy, in which caspofungin was the first medication administered, or noninitial therapy, in which caspofungin was added to another medication or another medication was exchanged with caspofungin. The medications used in caspofungin combination therapies were voriconazole (38%), amB or amB liposome (14%), itraconazole (16%), fluconazole (5%), and micafungin (1%). Treatment response was classified as complete response, partial response, stable disease, or failure. Complete response was defined as the resolution of all attributable symptoms and signs of pulmonary infection and radiologic abnormalities; partial response was defined as a substantial reduction in attributable symptoms and signs of pulmonary infection and radiologic abnormalities (450%); stable disease was defined as minimal or no reduction in attributable symptoms and signs of pulmonary infection and radiologic abnormalities; and failure was defined as worsening of pretreatment signs and symptoms of pulmonary infection or radiologic abnormalities. Favorable response rate was a composite of complete and partial responses, and unfavorable response rate comprised stable disease, failures, and mortality from any cause. Treatment response was evaluated at the end of caspofungin treatment (at least 7 days). The primary end point of this study was the favorable response rate at the end of caspofungin as the initial therapy for proven and probable/possible pulmonary IFD. A secondary end point was the survival rate after the completion of caspofungin treatment.
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Clinical Therapeutics
Statistical Analysis All statistical analyses were performed with SAS software version 9.2 (SAS Institute Inc, Cary, North Carolina). The primary and secondary end points of this study were descriptive analyses (ie, frequency, percentages, or 95% CIs). Treatment response was evaluated by descriptive analysis according to the different subgroup factors (IFD type, response type). A multivariate model was established following a univariate analysis of factors having a P value of o0.05 or with significant clinical meaning (eg, duration of therapy) defined as influencing treatment response using a logistic regression model. P values of o0.05 were considered to be statistically significant.
RESULTS Baseline Demographic and Clinical Characteristics of the Patients Data from 1118 patients who received caspofungin were reviewed, and a total of 414 patients were excluded from the final analysis, as shown in the Figure. Data from 704 patients were included. There were more female 278 (39.5%) than male (60.5%) patients, and the mean age of all patients was 46.0 (16.2) years. Comorbidities were present in 306 of the patients (43.5%). The most frequent hematologic diseases were acute myeloid leukemia (42.8%), acute lymphatic leukemia (18.8%), and non-Hodgkin lymphoma (8.8%). The main reasons for Total patients from 10 hospitals
(N = 1118)
Excluded because of lacking inclusion criteria (N = 227)
hospitalization were chemotherapy in 246 patients (34.9%) and hematopoietic stem cell transplantation in 87 patients (12.4%). Among the 704 patients, 122 probable/possible IFD cases were diagnosed during hospitalization according to EORGC/MSG criteria, without any proven cases. There were no statistically significant differences between the subgroups with classified and unclassified cases with regard to basic characteristics (Table I). In these 122 patients, specific abnormal radiology imaging led to 25 probable and 97 possible IFD cases during hospitalization (Table I). Nonspecific radiologic findings were, however, also abnormal in 8 of the probable cases (32.0%) and in 27 of the possible IFD cases (27.8%). Of the unclassified IFD cases, 539 (92.6%) presented with nonspecific abnormal radiology images (data not shown).
Caspofungin Treatment Pattern In the present study, most of the patients received caspofungin monotherapy (321/704 [45.6%]) as initial treatment versus combination caspofungin therapy (76/704 [10.8%]). For noninitial caspofungin treatments, monotherapies were the majority (167 vs 140) (Table II). Prophylaxis with antifungal drugs other than caspofungin was provided in 120 of the 704 patients (17.1%), with the most frequently prescribed prophylactic agents being itraconazole (45 [37.5%]), fluconazole (35 [29.2%]) and voriconazole (25 [21.0%]), followed by micafungin (11 [9.2%]) and amB (4 [3.3%]). Most of this prophylactic medication was applied before caspofungin was used as the initial monotherapy (58 [48.3%]) or initial combination therapy (22 [18.3%]), as well as before caspofungin as noninitial combination therapy (22 [18.3%]) followed by caspofungin as noninitial monotherapy (18 [15.0%]) (data not shown).
891 patients
Excluded because of incompletely recorded data (N = 10) 881 patients
Excluded because of prematurely discontinued CAS therapies (N = 177) Enrolled 704 patients
Probable/possible IFD cases (N = 122)
Unclassified IFD cases (N = 582)
Figure. Flow chart of the study. CAS ¼ caspofungin; IFD ¼ invasive fungal disease.
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Caspofungin Treatment Duration in IFD Patients in the Total Group Including Probable/Possible Cases Caspofungin initial monotherapy or combination therapy was applied for mean durations of 18.1 (13.6) and 23.6 (13.3) days, respectively, whereas caspofungin as noninitial monotherapy or combination therapy was applied for mean durations of 16.7 (15.1) and 20.4 (14.6) days. The most common antifungal drugs administered before caspofungin therapy were voriconazole (50%–460%) and itraconazole (20%–30%) alone or in combination with amB or micafungin as
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Table I. Demography and baseline characteristics of the study patients. Variable Age, mean (SD), y Sex, no. (%) Female Male BMI, mean (SD), kg/m2 IFD diagnostic status, no. (%) Possible Probable Proven Comorbidities, no. (%) Cardiovascular disease Endocrine disease Liver disease Respiratory disease Renal disease Hematologic disease Acute myeloid leukemia Acute lymphatic leukemia Non-Hodgkin lymphoma Myelodysplastic syndrome Aplastic anemia Mild Moderate Severe Malignant melanoma Chronic myeloid leukemia Acute promyelocytic leukemia Chronic lymphatic leukemia Hodgkin disease Other Malignancy intervention, no. (%) HSCT Chemotherapy Other therapy Neutropenic status, no. (%) ANC (before therapy) o500 cells/mm3 Duration ≤7 d Duration 47 d 500–1000 cells/mm3 41000 cells/mm3 Isolated organisms Candida sp
All Patients (N ¼ 704) Classified (n ¼ 122) Unclassified (n ¼ 582) 46.0 (16.2)
45.9 (15.4)
46.1 (16.4)
278 (39.5) 426 (60.5) 62.9 (11.4)
52 (42.6) 70 (57.4) 24.7 (33.5)
226 (38.8) 356 (61.2) 18.9 (14.6)
– – –
97 (79.5) 25 (20.5) 0
– – –
(15.2) (8.4) (9.2) (6.0) (4.7)
15 (12.3) 9 (7.4) 14 (11.5) 6 (4.9) 7 (5.7)
92 (15.8) 61 (10.5) 55 (9.5) 37 (6.4) 27 (4.6)
301 (42.8) 132 (18.8) 62 (8.8) 55 (7.8) 50 (7.1) 15 (2.1) 4 (0.6) 31 (4.4) 47 (6.7) 17 (2.4) 15 (2.1) 3 (0.4) 2 (0.3) 20 (2.8)
57 25 15 3 8 2 2 4 8 1 3
(46.7) (20.5) (12.3) (2.5) (6.6) (1.6) (1.6) (3.3) (6.6) (0.8) (2.5) 0 1 (0.8) 1 (0.8)
244 (41.9) 107 (18.4) 47 (8.1) 52 (8.9) 42 (7.2) 13 (2.2) 2 (0.3) 27 (4.6) 39 (6.7) 16 (2.7) 12 (2.1) 3 (0.5) 1 (0.2) 19 (3.3)
87 (12.4) 246 (34.9) 371 (52.7)
10 (8.2) 52 (42.6) 60 (49.1)
77 (13.2) 194 (33.3) 311 (53.4)
107 59 65 42 33
P 0.942 0.436
0.064 –
0.326 0.298 0.494 0.546 0.607 0.165
0.086
0.006 264 (37.5) 130 (18.5) 134 (19.0) 70 (9.9) 366 (52.0)
61 (50.4) 35 (28.7) 26 (21.3) 8 (6.6) 52 (43.0)
203 (35.1) 95 (16.3) 108 (18.6) 62 (10.7) 314 (54.2)
–
11 (9.0)
–
– (continued)
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Clinical Therapeutics
Table I. (continued). Variable
All Patients (N ¼ 704) Classified (n ¼ 122) Unclassified (n ¼ 582) – –
Aspergillus sp Other
1 (0.8) 0
P
– –
ANC, absolute neutrophil count; BMI, body mass index; HSCT, hematopoietic stem cell transplantation; IFD ¼ invasive fungal disease.
monotherapies for 13.3 (12.6) days and as combination therapies for 11.9 (11.8) days (Table II). The primary reason for adding/switching to caspofungin was poor efficacy of other antifungal agents in 60% to 80% of cases, with different treatment patterns and adverse events/intolerability in 15% to 30% of cases.
Treatment Outcomes Favorable Treatment Response Rates in IFD Patients The favorable response rates with caspofungin as initial and noninitial monotherapy and combination therapy are shown in Table III. There was no
significant difference between probable/possible cases compared with unclassified IFD cases (58.2% vs 57.0%; P ¼ 0.90).
Factors Influencing Caspofungin Treatment Response–on Univariate and Multivariate Analyses The univariate analyses revealed that age had a negative influence on favorable response, whereas a greater age was seen as less favorable. An absolute neutrophil count (ANC) of o500 cells/mm3 resolved within or after 7 days and an ANC of 41000 cells/mm3 were associated with a greater likelihood of favorable
Table II. Caspofungin treatment duration in all included invasive fungal disease (IFD) cases and in probable/ possible cases. Data are given as mean (SD) duration (in days).
Patients All patients (N ¼ 704)
Probable/possible IFD cases (n ¼ 122)
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Caspofungin Therapy Type
Type of Medication
Initial (n ¼ 397) Monotherapy (n ¼ 321) Combination (n ¼ 76) Noninitial Monotherapy (n ¼ 307) (n ¼167) Combination (n ¼ 140) Initial (n ¼ 54) Monotherapy (n ¼ 45) Combination (n ¼ 9) Noninitial Monotherapy (n ¼ 68) (n ¼ 36) Combination (n ¼ 32)
Duration of Caspofungin Medication
Duration of Antifungals Before Caspofungin
18.1 (13.6) 23.6 (13.3) 16.7 (15.1)
13.3 (12.6)
20.4 (14.6)
11.9 (11.8)
16.1 (8.9) 26.9 (9.9) 16.5 (9.2)
13.7 (13.3)
23.4 (19.7)
9.3 (8.9)
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Table III. Favorable outcomes for probable/possible as well as unclassified cases of invasive fungal disease (IFD) in this study. Caspofungin as Initial Therapy Parameter All patients Monotherapy Combination therapy Probable/possible IFD Monotherapy Combination therapy Unclassified IFD Monotherapy Combination therapy
n 397 321 76 54 45 9 343 276 67
Favorable Response 229 190 39 31 28 3 198 162 36
(57.7) (59.2) (51.3) (57.4) (62.2) (33.3) (57.7) (58.7) (53.7)
response compared with an ANC of o500 cells/mm3 and not recovered during the study period. Caspofungin as noninitial combination therapy had a negative influence on favorable response compared with caspofungin as noninitial monotherapy (Table IV). The multivariate analysis revealed similar results, with age as a negative factor for achieving a favorable response, and non-recovery of ANC o1000 cells/mm3 during the study period was a highly significant negative factor for treatment response. Caspofungin as noninitial combination therapy had a negative influence on favorable response compared with caspofungin as noninitial monotherapy (P o 0.001). For caspofungin as initial combination therapy compared with caspofungin as noninitial monotherapy, the negative influence on favorable response failed to reach significance (P ¼ 0.05) (Table V). The overall survival rates after continuously using caspofungin for at least 7 days were 95.1% in the probable/possible cases (n ¼ 122) and 90.6% in all patients (N ¼ 704). The rates of mortality related to IFD were 2.5% in the probable/possible cases and 4.1% among all included patients (Table VI).
DISCUSSION This study of data from 10 hospitals in China included 704 patients with hematologic diseases prescribed caspofungin for at least 7 days for pulmonary IFD treatment. A total of 122 cases (17.3%) were diagnosed as probable/possible pulmonary IFD according to the
] 2017
Caspofungin as Noninitial Therapy n 307 167 140 68 36 32 239 131 108
Favorable Response 174 107 67 40 25 15 134 82 52
(56.7) (64.1) (47.9) (58.8) (69.4) (46.9) (56.1) (62.6) (48.1)
n 704 488 216 122 81 41 582 407 175
Total Favorable Response 403 297 106 71 53 18 332 244 88
(57.2) (60.9) (49.1) (58.2) (65.4) (43.9) (57.0) (60.0) (50.3)
EORTC/MSG criteria, whereas 582 were unclassified IFD cases. These data are in accordance with a previous report in which only 21.5% of onco-hematology patients treated with antifungal medication were classified as having proven/probable/possible IFD.4 Also, in another previous study that included 170 patients with chemotherapy-induced neutropenia or allogeneic stem cell recipients, more than half could not be classified as proven/probable/possible, whereas CT scans revealed pulmonary infiltrates in 62%, which was also an indicator for mortality. The investigators concluded that CT is more appropriate for diagnosing early fungal infections, given that more than half of the radiologic signs could not be matched by mycologic findings,23 which was also the case in our study, with only 9.8% of 122 classified patients being diagnosed using mycologic evidence. There were more female than male patients, and the mean age of all patients was 46.0 (16.2) years. In our study, the most frequent hematologic disease was acute myeloid leukemia (42.8%), which is in accordance with a previous study.1 The primary reasons for switching to caspofungin therapy in our study was poor efficacy of other antifungals in 60% to 80% of cases, and adverse events/intolerability in 15% to 30% of patients. In addition, noninitial combination therapy showed inferior outcomes compared with noninitial monotherapy, which might have been due to the severity of IFD, given that the use of combination therapies indicate a higher likelihood of severe disease.
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Clinical Therapeutics Table IV. Factors influencing a favorable response: univariate analysis (N ¼ 704). Variable
Coeff.
OR (95% CI)
P
Age Sex Hematologic disease (vs AML and MDS) All Other ANC status (vs o500 cells/mm3, ≤7d) o500 cells/mm3, 47 d ≥500 cells/mm3 ANC o1000 duration (vs not resolved) ≤7d 47 d 41000 cells/mm3 Caspofungin: type and use (vs noninitial monotherapy) Noninitial combination therapy Initial monotherapy Initial combination therapy Caspofungin therapy duration (≥14 d vs o14 d) Previous prophylaxis therapy status (yes vs no) Hematologic patients* (other vs HSCT)
–0.01 0.214
0.99 (0.98– 1.00) 1.24 (0.91–1.68)
0.05 0.17
0.12 0.34
1.13 (0.76–1.69) 1.41 (1.00–1.99)
0.55 0.05
–0.25 –0.08
0.78 (0.46–1.31) 0.93 (0.62–1.38)
0.35 0.71
0.95 0.64 0.66
2.57 (1.42–4.53) 1.89 (1.15–3.14) 1.92 (1.25–2.96)
o0.001 0.01 o0.001
–0.68 –0.22 –0.54 0.04 –0.24 0.11
0.51 0.80 0.58 1.05 0.79 1.12
o0.001 0.26 0.05 0.78 0.27 0.57
(0.32–0.81) (0.54–1.18) (0.34–1.01) (0.77–1.41) (0.52–1.20) (0.77–1.63)
MDS ¼ myelodysplastic syndrome. ANC ¼ absolute neutrophil count; AML ¼ acute myeloid leukemia; Coeff. ¼ coefficient, OR ¼ odds ratio. ⁎ Hematopoietic stem cell transplantation (HSCT): including HSCT, post-HSCT, and post-HSCT graft-versus-host disease.
The mean duration of caspofungin application as initial monotherapy was 16.1 days, which is somewhat longer than the 13 days24 and 14 days17 reported in comparable previous studies, but shorter than the 27 days reported by Viscoli et al.25 The favorable response rate with caspofungin treatment in hematology patients with IFD classified as probable or possible according to the EORTC/MSG criteria after initial monotherapy was 62.2% (28/45) in our study. This rate is similar to the 69% with monotherapy and 67% with combination therapies reported by Egerer et al in a recent study of pulmonary aspergillosis treatments of mainly patients with hematologic malignancy.26 However, our rate is somewhat higher than the 56.4% reported in an assessment of caspofungin in mainly patients with invasive pulmonary aspergillosis in clinical practice.27 Glasmacher et al28 reported similar findings (66%) with caspofungin monotherapies for IFD, but they included 118 patients in whom only 21 of the 35
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proven cases were pulmonary IFD and 19% of all cases comprised malignancies other than hematologic disease. The overall favorable response rate was 57.2%, which is higher than that from another study which compared caspofungin with liposomal AmB for empirical antifungal monotherapies in a cohort of 94.2% hematologic cancer cases, with overall favorable response rates of 33.9% and 33.7% with caspofungin and liposomal AmB medications, respectively, whereas successful treatment of baseline fungal infections was achieved in 51.9% of the caspofungin group versus 25.9% of the liposomal AmB group, but the investigators included only patients with persistent fever and neutropenia.24 Other studies noted favorable response rates with first-line caspofungin monotherapy for IFD of 42%29 and 33%,25 but the investigators included only patients with hematologic disease who received HSTCs. With regard to other antifungal therapies, a comparison of voriconazole
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X. Zhang et al. Table V. Factors influencing a favorable response: multivariate analysis (N ¼ 704). Variable
Coeff.
OR (95% CI)
P
Intercept Age Hematologic disease (vs AML and MDS) All Other ANC o1000 duration (vs not resolved) ≤7d 47 d 41000 cells/mm3 Caspofungin: type and use (vs noninitial monotherapy) Noninitial combination therapy Initial monotherapy Initial combination therapy Caspofungin therapy duration (≥14 d vs o14 d)
0.50 –0.01
– 0.99 (0.98–1.00)
0.17 0.02
–0.08 0.30
0.92 (0.60–1.41) 1.35 (0.93–1.95)
0.71 0.11
1.00 0.55 0.59
2.72 (1.44–5.13) 1.73 (1.04–2.89) 1.81 (1.16–2.81)
o0.001 0.04 0.01
–0.75 –0.21 –0.57 0.10
0.47 (0.29–0.76) 0.81 (0.54–1.21) 0.57 (0.32–1.00) 1.10 (0.80–1.52)
o0.001 0.31 0.05 0.54
MDS ¼ myelodysplastic syndrome. AML ¼ acute myeloid leukemia; ANC ¼ absolute neutrophil count; Coeff. ¼ coefficient; OR ¼ odds ratio.
and AmB treatments of mainly patients with hematological disease (84%) and patients with pulmonary IFD (87%) revealed that 52.8% of the patients in the initial voriconazole group and 31.6% in the initial AmB monotherapy group achieved a favorable response.12 The overall favorable response rate in patients with unclassified IFD in our study was 57.0%, which was not significantly different from that in the probable/
Table VI. Summary of overall survival. Parameter Overall survival (censored) Death Related to IFD Not related to IFD
Probable/Possible Cases (n ¼ 122)
All Patients (N ¼ 704)
116 (95.1)
640 (90.9)
6 (4.9) 3 (2.5)
64 (9.1) 29 (4.1)
3 (2.5)
35 (5.0)
IFD ¼ invasive fungal disease.
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possible cases. This finding indicates that, in a large percentage of patients with hematologic disease, IFD was not diagnosed by the EORTC/MSG criteria. The finding also underlines the importance of timely empirical medication, which was reflected in the relatively low overall rate of IFD-related mortality of 4.1% in our study. The mortality can be favorably compared to the 13.5% to 28.6%2,3 rates documented in previous reports, given that a 46-day delay in initiating treatment after diagnosis has been found to result in a 2-fold increase in mortality rate.7 The major factor for a favorable response to caspofungin treatment was recovery of neutropenia, which is in agreement with findings from previous studies.25,30–34 Prolonged neutropenia has been suggested to serve as a powerful indicator of the need for initiating empiric antifungal therapy in high-risk patients.35 Advanced age is another risk factor for unfavorable IFD treatment outcomes, which has also been noted in previous studies.3,31,36
CONCLUSIONS Our retrospective study of data from 10 hospitals in China revealed that the favorable caspofungin response rates with IFD treatment of hematology
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Clinical Therapeutics patients were 58.2% in 122 probable/possible cases and 57.0% in 582 unclassified cases. Caspofungin as initial monotherapy led to a favorable response rate of 62.2% in the probable/possible cases. Univariate and multivariate analyses revealed that none recovering neutropenia and advanced age were significant factors for unfavorable outcomes, with an IFD-related overall mortality rate of 4.1%. Caspofungin might be considered as more efficacious option than AmB for IFD treatment in refractory disease or intolerance in hematology patients.
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ACKNOWLEDGMENTS We thank the Peking University People's Hospital; Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Union Hospital, Tongji Medical College, Huazhong University of Science and Technology; The First Affiliated Hospital, Zhejiang University; The Affiliated Hospital, Sun Yat-sen University; Nanfang Hospital; Tianjin Medical University General Hospital; Institute of Hematology and Blood Diseases Hospital; Chinese Academy of Medical Sciences and Peking Union Medical College; Chinese PLA General Hospital; and The First Affiliated Hospital, Soochow University, for their participation in this study. Xiaohui Zhang, Xiaojun Huang contributed to study concept and design. Xiaohui Zhang, Jiong Hu, Yu Hu, He Huang, Jie Jin, Juan Li, Qifa Liu, Zonghong Shao, Jianxiang Wang, Quanshun Wang, Depei Wu, Xiaojun Huang contributed to acquisition of data. Xiaohui Zhang, Jiong Hu, Yu Hu contributed to analysis and interpretation of data. Xiaohui Zhang contributed to drafting of the manuscript. Xiaojun Huang contributed to critical revision of the manuscript for important intellectual content. Xiaojun Huang contributed to study supervision.
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CONFLICTS OF INTEREST This study was supported by Merck Sharp & Dohme (China) Ltd. The authors have indicated that they have no other conflicts of interest with regard to the content of this article.
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Address correspondence to: Xiaojun Huang, Department of Hematology, Peking University People's Hospital, No 11 Xizhimen South Street, Beijing 100044, China. E-mail: [email protected]
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