We present a patient with acute myeloid leukaemia who developed subcutaneously disseminated aspergillosis after allogeneic peripheral stem cell transplantation (PSCT). Disseminated aspergillosis after stem cell transplantation has a high mortality despite treatment with amphotericin B or one of the azoles. Aspergillosis in our patient was refractory to amphotericin B and itraconazole but was successfully treated with caspofungin acetate

Chamuleau, M.E.D.

Deenik, W.

Janssen, J.J.W.M.

Jonkhoff, A.R.

Zaaijer, H.L.

Zweegman, S.

DSpace at VU

M.E.D. Chamuleau et al.
| 36 | haematologica/the hematology journal | 2003; 88(online)
Successful treatment of subcutaneously dissemi-
nated aspergillosis with caspofungin acetate in an
allogeneic peripheral blood stem cell transplanta-
tion patient
We present a patient with acute myeloid
leukaemia who developed subcutaneously dissem-
inated aspergillosis after allogeneic peripheral
stem cell transplantation (PSCT). Disseminated
aspergillosis after stem cell transplantation has a
high mortality despite treatment with ampho-
tericin B or one of the azoles. Aspergillosis in our
patient was refractory to amphotericin B and itra-
conazole but was successfully treated with caspo-
fungin acetate.Haematologica 2007; 88:(3)e36-e37
Introduction
Disseminated aspergillosis refers to an opportunistic
infection by Aspergillus species involving more than one
non-contiguous site. In 60% of cases disseminated
aspergillosis follows invasive pulmonary aspergillosis.
The incidence of pulmonary invasive aspergillosis after
allogeneic PSCT has been reported as 4-10%1,2. After
transplantation, mortality from disseminated aspergillo-
sis remains high (88.1%-90%) despite treatment with
amphotericin B and/or itraconazole2,3. Cutaneous
aspergillosis occurs primary at sites of skin injury or sec-
ondary to disseminated aspergillosis. Subcutaneous dis-
seminated aspergillosis in an immunocompromised
patient was only recently described4. This patient was
treated with amphotericin B but finally died. Here, we
present the second patient with disseminated subcuta-
neous aspergillosis. Her disease was refractory to
amphotericin B and itraconazole but was successfully
treated with caspofungin acetate.
Case report
A 53-year-old woman was diagnosed with acute
myeloid leukaemia (FAB classification M1) in September
1999. After two courses of induction chemotherapy she
received an allogeneic PSCT from an HLA identical sib-
ling after total body irradiation and cyclophosphamide.
At the end of the pancytopenic period she developed
severe desquamative mucositis leading to respiratory
failure which required two days of mechanical ventila-
tion. No infections were found. After three weeks she
developed graft-versus-host-disease (GVHD) grade 3 for
which treatment with high dose prednisone was started.
CMV reactivation was treated by ganciclovir. She recov-
ered and was dismissed six weeks after transplantation
with GVHD grade 1.
Fourteen weeks after transplantation she reported five
painful subcutaneous nodules and severe fatigue and
was admitted to the hospital. Medication consisted of
prednisone 40 mg daily, mycophenolate mofetil, ganci-
clovir, fluconazole and co-trimoxazole. Physical exami-
nation showed GVHD grade 1 of the skin, subcutaneous
nodules on her back, belly and thighs without ulceration
of the overlying skin. Body temperature was 36.2°C.
Laboratory tests revealed: haemoglobin 9.8 g/dl, WBC
7.0 x 109/l with normal differential count, platelets 6 x
109/l, alkaline phosphatase 105 U/l, gamma GT 346 U/l
and bilirubin 12 µmol/l. Biopsy specimen of one of the
nodules showed fungal hyphae typical of Aspergillus
species (figure 1 and 2) and culture confirmed Aspergillus
fumigatus. Computer tomography showed minimal
lesions suspected to be infectious in the right upper lobe
but no cavitation. Echocardiography was normal.
Amphotericin B 1 mg/kg was started and prednisone
tapered. After two weeks itraconazole 200 mg p.o. twice
daily was added because new lesions appeared. These
lesions were progressive and treatment was switched to
voriconazole (loading dose 6 mg/kg, daily dose 4 mg/kg
i.v.). Her clinical situation deteriorated due to sepsis with
E.Coli and to progressive GVHD of the skin and liver.
After successful treatment with antibiotics and
mycophenolate mofetil, she developed pancytopenia.
Recurrence of acute leukaemia was ruled out by marrow
examination. Short-tandem-repeat analysis revealed
100% donor cells. Persistent pancytopenia due to med-
ication was suspected. After discontinuation of co-tri-
moxazole without improvement of blood counts,
voriconazole was discontinued despite a slight positive
effect on the subcutaneous nodules. Caspofungin acetate
was started (loading dose 70 mg, daily dose 50 mg i.v.)
after which she slowly recovered. The dose was adjust-
ed to 50 mg every other day because of detoriating liver
function without other signs of progressive GVHD (high-
est bilirubin 228 µmol/L). Five weeks after starting
caspofungin acetate the subcutaneous nodules had
almost disappeared and she was discharged.
Caspofungin treatment was continued during five
months at a dose of 50 mg three times a week. Twelve
months after discontinuation of caspofungin acetate she
is in complete remission and in good condition. One of
three remaining little nodules was surgically excised and
showed no evidence of Aspergillus fumigatus.
Discussion
A review spanning 1995 through 1999 reports overall
mortality from aspergillosis of 58% and after bone mar-
row transplantation of 86.7%3. For years the treatment
of choice has been amphotericin B. Because of intolera-
ble side effects (nephrotoxicity, infusion-related fever
and chills), second line drugs like lipid formulations of
amphotericin B, itraconazole and voriconazole have
been introduced. A trend towards lower mortality after
use of lipid amphotericin B and itraconazole was report-
ed3, but no randomised studies have confirmed this.
Recently, lower mortality after treatment of invasive
aspergillosis with voriconazole was demonstrated in a
randomised study5. New therapeutic options have been
investigated due to intolerability of amphotericin B, the
price of the lipid formulation and the increasing
(acquired or intrinsic) resistance for azoles. The (1,3)-_-
Figure 1. Subcutaneous localisation of hyphae
D-glucan synthase inhibitors, now designated
echinocandins, disrupt cell wall glucan formation
through non-competitive inhibition of the enzyme com-
plex (1,3)-_-D-glucan synthase. This mechanism of
action is different from that of amphotericin B and
azoles. (1,3)-_-D-glucan synthase is absent from mam-
malian cells6. The spectrum of activity of echinocandins
includes Aspergillus and Candida species. Caspofungin
acetate was found to be superior to amphotericin B in
treating candidal esophagitis (response rates 89% vs.
63%). Furthermore, 56 immunocompromised patients
with sino-pulmonary or disseminated aspergillosis who
were refractory (82%) or intolerant (18%) to ampho-
tericin B, its lipid formulations or azoles were treated
with caspofungin acetate and a favourable response was
reported in 41% of cases8. For disseminated aspergillosis
the response rate was 20%. Caspofungin acetate was
generally well tolerated. Adverse effects included eleva-
tion of serum transaminases (in 10.8%), decreased serum
potassium (10.8%) and increased creatinin levels (1.5%).
The drug is cleared by the liver necessitating dosage
adjustments for patients with hepatic insufficiency. No
pharmacokinetic interaction with amphotericin B, itra-
conazole or mycophenolate was observed. Recently, suc-
cessful combination therapy of caspofungin acetate and
itraconazole in two patients with invasive aspergillosis
was reported9. Cyclosporine A elevates caspofungin
acetate levels and their concomitant use is not recom-
mended. We describe the second patient with proven
disseminated subcutaneous aspergillosis. The first
patient died, but our patient, who’s disease was refracto-
ry to amphotericin B and itraconazole, was successfully
treated with caspofungin acetate and 20 months after
transplantation she has no signs of Aspergillus infection.
Caspofungin acetate seems to be a promising drug for
patients with disseminated aspergillosis. 
M.E.D. Chamuleau, W. Deenik, S. Zweegman, A.R. Jonkhoff,
H.L. Zaaijer, J.J.W.M. Janssen
Correspondence: M.E.D. Chamuleau, MD,
Department of Haematology VU University Medical Centre De
Boelelaan 1117 1081 HV Amsterdam The Netherlands.
Telephone: +31-204442604 Fax: +31-204442601
References
1. Martino R, Subira M, Rovira M, Solano C, Vazquez L, Sanz GF
et al. Invasive fungal infections after allogeneic peripheral
blood stem cell transplantation: incidence and risk factors in
395 patients. Br J Haematol 2002; 116(2):475-482.
2. Jantunen E, Ruutu P, Piilonen A, Volin L, Parkkali T, Ruutu T.
Treatment and outcome of invasive Aspergillus infections in
allogeneic BMT recipients. Bone Marrow Transplant 2000;
26(7):759-762.
3. Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate:
systematic review of the literature. Clin Infect Dis 2001;
32(3):358-366.
4. Cornely OA, Pels H, Bethe U, Seibold M, Toepelt K, Soehngen
D et al. A novel type of metastatically spreading subcutaneous
aspergillosis without epidermal lesions following allogeneic
stem cell transplantation. Bone Marrow Transplant 2001;
28(9):899-901.
5. Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene
RE, Oestmann JW et al. Voriconazole versus amphotericin B
for primary therapy of invasive aspergillosis. N Engl J Med
2002; 347(6):408-415.
6. Hoang A. Caspofungin acetate: an antifungal agent. Am J
Health Syst Pharm 2001; 58(13):1206-1214.
7. Villanueva A, Gotuzzo E, Arathoon EG, Noriega LM,
Kartsonis NA, Lupinacci RJ et al. A randomized double-blind
study of caspofungin versus fluconazole for the treatment of
esophageal candidiasis. Am J Med 2002; 113(4):294-299.
8. Maertens J, Raad.I., Sable SA, Ngai A, Berman R, Patterson TF
et al. Multicenter, noncomparative study to evaluate safety
and efficacy of caspofungin acetate in adults with invasive
aspergillosis refractory or intolerant to amphotericin B,
amphotericin B lipid formulations, or azoles. Paper presented
at 40th Interscience Conference on Antimicrobial Agents and
Chemotherapy, Totonto, Ontario, abstract 1103 . 17-9-2000.
9. Rubin MA, Carroll KC, Cahill BC. Caspofungin in combina-
tion with itraconazole for the treatment of invasive aspergillo-
sis in humans. Clin Infect Dis 2002; 34(8):1160-1161.
haematologica online 2003
haematologica/the hematology journal | 2003; 88(online) | 37 |
Figure 2. Septated hypae with angle branching


Successful treatment of subcutaneously disseminated aspergillosis with caspofungin acetate in an allogeneic peripheral blood stem cell transplantation patient.

Successful treatment of subcutaneously disseminated aspergillosis with caspofungin acetate in an allogeneic peripheral blood stem cell transplantation patient.

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