Management of Invasive Mycoses in Hematology Patients: Current Approaches

Management of Invasive Mycoses in Hematology Patients: Current Approaches

ABSTRACT: Candidiasis and aspergillosis are the most common fungal infections in hematopoietic stem cell transplant recipients and other hematology/ oncology patients. Strategies for reducing the morbidity and mortality associated with these infections include antifungal prophylaxis, empiric therapy in patients with persistent fever and neutropenia, and preemptive therapy. Antifungal therapies include amphotericin B deoxycholate, lipid formulations of amphotericin B, the triazoles (fluconazole, itraconazole, and voriconazole), and the echinocandins (caspofungin and the investigational agents micafungin and anidulafungin). Fluconazole is a reasonable choice for the treatment of invasive candidiasis if the patient has not previously received a triazole and the institution has a low incidence of triazole resistance. If resistance is a concern, an echinocandin, such as caspofungin, is an appropriate option. Voriconazole may be the initial choice in most patients with invasive aspergillosis. If patients are intolerant of or refractory to conventional therapy, effective alternatives include a lipid formulation of amphotericin B or an echinocandin.

Invasive fungal infections continue
to be an important cause of morbidity
and mortality in hematology/
oncology patients, particularly
bone marrow or stem cell transplant
recipients. Amphotericin B deoxycholate
was once the standard of care;
however, this agent is associated with
significant adverse reactions, particularly
nephrotoxicity. The lipid formulations
of amphotericin B are less toxic
than amphotericin B deoxycholate, but
nephrotoxicity and infusion-related
reactions continue to be concerns.

These limitations have led to the
development of alternative antifungal
agents, such as the triazoles and, more
recently, the echinocandins. These
newer antifungals represent important
advances in the prevention and management
of invasive fungal infections.

This article will review the risk
factors for invasive fungal infections,
the common organisms, and the concepts
of prevention and treatment, focusing
on two major infectious
diseases-invasive candidiasis and
invasive aspergillosis. This review is
based on material presented by Dr.
Thomas Walsh.

Risk Factors and Organisms

Hematology patients at high risk
for invasive fungal infections include
those with the following:

  • Acute leukemia, particularly
    acute myelogenous leukemia, or those
    undergoing intensive consolidation
    and intensification and patients with
    high-risk acute lymphoblastic leukemia
  • Chronic leukemia-specifically
    subgroups with chronic myelogenous
    leukemia (CML) in blast crisis, multiply
    relapsed CML, and advanced
    chronic lymphocytic leukemia
  • Lymphoma (multiply relapsed)
  • Ongoing refractory myelodysplasia
  • Severe aplastic anemia
  • Transplantation (myeloablative
    or nonmyeloablative)

Risk factors for aspergillosis in hematology
patients include prolonged
or repeated episodes of profound neutropenia,
corticosteroid therapy, and
infliximab therapy. Because tumor
necrosis factor-alpha is a critical cytokine
in host defense against Aspergillus,
abrogating that cytokine can
lead to increased risk for invasive aspergillosis.
In addition to pharmacologic
immunosuppression, intrinsic
immune defects increase the risk of
aspergillosis. They include aplastic
anemia, advanced HIV infection,
chronic granulomatous disease, and
Job syndrome.

The most common fungal pathogens
to cause significant infections in
immunosuppressed patients with malignancy
and its treatment are Candida
and Aspergillus. Less common
species, but ones that are being seen
with increasing frequency, include
yeast-like pathogens such as Trichosporon
species and Cryptococcus neoformans.
Other fungal pathogens
include the filamentous fungi (particularly
the Fusarium species), the Zygomycetes,
Scedosporium species,
and a variety of dematiaceous molds.

Concepts of Prevention and

Over the past 25 years, different
strategies have emerged for the prevention
and treatment of invasive fungal
infections; where appropriate, the
early initiation of antifungal therapy
has been one of the hallmarks of the
attempt to reduce complications from
these infections. Three different-but
overlapping-strategies have been

  • Prophylaxis: The initiation of
    antifungal therapy at or near the beginning
    of antineoplastic chemotherapy
    or hematopoietic stem cell
    transplant (HSCT) preparative regimen,
    before any symptoms or signs
    of infection.
  • Empiric therapy: A risk-based
    intervention for patients with persistent
    fever and neutropenia despite
    broad-spectrum antibacterials and
    who are at risk for invasive fungal
  • Preemptive therapy: A riskbased
    intervention for high-risk patients
    who have persistent fever and
    neutropenia despite broad-spectrum
    antibiotics plus other evidence of invasive
    fungal infection, such as positive
    surveillance cultures, sinus
    opacification, pulmonary infiltrates,
    or positive galactomannan antigen.

These approaches have been most
clearly described in the setting of neutropenia
during the period of bone
marrow transplantation, as illustrated
in Figure 1. There is substantial overlap
between these strategies, especially
between empiric and preemptive therapy.
For example, approximately 45%
of patients enrolled in an empiric antifungal
trial may have pulmonary infiltrates;
if so, the intervention is-by
definition-preemptive therapy. Perhaps
what matters most is that a riskbased
approach is used to prevent
invasive fungal infections in high-risk
neutropenic patients.

Toxicity is a key factor in determining
whether a compound will be
used early (prophylactically) or later
(empirically) for the prevention of invasive
mycosis. For example, if amphotericin
B deoxycholate did not
have significant dose-limiting nephrotoxicity,
it would be given as prophylaxis
at a dosage of 1 mg/kg/d. In
a 1982 landmark study, Pizzo et al[1]
delayed initiation of empiric amphotericin
B (0.5 mg/kg/d) until at least
day 7 of persistent fever and neutropenia
to justify the use of this toxic
drug only for higher-risk neutropenic

This approach contrasts with the
use of fluconazole, where the therapeutic
dosage (400 mg/d) is used for
prophylaxis before the development
of neutropenia in HSCT recipients.
The seminal studies of Goodman et
al[2] and Slavin et al[3] and subsequent
trials[4,5] demonstrate that fluconazole
has stood the test of time as
an effective agent against Candida
, particularly for the prevention
of invasive candidiasis in HSCT
recipients. Fluconazole prevented infection
with all strains of Candida
except Candida krusei. Breakthrough
infections do occur with fluconazole,
and concerns about resistance of certain
yeast species and molds have led
to studies of prophylaxis with newer
antifungal drugs.

The use of itraconazole to prevent
fungal infections in this setting has
been studied,[6,7] and although it has
been shown to be effective in highrisk
patients, there continue to be concerns
about safety and potential
toxicity with this particular drug. For
instance, frequent gastrointestinal side
effects, including nausea, vomiting,
diarrhea, or abdominal pain, are associated
with itraconazole; this drug can
be difficult to administer in some patient
populations, and inconsistent oral
absorption is always an issue.

Van Burik et al,[8] of the Mycosis
Study Group, recently studied a strategy
of prophylaxis with the investigational
echinocandin micafungin. It
was compared with fluconazole as
prophylaxis in patients during the neutropenic
phase of HSCT. The overall
success rate was higher with micafungin
(80.0%) than with fluconazole
(73.5%). The antifungal agents were
equally effective in the prevention of
invasive candidiasis, but micafungin
was more effective than fluconazole
in preventing mold infections such as
aspergillosis. The two agents had comparable
safety profiles.

Mattiuzzi et al[9] compared caspofungin
(50 mg/d IV) and itraconazole
(200 mg/d IV) prophylaxis in 192 patients
with hematologic malignancies.
The incidence of invasive fungal infections
was similar: 5.7% in the
caspofungin group (n = 106) and 5.8%
in the itraconazole group (n = 86).
Fewer Candida infections developed
in the caspofungin group. It is clear
that in very high-risk patients, a prophylaxis
strategy that includes either
an extended-spectrum azole or an
echinocandin will be necessary to prevent
deadly mold infections.

Empiric Therapy
The rationale for empiric antifungal
therapy in persistently febrile neutropenic
patients is to provide early
treatment of occult invasive fungal
infection and prevent subsequent
breakthrough fungal infection in highrisk
patients. It is likely that early
treatment of a fungal infection is associated
with a better outcome. This
approach to therapy should complement
antifungal prophylaxis. The timing
of empiric therapy is later in the
course of neutropenia, so the population
receiving treatment is smaller,
but the risk of invasive fungal infection
is higher.

Many of the studies of empiric antifungal
therapy have been relatively
large. These studies have included
more than 3,000 patients and have
evaluated many different antifungal
agents, including amphotericin B
deoxycholate,[1,10] liposomal amphotericin
B,[11,12] fluconazole, and
itraconazole.[13] Voriconazole has
been demonstrated to be effective in
preventing breakthrough fungal infections
in high-risk patients with fever
and neutropenia.[14] This drug was
compared with liposomal amphotericin
B as empiric therapy in 837 patients
with neutropenia and persistent
fever. The overall success rates were
not significantly different. However,
the incidence of breakthrough infections
was significantly lower in the
voriconazole group compared with the
liposomal amphotericin B group
(1.4% vs 9.2%).

The number of patients discontinuing
the study drug because of toxic
effects was similar in the two groups.
However, there were more discontinuations
because of lack of efficacy in
patients who received voriconazole
(22 vs 5; P = .001), with persistent
fever being the most common reason
for withdrawal. Patients receiving voriconazole
also experienced more episodes
of infusion-related visual
toxicity (21% vs 1%; P < .001). This
agent is not currently FDA-approved
for this indication.

The recent data on the efficacy of
the echinocandins for empiric antifungal
therapy are very encouraging.
The echinocandins are a new class of
antifungal agent that inhibit the synthesis
of cell wall glucans critical to
the integrity of many yeasts and
molds. As such, they have a unique
mechanism of action; cross-resistance
with conventional antifungal agents
is unlikely.

The antifungal spectrum of the
echinocandins includes Candida species,
Aspergillus species, and Pneumocystis
. Although no clinical
data for pneumocystosis are available,
the in vivo data are noteworthy. However,
the echinocandins have no significant
activity against C neoformans.
The major antifungal activity of echinocandins
against Candida and Aspergillus
species can be explained by
their chemical structure (Figure 2).

The rationale for the early use of
echinocandins in the treatment and prevention
of invasive mycoses in patients
with hematologic malignancies is based
on the strong data on the impact of
these agents on invasive candidiasis and
refractory invasive aspergillosis.[15,16]
The echinocandins have demonstrated
encouraging activity against invasive
candidiasis and invasive aspergillosis,
both in the laboratory and in clinical

Laboratory investigations have
demonstrated that echinocandins are
particularly active in the early treatment
and prevention of invasive aspergillosis.
The impact on early
disease is striking. However, little clinical
evidence had been available concerning
the role of echinocandins in
empiric antifungal therapy in persistently
febrile neutropenic subjects.
Therefore, to address this lack of
knowledge, the largest empiric antifungal
therapy trial was conducted,
involving more than 1,000 patients.[
21] The patients had persistent
febrile neutropenia with hematologic
malignancies (Table 1). Approximately
three-quarters of the patients had
acute leukemia, and the treatment
groups were balanced with respect to
patient age, gender, and underlying

The trial compared caspofungin (70
mg on day 1, then 50 mg/d) with liposomal
amphotericin B (3 mg/kg/d) as
empiric antifungal therapy. The primary
end point was defined as survival to
7 days post treatment, successful outcome
of baseline invasive fungal infection,
the absence of breakthrough
fungal infections to 7 days post treatment,
no premature discontinuation
because of lack of efficacy or drug
toxicity, and resolution of fever during

The results are shown in Figure 3.
Overall success rates were equivalent
in the two treatments, but caspofungin
was much more effective against
baseline fungal infection. The groups
did not differ with respect to breakthrough
infections or resolution of fever,
but there was a significant survival
advantage in patients receiving caspofungin.
Also, in the caspofungin
group, there were fewer cases of discontinuation
of treatment.

In evaluating the efficacy against
baseline fungal infections, the results
were consistent with the activity observed
in the laboratory, with caspofungin
demonstrating virtually a
twofold higher rate of successful outcome
(Table 2). With respect to the
impact on survival at 7 days, caspofungin
was superior to liposomal amphotericin
B (92.6% vs 89.2%, P =
.044; Figure 4).

Findings from the safety analysis
showed that statistically fewer patients
treated with caspofungin suffered
drug-related adverse events, nephrotoxicity,
or infusion-related events
(Figure 5). Caspofungin was significantly
better tolerated throughout the

The results of this very large, rigorously
controlled clinical trial represent
an important advance in our
understanding of the impact of the
echinocandins on early intervention
in patients with hematologic malignancies.
The results could potentially
change the face of empiric antifungal
therapy. Since the final outcome of
most of these studies showed no difference
in final outcome with azoles,
polyenes, or echinocandins, there are
some choices for clinicians to make
in their strategies. However, it is clear
that caspofungin, with its safety, lack
of drug interactions, and efficacy, will
become an attractive choice to use as
empiric therapy in high-risk febrile
neutropenic patients.


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