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Long-Term Follow-up of Patients With Invasive Fungal Disease
Who Received Adjunctive Therapy With Recombinant
Human Macrophage Colony-Stimulating Factor
By John Nemunaitis, Kathleen Shannon-Dorcy, Frederick R . Appelbaum, Joel Meyers, Ada Owens, Richard Day,
Dale Ando, Catherine O’Neill, Dean Buckner, and Jack Singer
Mortality of bone marrow transplant (BMT) patients who
develop invasive fungal infection is greater than 80%.
Long-term follow-up of 46 consecutive BMT patients who
receivedrecombinanthuman macrophagecolony-stimulating factor (rhM-CSF) as adjunctive therapy with standard
antifungal treatment who were entered into phase 1/11
trials at The Fred Hutchinson Cancer Research Center is
reported. rhM-CSF (100 gg/mz to 2,000 pg/m2; Chiron/
Cetus Corporation, Emeryville, CA) was administeredfrom
day 0 to 28 after determination of progressive fungal disease. Results of long-term follow-up of fungal infection,
relapse, and survival were compared with 58 similar his-
torical controls. Multivariable analysis of the patients who
received rhM-CSF showed two factors that significantly
correlated with poor survival: Karnofsky score s 20% and
Aspergillus infection. Overall, survival of patients who received rhM-CSF was greater than that of historical patients (27%v 5%) and was entirely because of a 50% survival rate in patients with Candida infection and Karnofsky
scores greater than 20%. Prospective, randomized, controlled trials to determine efficiency of rhM-CSF are indicated and should be directed at patients with invasive candidiasis.
0 1993 by The American Society of Hematology.
T
MATERIALS AND METHODS
Patient selection. Patients with presumed or documented fungal infections before or after BMT were eligible. No exclusions were
made for diagnosis, age, graft-versus-host disease (GVHD) status or
Kamofsky performance scores. Results of the first 24 patients have
been previously published.’ Subsequently, an additional 22 consecutive patients who received rhM-CSF at 2,000 pg/m2/d were entered into trial. Clinical characteristics of the 46 patients who received rhM-CSF are shown in Table 1. Informed consent
conforming to Federal Drug Administration and Institutional Review Board Guidelines was required. Comparison of study patients
was made to historical control patients. A summary of the characteristics of both patient groups is shown in Table 2.
Patient eligibility. Patients were included if they had one of the
following characteristics: documented invasive fungal infection
demonstrated by histologic analysis or cultures of closed-body
fluids or tissue biopsies, a single, positive blood culture with radiologic evidence of invasive disease, two or more positive blood cultures for Candida species without a documented local site of infection, or persistent fever with fungi dated from bronchial alveolar
lavage fluid with radiologic studies suggestive of fungal infection.
Clinical monitoring. All patients were examined daily while receiving rhM-CSF. Bone marrow aspirates and biopsies were performed before therapy to rule out malignancy. Blood cultures were
taken as clinically indicated. Chemistries and complete blood cell
counts were performed daily. Evaluation of fungal infection was
performed by repeating the initial diagnostic procedure when possible or at autopsy. Long-term follow-up, evaluation for the persistence of fungal infection, cause of death, and survival was made by
review of medical records and phone conversations with the patient’s primary physician. Diagnostic procedures originally used to
document fungal infection were repeated when possible or at autopsy.
Study design. The design of the study into which the initial 24
patients were entered has been previously described? The subsequent 22 patients received rhM-CSF at a dose of 2,000 pg/m2/d by
2-hour intravenous infusion for 28 consecutive days. rhM-CSF (specific activity: 1 X 10’ U/mg; Cetus Corporation, Emeryville, CA)
was administered in 100 mL of normal saline with 0.25% albumin
by central venous catheter. All patients received amphotericin at
maximally tolerated doses (.5 to 1.0 pg/kg/d). Results were compared with 58 historical patients who were retrospectively identified
EN PERCENT of patients undergoing allogeneic bone
marrow transplantation (BMT) will develop invasive
fungal disease with an associated high morbidity and mortalit^.'*^ Prophylactic treatment with antifungal agents or use
of laminar air flow rooms may reduce the incidence of fungal infection4%’;
however, once infection develops, little therapy other than treatment with amphotericin is available.
Recombinant human macrophage colony-stimulating
factor (rhM-CSF) is a cytokine that stimulates the survival,
proliferation, and differentiation and enhances the function
of monocytes and macrophage^.^.' Preclinical studies show
that this activity is associated with a substantial increase in
the ability of monocytes and macrophages to kill fungi.’
rhM-CSF was well tolerated when administered to patients
who developed invasive fungal infection after BMT’ and in
patients with metastatic cancer.” Other than thrombocytopenia, which was a dose-limiting toxicity, no other significant side effects were observed. Several patients had resolution of fungal infection contemporaneously with rhM-CSF
and amphotericin treatment’; however, long-term assessments were not performed. This article reports long-term
follow-up of the 24 rhM-CSF-treated patients who were
originally reported in addition to 22 consecutive patients
who received rhM-CSF at the maximum tolerated dose of
2,000 pg/m2/d.
From the Fred Hutchinson Cancer Research Center, Seattle, WA:
the Western Pennsylvania Cancer Institute, Pittsburgh. PA: the University of Pittsburgh. Pittsburgh, PA; Chiron Corp, Emeryville, CA;
and Cell Therapeutics lnc. Seattle, WA.
SubmittedMarch 11, 1993: acceptedMay 16, 1993.
Address reprint requests to John Nemunaitis, MD, Texas Oncology, 3320 Live Oak, Suite 400, Dallas, TX 75204.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
“advertisement” in accordance with 18 U.S.C. seclion I734 solely to
indicate this fact.
0 I993 by The American Society of Hematology.
0006-49 71/93/8205-0036$3.00/0
1422
Blood, Vol 82, No 5 (September 1). 1993: pp 1422-1427
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
M-CSF IN FUNGAL INFECTION
1423
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From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
I424
NEMUNAlTlS ET AL
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Table 2. Comparison of Characteristics Between
rhM-CSF-Treated Patients and Historical Controls
: c JI
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Historical
Controls
5.g
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rhM-CSF-Treated
Patients
5127189-61319 1
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MM/MDS/AA/HD/Nb
Disease state:
relapse/remission/NA
1/ ~ / 3 / 5 /1
1 /1/5/2/0
5127189-6/3/91
46
31
28118
2911 118
28/5/6
CP/AP/BP
TBI: yes/no
LAF: yes/no
BMT type:
sibling/unrelated/autologous
mismatch related/syngeneic/
2/3/5
4011 8
23/35
4/21 1
33/13
20126
3211 019
2111216
NA
Karnofsky score:
>20%/<20%
Fungus type:
7/0/0
5/111
38/20
30116
4311411
30/15/1
3111213
17/10/9
6/2/1
211
5/2/1
210
21/25
organ infected:
~ Primary
~
blood/lung/liver
skin/central nervous
system/bone
sinus/kidney
Pentoxifylline: yeslno
? E s o
iGJ V
3 0
",0
1/29/88-5/26/89
58
32
34/24
CandidalAspergilIus/mold
zE $i ?z ?
- O E = O = O E = - = = =
-
Dates qualified
Number patients
Median age (years)
Sex: malelfemale
Disease:
AML/CML/ALL/NHL
0/58
Abbreviation: Nb, neuroblastoma.
P
$:z;> 6* Zm a
by evaluating all medical records from May 27, 1989, the date before the first patient entered into the rhM-CSF trial, to a random
c
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date of January 29, 1988. Consecutive patients who fulfilled the
P
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a € . o
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Statistical analysis. Logistic regression was performed on categorical outcome variables (ie, cause of death, evaluation of fungus).
<
t>
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Cox regression was performed on the continuous outcome variable
> <
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> t> >C C ' 1 5
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(survival in days). Kaplan-Meier curves were produced for survival
E c c
-an ua .-: z 5
times across relevant predictor characteristics. All analyses were
- L - - - $ - ~ z n - z z u ~ aE ~ - . ~ , S performed using the EGRET statistical package (Statistics & Epide?o??e<?<<zY?<<es5
.'--l'J-.Jd
miology Research Corp, Software Division, Seattle, WA). Outcome
3
$ ~ ~ Y r J z r & 5 5 5 r r J- . rS J m =
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variables included survival (continuous, days), cause ofdeath (cate.., m i -m = 3 , .
gorical, fungus/other), and evaluation of fungus on day of follow-up
.,8 B E. b
(categorical, fungus/no fungus). Predictor variables included age
(continuous), sex (categorical, male/female), treatment with peng g g 8 g g g g g 8 g g g g 8 8 8 5 .f y 0
0
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toxifylline (categorical, yes/no), maximum dose of rhM-CSF (conS a G 5 Z
tinuous), BMT type (categorical, autologous/allogeneic), pre-M.s 6 u:a g
CSF Karnofsky performance scores (continuous), pre-rhM-CSF
Qg;zD
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-5 5 p
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(categorical, 0-IV), organ of fungal involvement (categorical,
z > >- > > > z > > > t z z z > t 50 *Z v,
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blood/liver/other), fungus type (categorical, Aspergillus/Candida),
m g r d
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i'ab82
2
.i
air flow room, and day post BMT of rhM-CSFadministration. Vari;; % Q
3
ables other than rhM-CSF that significantly affected survival were
F
T F e e e e k ! = ? e hbeEz tF ~oe ev)!o= .gc .oE .i. m g,o
identified for patients who received rhM-CSF, then comparison to
w t m N o ~o E o w o
m t m o t
m m ~ m
- * e m "
, Z C historical controls was made controlling for the significant variables
> P S ' F Z
by Kaplan-Meier analysis. To increase the stringency ofanalysis the
ze Vr -nE ca 5
L o - - L o o m N N m N N o m z w w difference in overall survival was adjusted by Bonferroni adjustN w - w m N z h ~ - m ~ mV I W P I
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From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
1425
M-CSF IN FUNGAL INFECTION
RESULTS
Toxicity. Thrombocytopenia (reduction by more than
50%) was observed in 9 of the first 24 patients who received
rhM-CSF. Thrombocytopenia occurred in 2 of the subsequent 22 patients (UPNs 5074, 5929) and both required a
dose reduction of 50% (to 1,000 pg/m2/d). Platelet counts
remained low until rhM-CSF was discontinued; however,
platelet counts did not decrease further after institution of
the lower rhM-CSF dose. No other toxicity ascribed to rhMCSF was observed.
Presence of fungal infection at day of follow-up
evaluation. Twelve (87%) patients who did not survive 15
days had evidence of persistent fungal infection at the time
of death (Tables 1 and 3). Patients who survived and received more than 2 weeks of therapy with rhM-CSF had a
low incidence of fungal infection at time offollow-up (5/30,
17%). No patients who survived more than 150 days had
documentation of recurrent fungal infection.
Survival. Cox regression using survival time in days as
the outcome variable showed two significant independent
predictor variables: Kamofsky performance scores 5 20%
( P < .001; odds ratio = 6.97) and type of fungus (Aspergillus) ( P = .055; odds ratio = 2.01) that were associated with
lower survival. The logistic regression using evaluation of
the presence of fungus at time of follow-up evaluation (present or not present) as the outcome variable also showed the
same two significant predictors: Karnofsky performance
scores of 120% ( P < .OO 1, odds ratio = 37.94) and Aspergillus infection ( P = .OO 1, odds ratio = 2 1.69). Survival of all
patients who received rhM-CSF compared with historical
controls is shown in Fig 1. Median follow-up of surviving
patients who received rhM-CSF was 642 days (range 370
days to 903 days). Twelve patients remain alive and free of
fungal disease. Thirty-four patients did not survive. The incidence of recurrence of malignancy was similar in the rhMCSF-treated patients and the historical patients. Causes of
death are shown in Table 1. The difference in overall survival was entirely because of better survival of patients with
>20% Karnofsky score with invasive candidiasis. The survival of these patients compared with historical controls
matched for similar Karnofsky performance scores and
types of fungal infection is shown in Fig 2. A comparison of
survival of rhM-CSF-treated patients to historical controls
controlling for significant variables affecting survival is
shown in Table 4.No difference in survival was observed in
patients with 520% Karnofsky scores regardless of the type
of fungal infection or in patients with Aspergillus infection
regardless of the Karnofsky score. Other characteristics of
Table 3. Presence of Fungal Infection at Time of Evaluation
~
Davs of Survival
0-1 5
16-1 50
>150
~
Ratio (%) of Patients With Fungus
at Dav of Death or Last Follow-uo Dav
12115 (87)
5115 (33)
011 5 (0)
The persistence of fungus was undetermined in one patient who did
not undergo autopsy. He is not listed in this table.
'
I
0'
0
,m
2w
300
400
em
Joo
7w
800
900
Disease Free Survival (in days)
Fig 1. Survival by Kaplan-Meier analysis of 46 patients with invasive fungal infection who received rhM-CSF (-)
compared
with 58 historical controls (--).
Comparison was made using
Mantel-Cox statistics; P = ,027.
rhM-CSF-treated patients and historical controls were similar (Table 2); however, 2 1 of the rhM-CSF patients received
pentoxifylline during the past transplant course compared
with none of the historical controls. This was not felt to
affect the survival results because administration of pentoxifylline did not affect survival in patients who received rhMCSF. Variables such as age, sex, maximum dose of rhMCSF, type of BMT, GVHD, organ of fungal involvement,
disease, disease state, use of total body radiation, use of laminar air flow room, and day of rhM-CSF administration also
did not affect survival in patients who received rhM-CSF.
DISCUSSION
Overall, patients who received rhM-CSF had better survival then did historical controls or patients reported previ-
o
~
w
m
o
3
0
0
4
~
5
m
~
7
m
(
Disease Free Survival (in days)
Fig 2. Disease-freesurvival by Kaplan-Meier analysis of 2 0 patients with Karnofsky scores > 20% and Candida (n = 19) or Mucor (n = 1) infection (-)
who received rhM-CSF compared with
33 historical controls (- -) with the same Karnofsky scores and
fungal infection (32 Candida, 1 Mucor). Both patients with Mucor
died within 100 days after qualification. Comparison was made by
using Mantel-Cox statistics; P = .004.
1
w
~
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
NEMUNAITIS
1426
ET AL
Table 4. Survival of Patients Who Received rhM-CSF Compared With Historical Controls
Group
rhM-CSF
Control
P valuet
P value*
>20%
Karnofsky Candida
9 0 % Karnofsky Aspergillus
50% (n = 20)*
15% (n = 33)*
,004
c.05
20% ( n = IO)
0% (n = 5)
.675
ns
520%
Karnofsky Candida
0% In = 1 1 )
9% I n = 1 1 )
,565
ns
520% Karnofsky Aspergillus
Total
0% (n = 5)
27% (n = 46)
5% ( n = 58)
.027
ns
0% (n = 9)
.228
ns
Abbreviation: ns, not significant.
* Includes 1 patient with M u c o r w h o did not survive as a result of progressive infection.
t Mantel-Cox analysis.
$ Bonferroni adjustment.
ously.8 However, the difference in overall survival was entirely because of a subset of treated patients with Candida
infection and Karnofsky performance scores > 20%.
Whether this is related to improved critical care techniques
over time or the effect of rhM-CSF on monocyte/macrophage function awaits completion of an ongoing randomized, placebo-controlled trial. The majority of patients who
survived long enough to receive the entire course of rhMCSF did not develop recurrent fungal infection. These data
suggest that the improved survival resulted from resolution
of fungal disease. Potential beneficial activity of rhM-CSF
may be a result of its functional enhancing capacity in
monocytes and macrophages. Several in vitro studies have
shown activation of monocyte and macrophage function
with enhanced fungicidal activity after exposure to rhMCSF."-I4 Improved survival because of reduced mortality
was also observed in Candida-infected mice and rats given
rhM-CSF.'*,'' Enhanced function of monocytes occurs
within 2 hours of administration of M-CSF in patients with
lymphoma.I6 Some effects of M-CSF may also be via indirect mechanisms. rhM-CSF stimulates monocyte production of granulocyte CSF, granulocyte-macrophage (GM)
CSF, interleukin- 1, tumor necrosis factor-a, and interferon
in vivo. These cytokines may further enhance cellular abilities to kill infecting o r g a n i s m ~ . 'Determination
~
of monocyte and/or macrophage function and circulating cytokine
levels may identify patients likely or unlikely to respond to
rhM-CSF or other growth factors." rhGM-CSF may have
similar antifungal properties to rhM-CSF,L8,19
whereas rhGCSF is without affect."
Results of this trial further substantiate those of the previously reported data and suggest that rhM-CSF is well tolerated at doses u p to 2,000 pg/m2/d. Reduction of the dose by
50% seems to minimize the severity of thrombocytopenia
although the effects ofthe lower dose on functional enhancement of monocytes and macrophages may be reduced. Randomized placebo-controlled trials are needed to determine
definitively the effect of rhM-CSF o n resolution of fungal
infection and survival.
ACKNOWLEDGMENT
The authors wish to acknowledgethe secretarial support of Patricia A. Vasilatosand Christine M. Hall in preparation of this manuscript.
REFERENCES
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1993 82: 1422-1427
Long-term follow-up of patients with invasive fungal disease who
received adjunctive therapy with recombinant human macrophage
colony- stimulating factor
J Nemunaitis, K Shannon-Dorcy, FR Appelbaum, J Meyers, A Owens, R Day, D Ando, C O'Neill, D
Buckner and J Singer
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