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291
Failure of Fluconazole Prophylaxis to Reduce
Mortality or the Requirement of Systemic
Amphotericin B Therapy during Treatment for
Refractory Acute Myeloid Leukemia
Results of a Prospective Randomized Phase III Study
Wolfgang Kern, M.D.1
Gerhard Behre, M.D.1
Thomas Rudolf, M.D.1
Andrea Kerkhoff, M.D.2
Albert Grote-Metke, M.D.3
Hartmut Eimermacher, M.D.4
Ursula Kubica, M.D.5
Bernhard Wörmann, M.D., Ph.D.1
Thomas Büchner, M.D., Ph.D.2
Wolfgang Hiddemann, M.D., Ph.D.1
for the German AML Cooperative Group
1
Department of Hematology and Oncology, GeorgAugust-University, Göttingen, Germany.
2
Department of Hematology and Oncology, Westfälische Wilhelms University, Münster, Germany.
3
Evangelisches Krankenhaus, Hamm, Germany.
4
Katholisches Krankenhaus Hagen, Hagen, Germany.
5
Zentralkrankenhaus St. Jürgen, Bremen, Germany.
Presented at the Annual Congress of the German
Society for Hematology and Oncology, Düsseldorf,
Germany, 1996 (Kern W, Behre G, Büchner Th,
Hiddemann W, for the German AML Cooperative
Group. Failure of fluconazole prophylaxis to reduce
mortality during treatment for refractory acute myeloid leukemia: a phase III multicenter study. Ann
Hematol 1996;73[Suppl 2]:A10).
The following institutions and investigators
participated in the study (in order of the number
of enrolled patients): University of Münster
(Büchner T, Kerkhoff A); University of Göttingen (Hiddemann W, Wörmann B, Kern W); Evangelisches Krankenhaus, Hamm (Grote-Metke
A); St. Martin Hospital, Hagen (Eimermacher
H); Zentralkrankenhaus St. Jürgen, Bremen
(Kubica U); Städtisches Krankenhaus Süd,
Lübeck (Bartels H); Evangelisches Kranken© 1998 American Cancer Society
BACKGROUND. Invasive fungal infections have increasingly become a matter of
concern with regard to patients receiving intensive myelosuppressive therapy for
hematologic malignancies. Such infections, especially prolonged neutropenia systemic fungal infections, may contribute substantially to infectious complications
and early death. Measures for early detection and effective prophylactic strategies
using active and nontoxic antifungal agents are therefore urgently needed.
METHODS. The current randomized study was initiated to assess the efficacy of oral
fluconazole as systemic antifungal prophylaxis for high risk patients with recurrent
acute myeloid leukemia undergoing intensive salvage therapy.
RESULTS. Of 68 fully evaluable patients, 36 were randomized to fluconazole in
addition to standard prophylaxis with oral co-trimoxazol, colistin sulphate, and
amphotericin B suspension, and 32 were randomized to standard prophylaxis only.
No major differences between the two groups were observed in the number of
episodes of fever of unknown origin (61% vs. 50%) or clinically defined infections
(56% vs. 50%). Microbiologically defined infections were more frequent in the
fluconazole group (50% vs. 31%), mainly due to a higher incidence of bacteremias
(42% vs. 22%). There were two cases of proven invasive fungal infections in each
group. Systemic amphotericin B was administered more frequently to patients
receiving fluconazole prophylaxis (56% vs. 28%). Fluconazole prophylaxis had no
impact on the rate of early death or overall survival.
CONCLUSIONS. For patients with high risk recurrent acute myeloid leukemia undergoing intensive salvage therapy, antifungal prophylaxis with fluconazole was
not superior to standard prophylaxis only. Cancer 1998;83:291–301.
© 1998 American Cancer Society.
KEYWORDS: fluconazole, fungal infections, prophylaxis, acute myeloid leukemia.
haus, Essen (Tirier C); Allgemeines Krankenhaus Altona, Hamburg (von Seydewitz T); University of Kiel (Gassmann W, Zurborn KH); University of München (Emmerich B, Hanauske AR);
Krankenhaus Düren (Karow J); St. Johannes
Hospital, Duisburg (Schadek-Gressel B); University of Hamburg (Hossfeld D); Städtisches
Krankenhaus, Kaiserslautern (Grosshaus A);
Johanniter Krankenhaus Rheinhausen, Duisburg (Lang R); Kreiskrankenhaus Herford
(Lange B); Städtisches Krankenhaus, Karlsruhe
(Fischer J); Klinikum Stadt Ludwigshafen
(Brass H); Krankenhaus Maria Hilf, Mönchengladbach (Reis E); St. Willehad Hospital, Wilhelmshaven (Augener W); University of Würzburg (Gieseler F).
Address for reprints: W. Hiddemann, M.D., Ph.D.,
Department of Hematology and Oncology, GeorgAugust-University, Robert-Koch-Strasse 40, 37075
Göttingen, Germany.
Received October 15, 1997; accepted January 12,
1998.
292
CANCER July 15, 1998 / Volume 83 / Number 2
FIGURE 1.
The schedule for the sequential high-dose cytosine arabinoside
and mitoxantrone protocol used in this
study is shown.
I
nvasive fungal infections (IFIs) in patients receiving
intensive myelosuppressive therapy for hematologic
malignancies have increasingly become a matter of
concern.1– 4 Especially in cases with prolonged neutropenia,5 systemic fungal infections may contribute substantially to infectious complications and early deaths.
Measures for early detection and effective prophylactic strategies using active, nontoxic antifungal agents
are therefore urgently needed. Until now, oral administration of amphotericin B suspension was the most
frequently used approach. This treatment has been
found to reduce the rate of IFI during chemotherapyinduced neutropenia6 but is hampered by moderateto-poor patient compliance and a lack of systemic
activity. As a member of the new group of azole antifungals, fluconazole features a broad range of activity
and has an excellent oral bioavailability.7 It causes few
side effects and thereby offers a promising option for
systemic antifungal prophylaxis in immunocompromised patients with severe, prolonged granulocytopenia. Therefore, the German AML Cooperative Group
initiated a prospective randomized multicenter study
to evaluate the impact of fluconazole prophylaxis on
the incidence of proven or suspected IFI and the need
for systemic antifungal therapy with amphotericin B
in high risk patients with relapsed and refractory acute
myeloid leukemia (AML). In preceding Phase II studies, patients undergoing intensive salvage therapy
with sequential high dose cytosine arabinoside and
mitoxantrone (S-HAM) for refractory or relapsed AML
were found to experience a median duration of critical
neutropenia of more than 5 weeks and an early death
rate of 28%.8 These patients were therefore selected as
a main target group for whom a beneficial effect of
antifungal prophylaxis could be expected.
METHODS
Patients and Antileukemic Therapy
Consecutive patients with relapsed and refractory
AML who were admitted to the participating centers
were eligible to participate in this study. Refractoriness against standard chemotherapy was defined according to previously established criteria,9 which included 1) primary resistance against 2 cycles of
induction therapy, 2) first early relapse with a remission duration of less than 6 months, and 3) second and
subsequent relapse. Patients with first relapses after 6
months of remission were not considered refractory to
standard therapy and were included as relapsed AML.
All patients were recruited from the first-line trials
of the German AML Cooperative Group and had thus
received standardized first-line treatment. For patients younger than 60 years, first-line therapy consisted of double induction therapy with either the
repetitive application of the 9-day regimen of thioguanine, cytosine arabinoside (ara-C), and daunorubicin
(TAD-9/TAD-9) or the sequential application of TAD-9
followed by high dose ara-C and mitoxantrone. Older
patients all received one course of TAD-9 and were
given a second TAD-9 course only when there was
inadequate response to the first TAD-9 cycle. Patients
of all ages who achieved a complete remission subsequently received TAD-9 for consolidation and
monthly maintenance therapy for 3 years.10,11
Patients meeting the entry criteria were enrolled
into the current study and were treated with S-HAM,12
which consisted of high dose ara-C 3 g/m2 or 1 g/m2
every 12 hours by a 3-hour infusion on Days 1, 2, 8,
and 9 and mitoxantrone 10 mg/m2/day as a 30-minute
infusion on Days 3, 4, 10, and 11, respectively (Fig. 1).
The dose of ara-C was adjusted to the disease status
according to the results of a previous trial that compared 3 g/m2 with 1 g/m2 ara-C in the treament of
patients with refractory AML.8 Patients with refractory
disease who were younger than 60 years received 3
g/m2 ara-C, whereas all other cases were treated with
1 g/m2 ara-C.
To prevent photophobia and conjunctivitis induced by high dose ara-C, all patients received glucocorticoid eye drops every 6 hours starting before the
first dose of the drug and continuing for 24 hours after
the last dose. All patients also received granulocytecolony stimulating factor (G-CSF) 5mg/kg/day subcutaneously starting on Day 12 after the beginning of
therapy. G-CSF was discontinued if a bone marrow
examination on Day 18, i.e., 1 week after completion
of S-HAM, revealed more than 5% residual leukemic
blasts. In patients with adequate blast cell clearance
Fluconazole Prophylaxis in AML/Kern et al.
on Day 18, G-CSF was continued until the neutrophil
count reached a value of more than 1500/mm3 for 3
consecutive days.
Patients with antecedent hematologic disorders,
secondary leukemias, and a preceding autologous or
allogeneic bone marrow transplantation were excluded from the study. Other patients excluded were
those with abnormal liver function tests (aspartate
aminotransferase [AST], alanine aminotransferase
[ALT], or alkaline phosphatase [AP] more than 3 times
the upper normal limits, respectively; total bilirubin
2.0 mg/dL); impaired renal function (serum creatinine
2.0 mg/dL); severe infections; or pregnancy.
Study Design and Antimicrobial Strategies
On the basis of the above-mentioned antileukemic
strategy, the current study aimed to assess the efficacy
of fluconazole in addition to standard antimicrobial
prophylaxis for the prevention of IFI and the need for
empiric systemic antifungal therapy with amphotericin B. The study had the design of a prospective randomized multicenter analysis. Prior to the start of
chemotherapy, patients were randomly assigned to
either 1) systemic antifungal prophylaxis with fluconazole 400 mg administered orally (p.o.) daily in addition to standard antimicrobial prophylaxis consisting
of co-trimoxazol 960 mg p.o. 3 times daily, colistine
sulphate 2 million units p.o. 4 times daily, and amphotericin B suspension 40 mg p.o. 6 times daily; or 2)
standard antimicrobial prophylaxis only. To avoid imbalances in the risk profile, patients were stratified
according to age (, or $ 60 years) and disease status
(primary refractoriness, relapse after #6 months of
first remission, relapse after 6 months and #18
months of first remission, relapse after .18 months of
first remission, or second/subsequent relapse).13
Antimicrobial prophylaxis was continued until
parenteral antimicrobial therapy was required or until
a leukocyte count of more than 1000/mL was reached.
Parenteral antimicrobial therapy was initiated on the
occurence of fever of unknown origin (FUO) or fever
with clinical and/or microbiologically verified infection. Antimicrobial treatment for FUO comprised two
drug combinations of an aminoglycoside with either a
third-generation cephalosporin or ureidopenicillin.
On persistence or recurrence of fever, a combination
of carbapenems with glycopeptides was initiated. In
addition, intravenous antifungal therapy was begun.
This comprised amphotericin B in patients who were
randomized to fluconazole prophylaxis. In patients
randomized to the control, intravenous fluconazole
was given instead, which was replaced by amphotericin B only when there was no response. Patients with
pneumonia, however, were uniformly started on am-
293
photericin B in addition to antibiotic therapy. The
addition of other antifungal agents was dependent on
the patient’s clinical condition and was left at the
discretion of the responsible physician.
Study Parameters
Infectious complications were classified according to
the Consensus Report of the Immunocompromised
Host Society,14 as 1) FUO not accompanied by either
clinical or microbiologic evidence of infection; 2) clinically defined infections referring to the diagnosis of a
site of infection without determination of the infectious agent; or 3) microbiologically defined infections
consisting of bacteremia, fungemia, a microbiologically defined site of infection, or a combination of the
three. In addition, IFIs were classified according to
criteria suggested by Behre et al. (Table 1).15
Toxicity was evaluated according to the World
Health Organization (WHO) grading system.16
Response to therapy was assessed according to
Cancer and Leukemia Group B criteria.17 Complete
remission (CR) was defined as normal cellular bone
marrow with normal erythroid and myeloid elements
as well as myeloblasts, promyelocytes, and other leukemic cells totaling less than 5%, and with normal
peripheral blood platelet and white blood cell counts
for at least 4 weeks. Patients who had more than 5%
myeloblasts but fewer than 25% blasts, with otherwise
normal bone marrow, were considered to be in partial
remission (PR), as were patients who fulfilled the criteria of CR except for full recovery of peripheral blood
platelet and/or white blood cell counts. Patients with
persistent leukemic blasts in the bone marrow or
blood or with leukemic regrowth within 4 weeks after
initial response were considered nonresponders
(NRs). Patients dying within 6 weeks after completion
of antileukemic therapy without evidence of leukemic
regrowth were classified as early deaths (EDs).
The duration of critical cytopenia was evaluated
by the time of leukocyte recovery to more than
1000/mL from the onset of S-HAM treatment. The time
to CR was measured from the onset of treatment to the
date of documented CR, and disease free survival was
measured from the date of documented CR to relapse
or death during remission. Survival was measured as
the time from the beginning of treatment to death.
Time to treatment failure was measured as the time
from the beginning of treatment to death without
evidence of leukemia, documentation of persistent
leukemia, or relapse.
Statistics
The primary end point of the current study was the
impact of fluconazole prophylaxis in addition to stan-
294
CANCER July 15, 1998 / Volume 83 / Number 2
TABLE 1
Definition of Invasive Fungal Infections in Neutropenic Patients
Invasive pulmonary aspergillosis
Proven
Histology 6 culture
Probable
Pneumonia or other organ infection unresponsive to antibiotics, with no other
microbiologically documented causative organism and one of the following
conditions:
Culture of normally sterile tissues, bronchoalveolar lavage, blood sputum, or
nose
Repeated antigen detection or increasing antibody titers in blood
Pulmonary lesions with halo sign or air crescent sign in computed
tomography scan
Possible
Fever unresponsive to antibiotics, with no other microbiologically documented
causative organism and one of the following conditions:
Culture of normally sterile tissues, bronchoalveolar lavage, blood sputum, or
nose
Repeated antigen detection or increasing antibody titers in blood
Invasive candidiasis
Proven
Histology 6 culture or
Histology or culture of normally sterile tissues, including blood, with fever
unresponsive to antibiotics and no other microbiologically documented
causative organism
Probable
Pneumonia or other organ infection unresponsive to antibiotics, with no other
microbiologically documented causative organism and one of the following
conditions:
Culture or bronchoalveolar lavage
Increasing antigen or antibody titers in blood
Multiple hepatic and splenic lesions in computed tomography
scan/sonogram
Possible
Fever unresponsive to antibiotics with no other microbiologically documented
causative organism and one of the following conditions:
Culture, excluding blood
Increasing antigen or antibody titers in blood
Possible invasive fungal infection
No invasive pulmonary aspergillosis or candidiasis as defined above, but one of
the following conditions:
Pneumonia unresponsive to antibiotics and/or responsive to antimycotics 6
antibiotics
Fever unresponsive to antibiotics and responsive to antimycotics 6
antibiotics
dard antimicrobial prophylaxis on the incidence of IFI
and the requirement of additional systemic antifungal
therapy with amphotericin B as compared with a randomly assigned control group receiving standard antimicrobial prophylaxis alone. The secondary end
point was the ED rate. Assuming a reduction of 20% in
the incidence of IFI or the requirement of systemic
antifungal therapy by fluconazole prophylaxis, with a
5 0.05 and b 5 0.20, it was anticipated that 73 patients
would be enrolled into each treatment arm. Numeric
values were compared by the chi-square test, Fisher’s
exact test, and Student’s t test. Remission duration
and survival were calculated for the fluconazole and
control groups according to Kaplan–Meier estimates,
respectively, and were compared using the log rank
test.
After enrollment of 75 patients into the study, 68
of whom could be fully evaluated, a scheduled interim
analysis disclosed a difference between the study and
control groups in the number of patients who required
systemic amphotericin B. Based on these data, a hypothetical analysis of the total of 146 originally
planned patients was performed, assuming that none
of the following patients with fluconazole prophylaxis
and 50% of the following patients without fluconazole
prophylaxis would receive amphotericin B. Under this
best-case assumption, no significant advantage for
fluconazole prophylaxis could be detected. Therefore,
it was decided to stop further recruitment of patients
into the trial.
Study Conduct
Prior to receiving therapy, all patients gave their informed consent for participation in the current evaluation after having been advised about the purpose
and investigational nature of the study as well as the
potential risks of participation. The study design adhered to the Declaration of Helsinki and was approved
by the ethics committees of the participating institutions prior to its initiation.
RESULTS
Patient Characteristics
Between May 1992 and January 1996, 84 patients entered the study, 68 of whom could be fully evaluated.
Causes for exclusion from analysis were secondary
leukemia (for 3 patients), application of the study drug
before randomization (for 2 patients), treatment not in
accordance with the results of the randomization (for
1 patient), discontinuation of the S-HAM chemotherapy after the first 4 days (for 2 patients), and incomplete documentation (for 8 patients). Of the patients
who could be evaluated, 36 and 32 were randomized
to the fluconazole arm and the control arm, respectively. The patient characteristics and risk profiles of
the two groups were comparable. The patients’ ages
ranged from 21 to 73 and from 17 to 72 years (median,
52 and 45 years) for the fluconazole prophylaxis and
control groups (P . 0.05), respectively. All patients
had received prior chemotherapy for their disease as
indicated above. Two patients (6%) in each group
were younger than 60 years and had AML refractory to
first-line therapy. Early and late relapses after a first
complete remission of # and 6 months’ duration occurred in 7 (19%) and 19 (53%) vs. 7 (22%) and 18
(56%) patients younger than 60 years, respectively.
The patients were older than 60 years in 8 (22%) vs. 4
Fluconazole Prophylaxis in AML/Kern et al.
TABLE 2
Patient Characteristics and Risk Factors
Age, yrs (median/range)
Gender (male/female)
Disease status
age ,60 yrs 1 refractory AML
age ,60 yrs 1 CR duration #6 mos
age ,60 yrs 1 CR duration .6 mos
age ,60 yrs 1 2nd relapse
age .60 yrs
Antifungal treatment during preceeding
neutropenias
for invasive pulmonary aspergillosis
for invasive candidiasis
for suspected IFI
for FUO
Infections at study entry
FUO
Gastrointestinal tract infection
Soft tissue infection
Recovery of leukocytes to .1000/mL
(days after start of chemotherapy;
median/range)
Time to complete remission
(days after start of chemotherapy;
median/range)
Duration of fluconazole prophylaxis
(days; median/range)
295
Toxicity of Antileukemic Therapy
Fluconazole
(n 5 36)
Control
(n 5 32)
52/21–73
20/16
45/17–72
17/15
2 (6%)
7 (19%)
19 (53%)
—
8 (22%)
2 (6%)
7 (22%)
18 (56%)
1 (3%)
4 (13%)
30 (83%)
2
3
15
10
7 (19%)
6
1
—
24 (75%)
1
3
14
6
2 (6%)
1
—
1
35/22–58
34/19–59
51/30–71
57/37–93
23/2–56
—
AML: acute myeloid leukemia; CR: complete remission; IFI: invasive fungal infection; FUO: fever of
unknown origin.
(13%) cases (P . 0.05) (Table 2). All patients who could
be evaluated received one course of S-HAM therapy.
During preceding neutropenias, systemic antifungal therapy was given to 30 patients (83%) versus
24 patients (75%), in 9 of whom IFI had been documented (Aspergillus species, 2 vs. 1; Candida species, 3 vs. 3). Antifungal therapy had been initiated
for suspected IFI and for FUO resistant to antibiotic
treatment in 15 and 10 versus 14 and 6 cases, respectively. Infections at study entry were more frequent within the fluconazole prophylaxis group (7
patients [19%] versus 2 patients [6%]), mainly due to
a higher prevalence of FUO (6 [17%] vs. 1 [3%]; P 5
0.07). The median duration of critical cytopenia was
similar in both groups, with the recovery of leukocytes to more than 1000/mL occurring at a median of
35 versus 34 days after the start of therapy (Table 2).
Consequently, there was no significant difference in
the median time to CR (51 vs. 57 days after the start
of therapy; P 5 0.06; Fig. 2). Fluconazole prophylaxis
was carried out for a median of 23 days (range, 2–56
days).
Severe nonhematologic toxicities (WHO Grade 3/4)
during S-HAM therapy were not dependent on the use
of fluconazole prophylaxis and consisted mainly of
nausea/vomiting, stomatitis, and diarrhea (Table 3).
Furthermore, mild or severe elevation of liver enzymes
and parameters for cholestasis were not different between the fluconazole prophylaxis group and the control group.
Infectious Episodes
The median number of febrile episodes was 1 in both
groups (range, 0 –3), whereas the total number of febrile days was higher in the group receiving fluconazole prophylaxis (median, 9 vs. 6 days; range, 0 –29 vs.
0 – 60 days; P . 0.05; Table 4). The median time to the
first febrile episode was 10 versus 15 days after the
start of therapy (P . 0.05, Fig. 3).
The infectious complications that were encountered during S-HAM therapy are summarized in Table
4. Three patients remained free of infections throughout the whole study period. No major differences between the two study groups were observed for the
incidence of FUO (22 episodes [61%] vs. 16 episodes
[50%]) or clinically defined infections (20 [56%] vs. 16
[50%]). There was a trend toward more infections of
the gastrointestinal tract among patients who received
fluconazole prophylaxis; this trend was not statistically significant (9 vs. 3; P 5 0.08).
Marked differences were seen in the incidence of
microbiologically defined infections (18 [50%] vs. 10
[31%]; P 5 0.09), mainly due to a strong trend toward
more bacteremias in the fluconazole group (15 [42%]
vs. 7 [22%]; P 5 0.07), which reached significance for
gram positive bacteremias (33% vs. 13%; P 5 0.04).
Bacteremias also occurred earlier in this group. The
frequencies of all other categories of infection were
similar for both groups. Overall, 12 patients (33%)
versus 9 patients (28%) developed pneumonia, which
occurred earlier in patients who received fluconazole
prophylaxis.
In total, causative organisms were predominantly
gram positive and gram negative bacteria identified in
26 and 14 cases, respectively. Fungal infections were
documented in only 4 patients (Table 5). There were 2
versus 2 cases with proven invasive candidiasis,
whereas invasive pulmonary aspergillosis was not observed. Possible IFI occurred in 19 (53%) versus 11
(34%) patients (P 5 0.10; Table 6).
Antimicrobial Therapy
Antifungal therapy was initiated in 22 (61%) versus 18
(56%) patients (Table 7). Systemic amphotericin B was
296
CANCER July 15, 1998 / Volume 83 / Number 2
FIGURE 2.
Time to complete remission is shown.
TABLE 3
Nonhematologic Toxicity
TABLE 4
Infectious Complications
Fluconazole (n 5 36)
Nausea/vomiting
Stomatits
Diarrhea
Bilirubin
AP
AST/ALT
Bleeding
Creatinine
Lung
Allergy
Cardiac rhythm
Cardiac function
Pericarditis
Peripheral nervous
system
Consciousness
Control (n 5 32)
WHO 3/4
WHO 3/4
WHO 3/4
WHO 3/4
5 (14%)
13 (36%)
8 (22%)
10 (28%)
7 (19%)
3 (8%)
11 (31%)
7 (19%)
—
3 (8%)
3 (8%)
1 (3%)
—
14 (39%)
5 (14%)
6 (17%)
1 (3%)
—
2 (6%)
—
—
1 (3%)
—
1 (3%)
1 (3%)
—
10 (31%)
10 (31%)
5 (16%)
4 (13%)
2 (6%)
5 (16%)
2 (6%)
1 (3%)
—
—
2 (6%)
—
1 (3%)
7 (22%)
5 (16%)
5 (16%)
3 (9%)
—
1 (3%)
2 (6%)
—
2 (6%)
—
2 (6%)
1 (3%)
—
1 (3%)
1 (3%)
—
1 (3%)
—
—
—
1 (3%)
WHO: World Health Organization; AP: alkaline phosphatase; AST: aspartate aminotransferase; ALT:
alanine aminotransferase.
given to more patients in the fluconazole prophylaxis
group (20 [56%] vs. 9 [28%]). Seven patients within the
control group received fluconazole intravenously as
initial antifungal therapy, none of which required subsequent parenteral amphotericin B. The median number of antibiotic regimens was 3 versus 2 (range, 0 –7
vs. 0 – 6).
The antimicrobial therapy was successful in 25
(71%) versus 21 (70%) of 35 versus 30 patients with
infections (Table 8), whereas in 3 patients (9%) versus
3 patients (10%) only an incomplete control of the
infections was obtained. Fatal infectious complications occurred in 7 patients (19%) versus 6 patients
No. of febrile episodes (median/range)
No. of febrile days (median/range)
Time to first infection (days; median/range)
No infection
FUO
Clinically defined infections
Pneumonia
Sepsis syndrome
Septic shock
Gastrointestinal tract infection
Perianal infection
Catheter-related infection
Other
Microbiologically defined infections
Bacteriemia
Gram positive
Gram negative
Fungemia
Pneumonia
Sepsis syndrome
Septic shock
Gastrointestinal tract infection
Perianal infection
Catheter related infection
Other
Fluconazole
(n 5 36)
Control
(n 5 32)
1/0–3
9/0–29
10/0–33
1(3%)
22 (61%)
20 (56%)
6 (17%)
—
2 (6%)
9 (25%)
—
1 (3%)
2 (6%)
18 (50%)
15 (42%)
12 (33%)
3 (8%)
2 (6%)
6 (17%)
2 (6%)
2 (6%)
1 (3%)
—
1 (3%)
2 (6%)
1/0–3
6/0–60
15/0–22
2 (6%)
16 (50%)
16 (50%)
6 (19%)
—
1 (3%)
3 (9%)
3 (9%)
2 (6%)
1 (3%)
10 (31%)
7 (22%)
4 (13%)
3 (9%)
1 (3%)
3 (9%)
2 (6%)
2 (6%)
2 (6%)
—
2 (6%)
1 (3%)
FUO: fever of unknown origin.
(19%), in 4 of whom fungi or bacteria were documented to be the causative organism.
Overall Response and Antileukemic Activity of S-HAM
Corresponding to the similarity of results on the frequency and severity of infectious complications, no
significant differences were observed in overall re-
Fluconazole Prophylaxis in AML/Kern et al.
297
FIGURE 3. Time to the first febrile
episode is shown.
TABLE 5
Isolated Causative Organisms
Gram positive bacteria
Gram negative bacteria
Fungi
Fluconazole
(n 5 26)
Control
(n 5 19)
Total
(n 5 44)
17 (68%)
6 (24%)
2 (8%)
9 (47%)
8 (42%)
2 (11%)
26 (59%)
14 (32%)
4 (9%)
sponse, disease free survival, and overall survival. The
rates of ED were 22% versus 19%, respectively; 61%
versus 50% of patients achieved a CR and 17% versus
31% had NR (Table 9). Median time to treatment failure was 5.2 versus 3.2 months, median disease free
survival for patients in complete remission was 6.7
versus 5.1 months, and median total survival was 7.3
versus 6.8 months (Fig. 4).
DISCUSSION
The German AML Cooperative Group conducted the
current study with the aim of reducing the incidence
of IFI and the requirement of systemic antifungal therapy with amphotericin B by administering antifungal
prophylaxis with fluconazole in addition to standard
antimicrobial therapy to patients receiving intensive
chemotherapy for high risk AML. In these patients,
infectious complications were often encountered, a
considerable proportion of which were proven or suspected to be of fungal origin. Furthermore, the high
ED rate of more than 25% demands improved antimicrobial therapy. Among the candidate drugs, fluconazole was the most attractive because of its pharmacokinetic profile, its broad range of antifungal activity,
and its good tolerability.18 –21
Fluconazole prophylaxis had already been as-
sessed in randomized studies of patients receiving
intensive chemotherapy or bone marrow transplantation mainly for acute leukemias. The majority of these
trials revealed that fluconazole significantly reduced
the incidence of candida colonization but was not
superior in the prevention of IFI.22–30
Only a few placebo-controlled studies have evaluated the prophylactic antifungal efficacy of fluconazole. Two early trials involved heterogenous collectives of oncologic patients receiving chemotherapy,
radiotherapy, antibiotic therapy, or glucocorticoid
therapy.31,32 Fluconazole significantly reduced the incidence of oropharyngeal candidiasis among those patients but had no effect on the occurrence of IFI. This
negative result was thought to emerge from the application of low doses of 50 mg fluconazole only, which
was well below currently used doses.
In fact, in two subsequent trials, the daily administration of 400 mg of fluconazole not only reduced the
incidence of not only superficial fungal infections but
also IFIs in patients undergoing bone marrow transplantation. In one of these studies, reduced overall
mortality until Day 110 after transplantation was observed in the fluconazole arm.33,34
Winston et al. were the first to provide data on
prophylaxis with fluconazole (400 mg daily) in patients receiving intensive chemotherapy mainly for
acute leukemias.35 In a randomized multicenter study,
a significant decrease in fungal infections was shown
in the fluconazole arm (9% vs. 21%; P 5 0.02), mainly
due to a reduction in superficial fungal infections. At
the end of the study period, the colonization of patients with Candida albicans was also reduced significantly. However, neither the incidence of IFI (4% vs.
8%; P 5 0.30) nor the frequency of the application of
systemic amphotericin B (64% vs. 74%; P 5 0.10) were
298
CANCER July 15, 1998 / Volume 83 / Number 2
TABLE 6
Fungal Infections
Fluconazole
Invasive fungal infection
Invasive candidiasis
Invasive aspergillosis
Control
Proven
Probable
Possible
Proven
Probable
Possible
2
—
—
—
19
—
—
2
—
—
—
11
—
—
TABLE 7
Antimicrobial Therapy
TABLE 9
Antileukemic Activity of S-HAM
P value
Systemic antifungal therapy
Amphotericin B
Fluconazole
5-Flucytosine
Itraconazole
Ambisome
No. of antibiotic regimens (median/range)
0.02
—
0.07
0.07
0.72
Fluconazole
(n 5 36)
Control
(n 5 32)
22 (61%)
20 (56%)
—
15 (42%)
1 (3%)
1 (3%)
3/0–7
18 (56%)
9 (28%)
7 (22%)
7 (22%)
5 (16%)
1 (3%)
2/0–6
Complete remission
Nonresponse
Early death
Time to treatment failure (mos, median)
Disease free survival (mos, median)
Total survival (mos, median)
Fluconazole
(n 5 36)
Control
(n 5 32)
Total
(n 5 68)
22 (61%)
6 (17%)
8 (22%)
5.2
6.7
7.3
16 (50%)
10 (31%)
6 (19%)
3.2
5.1
6.8
38 (56%)
16 (24%)
14 (21%)
4.8
5.5
7.2
S-HAM: sequential high dose cytosine arabinoside and mitoxantrone.
TABLE 8
Efficacy of Antimicrobial Therapy
Result of therapy
Fluconazole
(n 5 35)
Control
(n 5 30)
Complete remission
Improvement
Death due to infection
Septic shock
Candida krusei
Candida tropicalis
Streptococcus viridans
Enterococcus species
Pneumonia
25 (71%)
3 (9%)
7 (20%)
5
1
—
—
1
2
20 (70%)
3 (10%)
6 (20%)
3
—
1
1
—
3
influenced by the fluconazole prophylaxis. As a result,
the mortality was the same for both groups (21% vs.
18%).
Another analysis was performed by Schaffner et
al. in a randomized single-center study evaluating antifungal prophylaxis with fluconazole (400 mg daily) in
patients receiving chemotherapy for acute leukemias
and high grade lymphomas.36 These authors also
found a significant reduction in the incidence of oropharyngeal candidiasis (1% vs. 12%; P 5 0.01) as well
as a reduction in colonization with Candida species
(8% vs. 37%; P , 0.0001) in patients who received
fluconazole prophylaxis. In contrast to the results obtained by Winston et al., a trend toward a reduced
need for systemic amphotericin B was reported (33%
vs. 47%; P 5 0.08), which reached statistical significance for patients with FUO (16% vs. 30%; P 5 0.04).
However, as in the above-mentioned study, neither
the incidence of IFI (11% vs. 11%) nor the mortality
rate (5% vs. 7%) could be diminished by fluconazole
prophylaxis. Furthermore, the significance of this
analysis was restricted by the relatively short duration
of neutropenia (median, 22 days), thereby raising the
question of whether immunosuppression was severe
enough to allow fluconazole prophylaxis to be effective.
Further evidence of the efficacy of fluconazole
prophylaxis came from a placebo-controlled randomized single-center study37 of a series of patients undergoing allogeneic or autologous bone marrow transplantation or intensive chemotherapy for acute
leukemia or blast crisis of chronic myelogenous leukemia. This study revealed a significant reduction in
the need for systemic amphotericin B therapy (22% vs.
58%; P , 0.01). In addition, the number of days with
fever was significantly diminished (5 days vs. 9 days;
P , 0.05). Besides by the heterogeneity of the study
population, the results of this study were compromised by a relatively short duration of critical neutropenia (only 16 days). As could have been anticipated,
no differences were observed in either the incidence
of IFI or the mortality rate.
Taking the shortcomings of the above-mentioned
analyses into account, the current study was carried
out with a homogenous group of patients with advanced AML who all received an identical type of
intensive antileukemic therapy and standardized an-
Fluconazole Prophylaxis in AML/Kern et al.
299
FIGURE 4. Total survival is shown.
timicrobial prophylaxis and intervention. These patients were chosen for the current approach because
they faced a prolonged period of severe neutropenia
regularly exceeding 30 –35 days and a high risk of
lethal complications from severe infections in the
range of 25–30%.
The randomization resulted in a similarity in the
patients’ risk profiles between the two groups, excluding potential biases by differences in disease status,
prior infections, infections at study entry, or duration
of critical neutropenia. All patients randomized to receive fluconazole tolerated the drug very well for a
median duration of 23 days. Whereas the time to the
occurrence of infectious episodes and their duration
as well as the incidences of FUO and of clinically
defined infections did not differ between the two
groups, an excess of bacteremias led to a higher frequency of microbiologically defined infections in patients receiving fluconazole prophylaxis. Systemic antifungal therapy with amphotericin B was initiated
more often in the group with fluconazole prophylaxis,
whereas fluconazole was used successfully as interventional therapy in seven patients of the control
group. There were seven and six cases with fatal infections in the two groups, respectively. No differences
in the antileukemic activity of the S-HAM regimen
were observed between the two groups.
Overall, the infectious complications manifested
themselves similarly in both study arms. In particular,
pneumonia which is a major threat to patients with
prolonged severe immunosuppression38 was not less
frequent among patients with fluconazole prophylaxis
(33% vs. 28%). More episodes of bacteremia were encountered in the fluconazole prophylaxis group (42%
vs. 22%; P 5 0.07), mainly due to gram positive bacteria (33% vs. 13%; P 5 0.04). Similar observations had
been made in two previous studies.20,36 Schaffner et al.
also detected more bacteremias during fluconazole
prophylaxis (36% vs. 21%; P 5 0.04), the difference
being mainly due to gram negative bacteria (15% vs.
5%; P 5 0.05). In a placebo-controlled trial, Palmblad
et al. observed more bacteremias during ketoconazole
prophylaxis (74% vs. 37%; P 5 0.0001). However, it was
unclear whether there was a causal connection between the prophylaxis and the bacteremia or whether
there were differences between the study and control
groups with regard to patients’ conditions.
The current study failed to detect a difference in
the incidence of IFI between the study group and the
control group, and these results were in accordance
with previous analyses.35–37 This was based in part on
the overall low rate of proven IFI and reflected the
difficulties of this diagnosis when the rigid criteria
suggested by Behre et al were used.15
A major and yet not previously reported finding of
the current study was an excess use of systemic amphotericin B therapy in patients receiving fluconazole
prophylaxis. Because the analysis of the study was
one-sided, only a possible advantage of fluconazole
could be analyzed, and no determination of the significance of the observed difference favoring the control group could be performed. However, this finding
probably resulted from the general strategy of antifungal therapy that was used in this study. In most other
trials, patients with fever or infections and no response to antibiotics for 3– 6 days usually received
amphotericin B as antifungal therapy.33–37 In contrast,
patients within the control group of the current study
were scheduled to receive intravenous fluconazole for
systemic antifungal treatment when FUO persisted for
3 days during antibiotic therapy. Systemic amphotericin B was initiated only if FUO persisted for 3 more
300
CANCER July 15, 1998 / Volume 83 / Number 2
days. As a result, seven patients within the control
group received antifungal therapy with fluconazole,
none of whom had to proceed to systemic amphotericin B. This finding suggests that, at least in FUO,
fluconazole may be effective and thus replace the
more toxic treatment with systemic amphotericin B.
Furthermore, these results suggest that the need for
systemic amphotericin B therapy may have been overestimated in previous investigations. In fact, a more
recent trial by the Paul Ehrlich Society for Chemotherapy emphasized that fluconazole serves as a valuable
therapeutic alternative to intravenous amphotericin B
for interventional therapy in patients with FUO that is
resistant to antibiotic regimens.39 This finding
prompts reconsideration of the most appropriate circumstances for fluconazole treatment and favors its
application as an intervention rather than an antifungal prophylaxis. This conclusion is supported by the
potential risks of fluconazole prophylaxis, including
breakthrough candidemias and an increasing incidence of infections due to Candida non-albicans species.40 – 44 However, additional trials addressing the use
of fluconazole as preemptive antifungal therapy in
neutropenic patients with FUO persisting after 3 days
of antibiotic therapy must be conducted to determinate the appropriate role of this drug in this setting.
Given the secondary end point of the current trial,
with fluconazole failing to reduce the mortality rate
within the study group, the general use of the drug as
antifungal prophylaxis cannot be supported. Rather,
fluconazole as a potent antifungal agent should be an
option for interventional therapy for patients with suspected or proven IFI. This strategy seems appropriate
at least for nonneutropenic patients, for whom fluconazole was shown to be aseffective as intravenous amphotericin B in the treatment of candidemia in a randomized study.45 Further evidence of the efficacy of
fluconazole as interventional antifungal therapy for
neutropenic patients came from a matched cohort
study in which cancer patients with candidemia
treated with fluconazole had the same response rate
as those who received amphotericin B therapy.46 The
validity of these results for neutropenic patients in
general is hampered by a proportion of only 24% of
the patients’ being neutropenic at the time of enrollment in the study. Therefore, further assessment of
the applicability of fluconazole to severely immunocompromised neutropenic patients with suspected or
proven IFI should focus on randomized comparisons
with intravenous amphotericin B, which has hitherto
comprised the standard interventional antifungal
therapy.
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