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Blood, 1 April 2002, Vol. 99, No. 7, pp. 2615-2616
BRIEF REPORT
Transient hematologic and clinical effect of E21R in a child with
end-stage juvenile myelomonocytic leukemia
Frédéric Bernard,
Caroline Thomas,
Jean
François Emile,
Timothy Hercus,
Bruno Cassinat,
Christine Chomienne, and
Jean Donadieu
From the Pediatric Department, Hemato-Oncology Unit,
CHU Montpellier, France; Pathology Department, Hôpital P Brousse,
Villejuif, France; Pediatric Hémato-Oncology Department, CHU,
Nantes, France; Cytokine Receptor Laboratory, Hanson Institute,
Adelaide, Australia; Laboratory of Biology of Hematopoietic cells,
Hôpital Saint Louis, Paris, France; and the Pediatric
Hemato-Oncology Department, Hôpital Trousseau, Paris, France.
 |
Abstract |
E21R is a modified granulocyte macrophage-colony-stimulating
factor (GM-CSF) protein which results in antagonism of GM-CSF function
via selective binding to the GM-CSF receptor complex. Juvenile chronic
myelomonocytic leukemia (JMML) is a rare leukemia where spontaneous
proliferation of myeloid and monocytic precursors in patients' bone
marrow cultures is dependent on GM-CSF. For patients who progress after
systemic chemotherapy, there are no effective therapies. In vitro and
in vivo studies in an animal model demonstrating that E21R exerts an
antileukemic action prompted us to consider its potential utility in a
child with end-stage JMML. E21R was well-tolerated during the 3 courses
of subcutaneous treatment. A clear in vivo efficacy was observed after
2 courses of E21R but the disease appeared completely refractory during the third course. This novel therapeutic approach clearly deserves further evaluation in JMML.
(Blood. 2002;99:2615-2616)
© 2002 by The American Society of Hematology.
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Introduction |
Juvenile chronic myelomonocytic leukemia
(JMML) is a rare leukemia characterized by monocytosis and a moderate
increase in blasts.1 Spontaneous proliferation of myeloid
and monocytic precursors, dependent on granulocyte
macrophage-colony-stimulating factor (GM-CSF), is a characteristic of
these patients' bone marrow cultures. Myeloid and monocytic JMML
progenitors are hypersensitive to GM-CSF. For patients exhibiting poor
prognostic features, mainly thrombocytopenia, bone marrow
transplantation is the only curative therapeutic option.2
A transient response may result from chemotherapy such as Ara-C, VP-16,
6-mercaptopurine, and hydroxyurea, but these responses are never
complete. For patients who progress after systemic chemotherapy there
are no effective therapies.
| |
Study design |
E21R is a GM-CSF analogue generated by substitution of the
glutamate (E) at position 21 with an arginine (R) residue, the overall
result being to abolish the interaction of GM-CSF with the beta chain
of its receptor, and thus eliminate signaling.3,4 E21R has
a dual mechanism of action: antagonism of GM-CSF function, via
selective binding to the receptor alpha chain, and induction of
apoptosis in cells carrying the GM-CSF receptor. In vitro, E21R
inhibits GM-CSF activity on myeloid leukemic cells5 and in
vivo, E21R exerts an antileukemic action in a transplanted animal
model,6 prompting us to consider its potential utility in JMML.
The protein is produced by BresaGen (Adelaide, Australia). A phase I
study in adult solid tumor patients indicated that at the maximum dose
tested subcutaneously (1 mg/kg per day for 10 days), E21R has a good
safety profile (Olver et al, unpublished data, December
2001) and thus, these conditions were utilized in the current
study. The level of E21R and anti-E21R antibodies were monitored during
each course of treatment. Serum concentrations of E21R were determined
using a quantitative human GM-CSF enzyme-linked immunosorbent assay
(ELISA) kit from R&D Systems (Minneapolis, MN). Measurement of
antibodies toward E21R was performed using a sandwich
ELISA (Olver et al, unpublished data, December 2001).
Our patient is a boy who was born in 1992. The diagnosis
of JMML was made in 1996, with associated liver and spleen enlargement and skin infiltration. Initial complete blood count (CBC) showed 28 400 white blood cells (WBC)/µL, 10 508 monocytes/µL, 10 224 neutrophils/µL, 6248 lymphocytes/µL, Hb 9.7 g/dL, and 26 000
platelets/µL. Initial bone marrow cytogenetics were normal. Oral
chemotherapy (hydroxyurea) was ineffective. Since his brother was HLA
antigen identical, an allogeneic bone marrow transplantation was
performed in 1997 with busulfan/cyclophosphamide as the conditioning
regimen. Complete remission occurred but the disease relapsed 18 months later and a second transplantation was performed in 1999 with the same
donor and with TBI/Ara-C/melphalan as the conditioning regimen. The
disease relapsed again 6 months later. No graft-versus-host-disease was
observed after either transplantation. Three donor lymphocyte infusions
were performed without any response. Different chemotherapy was
attempted (hydroxyurea, 6-mercaptopurine) with no antileukemic effect.
The general status rapidly worsened with pain, fever, and splenomegaly
at 12 cm below the left costal margin as well as hematologic
deterioration with leukocytosis, monocytosis, and peripheral blasts. At
the beginning of August 2000, CBC showed 51 700 WBC/µL, 20 163
monocytes/µL, 3619 blasts/µL, and 31 000 platelets/µL. A bone
marrow examination showed infiltration with 17% blast cells. Bone
marrow cultures were unsuccessful. After informed consent was signed by
the parents and an individual authorization for compassionate use was
provided by the French drug agency, treatment with E21R was commenced.
Three courses were administered. The first 2 courses lasted 10 days and
the third lasted 14 days. The second course began on day 21 and the
third on day 70. The delay for the third course was due to shipping
considerations. No other treatment was given except prednisolone at 0.5 mg/kg per day.
| |
Results and discussion |
E21R was safe and well tolerated, based on standard blood and
urine chemistry analysis, as well as clinical cardiac and pulmonary functions. The only clinical side effect was minor local pain at the
site of injection. The response to the first 2 courses was clear and
unexpectedly favorable. Clinically, we observed a dramatic improvement
a few days after the end of the first course, with an increase in the
Karnofsky index from 50% to 90% (for one month, this boy was able to
return to school), and diminution of the size of splenomegaly (to 2 cm
below the left costal margin). Laboratory tests showed a decrease in
WBC, monocyte, and blast counts (Figure
1), and in bone marrow blasts (8% at day
21 and 13% at day 70). The only adverse hematologic effect noted
during the 3 courses was persistent thrombocytopenia. At the beginning of the third course, the clinical situation was clearly bad, with bone
pain, skin nodules, and a low Karnofsky index. During and after the
third course, monocytosis, and blast cell counts, blast cell percentage
increased, and the disease appeared to have become completely
refractory to E21R. Our patient died one month after the commencement
of the third course, from bleeding and multiorgan failure.
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| Figure 1.
CBC evolution and outcome.
A dramatic response was observed after the end of the first course.
During and after the third course, WBC, monocytosis, and blast cell
counts increased.
|
|
The serum level of E21R was monitored through the 3 courses of
treatment. A maximum E21R concentration was observed 3 hours after E21R
injection. This is comparable with the levels observed in the adult
phase I study (Olver et al, unpublished data, December 2001).
Further levels are lower than those observed in the phase I study
(Figure 2). A modest IgG and IgM response
toward the injected E21R was observed at the beginning of the third
course (data not shown) and may have resulted in the decreased effect
of the drug during this course.
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| Figure 2.
Kinetics of E21R.
The serum level of E21R was monitored through the first and second
courses of treatment and compared with the levels observed in 3 adult
solid tumor patients during the phase I study.
|
|
This is the first time that E21R, a specific GM-CSF inhibitor, has been
used for the treatment of JMML. The schedule and the dose were based on
the phase I study previously performed on solid tumor patients in
Australia. The patient had end-stage disease, relapsing after 2 bone
marrow transplants. Despite all these difficulties, clear in vivo
efficacy was observed after only 2 courses of E21R, and lasted for
approximately 60 days. The third course commenced 40 days after the end
of the second, at which time the clinical status was poor (although not
reflected by the CBC performed, with only a moderate increase in blast
cell count compared with the previous counts). In JMML, especially in
an acute transformation, such a delay is likely to preclude cumulative
benefit following the first 2 courses. Moreover, during this time the
sensitivity of the disease may have changed. The overall tolerance of
E21R appeared to be very good, without the side effects of chemotherapy regimens usually employed in such situations. More studies are necessary in order to investigate the dose and schedule of
administration of the drug and to study its pharmacokinetics, but this
novel therapeutic approach clearly deserves further evaluation in JMML, and may be of potential interest in myeloid malignancy in general.
| |
Acknowledgments |
The authors thank Bresagen Ltd for kindly providing E21R for
compassionate use, and Dr Naomi Taylor for valuable comments on the manuscript.
| |
Footnotes |
Submitted August 15, 2001; accepted November 21, 2001.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Frédéric Bernard, Service de
Pédiatrie III, Unité d'Hémato Oncologie,
Hôpital Arnaud de Villeneuve, Avenue du Doyen Giraud, F-34000
Montpellier, France; e-mail: f-bernard{at}chu-montpellier.fr.
| |
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Abstract
Introduction