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Blood, Vol. 93 No. 11 (June 1), 1999:
pp. 3654-3661
Aerosolized Amphotericin B Inhalations as Prophylaxis of Invasive
Aspergillus Infections During Prolonged Neutropenia: Results of a
Prospective Randomized Multicenter Trial
By
S. Schwartz,
G. Behre,
V. Heinemann,
H. Wandt,
E. Schilling,
M. Arning,
A. Trittin,
W.V. Kern,
O. Boenisch,
D. Bosse,
K. Lenz,
W.D. Ludwig,
W. Hiddemann,
W. Siegert, and
J. Beyer
From the Department of Hematology and Oncology,
Universitätsklinikum Benjamin Franklin, Berlin, Germany; the
Department of Hematology and Oncology, Universitätsklinikum
Göttingen, Göttingen, Germany; the Department of Hematology
and Oncology, Klinikum Gro hadern der Universität
München, München, Germany; the Department of Hematology and
Oncology, Klinikum der Stadt Nürnberg, Nürnberg, Germany;
the Department of Hematology and Oncology, Städtisches Klinikum
Neukölln, Berlin, Germany; the Department of Hematology and
Oncology, Universitätsklinikum Düsseldorf,
Düsseldorf, Germany; the Department of Hematology and Oncology,
Universitätsklinikum Charité, Campus Charité, Berlin,
Germany; the Department of Hematology and Oncology,
Universitätsklinikum Ulm, Ulm, Germany; the Department of
Hematology and Oncology, Universitätsklinikum Charité,
Campus Virchow, Berlin, Germany; and the Department of Hematology and
Oncology, Universitätsklinikum Charité, Campus Buch,
Berlin, Germany.
 |
ABSTRACT |
We performed a prospective, randomized, multicenter trial to
evaluate the effectiveness of prophylactic inhalations with aerosolized amphotericin B (aeroAmB) to reduce the incidence of invasive
aspergillus (IA) infections in patients after chemotherapy or
autologous bone marrow transplantation and an expected duration of
neutropenia of at least 10 days. From March 1993 until April 1996, 382 patients with leukemias, relapsed high-grade non-Hodgkin lymphomas, or solid tumors were randomized with a 13:10 ratio to receive either prophylactic aeroAmB inhalations at a dose of 10 mg twice daily or no
inhalation prophylaxis in an unblinded fashion. The incidence of
proven, probable, or possible IA infections was 10 of 227 (4%) in
patients who received prophylactic aeroAmB. This did not differ significantly from the 11 of 155 (7%) incidence in patients who received no inhalation prophylaxis (P = .37). Moreover, no
differences in the overall mortality (13% v 10%; P
= .37) or in the infection-related mortality (8% v 7%;
P = .79) were found. In contrast to other nonrandomized
trials, we observed no benefit from prophylactic aeroAmB inhalations,
but the overall incidence of IA infections was low.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
INVASIVE ASPERGILLUS (IA) infections have
become an increasingly frequent and serious complication from prolonged
neutropenia after chemotherapy or bone marrow transplantation
(BMT).1-3 Yet, the incidence of IA infections in this
setting is highly variable, ranging from as low as 0% to as high as
25% or more, depending on the epidemiologic exposure to aspergilli,
the duration of neutropenia, and other individual risk
factors.1,2,4,5 Difficulties in establishing an early
clinical diagnosis, the poor response to antifungal treatment, and the
resulting high morbidity and mortality from IA infections prompted
widespread efforts to develop preventive strategies.6,7
Because IA infections are usually acquired by inhalation of aspergillus
conidia and because the lungs are the primary site of infection in the
majority of patients, we investigated aerosolized amphotericin B
(aeroAmB) as prophylaxis of IA infections in a prospective randomized
multicenter trial in patients with hematologic malignancies or solid
tumors and an expected duration of neutropenia of at least 10 days.
| |
PATIENTS AND METHODS |
Study design.
Between March 1993 and April 1996, 382 patients were entered in a
prospective randomized multicenter trial at 11 participating centers
throughout Germany. Patients were randomized into two arms of the trial
to receive either prophylactic inhalations with aeroAmB (group A) or no
inhalation prophylaxis (group B) in an unblinded fashion
(Fig 1). Results from a preliminary interim analysis that would have allowed us to stop the trial early have already been reported.8 However, because none of the
predefined stopping rules was fulfilled in the initial 115 patients,
the trial continued to recruit to its full calculated sample size. The
study was approved by local ethics committees at each participating center and conducted according to the guidelines established by the
Declaration of Helsinki. Eligibility criteria were as follows: (1)
patients scheduled to receive intensive chemotherapy with an expected
duration of neutropenia less than 0.5/nL for at least 10 days because
of either de novo or relapsed acute myeloid leukemia (AML), high-risk
myelodysplasia (MDS), chronic myeloid leukemia (CML) in blast crisis,
high-risk de novo or relapsed acute lymphocytic leukemia (ALL), or
relapsed high-grade non-Hodgkin's lymphoma (NHL), or patients with
solid tumors undergoing high-dose chemotherapy with autologous BMT
(auto-BMT); (2) age greater than 18 years; (3) a Karnofsky index
greater than 50%; and (4) written informed consent. Patients were
excluded from the trial if one or more of the following criteria was
fulfilled: (1) patients with a history of a proven, probable, or
possible invasive aspergillus infection during any preceding
neutropenic episode; (2) treatment with intravenous amphotericin B
(AmB) or oral itraconazol during the previous 3 months; (3)
concurrent or planned prophylaxis with intravenous AmB or
itraconazol; (4) pulmonary infiltrates at the time of randomization; or
(5) prior participation in the trial. All patients were required to be
nursed in rooms without high-particulate air filtration.
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| Fig 1.
(#) Randomization was stratified according to treatment
center and three disease categories. (§) Inhalation prophylaxis was
scheduled to begin before the onset of neutropenia at a dose of 2 × 10 mg aerosol AmB daily until one of four observation endpoints was
reached: (1) recovery of neutropenia to greater than 1.0/nL for more
than 2 consecutive days; (2) day +50 after randomization in patients
without recovery of the neutrophil count to greater than 1.0/nL; (3)
stable neutrophil counts for at least 1 week in patients without
neutropenia less than 0.5/nL; or (4) death during the trial period. IA
= proven, probable, or possible IA.
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Randomization was performed by computer-generated random numbers in
sealed envelopes and permuted blocks of 10 in a 13:10 ratio in favor of
group A, because we anticipated approximately 30% premature
discontinuations of the prophylactic inhalations.9 Envelopes were opened for each consecutive patient either at the coordinating center or at one of the participating centers after checking all of the inclusion and exclusion criteria. Randomization was
stratified according to treatment center and the following three
groups: (1) AML, high-risk MDS, and CML blast crisis; (2) high-risk de
novo or relapsed ALL and relapsed NHL; and (3) solid tumors undergoing
auto-BMT. Randomization was scheduled to be performed immediately
before the initiation of antineoplastic chemotherapy, ie, before the
onset of neutropenia less than 0.5/nL. However, patients who were
neutropenic at the time of initiation of chemotherapy could also be
randomized. Each patient entered the trial only once for a single
neutropenic episode.
The trial period started with the random assignment of patients into
one of the two arms of the trial and ended with one of the four
predefined trial endpoints, whichever occurred first: (1) recovery of
the neutrophil count to greater than 1.0/nL for more than 2 consecutive
days; (2) day +50 after randomization in patients without recovery of
the neutrophil count to greater than 1.0/nL; (3) stable neutrophil
counts for at least 1 week in patients without neutropenia less than
0.5/nL; or (4) death during the trial period. All surviving patients
were observed for at least 2 more weeks after one of the trial
endpoints was reached.
The primary outcome variable was the cumulative incidence of proven,
probable, or possible invasive aspergillus infections in each trial
arm. Secondary outcome variables were incidence of fever refractory to
antibiotic treatment, frequency and cumulative doses of intravenous
AmB, overall and infection-related mortality in each trial arm, side
effects of the prophylactic inhalations with aeroAmB as well as
frequency, and causes of premature discontinuation of the allocated
treatments. Overall incidence, type, and localization of all fungal and
bacterial infections were also documented. To assure the quality of the
data collection, charts and radiologic films of all patients were
reviewed by one of the three principal investigators (J.B., S.S., or
G.B.). In reviewing the source data, defining the trial endpoints, and
analyzing the trial results, identical criteria were applied for all
patients. No particular attention was given as to the randomization
status of an individual patient. However, no formal attempt was made to
blind for this information.
Interventions and treatments.
Overall, 227 patients were randomly assigned to group A and scheduled
to receive prophylactic inhalations with aeroAmB at a dose of 10 mg AmB
twice daily, starting with the day of randomization until one of the
study endpoints was reached. Further continuation with prophylactic
aeroAmB was optional in patients of group A when intravenous AmB
treatment was started. For each inhalation, 10 mg of AmB for
intravenous use (Bristol Myers Squibb, Munich, Germany) was diluted
with sterile water to a total volume of 5 mL. Only three devices were
allowed for nebulizing AmB: RespirGard II (Marquest, Englewood, CO) and
PariBoy or Pari IS II (both Pari Werke, Starnberg, Germany). All three
devices had been previously shown to generate particles that would
allow alveolar as well as tracheal and nasopharyngeal deposition of
AmB.10 The RespirGard II nebulizer was driven either by a
bedside compressor (Lifetec jetair 10; Salvia, Schwalbach, Germany) or
by pressured oxygen from hospital supplies with a pressure of at least
2 × 105 Pa. PariBoy and Pari IS II nebulizers were
driven by their corresponding compressors, which were provided by the
manufacturer (Pari Werke). Each inhalation lasted for about 15 to 20 minutes and each nebulizer was only used twice to avoid bacterial
contamination. The 155 patients of group B were scheduled to receive no
inhalation prophylaxis.
Definitions.
Proven invasive aspergillosis was defined as histologic evidence of
invasive aspergillus infection with or without cultural evidence of the
invading pathogen. Probable invasive aspergillosis was defined as
pneumonia or any other organ infection unresponsive to antibiotic
treatment with no other microbiologically documented causative organism
and at least one of the following criteria: (1) aspergillus cultured
from normally sterile tissues, bronchoalveolar lavage, blood, sputum,
or nose; (2) repeated positive serological testing; or (3) pulmonary
lesion with a halo sign in computed tomography (CT) scans or an air
crescent sign. Possible invasive aspergillosis was defined as fever
unresponsive to antibiotic treatment with no other microbiologically
documented causative organism and at least one of the following
criteria: (1) aspergillus cultured of normally sterile tissues,
bronchoalveolar lavage, blood, sputum, or nose; or (2) repeated
positive serological testing. Serological testing was performed using
the commercially available Pastorex latex agglutination test (Sanofi
Diagnostics Pasteur, Marnes-La-Coquette, France) for detection of
aspergillus galactomannan.11 Serological
testing would have also been considered positive in patients with
increasing antibody titers in at least two consecutive serum samples.
Infections were otherwise classified in either bacteremia/fungemia,
other microbiologically documented infections, clinically documented
infections, fever of unknown origin, and no evidence of
infection.12 Pneumonia was diagnosed clinically in any
febrile patient by typical auscultation findings or radiologic
infiltrates on chest x-rays or CT scans. Infiltrates were classified as
interstitial or focal, and only focal lesions with an air crescent sign
or a halo sign were considered to be suggestive of IA infections.
Fever was defined as a single oral temperature of greater than
38.5°C or two consecutive oral temperatures of greater than 38°C. Fever refractory to antibiotic treatment was defined as persisting fever despite broad spectrum intravenous antibiotics for
more than 5 days, which included a nonresponse to at least one
modification of the initial antibacterial regimen.
Supportive care.
All patients were hospitalized and reverse isolation measures were
instituted during periods of neutropenia less than 0.5/nL. Antibacterial prophylaxis was performed at the discretion of each participating center. If performed, antibacterial prophylaxis consisted
of oral cotrimoxazole or a quinolone. Patients were allowed to receive
prophylactic oral amphotericin B, fluconazole, or both as prophylaxis
of candida infections, because no influence of these drugs on the
incidence of IA infections was anticipated. However, with the
intravenous administration of AmB, prophylactic fluconazole was
stopped. Antiviral prophylaxis with acyclovir was allowed, but was not
routinely administered.
Empiric antibiotic treatment was initiated in febrile patients
according to published guidelines.13 A broad spectrum
penicillin or a third-generation cephalosporin in combination with an
aminoglycoside was used as initial treatment. Alternatively, a
combination of two broad spectrum -lactam drugs or single-agent
carbapenem was also allowed. In patients who remained febrile after 3 days, a glycopeptide drug was added. The empiric antibiotic treatment was modified according to clinical or microbiological findings. After a
minimum of 5 days with fever unresponsive to antibiotic treatment,
empiric intravenous AmB was initiated at a minimum dose of 0.5 mg/kg
and continued at least until neutrophil recovery. Because of an
anticipated high incidence of fungal infections, empiric intravenous
AmB was also started in patients with clinical or radiological evidence
of pneumonia.14
Diagnostic procedures included daily clinical evaluations as well as
conventional chest x-rays of the lungs, blood cultures, and serologic
testing for fungal pathogens at the time when fever first developed. In
patients with pulmonary infiltrates on conventional films, CT scans of
the thorax were recommended, preferably using the high-resolution
technique. In these patients, x-rays of the sinuses, microbiologic
examination of sputum, and serologic testing for fungal pathogens were
also indicated. Bronchoalveolar lavage was performed if it was
considered safe for an individual patient by the local investigator.
Other diagnostic procedures were performed as clinically indicated.
Surveillance with weekly chest x-rays and microbiologic examination of
sputum and swabs from the nose and pharynx were recommended.
Statistical methods.
The analysis of the trial was planned and performed on an
intention-to-treat basis. Therefore, all patients were analyzed in the
trial arm to which they were initially randomized, regardless of
whether they received the allocated prophylaxis or discontinued the
allocated prophylaxis prematurely and irrespective of the trial
endpoint that was reached. The primary outcome variable on which the
sample size calculation was based was the cumulative incidence of
proven, probable, or possible IA infections in each arm of the trial.
Based on the results of the pilot study for this trial, a cumulative
incidence of 1% was anticipated in group A with prophylactic
inhalations; in group B, without the prophylactic inhalations, a
cumulative incidence of 10% was anticipated, for an overall difference
of 9% between the two arms.9 With these figures and an
 -error of 5% and a -error of 10%, the minimal sample size was
calculated to be at least 165 patients per arm. Because a rate of 30%
premature discontinuations of prophylactic aeroAmB was expected from
the pilot study, 50 additional patients were randomized to group A for
an overall sample size of 380 patients and a ratio of 13:10 (215 patients in group A with prophylactic inhalations and 165 patients in
group B without prophylactic inhalations).9 To detect
unexpected side effects of the prophylactic inhalations and to stop the
trial early in case of unequivocal efficacy of aeroAmB, one interim
analysis was performed after one third of patients in each arm were recruited.
Data were analyzed using the Prism (GraphPad, San Diego, CA)
statistical software. The  2 test was used for
differences in categorical variables with the Yates correction whenever
applicable. For continuous variables, the Student's t-test or
the Mann-Whitney U-test was used. Time-dependent variables were
compared using the log-rank test on Kaplan-Meier estimates. All
differences between the trial arms were tested two-sided and considered
significant if their probabilities were less than 1% in the interim
analysis and less than 4% in the final analysis for an overall
two-sided significance level of P < .05.
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RESULTS |
Patient characteristics and study endpoints.
Figure 1 summarizes the trial design. Details of the patient
characteristics are shown in Table 1. With
the stratified randomization, the disease entities and consequently the
duration of neutropenia were well balanced between the two groups
(Fig 2). More than 70% of the study
population were patients with de novo or relapsed AML, because we
stopped recruiting auto-BMT patients with the increasing use of
peripheral blood stem cells and the resulting shorter periods of
neutropenia. Other potential confounding factors for the development of
IA infections, such as age, steroid comedication, and building
reconstruction activity in vicinity to study patients, were also
equally distributed. However, hematopoietic growth factors were used
more frequently in group A with prophylactic aeroAmB inhalations as
compared with group B.
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| Fig 2.
Distribution of the duration of neutropenia in patients
of group A with prophylactic inhalations ( ) and group B without
prophylactic inhalations ( ). For patients with proven, probable, or
possible IA, the number of neutropenic days until an IA infection was
suspected or proven are marked with squares ([ ] in group A and
[ ] in group B).
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No differences in the study endpoints were found between group A and
group B. Although a minority of patients in each group did not become
neutropenic, the majority of patients in both groups developed
significant neutropenia at a median of 19 days in group A and 21 days
in group B (P = .84; Fig 2). About 12% of the patients in each
group did not even recover with their neutrophil count until the
maximal study period of 50 days after randomization (Table 1). There
were 4% inadequate inclusions in each group, ie, disease entities not
covered by the inclusion criteria (n = 6), chemotherapy regimens used
without an expected neutropenia less than 0.5/nL (n = 7), and a
pulmonary infiltrate at randomization (n = 1). However, because all of
these patients were randomized, they were included in the final
analysis of the trial.
Primary and secondary outcome variables.
The overall incidence of proven, probable, or possible IA infections
was 21 of 382 (5%). There was no statistical difference in the
cumulative incidences of proven, probable, and possible IA infections
between the two trial arms. The incidence of IA infections was 10 of
227 (4%) in group A in patients with prophylactic inhalations and 11 of 155 (7%) in group B in patients without prophylactic inhalations
(P = .37; Table 2). Repeated
positive aspergillus antigen testing contributed to the diagnosis of an IA in 2 patients (UPN 79 and UPN 305) who were classified as having possible infections. Among 71 patients of group A who discontinued the
inhalation prophylaxis prematurely, 5 of 71 (7%) developed a proven (n = 3) or probable (n = 2) IA infection. Three patients of group B
started aeroAmB inhalations in violation of their randomized assignment. Thus, when the analysis was limited to patients who continued with their allocated treatments throughout the trial, 5 of
156 (3%) patients of group A and 10 of 152 (7%) patients of group B
developed a proven, probable, or possible IA infection (P = .27). Details of all 21 patients who developed a proven, probable, or
possible IA infection are shown in Table 3.
Among the secondary outcome variables, there were also no statistical
differences between the two trial arms, despite a trend to less fever
refractory to antibiotic treatment (25% v 32%; P = .16), fewer patients who required intravenous AmB (32% v 40%; P = .11), and a lower mean cumulative dose of AmB (860 v 1,068 mg; P = .16) in favor of group A with
prophylactic inhalations (Table 4). The
overall mortality in the trial was 45 of 382 (12%); the
infection-related mortality was 30 of 382 (8%) with no statistically significant differences between the two trial arms. Noninfectious causes, bacterial infections, and fungal infections each accounted for
approximately one third of the deaths that occurred during or within 14 days of the trial period (Table 4). Only 5 of 382 (1%) patients died
due to IA infections. Therefore, the early mortality was only 5 of 21 (24%) among patients who developed an IA infection.
The overall incidence of infections was as expected in patients with
hematologic malignancies and prolonged neutropenia. The rates of fever
of unknown origin (38% v 37%; P = .89), bacteremia or
fungemia (14% v 11%; P = .54), other
microbiologically documented infections (16% v 17%; P = .79), clinically documented infections (20% v 28%;
P = .08), and no evidence of infection (13% v 7%, P = .10) were not significantly different between group A and group B.
Despite initial concerns about a possible increase of bacterial
pneumonias or sepsis as a result of contaminated inhalation equipments
in group A, the incidence of microbiologically documented pneumonias
(8% v 10%; P = .56) and gram-negative bacteremias
(6% v 9%; P = .60) did not differ between the two
arms of the trial. The overall incidence of pneumonias with or without
microbiologic confirmation was even lower in group A as compared with
group B (19% v 30%; relative risk, .86; 95% confidence
interval, 0.77 to 0.98; P < .02).
Risk factors of IA infections.
The duration of neutropenia before the diagnosis of an IA infection was
not different in 10 patients of group A with prophylactic inhalations
as compared with 11 patients of group B without prophylactic inhalations, with medians of 14 and 15 days, respectively (P = .51 by the log-rank test). Unexpectedly, the incidence rates of IA
infections also did not differ significantly between the three major
disease entities: 15 of 283 (5%) in AML/MDS/CML, 2 of 35 (6%) in
ALL/NHL, and 4 of 64 (6%) in auto-BMT. However, there was a wide local
variation in the incidence of IA infections. Despite comparable
durations of neutropenia, three centers that included 43% of the
patients reported 81% of all IA infections (relative risk, 1.10; 95%
confidence interval, 1.04 to 1.16; P < .003 for the
comparison of these 3 centers with all other centers), corresponding to
incidence rates at the participating centers ranging from 0% to 19%.
Patients with IA infections had longer durations of neutropenia less
than 0.5/nL, with a mean of 27 days (range, 6 to 50 days) as compared
with patients without IA infections, with a mean of 22 days (range, 0 to 50 days; P = .07). Other potential risk factors, such as
pre-existing neutropenia at the time of randomization, concomitant use
of corticosteroids, cytokine administration, and even building
reconstruction activity reported by individual centers, had no obvious
influence on the incidence of IA infections.
Side effects and premature discontinuation of prophylactic aeroAmB.
Although no serious side effects occurred, about two thirds of patients
reported some form of unpleasant sensation. In patient questionnaires,
cough was graded as absent, mild, moderate, or severe by 57%, 29%,
7%, and 7% of patients, respectively. Bad taste was graded as absent
by 48%, mild by 28%, moderate by 18%, and severe by 6% of patients.
Nausea was graded as absent by 62%, mild by 21%, moderate by 9%, and
severe by 8% of patients. Other side effects, such as dizziness or
tightness of the chest, were mentioned infrequently. No systemic side
effects and no infections could be attributed to the prophylactic
aeroAmB inhalations.
As anticipated from pilot studies, 71 of 227 (31%) patients of group A
discontinued prophylactic aeroAmB inhalations prematurely after a
median of 6 days (range, 0 to 27 days).9 The reasons for
premature discontinuation were side effects of the inhalations in 55%,
inability to further cooperate in 30%, violation of the study protocol
in 11%, and noncompliance in 4% of patients, respectively.
| |
DISCUSSION |
Numerous strategies to prevent IA infections have been reported,
including prophylactic intranasal application of AmB sprays, low or
even therapeutic doses of prophylactic intravenous AmB desoxycholate or
AmB in liposomal preparations, as well as prophylactic oral
itraconazol.6,7,15-20 Many of these strategies have been reported as clinically effective.15,16,22,24 However, with the large variation in the incidence rates of IA infections even within
the same institution, the level of evidence from these retrospective
analyses in favor of the prophylaxis is low. The few trials that
investigated prophylaxis of IA infections prospectively failed to
demonstrate a benefit of any of these strategies.19-21 AmB
aerosol inhalations may also prevent IA infections according to several
retrospective analyses and uncontrolled trials and are generally
considered safe for application in neutropenic
patients.9,22-25 Reductions in the incidence rates of more
than 10% have been reported in patients who received prophylactic AmB
aerosols as compared with historical controls.22 AmB
aerosol particles are of the same size and should ideally travel the
same routes as aspergillus conidia that are readily inhaled and cause
IA infections in susceptible individuals.9,10 Therefore,
this form of prophylaxis seemed particularly attractive in patients
with prolonged neutropenia.
Over a period of 3 years, we recruited and randomly assigned 382 patients to receive either prophylactic inhalations with 10 mg of
aeroAmB twice daily or no inhalation prophylaxis. A neutropenic period
of 10 days or more has been reported to be associated with a high
incidence of IA infections and was chosen as the entry criteria for the
trial.4,26 Patients with a history of a proven, probable,
or possible IA infection as well as those with pulmonary infiltrates at
the time of randomization were excluded from the trial, because aeroAmB
was not expected to be effective as secondary prophylaxis or as
treatment of established IA infections. At present, therapeutic doses
of intravenous AmB are recommended in those patients.18 To
define a homogenous study population, we also excluded patients
scheduled for allogeneic BMT for whom many confounding risk factors
apart from neutropenia would have been present.5,17 An
interim analysis that would have allowed us to stop the trial early was
performed and published previously.8 Because no unexpected toxicity was observed and no unequivocal efficacy could be demonstrated after recruitment of the initial 115 patients, the trial continued to
its full calculated sample size. Characteristics of patients and
conduct of the trial did not change after the results of the interim
analysis became available.
The majority of patients developed significant neutropenia predisposing
them for the development of IA infections. The duration of neutropenia
as well as the distribution of other potential risk factors for IA
infections did not differ between the two arms of the trial. Similarly,
as a result of the stratification, approximately equal proportions of
patients at each center were randomized to receive prophylactic
inhalations or no inhalation prophylaxis. Hematopoietic growth factors
were more frequently used in patients who received prophylaxis with
aeroAmB, but because we did not stratify randomization according to
this variable, this difference might have occurred by chance alone.
Generally, these agents were used as part of the routine supportive
care during the trial rather than as treatment of suspected or proven IA infections. Because the duration of neutropenia did not differ between the two arms of the trial, we do not expect this imbalance to
be relevant to the incidence of IA infections. Yet, some of the
secondary outcome variables in the trial, such as the use of
intravenous AmB or the resolution of fever, might have been influenced
by this fact.
The optimal strategy to diagnose IA infections remains controversial.
Whereas histologic evidence of an invasive infection in combination
with a positive aspergillus culture is required to prove an IA
infection, such a high level of evidence can rarely be achieved
clinically. Indirect evidence for an IA infection can be obtained using
clinical, radiologic, histologic, cultural, and serologic information,
but particularly the usefulness of serologic tests has been debated.
The primary outcome measure in the trial was the overall incidence of
proven, probable, or possible IA infections. These detailed and
predefined categories were constructed to integrate all available
information and at the same time reflected the level of evidence in
favor of the diagnosis of an IA infection. This allowed us to measure
the effect of prophylactic aeroAmB according to very strict or less
stringent outcome criteria.
We observed no statistically significant differences in the incidence
of proven, probable, or possible IA infections in patients with or
without prophylactic aeroAmB inhalations irrespective of whether we
analyzed all randomized patients or only those who were fully compliant
with the inhalation prophylaxis. The 4% incidence of IA infections in
patients with aeroAmB prophylaxis was greater than anticipated.
Likewise, the 7% incidence of IA infections in patients without
aeroAmB prophylaxis was less than anticipated and equal to the 7%
incidence in patients who discontinued aeroAmB prophylaxis prematurely.
One patient who was fully compliant with the aeroAmB prophylaxis
developed a proven IA infection as well as 3 patients who discontinued
the prophylaxis prematurely after 1 and 8 days, respectively. The
differences in the incidence rates of IA infections that we observed in
the present trial might represent a more accurate estimation of the
incidence of IA infections in a population of neutropenic patients as
compared with previous reports. Institutional and temporal clustering
of IA infections, the lack of a prospective control group, and
publication bias might have previously contributed to an overestimate
of IA infections in patients without inhalation prophylaxis as well as
to an underestimate of their incidence in patients with inhalation prophylaxis.
Although there was a trend to less fever refractory to antibiotic
treatment and less use of intravenous AmB in patients who received
prophylaxis with aeroAmB as compared with those who did not, none of
these differences was either statistically significant or clinically
relevant. The mortality rates from all causes combined, as well as
those from bacterial or fungal infections, were equal in both arms of
the trial. Fungal infections combined accounted for about one third of
all deaths that occurred during or within 14 days of the study period.
The early mortality from IA infections was 24%, which is substantially
lower than reported in the literature.3,27 The exclusion of
some high-risk groups (ie, patients after allogeneic BMT), the greater
awareness for IA infections in the present trial, the fact that most
patients with IA infections recovered with their neutrophil counts, as
well as better and more aggressive treatments might have contributed to
the low early mortality from IA infections in the present
trial.27,28
Side effects from the inhalations were reported by about two thirds of
patients. Although most of these side effects were mild and no serious
side effects or an increased incidence of bacterial infections could be
attributed to the prophylactic inhalations, 31% of patients
discontinued aeroAmB inhalations prematurely. Moreover, 30% of
patients who discontinued the prophylaxis prematurely did so because
they were too ill to continue with the inhalations. In these patients,
systemic rather than topical prophylaxis of IA would clearly be desirable.
Several conclusions can be drawn from this final analysis and extend
the conclusions from the interim analysis of the trial. IA infections
remain a significant cause of morbidity and mortality in patients with
prolonged neutropenia. Apart from the early mortality, delays in the
antileukemic treatment and reactivation of IA infections during
repetitive periods of neutropenia or after allogeneic BMT may all lead
to an inferior overall treatment outcome in patients with IA infections
that was not studied in the present trial. The incidence rates of IA
infections varied widely among participating centers. This fact must be
considered in the design of future trials as well as in the decision of
whether it is worthwhile to explore prophylaxis of IA infections at an
individual center. Although we could demonstrate that prophylactic
aeroAmB inhalations do not completely eliminate the risk of IA
infections during prolonged neutropenia, we cannot exclude the
possibility that they might reduce the frequency of such infections.
Given the low incidence rates and size of the present trial, we only
had a 20% power to detect even a 50% reduction of IA infections using
aeroAmB inhalations; conversely, to prove with a power of 90% that the
differences found in the present trial did not just occur by chance, a
sample size of more than 1,000 patients per arm would have been
required. Prophylactic aeroAmB inhalations should therefore be
studied and indeed might be effectivein patients at an even higher
risk for the development of IA infections, ie, after allogeneic BMT or during local epidemiologic outbreaks. The results of the present trial
are limited to patients with neutropenia as their single or at least predominant risk factor for the development of IA infections and cannot be generalized to other patient populations. Because of acute or chronic graft-versus-host disease,
immunosuppressive treatment, and other factors, many patients after
allogeneic BMT are at continued risk for the development of IA
infections despite recovery from neutropenia and might profit from
prolonged administration of aeroAmB. Also, aerosolized lipid
formulations of AmB have been successfully used as prophylaxis of IA
infections in animal models. Such preparations might be considered in
future trials. However, it is most important that any trial involving
topical as well as systemic prophylaxis of IA infections should be
performed prospectively with well-defined clinical outcome variables,
as proposed for the present trial, and should consider the highly
variable incidence rates of IA infections.
| |
ACKNOWLEDGMENT |
Investigators of the Departments of Hematology and Oncology from the
following institutions in Germany contributed to the trial: Klinikum
Rudolf Virchow (Berlin, Germany): J. Beyer, O. Boenisch, M. Ruhnke, K. Lenz, W. Siegert, and D. Huhn; Universitätsklinikum Benjamin
Franklin (Berlin, Germany): S. Schwartz and E. Thiel; Universitätsklinikum Göttingen (Göttingen, Germany):
G. Behre, W. Treder, B. Wörmann, and W. Hiddemann; Klinikum
Grohadern der Universität München (München,
Germany): S. Bercht, D. Bosse, V. Heinemann, U. Jehn, and W. Wilmanns;
Klinikum der Stadt Nürnberg (Nürnberg, Germany): R. Roidl
and H. Wandt; Städtisches Klinikum Neukölln (Berlin,
Germany): A. Grüneisen, B. Krause, E. Schilling, and C.A. Mayr;
Medizinische Hochschule Hannover (Hannover, Germany): U. Paaz and H. Link; Robert Rössle Klinik (Berlin, Germany): F. Weber and W.-D.
Ludwig; Universitätsklinikum Charité (Berlin, Germany): A. Trittin, G. Massenkeil, and K. Possinger; Universitätsklinikum Ulm (Ulm, Germany): W. Kern; Universitätsklinikum
Düsseldorf (Düsseldorf, Germany): B. Arning and M. Arning;
and Universitätsklinikum Münster (Münster, Germany):
G. Silling-Engelhard.
| |
FOOTNOTES |
Submitted September 22, 1998; accepted January 26, 1999.
Supported in part by a grant from Bristol-Myers Squibb (Munich, Germany).
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to J. Beyer, MD, Department of Hematology and
Oncology, Universitätsklinikum Charité, Campus Virchow,
Augustenburger Platz 1, 13353 Berlin, Germany; e-mail:
jbeyer{at}charite.de.
| |
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ABSTRACT
INTRODUCTION