Annals of Oncology Advance Access originally published online on June 9, 2006
Annals of Oncology 2006 17(8):1306-1312; doi:10.1093/annonc/mdl128
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© 2006 European Society for Medical Oncology
Low-dose liposomal amphotericin B in the prevention of invasive fungal infections in patients with prolonged neutropenia: results from a randomized, single-center trial
1 Department of Hematology, Oncology, and Transfusion Medicine, 2 Department of Biostatistics and Clinical Epidemiology, Charité-Campus Benjamin Franklin, Berlin, Germany
* Correspondence to: Dr O. Penack, Hematology and Oncology, Campus Benjamin Franklin, Charité, Hindenburgdamm 30, D-12200 Berlin, Germany. Tel: +49-30-8445-2310; Fax: +49-30-8445-2361; E-mail: olaf.penack{at}charite.de
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Abstract |
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Background: We performed a prospective, randomized, open-label trial to evaluate the efficacy of low-dose liposomal amphotericin B (L-AmB) to reduce the incidence of invasive fungal infections (IFI) in patients with hematological malignancies and prolonged neutropenia (>10 days) following intensive chemotherapy.
Patients and methods: In 219 neutropenic episodes (NE) of 132 patients randomization was performed. Patients received either 50 mg L-AmB every other day (arm A) or no systemic antifungal prophylaxis (arm B).
Results: In the first NE of each patient the incidence of proven or probable IFI (primary end point) was five of 75 patients (6.7%) in arm A and 20 of 57 patients (35%) in arm B (P = 0.001). Invasive aspergillosis occurred less frequently in patients receiving L-AmB-prophylaxis (P = 0.0057), whereas the reduction of invasive candidiasis did not reach statistical significance (P = 0.0655). In all NE the incidence of IFI was five of 110 NE (4.6%) in arm A versus 22 of 109 NE (20.2%) in arm B (P <0.01). Adverse events, possibly related to L-AmB, were observed in five NE (4.6%) and L-AmB was discontinued in three NE (2.8%). No grade 3 or 4 toxicities were observed.
Conclusions: Antifungal prophylaxis with low-dose L-AmB proved to be feasible and effective in our trial.
Key words: prophylaxis, liposomal amphotericin B, fungal infection, neutropenia
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Patients with profound neutropenia following intensive cytotoxic therapy are at high risk for invasive fungal infections (IFI). Incidences of proven IFI are reported to be in a range between 3% and 30% [1
–5]. Mortality rates of patients with IFI remain high despite improved diagnostic tools and new antifungal drugs with enhanced efficacy being available. This provides a rationale for the prophylactic use of antifungal agents. In patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) antifungal prophylaxis not only reduces the incidence of IFI, but is also associated with an improved survival [6]. However, studies investigating antifungal prophylaxis in patients with autologous stem cell transplantation or intensive chemotherapy gave contradictory results and do not justify its general use [7–9]. Furthermore, it is yet unclear which antifungal agent might be an ideal candidate for prophylactic use. Lipid amphotericin B (L-AmB) based preparations appear to be promising due to their broad antifungal activity and low toxicity. Results of clinical and preclinical studies suggest that intermittent application of low-dose L-AmB may be effective and has a favorable toxicity profile [10–12]. Thus, we performed a prospective, randomized trial, which compares prophylaxis with intermittent low-dose L-AmB to no systemic prophylaxis in patients with hematological malignancies undergoing intensive chemotherapy. |
patients and methods |
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participants
All patients were enrolled and treated at the department of Hematology, Oncology and Transfusion Medicine, Charité-Campus Benjamin Franklin, Berlin. Adult patients (
18 years) with hematological malignancies, receiving chemotherapy likely to induce long-term neutropenia (neutrophil count, <500/mm3 for >10 days) or undergoing autologous HSCT were eligible. These patients could be included more than once, if no fungal infection was observed in the previous treatment period. The study was approved by the Ethical Committee of the Charité and written informed consent was obtained from each patient prior to study entry. Randomization was performed 1–3 days prior to the expected onset of neutropenia. Subjects were uneligible for inclusion, if they had evidence or history of probable or proven IFI. Other exclusion criteria were pneumonia, fever of unknown origin (FUO), hypersensitivity to polyene antifungal agents, allogeneic HSCT, renal insufficiency (GFR <70 ml/min) or liver dysfunction (bilirubin >50 µmol/l).
interventions
The study was a prospective, randomized, non-stratified and unblinded trial comparing intravenous (i.v.) L-AmB prophylaxis with no systemic antifungal prophylaxis during neutropenia. Patients received either 50 mg of L-AmB as a 1-h infusion every other day or no systemic antifungal therapy. Neutropenic episodes, not patients, were randomly assigned by a study nurse in a 1:1 ratio to arm A or arm B using a central computer system that was based in the documentation office of the department of hematology. Due to the procedure of randomization some patients were randomized more than once (for first and further neutropenic episodes; Figure 1). Systemic antifungal prophylaxis was continued until one of the following occurred: neutrophil count >0.5/nl after the nadir; development of proven, probable or possible IFI; more than 4 days of persistent fever of unknown origin (FUO), unacceptable drug toxicity or patient's decision.
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objectives
The objective of this trial was to assess the efficacy of L-AmB to reduce the incidence of proven and probable IFI compared with no systemic antifungal prophylaxis.
outcomes
The primary end point was failure of antifungal prophylaxis defined as occurrence of proven or probable IFI under prophylactic study treatment. Criteria used to define IFI were those of the Invasive Fungal Infections Cooperative Group of the European Organization for Research and Treatment of Cancer and the Infectious Diseases Mycosis Study Group of the National Institute of Allergy [13]. In brief there are three categories of invasive fungal infections: proven, probable and possible. The proven category consists of criteria that allow IFI to be diagnosed with certainty and that differentiates between deep-tissue infections and fungemia. For a case of IFI to be considered probable each of the three elements of host factor, clinical features and mycological evidence has to be present. By contrast, a patient who has at least one criterion from the host factors category but who does not have clinical features or mycological evidence can be classified only as possible (table online).
Superficial fungal infections were defined as clinically apparent infection of the upper gastrointestinal tract (oropharynx, esophagus) or skin along with positive cultures. Patients with superficial fungal infection continued to receive study treatment unless systemic antifungal treatment was given due to progression.
Pneumonia without identification of a causative organism, the use of systemic antifungal therapy other than the study treatment, occurrence of superficial fungal infections, FUO, mortality from any cause and mortality related to IFI were analyzed as secondary outcome variables. Fever was defined as a single oral temperature >38.3°C or two consecutive oral temperatures >38°C. Safety analyses included adverse events, results of clinical laboratory tests and vital signs.
supportive care and diagnostic procedures
According to the standard clinical protocol in our institution all patients received topical AmB four times daily plus antibacterial prophylaxis with 500 mg/day levofloxacin orally. Patients were examined daily for clinical signs of fungal infections. Surveillance cultures for fungal organisms (throat, urine, stool) were performed prior to the start of prophylaxis, once weekly thereafter and on completion of study therapy. The galactomannan aspergillus antigen ELISA (Platelia®, Bio-Rad, Paris, France) was performed in serum samples twice weekly and in broncheoalveolar fluid whenever available. The aspergillus antigen ELISA was considered to be positive when the optical density index exceeded 1.0 in two consecutive serum samples or once in bronchoalveolar fluid. Safety laboratory tests (e.g. whole blood count, serum creatinine) were performed at least every other day.
Two separate sets of blood cultures plus a urine culture were obtained in all patients who developed fever. A chest X-ray was performed 1–3 days prior to neutropenia and at onset of fever. In all patients with atypical infiltrates in the chest X-ray, high resolution CT-scan and bronchoscopy were performed. Patients without lung infiltrates but persisting fever despite broad spectrum antibiotic therapy underwent high resolution CT-scan within 5 days after the onset of fever.
Patients with neutropenia and FUO immediately received broad-spectrum antibiotics. Treatment success was re-evaluated after 3 days. In case of defervescence the regimen was continued for 7 days in total. In case of persistent fever antibacterial therapy was changed. A glycopeptide drug was added in patients with severe mucositis or suspected CVC infection. According to the study protocol, systemic antifungal treatment other than the scheduled study treatment was given in case of persistent fever after 4–6 days therapy with broad-spectrum antibiotics or when IFI (possible, probable or proven) occurred.
statistical analysis
All patients who received at least one dose of study drug were included in both the efficacy and safety analysis. Patients were followed until the end of fungal prophylaxis or death. The primary end point was the incidence of proven or probable fungal infections. External data review was not intended in the study planning. Two different analyses for efficacy were performed: in the first analysis, for each patient only the first episode was included. In the second analysis, all episodes were analyzed. Statistical dependency of different episodes from the same patient was adjusted by using generalized estimating equations (GEE) [14]. The level of significance was 0.05 (two-sided testing) for all statistical analyses. Calculations were performed using commercially (SPSSWIN 12.0) software, the calculations for GEE were performed using the software MAREG [15]. The planning of sample size was based on the following assumptions: infection rate without prophylaxis: 40%, with prophylaxis 20%, significance level 0.05 (two-sided), power: 80%. The sample size was determined using the software nquery, release 3.1. An interim analysis was planned after 20 patients in each arm had completed the first neutropenic episode. In the interim analysis we found no significant differences in mortality between the study arms. Study recruitment was continued because, according to the stopping rules, early trial termination was only planned in case of significant differences in overall mortality.
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results |
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patient characteristics
Between December 2002 and March 2005, 140 patients with 232 neutropenic episodes (NE) were enrolled. Efficacy evaluation was based on the intention-to-treat sample of 132 patients (219 NE) who underwent randomization 1–3 days prior to neutropenia. Eligible patients comprised 75 and 57 (110 versus 109 NE) in arm A and arm B, respectively. Reasons for exclusion are shown in the flow diagram (Figure 1). The treatment groups did not differ significantly in baseline demographic characteristics and risk factors for the development of IFI (Table 1).
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efficacy
Primary end point (Figure 2, Table 2)
By analyzing the first NE we found an IFI (proven or probable) in five of 75 patients (6.7%) in arm A and in 20 of 57 patients (35%) in arm B (P = 0.001). Prophylaxis with L-AmB reduced the incidence of invasive aspergillus infections (P = 0.0057), whereas statistical significance was not reached for reduction of invasive candidiasis (P = 0.0655). In all NE the incidence of IFI (proven or probable) was five of 110 NE (4.6%) in arm A compared with 22 of 109 NE (20.2%) in arm B (P <0.01).
Breakthrough infections (Table 3)
In the control arm, three cases of proven Aspergillus fumigatus pneumonia occurred. Diagnosis was based on autopsy (one case) and on in vivo lung biopsy (two cases). All patients with probable or proven invasive aspergillosis (12 cases) were treated with intravenous antifungals. However, three of these patients died due to respiratory insufficiency and one died due to fatal pulmonary hemorrhage. Proven invasive candidiasis occurred in five patients in the control arm (three C. tropicalis, one C. albicans and one C. glabrata). Diagnosis was based on autopsy (two) and positive blood culture results (three). In all cases of probable and proven invasive candidiasis (10) the central venous line was removed and antifungal therapy was given. However, fatal multiorgan failure occurred in four of these patients.
In the L-AmB arm, all proven IFI were ‘real breakthrough infections’ and patients were under continuous prophylaxis with L-AmB. Two cases of proven Aspergillus fumigatus pneumonia were documented in the prophylaxis arm. Diagnosis was made by bronchoscopy and by autopsy in one case each. One patient was successfully treated with voriconazole, the other unfortunately died due to progressive IFI and respiratory failure despite therapy with voriconazole. Three cases of proven candidemia occurred in the prophylaxis arm. In one patient who died due to fungal sepsis, Candida tropicalis was identified at autopsy. However, two patients with positive blood culture results (Candida albicans 1, Candida krusei 1) rapidly recovered after removal of the central venous line and start of systemic antifungal therapy with caspofungin.
Secondary end points (Table 2)
Pneumonia without identification of a causative pathogen occurred in six versus 28 NE in the prophylaxis arm and control arm, respectively (P < 0.001). The incidence of superficial fungal infections was also lower in the prophylaxis group (two versus 10, P = 0.03).
In the control group systemic antifungal therapy was given in 64 of 109 (58.7%) NE: Amphotericin B (seven), L-AmB at a dosage 1 mg/kg/daily (five), fluconazole (13), voriconazole (24), caspofungin (eight) and itraconazole (seven). Use of systemic antifungals in the L-AmB arm was considerably lower with 24 of 110 (21.8%) NE (P < 0.001): Amphotericin B (two), L-AmB (two), fluconazole (four), voriconazole (eight), caspofungin (three) and itraconazole (five). The rate of bacterial blood stream infections (eight versus eight) and the incidence of fever of unknown origin (30 versus 37) was not different between the study arms. Furthermore, we found a trend towards a reduction of overall mortality (four versus nine, P = 0.13) and mortality related to IFI (two versus eight, P = 0.07) in the patient group receiving L-AmB prophylaxis, but the overall mortality was only 5.9% at a median observation time of 17 days. Autopsy was performed in six patients (two in arm A versus four in arm B).
safety and toxicity
All NE in which at least one dose of study medication (L-AmB) was given were included for safety analysis (n = 110). A high incidence of laboratory abnormalities was to be expected in this group of neutropenic patients given the serious nature of their underlying disorders and concomitant medications, but no significant difference was found between treatment arm A and control arm B. In particular, there were no differences in the incidence of abnormal liver function tests, renal function parameters and hypokalemia. Treatment with L-AmB was tolerated well by most patients. However, study treatment was discontinued due to adverse events in 2.8% of NE in arm A: skin rash (n = 2) and infusion-related fever (n = 1). Adverse events including rash (n = 4), nausea (n = 3) and fever (n = 1) possibly related to study treatment occurred in 4.6% of NE. No grade 3 or 4 toxicities occurred, which were attributed to L-AmB administration.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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In this randomized trial, low-dose intravenous L-AmB reduced the incidence of IFI in high risk patients with hematological malignancies and prolonged neutropenia. Despite the short follow-up period, until the end of neutropenia, there was a trend towards a reduction of overall mortality and deaths caused by IFI in the prophylaxis group. Secondary efficacy variables, such as the incidence of pneumonia without identification of a causative pathogen, superficial fungal infections and empirical use of systemic antifungals were significantly lower in the L-AmB arm. However, the open trial design may have been biased towards a more frequent use of systemic antifungal therapy in the control arm. A further limitation of our trial could be a bias caused by the use of antifungal prophylaxis in the first NE on the incidence of IFI in the following NE. To address this issue we separately performed statistical analysis of the first NE of each patient and all NE and found that the incidence of IFI was equally reduced.
Our results contrast with some of the previous studies investigating antifungal prophylaxis in patients with hematologic malignancies failing to show a protection against IFI [16]. A possible explanation might be that the majority of studies evaluated fluconazole, itraconazole or amphotericin B deoxycholate and these drugs have some limitations. Prophylaxis with fluconazole is not active against Aspergillus spp., Candida krusei and Candida glabrata due to drug resistance or low susceptibility of these fungi. Itraconazole has in vitro activity against Aspergillus spp. compared to fluconazole. However, prophylactic use of itraconazole failed to reduce Aspergillus infections in randomized trials probably because of limitations in safety profile, wide variations of bioavailibility and various drug–drug interactions [2, 9, 17]. Conventional Amphotericin B has a broad antifungal spectrum, but causes relevant toxicity in 20%–100% of patients on antifungal prophylaxis [18–20]. L-AmB has a more favorable toxicity profile and most side-effects in the current trial were mild and no serious adverse events occurred. L-AmB prophylaxis was discontinued in only 2.8% of patients (two erythema, one infusion-related fever). We found no differences in nephrotoxicity between the treatment group and the control group. In previous trials using higher dosages of L-AmB, considerable liver toxicity was reported including reversible elevation of bilirubin and aminotransferase levels [21, 22]. In our trial we found no differences in liver function tests between the patient groups, indicating a negligible hepatotoxicity of intermittent low-dose L-AmB.
Reasons for our significant findings might be that we selected a patient population at very high risk for IFI, mostly patients with acute leukemia and prolonged neutropenia (median 15 days) and inclusion of elderly patients. Therefore, we observed a high incidence of proven and probable IFI in the control arm: 20.2% (7.3% proven) in all NE and 35% (14% proven) in the first NE of each patient. Possible reasons for the higher incidence of IFI in the first NE of each patient compared with further NE are: (1) the more intense induction chemotherapy compared with post remission chemotherapy; and (2) patients with IFI in the first NE were not eligible for inclusion in further NE. The high incidence of IFI in the control arm of our trial was stable during the study period (data not shown) and was not related to seasonal changes or to construction works. Importantly, the incidence of IFI in our trial (7.3%) is in line with previous trials investigating antifungal prophylaxis in comparable patient populations showing a 3%–30% incidence of proven IFI during neutropenia [2, 3, 5, 23].
In conclusion, we found that low-dose intravenous application of L-AmB is feasible and effective as antifungal prophylaxis in patients with hematological malignancies and prolonged neutropenia. However, our results do not justify the uncritical prophylactic use of antifungal agents because the observed benefit refers to the specific patient population at very high risk for IFI studied here.
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Acknowledgements |
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Research funding was obtained from Gilead Sciences, Martinsried, Germany.
Received for publication January 28, 2006. Revision received April 20, 2006. Accepted for publication April 27, 2006.
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References |
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