mucormycosis in a patient with acute myeloid leukemia successfully treated with liposomal...

Mucormycosis in a Patient with Acute Myeloid LeukemiaSuccessfully Treated with Liposomal Amphotericin BAssociated with Deferasirox and Hyperbaric Oxygen

Eduardo Flavio Oliveira Ribeiro • Vitorino Modesto dos Santos •

Guilherme Teixeira Guimaraes Paixao • Leonardo Rodrigues Cruz •

Milena Zamian Danilow • Vinicius Ferreira Campos

Received: 27 August 2012 / Accepted: 18 February 2013 / Published online: 27 February 2013

� Springer Science+Business Media Dordrecht 2013

Abstract We report a 38-year-old woman presenting

with febrile neutropenia, acute myeloid leukemia (AML)

and invasive mucormycosis. Bone marrow aspirate was

characteristic of AML minimally differentiated (WHO

classification 2008). Flow cytometric immunophenotyp-

ing analysis showed blasts positive for CD7, CD33,

CD34, CD71, CD117, HLA-DR, MPO, and TdT, with

normal karyotype (46, XX), and the absence of the

FLT3-ITD and NPM1 mutations. The patient’s manage-

ment included chemotherapy with cytarabine and idaru-

bicin, and treatment with liposomal amphotericin B,

deferasirox, hyperbaric oxygen therapy, and antibiotics.

Nowadays, she is in complete hematological remission,

and CT images of control are normal. Invasive mucor-

mycosis is an uncommon and severe condition, which

involves diagnosis and treatment challenges. Clinical

features and predisposing factors should be highlighted

in order to enhance the suspicion index, contributing to

early diagnosis and disease control. Our aim is to report

classical features of this uncommon condition and to

emphasize usual management challenges.

Keywords Acute myeloid leukemia � Candida

zeylanoides � Deferasirox � Hyperbaric oxygen �Liposomal amphotericin B �Mucormycosis/zygomycosis

Introduction

Mucormycosis/zygomycosis is a rare life-threatening

infection caused by filamentous fungi from the orders

of Mucorales and Entomorphtorales [1, 2], which

are ubiquitous in the soil and vegetable- and

E. F. O. Ribeiro

Onco-Hematology Division, Armed Forces Hospital,

Brasılia, DF, Brazil

e-mail: [email protected]

V. M. dos Santos

Department of Internal Medicine of Armed Forces

Hospital, and Medical Course of Catholic University,

Brasılia, DF, Brazil

V. M. dos Santos (&) � G. T. G. Paixao �L. R. Cruz � M. Z. Danilow � V. F. Campos

Department of Internal Medicine, Armed Forces Hospital,

Estrada do Contorno do Bosque s/n, Cruzeiro Novo,

Brasılia, DF 70658-900, Brazil


G. T. G. Paixao


L. R. Cruz


M. Z. Danilow


V. F. Campos


123

Mycopathologia (2013) 175:295–300

DOI 10.1007/s11046-013-9629-0

animal-decomposing matter [3–7]. The main routes of

infection are percutaneous (trauma, catheters, veni-

punctures, tattoos, bandages, animal bites, insect

pricking) and spores inhalation; people can also

accidentally ingest spores [4, 7]. Predisposing condi-

tions to mucormycosis are uncontrolled diabetes,

hematological malignancies, and hematopoietic stem

cell or organ transplantations [1–10]. This entity

constitutes the third cause of invasive mycosis, after

candidiasis and aspergillosis [5, 7, 11]. Etiological

agents include Mucorales spp., Mucor spp., Rhizopus

spp., Cunninghamella, and Lichtheimia corymbifera

[2, 4, 5, 10]. Mechanisms of disease are related to

conspicuous deficient action of polymorphonuclear

and mononuclear phagocytes [7]. The invasive form of

mucormycosis may occur in 40 % of cases [5], more

often developing in neutropenic patients with acute

leukemia (up to 78 %) [3, 5, 7, 11]. The frequency is

increasing, with high mortality (40–95 %), [1, 5–7, 9],

but case reports are scarce. Diagnosis challenges are

usual in daily practice [1, 5], and routine investigation

includes radiological, microbiological, histological,

and cytological findings [3, 5, 7, 11, 12]. Characteristic

histopathologic findings include necrosis and angio-

invasion by hyaline, broad thin-walled nonseptate

hyphae, with variable diameters, irregular branching,

and ending in right angles [3, 4, 7, 8, 11]. Although

polymerase chain reaction (PCR) might constitute a

promissory tool, it is not widely available and is not

clinically validated yet [3, 11, 12]. Control of mucor-

mycosis may be favorably influenced by amphotericin

B, deferasirox, and hyperbaric oxygen [3, 6, 9, 13].

Good outcomes depend on high suspicion index, early

diagnosis, and adequate therapy schedules [3, 4, 8].

Patients with febrile neutropenia must be closely

followed with special attention on prophylaxis and

early treatment of possible opportunistic infections

caused by bacteria or fungi [4, 8, 11]. Considering that

true incidence of mucormycosis seems to be underes-

timated [3], descriptions of case studies could con-

tribute to better knowledge about this life-threatening

and scarcely reported condition.

Case Report

A 38-year-old woman was admitted to Internal Med-

icine ward with four days history of odynophagia and

fever. Laboratory tests showed hemoglobin 9.4 g/dl,

leukocytes 1,400/mm3, 700 neutrophils/mm3 and

platelets 54,000/mm3 (Table 1). Three months before

admission, her blood counts revealed leucopenia

without anemia or low platelets. With diagnosis of

febrile neutropenia, her initial treatment consisted of

cefepime 2.0 g tid IV. Bone marrow aspirate detected

90 % of undifferentiated small blasts, morphologically

compatible with AML minimally differentiated (WHO

classification 2008). Flow cytometric immunopheno-

typing analysis showed 87.8 % of blasts that were

positively marked for CD7, CD33, CD34, CD71,

CD117, HLA-DR, MPO, and TdT, with normal

karyotype (46, XX), and the absence of the FLT3-

ITD and NPM1 mutations. She underwent the chemo-

therapy protocol 7 ? 3 (continuous infusion of cyt-

arabine 100 mg/m2 IV D1-7, and idarubicin 12 mg/m2

IV 1 h infusion D1-3). Initial thoracic and abdominal

tomography studies showed only a discrete pleural

effusion, and repeated blood cultures were negative.

Due to the persistence of fever, vancomycin was

associated on D2 and cefepime was further changed by

meropenem on D4, with addition of liposomal ampho-

tericin B (L-AmB) on D7. Her left ventricle ejection

fraction decreased from 67 % (pretreatment) to 39 %

on D12, with clinical features of congestive car-

diac insufficiency. Pro-BNP serum levels (normal:

\125 pg/dl) were 3,498 pg/dl on D18 and 576.9 pg/dl

on D22, findings highly indicative of cardiotoxicity by

chemotherapy, which was clinically controlled.

Because of a febrile reaction during amphotericin

infusion, supportive measures were undertaken on D11

and the L-AmB infusion was stopped. Administration

of voriconazole was started on D12. She evolved with

abdominal pain and diarrhea, but stools cultures were

negative and Clostridium difficile toxins A and B were

absent. Abdominal CT showed voluminous ascites,

while thoracic CT revealed pleural effusion and

bilateral interstitial infiltrate. The test for galactoman-

nan antigen detection was negative. Control abdominal

CT showed minute hepatic lesions and conspicuous

splenic lesions (Fig. 1a, b). With hypothesis of hepa-

tosplenic candidiasis, caspofungin was associated with

voriconazole on D21. In addition to a persistent fever,

the patient had dyspnea, low arterial O2 saturation,

and progressive bilateral pleural effusions. Moreover,

bronchoalveolar lavage detected development of Can-

dida spp., and blood cultures were positive for

Candida zeylanoides on D22. Isolates cultured on

Sabouraud-dextrose-agar were seeded and incubated

296 Mycopathologia (2013) 175:295–300

123

for selective yeast isolation, showing colonies of

C. zeylanoides by morphology and color reaction.

The patient evolved with cough and hyaline sputum,

but her respiratory pattern did not improve despite

antifungal therapy. Images of CT obtained on D33

showed nonspecific pulmonary nodules and a more

voluminous splenomegaly with scattered hypoattenu-

ated lesions. Even after the improvement of neutrope-

nia on D35, the patient persisted with daily fever and

CT imaging of conspicuous splenomegaly (Fig. 1a, b).

For diagnosis purpose, total splenectomy (Fig. 1c, d)

and excision of some hepatic implants were performed

on D52, and the specimens were submitted to histo-

pathology and culture evaluations. Respective studies

contributed to characterize the histopathology

diagnosis of hepatosplenic mucormycosis (Fig. 1e, f).

L-AmB was reintroduced (3 mg/kg) in association

with deferasirox (20 mg/kg), and a significant

improvement was observed in her clinical status and

blood counts on D12 of therapy. Because of the high-

risk AML, the option for the consolidation therapy

schedule was high-dose cytarabine—HD-AraC (3 g/

m2 12/12 h)—on D1, D3, and D5. L-AmB and

deferasirox constituted the secondary prophylaxis until

the bone marrow recovery, which occurred on D12 of

24 days of antifungal therapy. After hospital dis-

charge, there was recurrence of fever and leukocytosis,

and CT also showed implants in the vertebrae, pelvic

bones, and lungs, in addition to the liver and kidneys.

The schedule of choice was reintroduction of L-AmB

and deferasirox, at the same previous doses, but

associated with sessions on the hyperbaric camera.

After the first session of hyperbaric oxygen, there were

accentuated leukocytosis (38,000 mm3) and moderate

low platelet level (98,000/mm3), which rapidly

improved after 3 days under this treatment. The patient

underwent 60 sessions on the hyperbaric camera

(5 days a week, during 12 weeks). Concomitant use

of L-AmB was utilized for 21 days, while deferasirox

was used during all the time of hyperbaric oxygen

therapy. After the first consolidation therapy, the

patient is in total hematological remission and CT

images of control remain unremarkable.

Discussion

The case study described herein is about a young woman

with febrile neutropenia secondary to chemotherapy

for AML minimally differentiated, who presented with

an invasive disseminated mucormycosis successfully

controlled by L-AmB in association with deferasirox

and hyperbaric oxygen therapy. The actual increase

in mucormycosis incidence may be related to the

enhanced life expectancy of general population and

growing number of patients with predisposing condi-

tions, in special the immunosuppressant therapies

[1, 4]. Pagano et al. [5] reviewed data from 59 patients

with mucormycosis and hematological malignancies

and found the following distribution by frequency:

AML (51 %), acute lymphoid leukemia (27 %), non-

Hodgkin lymphoma (10 %), hairy cell leukemia and

myelodysplastic syndrome (3 % each), and multiple

myeloma, chronic myeloid leukemia, and Hodgkin’s

lymphoma (2 % each). The mortality rate by mucor-

mycosis is over 40 %, mainly among patients

with hematological malignancies (65 %) or bone

marrow transplants (90 %) [5]. Clinical presentations

of mucormycosis include rhino-orbital-cerebral,

pulmonary, cutaneous, gastrointestinal, disseminated,

and miscellaneous [2, 7, 9, 10]. According to Marques

et al. [4], the most common affected sites are rhino-

sinusoidal (44–49 %), primary cutaneous—localized

or generalized—(10–19 %), pulmonary (10–11 %),

disseminated (6–11 %), and gastrointestinal (2–11 %).

Fever, cough, dyspnea, thoracic pain, and hemoptysis

are usual symptoms of the pulmonary infection [4].

Features of the rhino-sinusoidal disease include fever,

facial pain and edema, nasal obstruction, rhinorrhea,

proptosis, chemosis, and palate damage [4, 10]. Fever,

headache, ptosis, diplopia, hemiplegia, and seizures

can be hallmarks of central nervous system involve-

ment [4]. Fever was the most common finding (80 %)

in patients studied by Pagano et al. [5] who considered

clinical diagnosis of mucormycosis a challenging task.

Disseminated infections more frequently have origin

from pulmonary involvement and the agent causes

scattered foci by hematogenous route. Clinical features

of disseminated disease are nonspecific, leading to

diagnostic pitfalls and late diagnoses, with high

mortality rates. Amphotericin B is not effective to

treat disseminated disease. Routine laboratory data are

nonspecific, but CT and MRI images can reinforce the

early suspicion and contribute to prompt initiation of

adequate therapy [12]. Imaging studies can disclose

hypodense nodules in abdominal viscera or in central

nervoussystem[12,14].ThoraxCTcanshowsuggestive

images of an angiotropic fungal infection, which can be

Mycopathologia (2013) 175:295–300 297

123

distinguished from aspergillosis by the presence of

multiple nodules ([10 mm) and pleural effusions [3].

Quantitative PCR has been a potential molecular

biology resource for diagnosis in developed countries,

but is not included in general routine practice, and

prospective studies are necessary to confirm the initial

results [3, 11, 12]. Fungal culture constitutes the best

method to establish the diagnosis, but this procedure is

time consuming and cannot contribute to the early

treatment for the life-threatening invasive infections

[12]. Moreover, identification of the fungus by seeding

on Sabouraud-dextrose-agar occurs in only one-third

of the surgical specimens [4]. Therefore, biopsy

histopathologic study constitutes the main definitive

diagnostic method in daily practice [3, 11, 12].

Mucorales typically appear as broad nonseptate

hyphae with right angle branching, and vascular

invasion, thrombosis, and necrosis [5, 7, 8, 11]. Our

initial concern was about the finding of Candida spp.

in bronchopulmonary secretions [10] and the further

positivity for Candida zeylanoides in blood cultures.

This novel agent of opportunistic infection produces

blue-green colonies on CHROM-agar Candida culture

medium [15] and presents 50 % of sensitivity to

voriconazole [16]. According to Ricciardi et al. [16],

the in vitro resistance of C. zeylanoides is 100 %

to amphotericin B, flucytosine, fluconazole, and

itraconazole. Therefore, the blood-born infection due

to C. zeylanoides was treated with caspofungin

associated with voriconazole [16, 17]. Association

between caspofungin and voriconazole is scarcely

used, but was prescribed because of Candida growing

in blood cultures, and spleen lesions were initially

attributed to disseminated candidiasis. Moreover, we

were not certain about possible existence of concom-

itant aspergillosis; so, other major concern was about

this angiotropic fungal infection, which is more

frequent than mucormycosis [5, 7, 11, 12]. As the

serum galactomannan test was negative, this differ-

ential diagnosis might be discarded; nevertheless,

inadequate antibody responses are usual in immuno-

suppressed patients, and the sensitivity of serum test

for aspergillosis varies from 22 to 91 % [12]. Alter-

native hypothesis of some more common invasive

infection was further ruled out by direct microscopic

exclusive detection of Mucorales in tissue samples

from the spleen [2]. Although prophylactic antifungal

therapy could be of real benefit to high-risk neutro-

penic patients with hemato-oncological diseases, there

is no consensual drug schedule to be utilized [12].

Successful treatment of mucormycosis is based on

four steps: (1) early diagnosis, (2) elimination of risk

factors if possible, (3) surgical debridement whenever

indicated, (4) and adequate antifungal therapy [3, 4,

Table 1 Laboratory data of a 58-year-old woman with acute leukemia and mucormycosis

Parameters/date D1 D7 D11 D14 D22 D29 D34 D39 D58 D88a

Red cells (4.5–6.1 9 1012/l) 2.52 2.19 2.23 2.72 2.31 2.86 3.09 2.37 2.38 3.74

Hemoglobin (13–18 g/l) 9.4 7.9 7.3 8.7 6.9 8.1 9.6 6.9 6.9 11.2

Hematocrit (42–52 %) 26.4 21.7 21.0 23.9 19.9 25.0 27.3 21.0 21.6 33.2

WBC (4.0–10.0 9 109/l) 1.4 0.7 0.5 0.4 0.4 1.0 3.0 13.1 22.1 1.1

ANC (1.8–7.0 9 109/l) 0.182 0.014 0 0 0 0.790 2.58 11.40 19.23 0.451

Platelets (140–450 9 109/l) 54 32 32 16 23 54 194 282 625 29

Glucose (70–99 mg/dl) 111 ND 76 77 105 92 ND ND 101 93

Urea (16.6–48.5 mg/dl) 17.1 23.6 14.9 15.5 18.6 47.4 9.6 ND ND 24.5

Creatinine (0.7–1.2 mg/dl) 0.6 0.4 0.4 0.3 0.4 0.6 0.4 ND ND 0.6

AST (\40 U/l) 12.1 20.3 12.7 10.9 ND 121 41.2 18.2 ND 14.5

ALT (\41 U/l) 21.0 37.0 28.7 17.7 ND 41.5 23.1 15.0 ND 12.8

ESR (\15 mm/1st h) 12.0 ND 14.0 90.0 ND 34.0 37.0 57.0 91.0 99.0

CRP (\1 mg/dl) 15.6 ND ND 15.7 ND ND 42.4 25.0 ND 8.78

Abnormal data are in bold

WBC white blood cells, ANC absolute neutrophil count, ESR erythrosedimentation rate, CRP C-reactive protein, ND not donea Hospital discharge

298 Mycopathologia (2013) 175:295–300

123

7, 9]. L-AmB has been used for primary antifungal

therapy [2, 9, 18] and may be utilized at higher doses

and for longer periods with lower renal toxicity and

can yield better therapeutic responses [3, 4, 7, 19]. The

dose of L-AmB usually employed is 5–10 mg/kg [3, 4,

6, 19], and clinical improvement depends on the site of

infection and the predisposing conditions. Low dose of

L-AmB (3 mg/kg) was utilized because of the asso-

ciation with other therapeutic agents. The poorest

prognosis has been described in patients with hema-

tological malignancies, who have 32 % of complete or

partial responses [18]. Higher concentrations of

L-AmB have been detected in the following sites, in

a decreasing order: liver, spleen, kidney, lung, myo-

cardium and brain [19]. Monotherapy with azoles

(fluconazole, voriconazole) is not considered useful for

patients with mucormycosis [3, 8]. Association of

caspofungin with amphotericin B showed better results

than monotherapy with this antifungal agent [3, 9].

Although seemingly paradoxical, posaconazole (tria-

zole derivative of second generation) and deferasirox

(iron chelator) are employed as salvage therapy options

for patients refractory or intolerant to amphotericin

utilization [3, 4, 6, 13]. Deferasirox (20 mg/kg) for

2–4 weeks can block the iron influx bomb used by

Mucorales to stabilize its lipid membrane, phenome-

non that makes the fungi more vulnerable to the action

of amphotericin [3]. Although not consensual, invasive

fungal infections may be improved by enhanced

arterial perfusion of infected tissues exposed to oxy-

gen in supra-atmospheric pressures, and potentially

positive results were reported with hyperbaric oxygen

Fig. 1 a, b CT images of small hypodense nodules in the liver

parenchyma (arrows) and accentuated splenomegaly associated

with scattered hypodense nodules (arrowheads); c, d postoper-

ative gross features of the enlarged spleen containing multiple

necrotic nodules; e photomicrography of liver biopsy sample

showing parenchymal changes surrounding a fungal abscess

(HE 9100); f aspect of the hyaline, broad thin-walled

nonseptate hyphae, with variable diameters, irregular branching,

and ending in right angles, typical of Mucorales (Grocott 9200)

Mycopathologia (2013) 175:295–300 299

123

[3, 9, 13]. Local reduction of tissue acidosis can play a

favorable role, but the entire mechanisms of these

favorable results are not yet well understood [13].

Interestingly, Gonzales et al. [20] described a 59-year-

old neutropenic male with disseminated infection

by Rhizomucor pusillus (mucormycosis) successfully

treated with L-AmB and granulocyte colony-stimulat-

ing factor (G-CSF). The opportunistic infection devel-

oped after administration of a protocol for aplastic

anemia (cyclosporine, antithymocyte globulin, and

methylprednisolone). The authors highlighted their

novel therapeutic schedule to improve the severe

prognosis of this condition, emphasizing the search for

efficacious and less toxic agents [20]. Lin et al. [9]

reported successful control of mucormycosis with

posaconazole and hyperbaric oxygen. Our case study

focuses in the association of L-AmB (3 mg/kg) with

deferasirox (20 mg/kg) and hyperbaric oxygen (60

daily sessions, 5 times per week) as alternative

potential therapy for severe mucormycosis, which

should merit further experimental studies. The thera-

peutic association of L-AmB and deferasirox was

performed in the initial febrile stage of disease, with

good response. The triple association, which included

hyperbaric oxygen, was utilized after the patient

discharge from induction chemotherapy. It was main-

tained through the first and second consolidation

chemotherapy with HD-AraC, including the highly

dangerous neutropenic period after consolidation.

Notably, AML treatment was concluded and the

patient is in a good health status.

Conflict of interest There are no conflicts to disclaim.

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