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Blood, 1 April 2002, Vol. 99, No. 7, pp. 2599-2602
BRIEF REPORT
Development of pancytopenia with neutralizing antibodies to
thrombopoietin after multicycle chemotherapy supported by megakaryocyte
growth and development factor
Russell L. Basser,
Elizabeth O'Flaherty,
Michael Green,
Maria Edmonds,
Janet Nichol,
Dora M. Menchaca,
Brian Cohen, and
C. Glenn Begley
From the Centre for Developmental Cancer Therapeutics,
Ludwig Institute for Cancer Research, Department of Haematology and
Medical Oncology, Rotary Bone Marrow Research Laboratories, Royal
Melbourne Hospital; Walter and Eliza Hall Institute for Medical
Research; Department of Haematology and Medical Oncology, Western
Hospital, Parkville, Victoria, Australia; Amgen Australia, Kew; and
Amgen, Thousand Oaks, CA.
 |
Abstract |
Clinical trials of thrombopoietin (TPO), the central regulator of
megakaryocytopoiesis, have revealed few side effects associated with
its use. We here report a case of pancytopenia associated with the
development of neutralizing antibodies to TPO that occurred in a
patient who had undergone multicycle chemotherapy with multiple cycles
of subcutaneous administration of pegylated recombinant human
megakaryocyte growth and development factor. Samples of the patient's
bone marrow showed trilineage hypoplasia with absence of myeloid,
erythroid, and megakaryocyte progenitor cells but with elevated
endogenous levels of erythropoietin, granulocyte colony-stimulating
factor, and stem-cell factor. To our knowledge, this is the first
report of an aplastic anemia-like syndrome associated with
neutralizing antibodies to TPO.
(Blood. 2002;99:2599-2602)
© 2002 by The American Society of Hematology.
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Introduction |
Two different forms of thrombopoietin (TPO)
have entered clinical trials.1 One is a recombinant form
of the native molecule (rhTPO) and the other a pegylated, truncated
version (pegylated recombinant human megakaryocyte growth and
development factor [PEG-rHuMGDF]) with biologic activity similar to
that of the native molecule. Early studies showed that both
rhTPO2 and PEG-rHuMGDF3 are potent
stimulators of thrombopoiesis and enhance platelet recovery when given
after chemotherapy.4,5 Both agents were reported to have
minimal toxic effects; in particular, platelets produced after their
administration function normally and have no evidence of
activation.2,5,6 Although antibodies to TPO were observed
in the initial study of rhTPO, they were nonneutralizing and
transient.2 Here, we describe a case in which prolonged pancytopenia with neutralizing antibodies to TPO developed in a woman
with ovarian cancer who had undergone 6 cycles of chemotherapy associated with administration of PEG-rHuMGDF.
| |
Study design |
Granulocyte-macrophage colony-forming cells, erythroid
burst-forming units, and megakaryocyte colony-forming cells were
assayed as described previously7-9 by using freshly
obtained bone marrow cells. Serum from the patient (stored at  20°C)
was incubated with growth factors for in vitro cultures at 37°C for
60 minutes and examined for its activity on normal bone marrow cells.
The highest concentration of patient's serum used was 10% of the
final culture volume.
Standard solid-phase sandwich enzyme immunoassays were used to measure
serum levels of TPO,10 granulocyte colony-stimulating factor (G-CSF), and erythropoietin (EPO) (R&D Systems, Minneapolis, MN). Cytokine levels were calculated from a standard curve generated by
analysis of recombinant cytokines. Stem-cell factor (SCF) was assayed
as described previously.11 More than 200 samples of normal
human serum were used to establish the SCF standard of 0.78 ± 0.25
ng/mL (range, 0.29-1.62 ng/mL).
Two established assays were used to detect neutralizing
antibodies. The first was a solid-phase radioimmunoassay
(RIA).12 Reactivity was determined on the basis of the
ratio of counts per minute in the posttreatment sample to the counts
per minute in the pretreatment (normal control) sample. A ratio of 2.0 or higher derived from 2 independent assays was considered to indicate reactivity. Reactive samples were titrated. The use of controls demonstrated specificity; for example, samples of antiserum to EPO,
G-CSF, SCF, and keratinocyte growth factor (KGF) were unreactive and
anti-TPO antiserum samples did not cross-react with EPO, G-CSF, SCF, or
KGF. The second assay was a neutralizing-antibody bioassay using
Mpl-transfected 32D cells. Again, specificity was demonstrated: there
was no inhibition of control cultures.12 Serum samples were considered inhibitory if cell growth was less than 50% with 250 pg/mL TPO. Results were expressed as the titer of serum at which
inhibition occurred.12 Both assays were done on all serum samples and on several separate occasions.
| |
Results and discussion |
A 58-year-old woman with stage 3 ovarian
adenocarcinoma underwent debulking laparotomy in December 1997. Her
past medical history included hypertension and depression, controlled
with propanolol and alprazolam, respectively. In January 1998, she began treatment in a phase 1 trial of PEG-rHuMGDF (Amgen, Thousand Oaks, CA).13 At that time, blood counts and renal and
hepatic function were normal, and her performance status was 0 according to Eastern Cooperative Oncology Group criteria. Neither RIA
nor bioassay detected any antibodies to megakaryocyte growth and
development factor (MGDF) or TPO.
A single dose of PEG-rHuMGDF (3 µg/kg of body weight; total,
200 µg) was given 7 days before the first dose of chemotherapy. The
first cycle of chemotherapy (consisting of 600 mg/m2 of
body-surface area of carboplatin [total, 980 mg] and 1200 mg/m2 cyclophosphamide [total, 1950 mg]) was followed by
administration of filgrastim (5 µg/kg per day; Amgen) but not
PEG-rHuMGDF. For cycles 2 to 6, the patient received the same
chemotherapy regimen with filgrastim, along with PEG-rHuMGDF (5 µg/kg
per day; total, 332 µg) for 3 days. Chemotherapy was given at 28-day
intervals. There were no substantial delays in treatment; the last
course was given 5 months after the first.
Blood counts were done at least every other day after
chemotherapy until hematopoietic recovery and thereafter as clinically indicated. Platelets were transfused (5 units, random donor) when the
platelet count was under 20 × 109/L, and red blood cells
were given when the hemoglobin level was less than 90 g/L. The
chemotherapy dose was reduced by 25% after the third cycle of
chemotherapy because of fever with neutropenia and by an additional
25% after the fourth cycle because of thrombocytopenia. Transfusion of
platelets was required after cycles 1, 2, 3, and 6; transfusion of red
blood cells was necessary after every cycle. After the first 5 cycles
of chemotherapy, blood counts became normal (Figure
1). The results of RIA and bioassays were
negative for antibodies to MGDF and TPO throughout the chemotherapy
regimen.
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| Figure 1.
Development of anti-TPO antibodies and association
with thrombocytopenia, neutropenia, and anemia.
Shown is the development of anti-TPO antibodies in the patient in
relation to administration of PEG-rHuMGDF (shaded boxes) with
chemotherapy (arrows) and G-CSF. Inhibitory antibody to TPO was not
detected by RIA or bioassay on 6 occasions (minus signs). Inhibitory
antibody to TPO was detected by RIA on 5 occasions (plus signs) and
also by bioassay on 4 of these. The first sample positive on RIA was
negative on bioassay. In the 4 samples positive on bioassay, inhibitory
antibody to TPO was detected at serum dilutions of 1:200, 1:100, 1:100,
and 1:100. (A) Platelet count, platelet transfusion requirements, and
serum TPO levels (asterisks). (B) ANC. (C) Hemoglobin levels and red
blood cell transfusion requirements.
|
|
After the sixth cycle of chemotherapy, platelet and hemoglobin levels
failed to return to normal. Although the absolute neutrophil count
(ANC) initially reached normal levels, it decreased to subnormal levels
after filgrastim treatment was discontinued. At that time, neutralizing
TPO antibodies were first detected by RIA, although bioassay results
were negative. On 4 subsequent occasions, both RIA and bioassay
indicated the presence of neutralizing antibodies (Figure 1). After the
antibodies were detected, serum TPO levels fell despite persistent
thrombocytopenia, and regular transfusions were required.
It was surprising that the thrombocytopenia was associated with
neutropenia, anemia, and bone marrow changes of trilineage hypoplasia.
Consistent with this finding, assays of bone marrow progenitor cells
from the patient revealed an almost complete absence of erythroid,
myeloid, and megakaryocytic precursors. The patient's serum was
examined by using in vitro cultures with normal bone marrow cells as
the target. Rather than inhibiting the growth of bone marrow progenitor
cells, the serum dramatically stimulated the growth of myeloid and
erythroid colonies (Table 1). Specific
assays confirmed elevated levels of EPO (723.9 arb U/L; normal,
3.3-16.6 arb U/L), G-CSF (39 ng/L; normal, 35 ng/L), and SCF
(1.21 ng/mL; normal, 0.53-1.03 ng/mL). The ANC at the time of the G-CSF
assay was 2.4 × 109/L.
During the 6 to 12 months after the patient completed chemotherapy,
when neutralizing antibodies present, the mean (± SD) platelet count
was 27 ± 17 × 109/L with transfusion support, the
hemoglobin level was 95 ± 13 g/L with red blood cell transfusions,
and the ANC was 1.6 ± 0.6 × 109/L. A bone marrow
aspirate and trephine sample were obtained 7 and 11 months after
chemotherapy. On each occasion, the aspirates were
aparticulate, but both trephine samples showed trilineage hypoplasia
primarily affecting erythroid and megakaryocytic cells. There were no
increases in reticulin and no cytogenetic abnormalities. During this
time, the patient had lethargy, easy bruising, and occasional epistaxis
but no episodes of fever. No alterations in renal or hepatic function
were observed at any time.
The patient was given prednisolone (50 mg/day for 21 days)
beginning 6 months after chemotherapy, but the platelet count did not
increase and the antibody titer did not change. Ten months after
completing chemotherapy, the patient still required platelet and red
blood cell transfusions for maintenance of adequate blood counts. At
that time, the level of CA 125 antigen (a marker of ovarian cancer),
which had been mildly elevated before chemotherapy (40 U/mL), was
normal and there was no evidence of ovarian cancer.
Several findings suggest the existence of a causal relation
between the appearance of the neutralizing antibody and the development of trilineage bone marrow hypoplasia in this patient. First, the patient had not previously received chemotherapy and had no known condition associated with a predisposition to prolonged
chemotherapy-induced myelosuppression. Second, prolonged
myelosuppression was not observed in other patients treated with the
same chemotherapy regimen, although lower peak platelet counts with
successive cycles are characteristic of this
treatment.5,13-15 Third, the development of neutralizing
TPO antibody was coincident with the development of pancytopenia
and was specific (eg, anti-EPO antibodies were never detected). Fourth,
the elevated levels of EPO, G-CSF, and SCF indicated the presence of an
aplastic anemia-like, multilineage, stem cell defect that is known to
be mediated by TPO.7,16-19
Development of neutralizing antibodies to endogenous cytokines
after administration of growth factors occurs rarely. One patient with
chronic renal failure was observed to have onset of EPO-resistant anemia after an initial response to EPO.20 Multicycle
GM-CSF therapy has resulted in anti-GM-CSF antibodies that blunted the GM-CSF response.21 Development of antibodies to G-CSF did
not alter resting blood counts or G-CSF response.22
The mechanism for the immune response to PEG-rHuMGDF and TPO is
unknown. Although protein conjugation with polyethylene glycol was
previously found to reduce antibody responses compared with results
with the unmodified molecule,23 the prolonged, repeated exposure of skin dendritic cells to PEG-rHuMGDF likely assisted in the
development of an immune response.24 This was probably exacerbated by the 36-hour half-life of PEG-rHuMGDF.25 It
is also possible that truncation of the native TPO molecule to generate MGDF exposed a unique and antigenic carboxyl-terminal or that the
absence of serine-linked carbohydrate altered the immunogenicity of
PEG-rHuMGDF compared with native TPO. Whatever the mechanism of the
response, our case illustrates a potential obstacle to additional
clinical development of this cytokine and reveals an interesting
clinical consequence of the multilineage action of TPO.
| |
Acknowledgments |
We thank Linda Shaner, Amgen, Thousand Oaks, CA, for assistance in
conducting the cytokine assays. This work is dedicated to the memory of
Dora Menchaca, who was tragically killed in the events of September 11, 2001.
| |
Footnotes |
Submitted January 3, 2001; accepted October 26, 2001.
Supported in part by grants from the Anti-Cancer Council of Victoria,
Carlton; the National Health and Medical Research Council, Canberra;
the Cooperative Research Centre for Cellular Growth Factors, Parkville,
Australia; and Amgen, Thousand Oaks, CA.
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: Russell Basser, CSL Ltd, 45 Poplar Rd, Parkville,
Victoria, 3052, Australia; e-mail: russell_basser{at}csl.com.au.
| |
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Top
Abstract
Introduction