Bone Marrow Transplantation (2010) 45, 1227–1233

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ORIGINAL ARTICLE

Caspofungin first-line therapy for invasive aspergillosis in allogeneic

hematopoietic stem cell transplant patients: an European Organisation
for Research and Treatment of Cancer study

R Herbrecht1, J Maertens2, L Baila3, M Aoun4, W Heinz5, R Martino6, S Schwartz7, AJ Ullmann8,

L Meert3, M Paesmans3, O Marchetti9, H Akan10, L Ameye4, M Shivaprakash11 and C Viscoli12,
for the Infectious Diseases Group of the EORTC
1
Department of Oncology and Hematology, Hôpital de Hautepierre, Strasbourg, France; 2Department of Hematology, Acute
Leukemia and Transplantation Unit, Universitaire Ziekenhuizen Leuven, Campus Gasthuisberg, Leuven, Belgium; 3European
Organization for Research and Treatment of Cancer (EORTC), Brussels, Belgium; 4Jules Bordet Institute, Free University of
Brussels, Brussels, Belgium; 5Department of Internal Medicine II, Division of Infectious Diseases, University of Wuerzburg Medical
Center, Würzburg, Germany; 6Servicio de Hematologı´a, Hospital de la Santa Creu i Sant Pau, Universitat Autónoma de Barcelona,
Barcelona, Spain; 7Department of Hematology and Oncology, Charité B. Franklin, Berlin, Germany; 8Universitätsmedizin, Johannes
Gutenberg-University, Mainz, Germany; 9Infectious Diseases Service, Department of Medicine, Centre Hospitalier Universitaire Vaudois
and University of Lausanne, Lausanne, Switzerland; 10Department of Hematology and Stem Cell Transplantation Unit, Ankara University
Medical School, Cebeci Campus, Cebeci, Ankara, Turkey; 11Merck & Co, White House Station, NJ, USA and 12Division of Infectious
Disease, San Martino University Hospital, University of Genova, Genova, Italy

Caspofungin at standard dose was evaluated as first-line Bone Marrow Transplantation (2010) 45, 1227–1233;
monotherapy of mycologically documented probable/ doi:10.1038/bmt.2009.334; published online 11 January 2010
proven invasive aspergillosis (IA) (unmodified European Keywords: allogeneic; aspergillosis; caspofungin;
Organisation for Research and Treatment of Cancer/ hematopoietic SCT
Mycosis Study Group criteria) in allogeneic hematopoie-
tic SCT patients. The primary efficacy end point was
complete or partial response at end of caspofungin
treatment. Response at week 12, survival and safety were Introduction
additional end points. Enrollment was stopped prema-
turely because of low accrual, with 42 enrolled and 24 Invasive aspergillosis (IA) may develop as a complication in
eligible, giving the study a power of 85%. Transplant was up to 30% of patients undergoing allogeneic hematopoietic
from unrelated donors in 16 patients; acute or chronic SCT (HSCT).1–3 Data from prospective and retrospective
GVHD was present in 15. In all, 12 patients were studies indicate that response rates for IA are low among
neutropenic (o500/ll) at baseline, 10 received steroids allogeneic HSCT recipients, and mortality is higher compared
and 16 calcineurin inhibitors or sirolimus. Median duration with autologous HSCT patients.4–6 Therapeutic decisions for
of caspofungin treatment was 24 days. At the end of these patients are difficult and it is not always possible to
caspofungin therapy, 10 (42%) patients had complete maintain an acceptable balance between toxicity and efficacy
or partial response (95% confidence interval: 22–63%); with commonly used antifungal regimens for IA.7–9 Caspo-
1 (4%) and 12 (50%) had stable and progressing disease, fungin is an exception in that, it has proven not only to be
respectively; one was not evaluable. At week 12, eight effective against IA, but has been well tolerated even among
patients (33%) had complete or partial response. Survival patients who were intolerant to or failed previous therapy.9–11
rates at week 6 and 12 were 79 and 50%, respectively. The objective of this study was to evaluate caspofungin as
No patient had a drug-related serious adverse event or dis- first-line therapy in the treatment of proven and probable
continued because of toxicity. Caspofungin first-line therapy IA in patients who had received allogeneic HSCT. Proven
was effective and well tolerated in allogeneic hematopoietic or probable IA was defined by European Organisation for
SCT patients with mycologically documented IA. Research and Treatment of Cancer–Mycosis Study Group
(EORTC–MSG) criteria, and based on microscopy, culture,
histopathology or Aspergillus galactomannan detection
assay.12 Unlike most studies in IA, patients with a halo
sign only (without proper microbiological documentation)
Correspondence: Dr R Herbrecht, Department of Oncology and were excluded. A second stratum of this study evaluating
Hematology, Hôpital de Hautepierre, Strasbourg 67098, France.
E-mail: [email protected]
caspofungin first-line monotherapy in patients with hema-
Received 10 July 2009; revised 29 September 2009; accepted 16 October tological malignancies and autologous HSCT was designed
2009; published online 11 January 2010 separately and the results have been reported separately.13
 Caspofungin in invasive aspergillosis
R Herbrecht et al
1228
Patients and methods at the end of caspofungin therapy. Secondary end points
included the response rate at week 12 after the start of
Study design caspofungin treatment, survival rate at week 12 and safety.
This phase II, open-label, non-randomized, multicenter study The primary response and survival analyses were
was designed to evaluate the efficacy and safety of caspofungin performed in the modified intent-to-treat patient popula-
as first-line monotherapy in patients with IA and allogeneic tion, which included all patients with mycologically
HSCT. The protocol was approved by the EORTC protocol confirmed probable/proven IA who received at least one
review committee and the institutional review boards of all dose of caspofungin treatment. The per protocol group
participating centers, and the trial was conducted in accordance included eligible patients who received a minimum of 15
with Good Clinical Practices and the Declaration of Helsinki. days of caspofungin treatment but excluded those whose
Written informed consent was obtained from each patient and treatment was modified without adequate reason, accord-
enrollment was centrally coordinated at the EORTC Data ing to the Data Review Committee. Safety was assessed in
Center using a secure web-based system. A Data Review all patients who started treatment, including those who
Committee assessed eligibility and response for each case. were ineligible or not upgraded.
Patient evaluations included medical history, physical
Patient population examination, Karnofsky score, laboratory assessments (hema-
EORTC-MSG definitions were used to determine whether tology and chemistry profiles) at study entry, weekly while on
patients had proven, probable, or possible IA.12 Only treatment, and up to 30 days after end of study treatment.
patients with proven or probable IA strictly according to Repeated Aspergillus galactomannan tests and computed
EORTC–MSG criteria that require positive microscopy, tomography scans or magnetic resonance imaging of chest
culture, histopathology or galactomannan Ag in serum or or any other site of infection were carried out in patients if
in bronchoalveolar lavage (BAL) fluid were eligible for this clinically indicated. Sputum cultures, BAL, biopsy of pulmon-
study. Patients with possible IA, namely those with halo ary and extrapulmonary lesions, and CSF examination were
sign only but without mycological documentation, could be carried out if clinically appropriate. A galactomannan index
enrolled but had to be upgraded to proven or probable IA X0.7 was considered to be positive.14,15 Definite infection
within 7 days of registration based on tests performed required a positive histopathology or culture from a sterile site
before or within 48 h after registration. Patients not (for example, lung biopsy). Two consecutive positive galacto-
upgraded were discontinued from the study but assessed mannan tests in blood or one positive test in BAL or a positive
for safety and treated for IA at the discretion of the sputum or BAL microscopy or culture were needed for a
investigator. All patients were at least 18 years of age and diagnosis of probable infection.
had not received previous therapy with an echinocandin, Study evaluations were carried out using standard
more than 72 h of previous empirical antifungal therapy, or response assessment criteria.16 Complete response required
any investigational agent within 14 days before registration. resolution of all attributable clinical signs and symptoms,
Antifungal prophylaxis was discontinued at study entry. disappearance of all radiological lesions, and no new
Patients were excluded on the basis of known allergy or clinical symptoms or signs or radiological abnormalities
adverse reaction to echinocandins, severe renal failure, compatible with IA (in the case of a residual scar, a
significant liver function test abnormalities (increases in decrease of at least 90% in the sum of the area of the
alanine aminotransferase or aspartate aminotransferase attributable measurable lesions was required). Partial
45  upper limit of normal; serum bilirubin/alkaline response required major improvement of fever and
phosphatase 45  upper limit of normal; Child Pugh attributable clinical signs and symptoms, with no new
score X9), hepatic insufficiency, known bacterial infection clinical symptoms or signs or radiological abnormalities
not adequately treated, documented human immuno- and at least a 50% decrease in the sum of the areas of the
deficiency virus infection, pregnant/lactating women, con- attributable measurable lesions. Stable disease was defined
ditions hampering compliance or a Karnofsky score p20. as the absence of complete or partial response or
progression. Disease progression was defined as worsening
of baseline clinical signs and symptoms attributable to IA,
Treatment or appearance of new clinical signs or symptoms or new
Patients received a 70 mg loading dose of caspofungin on radiological lesions compatible with IA regardless of
day 1, followed by 50 mg/day for at least 15 days and up to localization, or an increase in the sum of areas of the
12 weeks (maximum treatment duration). Dose modifica- attributable measurable clinical and radiological lesions, or
tions were made for patients with body weight 480 kg death likely because of aspergillosis and death because of
(70 mg/day) or moderate hepatic insufficiency (after 70 mg any cause at any time if response could not be assessed
loading dose, 35 mg/day). Addition or modification to before death.
protocol therapy in the absence of an evaluation of efficacy
was considered a treatment failure. Patients with stable
disease were requested to continue study treatment for at Statistical considerations
least 28 days to obtain a final efficacy evaluation. On the basis of a one-stage Fleming design with significance
level of 0.10 and 95% power to detect an effective therapy if
Efficacy and safety end points and evaluations the true response rate was at least 33% (null hypothesis:
The primary end point was the proportion of patients true response rate p13%), this therapy would be recom-
with complete response or partial response to caspofungin mended for further investigation in a phase III trial if at

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 Caspofungin in invasive aspergillosis
R Herbrecht et al
1229
least 8 out of 37 eligible patients had a response. It was Table 1 Baseline characteristics in the modified intent-to-treat
estimated that a total of 62 patients had to be registered to patient population (n ¼ 24)
have 37 eligible patients. Fisher’s exact test was used to test Characteristic n (%)
the statistical significance of differences in response rates
in discrete data. Baseline and end of therapy hepatic and Median age, years (range) 50 (19–65)
renal function tests were compared using the Wilcoxon
Gender
matched pairs test. The 95% confidence intervals for Male 8 (33)
proportions were calculated using exact binomial distribu- Female 16 (67)
tion probabilities.
Previous anti-mold active therapy
Yesa 10 (42)
No 14 (58)
Results
Uncontrolled cancer (not in CR)b 5 (22)
In all, 42 patients were enrolled at 13 centers between May Underlying conditions
2005 and February 2008. At enrollment, 11 patients had Acute myeloblastic leukemia 9 (38)
proven/probable IA and 31 had possible IA. A total of 13 Acute lymphoblastic leukemia 2 (8)
(42%) of the 31 patients with possible IA were upgraded Myelodysplastic syndrome 3 (13)
Chronic myelogenous leukemia 3 (13)
to proven/probable IA. The study was terminated early Chronic lymphocytic leukemia 1 (4)
because of slow accrual. Twenty-four patients were eligible Hodgkin’s/non-Hodgkin’s lymphoma 6 (25)
for the modified intent-to-treat population and all of these
patients were also included the per protocol population. GVHD
With 24 evaluable patients, the study had a power of 85% Yes 15 (63)
No 9 (38)
to reject the null hypothesis in the case of a true response
rate of at least 33% at the chosen significance level of 10%. Diagnosis of IA at the start of treatment
Proven 0
Probable 11 (46)
Patient baseline characteristics and demographics Possible, upgraded to probable within 7 days 13 (54)
All patients enrolled in this study had allogeneic HSCT
and mycological documentation of proven or probable IA Type of transplantation
Related donor 8 (33)
(Table 1). All infections were localized to the lower Unrelated donor 16 (67)
respiratory tract. Acute or chronic GVHD was present in
15 patients (63%). Acute leukemia and lymphoma were the Neutropenia (o500/ml) at the start of study treatment 12 (50)
Neutropenia (o500/ml) for 410 days in previous 60 days 13 (54)
most common reasons for the transplantation. Twelve
patients (50%) were neutropenic (o500 cells/ml) at the start Mycology
of caspofungin therapy; 54% had been neutropenic for Galactomannan in blood X0.7 (X2 positive samples) 15 (63)
more than 10 days during the 60 days before enrollment. Galactomannan in bronchoalveolar lavage X0.7 7 (29)
The median Karnofsky score at enrollment was 70 Positive culture (sputum or bronchoalveolar lavage) 9 (38)
(range: 30–90). Transplants were from unrelated donors Immunosuppressive drugsc
in 16 patients (67%). In total, 10 patients (42%) received Steroids 10 (42)
steroids, 14 (58%) received a calcineurin inhibitors, 2 (7%) Calcineurin inhibitors 14 (58)
received sirolimus and 7 (29%) received other immunosup- Sirolimus 2 (8)
Otherd 7 (29)
pressive agents at baseline or during caspofungin therapy. None 6 (25)
Previous mold-active antifungal therapy was given to 10
patients as prophylaxis or empiric therapy (Table 1). Abbreviation: IA ¼ invasive aspergillosis.
The causative pathogen was isolated in 9/24 patients a
Prophylactic itraconazole: 3 (6, 23 and 112 days), prophylactic posaco-
(Aspergillus fumigatus, n ¼ 4; Aspergillus flavus, n ¼ 1; nazole then empiric voriconazole: 1 (25 and 2 days, respectively); empiric
A. fumigatus and A. flavus, n ¼ 1; Aspergillus nidulans, amphotericin B deoxycholate: 3 (3, 3 and 5 days); empiric voriconazole:
3 (2, 3 and 4 days).
n ¼ 1; Aspergillus spp. n ¼ 2). Positive Aspergillus galacto- b
Not available in one case.
mannan Ag in BAL (n ¼ 7) or serum (n ¼ 15) was found in c
Immunosuppressant administered at baseline and/or during caspofungin
22 out of 24 patients. therapy; patients could have received more than one agent.
d
Mycophenolate mofetil (5), etanercept (1), anti-T lymphocyte monoclonal
antibody (1).
Response to treatment
The median duration of caspofungin treatment was 24 days
(range: 2–85 days). At the end of caspofungin therapy, 10 The survival rate at week 6 was 79% (19 out of 24).
out of 24 patients (42%; 95% confidence interval 22–63%) At week 12, 50% of patients (n ¼ 12)) were alive (Figure 1).
achieved treatment success (complete or partial response) Twelve patients died because of IA (n ¼ 5), hemorrhage
(Table 2). At week 12, 8 out of 24 patients (33%; 95% with aspergillosis (n ¼ 1), underlying disease with aspergil-
confidence interval 16–55%) achieved treatment success. losis (n ¼ 3), and concomitant (n ¼ 1) or subsequent
Success rates at the end of caspofungin therapy by baseline infection without aspergillosis (n ¼ 2). Nine out of 18
characteristics are shown in Table 3. Baseline neutropenic patients (50%) with controlled cancer were alive at week 12
status did not appear to affect the success rate. compared with two out of five patients (40%) with

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 Caspofungin in invasive aspergillosis
R Herbrecht et al
1230
Table 2 Response rates at the end of therapy in the modified hypokalemia (n ¼ 1, grade 3). Creatinine, alanine amino-
intent-to-treat patient population (n ¼ 24) transferase, aspartate aminotransferase, g-glutamyltrans-
Response End of caspofungin At week 12 ferase and alkaline phosphatases serum levels did not differ
therapy n (%) n (%) at end of caspofungin therapy as compared with baseline in
the 42 patients of the safety population (median duration of
Success caspofungin therapy: 13 days, range: 2–85 days) (Figure 2).
Complete response 0 4 (17)
Partial response 10 (42) 4 (17)
Results did not differ when analysis was restricted to
the 24 patients in the modified intent-to-treat population
Failure (median duration of caspofungin therapy: 24 days, range:
Stable disease 1 (4) 1 (4) 2–85 days).
Disease progression 12 (50) 2 (8)
Not done 1 (4) 1 (4)
Death before assessment — 12 (50)
Discussion

Caspofungin was found to be a well-tolerated, effective

Table 3 End of caspofungin treatment response rates according to first-line therapy in patients with IA and allogeneic HSCT.
baseline characteristics (n ¼ 24) At the end of caspofungin therapy, 42% (95% confidence
Characteristic Success P-value interval 22–63%) of patients had a favorable outcome. The
n/N (%) survival rate was 79% at week 6 and 50% at week 12.
The response rates achieved at the end of caspofungin
Status of underlying cancera therapy were notable considering the 24 day median
CR 6/18 (33) 0.34
Not in CR 3/5 (60)
duration of therapy and the severity of the underlying
immunosuppression. Our study included only patients with
Diagnosis of IA at the start of treatment the highest risk of IA who had the worst prognosis:
Probable 5/11 (45) 1 allogeneic HSCT recipients.17 In contrast, allogeneic
Possible at baseline, upgraded to probable 5/13 (38)
HSCT patients represented a minority of the cases in the
within 7 days
two major clinical trials conducted in IA during the
Underlying condition last decade.16,18 A favorable response rate of 32.4% was
Acute leukemia 6/11 (55) 0.35 reported in 37 patients treated with voriconazole and
Chronic leukemia 2/4 (50) 13.3% in 30 patients treated with amphotericin B
Other 2/9 (22)
deoxycholate.16 In a study comparing two doses of
Presence of GVHD liposomal amphotericin B (AmBiLoad trial), the best
Yes 6/15 (40) 1 tolerated dose (3 mg/kg daily) provided a 47% favorable
No 4/9 (44) response rate in 17 patients with allogeneic HSCT.18
In both of these studies, allogeneic HSCT was associated
Neutropenia (o500/ml) at the start of treatment
Yes 5/12 (42) 1 with a worse outcome than other hematologic conditions.
No 5/12 (42) Similar observations have been reported from a large,
retrospective single-center study.4
Previous mold active antifungal therapy Our study was characterized by very stringent inclusion
Yesb 6/10 (60) 0.21
No 4/14 (29)
and assessment criteria. Strict adherence to EORTC/MSG
criteria for the case definition is the exception rather than
Abbreviation: IA ¼ invasive aspergillosis. the rule in designing trials evaluating regimens for IA.
a
Not available in one case. Following these criteria strictly made our trial unique.
b
For type and duration of previous mold active therapy refer to Table 1. Only patients with documented mycological criteria were
considered to have probable or proven IA and enrolled in
our study. In contrast, a high proportion of high-risk
patients with halo sign only were enrolled in the AmBiLoad
uncontrolled cancer (P ¼ ns). A similar proportion of trial and to a lesser extent in the voriconazole trial;16,18
patients with (50%) and without neutropenia at entry thus, many patients did not have mycological confirmation
(50%) were alive at week 12. of IA in these two studies. It has been shown that patients
with non-mycologically confirmed IA (possible cases
Safety according to EORTC/MSG criteria) have much better
No serious caspofungin-related adverse events or adverse outcomes than patients with strictly defined disease.4 As
events leading to discontinuation were observed in this such, our results are not suitable for comparison with these
study. Drug-related adverse events were reported for 3 of other trials that included patients with less rigorously
the 42 patients included in the safety analysis (7%). These defined disease.16,18
laboratory adverse events, categorized as likely related to In addition, the response criteria used in the AmBiLoad
caspofungin by the investigators, included increased study allowed the disappearance of a halo sign or a
bilirubin and increased g-glutamyltransferase (n ¼ 1, grade decrease in lesion size without indication of the percentage
4 and grade 2, respectively), increased alanine aminotrans- reduction as a criteria for partial response.19 Our assess-
ferase and aspartate aminotransferase (n ¼ 1, grade 3) and ments were based on stringent, predefined criteria similar to

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 Caspofungin in invasive aspergillosis
R Herbrecht et al
1231
100

80

Percent survival
60

40

20

0
0 2 4 6 8 10 12
Time (weeks)

Figure 1 Survival in 24 allogeneic hematopoietic SCT recipients with mycologically documented invasive aspergillosis (IA) and treated in first line with
caspofungin.

240 1000
900
200 800
Creatinine (μmol/L)

700
160 γ-GT (IU/L)
600
120 500
400
80 300
200
40
100
0 0
Baseline EOT Baseline EOT

200 200

160 160
AST (IU/L)

ALT (IU/L)

120 120

80 80

40 40

0 0
Baseline EOT Baseline EOT

1000
900
800
a: Creatinine; P =0. 16
700
ALP (IU/L)

600
b: γ-glutamyltransferase; P =0.19
500
c: Aspartate aminotransferase; P =0.08
400
300
d: Alanine aminotransferase; P =0.93
200
100
e: Alkaline phosphatases; P =0.75
0
Baseline EOT
Figure 2 Renal and liver function tests at baseline and end of caspofungin therapy (EOT). Box plots show median values (line in box), 25th and 75th
percentiles, and outlying values (vertical lines). Safety population comprises 42 patients.

those used for the voriconazole trial; a partial response Recent data suggest that survival should be assessed at
required a decrease of at least 50% of the sum of the area of week 6 rather than week 12 as most deaths occurring
the baseline radiological lesions in conjunction with after week 6 are related to the underlying condition.20,21
significant symptomatic improvement. Interestingly, survival analysis showed 79% survival at

Bone Marrow Transplantation

 Caspofungin in invasive aspergillosis
R Herbrecht et al
1232
week 6 in our patients confirming the efficacy of travel grants and honoraria from MSD and Pfizer.
caspofungin against IA in allogeneic HSCT patients. Even M Shivaprakash is employed by Merck & Co, Inc. C
at 12 weeks, half the patients survived. Viscoli has been a consultant to Astellas, Gilead, Merck &
As in previous studies caspofungin had a favorable safety Co, Pfizer, Schering-Plough, has been member of speaker’s
profile.22,23 This point is critical in allogeneic HSCT bureaus for Gilead, Pfizer, Schering-Plough and has
recipients who usually require multiple concomitant received research grant from Pfizer, Merck & Co, Gilead,
medications including immunosuppressive agents. The BMS and Abbott. L Baila, L Ameye, L Meert, M Paesmans
absence of nephrotoxicity with caspofungin is in contrast and R Martino declare no conflict of interest.
to the high rate of nephrotoxicity observed with amphoter- Data Review Committee: H Akan, L Baila, R Herbrecht
icin B and its lipid formulations.16,18,24 Importantly, drug– (chairman), O Marchetti, R Martino, L Meert (data
drug interactions leading to potentially severe adverse manager), M Paesmans (statistician) and AJ Ullmann.
events have been reported between triazole antifungal
agents and various other drugs, especially the calcineurin
inhibitors and sirolimus. These interactions are explained Acknowledgements
by inhibition of various cytochrome P450 isoenzymes by
the triazole antifungals.9,25 Two-thirds of our patients We thank Wendy Horn, PhD for writing and editorial
received cyclosporine, tacrolimus or sirolimus concomi- assistance, which was funded by Merck & Co, Inc. Presented
tantly with caspofungin without any indication of relevant in part as a poster at the 48th Annual Meeting of the
interactions. No renal toxicity, except one case of Interscience Conference on Antimicrobial Agents and
hypokalemia, was attributed by investigators to caspofun- Chemotherapy, 25–28 October 2008, Washington, DC.
gin, and neither of the two patients who experienced
increased transaminases or increased bilirubin received any
of these immunosuppressants concomitantly with caspo- References
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