Blood, 15 November 2000, Vol. 96, No. 10, pp. 3647-3649
BRIEF REPORT
Spontaneous remission of granulocyte colony-stimulating
factor-associated leukemia in a child with severe congenital
neutropenia
Sima Jeha,
Ka Wah Chan,
Andrew G. Aprikyan,
W. Keith Hoots,
Steven Culbert,
Hallie Zietz,
David C. Dale, and
Maher Albitar
From the Departments of Pediatrics and Hematopathology,
University of Texas M.D. Anderson Cancer Center, Houston, TX, and the
Department of Medicine, University of Washington, Seattle, WA.
 |
Abstract |
Leukemia is observed with increased frequency in patients with
severe congenital neutropenia (SCN). In the past decade, recombinant human granulocyte colony-stimulating factor (rh G-CSF) has prolonged the survival of patients with SCN increasingly reported to have leukemias. In this communication acute myelogenous leukemia (AML) associated with a mutation of the G-CSF receptor (G-CSF-R) developed in
a patient with SCN maintained on long-term G-CSF therapy. The blast
count in the blood and bone marrow fell to undetectable levels twice on
withholding G-CSF and without chemotherapy administration, but the
mutant G-CSF-R was detectable during this period. The patient
subsequently underwent successful allogeneic bone marrow transplantation. After transplantation, the patient's neutrophil elastase (ELA-2) mutation and G-CSF-R mutation became undetectable by
polymerase chain reaction. This report provides novel insights on
leukemia developing in congenital neutropenia.
(Blood. 2000;96:3647-3649)
© 2000 by The American Society of Hematology.
| |
Introduction |
Severe congenital neutropenia (SCN), first
described by Kostmann in 1956, is a disorder of myelopoiesis
characterized by impaired neutrophil differentiation with maturation
arrest at the promyelocyte stage.1,2 The resultant
profound neutropenia usually leads to fatal infections early in
infancy, but in a few instances it has remitted or has been mild enough
to allow prolonged survival. Transition to leukemia has been reported
in 3 patients who survived through adolescence with no cytokine
treatment.3-5 Bone marrow transplantation was the only
effective therapy to prolong the survival of patients with
SCN6,7 until granulocyte-colony-stimulating factor (G-CSF)
was introduced.8-10 However, an apparent increase in the
incidence of leukemia has also been observed in the past few
years.11,12 This phenomenon could be related to prolonged survival of children who have a preleukemic disorder, thus allowing the
disease to follow its natural course. Prolonged hematopoietic stimulation with G-CSF has also been suggested to contribute to the
development of leukemia.13-15 We present a patient with
SCN in whom acute myelogenous leukemia (AML) developed after 9 years of
G-CSF treatment. The leukemia remitted spontaneously with the discontinuation of G-CSF alone, allowing the patient to receive a
successful unrelated bone marrow transplant without the morbidity of
induction chemotherapy.
| |
Study design |
M.P. is a 12-year-old boy who received a diagnosis of severe
neutropenia at the age of 3 months. There is no family history of
consanguinity or hematologic disorders. During the first 3 years of his
life, he was admitted to the hospital more then 30 times for
life-threatening infections. At age 3, G-CSF treatment was begun, and
the patient was maintained on 5 µg/kg subcutaneously twice a day. He
responded excellently to G-CSF, allowing him to lead a normal life for
9 years. On March 17, 1999, a surveillance bone marrow aspirate was
within normal limits with a diploid male karyotype (46,XY) in 20 metaphases. On June 8, 1999, severe left otitis associated with
extensive cellulitis developed on the left side of the face. Complete
blood count showed hemoglobin 11.0, platelets 153 000, white blood
cell count 11 800, and 32% myeloperoxidase-positive blasts. Bone
marrow aspirate confirmed the diagnosis of AML with 73% blasts,
myeloperoxidase positive, CD34 97.5%, CD13 92.6%, and CD33 31.4%.
Cytogenetics assay showed a pseudodiploid clone 46,XY, add (18) (q23),
in 18 metaphases and a diploid male karyotype 46,XY in 2 metaphases.
G-CSF was discontinued, and the patient begun treatment with
intravenous antibiotics. After 5 days, the infection had markedly
improved and the white blood cell count gradually decreased. Because of
the patient's stable clinical condition and the clearance of
circulating blasts, the decision was made not to begin chemotherapy and
to continue withholding G-CSF while maintaining close observation and
prophylactic antibiotics. After 4 weeks without G-CSF, a repeat bone
marrow aspirate documented complete morphologic and cytogenetic
remission that lasted for 11 weeks, at which time the family declined
bone marrow transplantation and restarted the patient on 3 µg/kg
G-CSF twice a day to maintain his absolute neutrophil count in the 1000 range. A surveillance bone marrow aspirate taken 7 weeks after G-CSF
was restarted showed 40% myeloperoxidase-positive blasts with
reappearance of the old 18q+ clone and a new clone with trisomy 21. G-CSF administration was interrupted again, and the patient achieved a
second remission in 14 days without chemotherapy. After 6 weeks in
complete remission, he underwent matched, unrelated bone marrow
transplantation. Six months after transplantation, the leukemia remains
in remission.
Cytochemical assays, flow cytometry studies, and cytogenetic analysis
were performed on bone marrow aspirates using standard methology.16 Neutrophil elastase (ELA-2) and granulocyte
colony-stimulating factor receptor (G-CSF-R) were analyzed by
polymerase chain reaction (PCR) and reverse transcription (RT)-PCR
using genomic DNA and RNA, respectively. All 5 exons for ELA-2 were
sequenced as previously reported.17 For G-CSF-R analysis,
the entire intracellular domain was sequenced.
| |
Results and discussion |
Although it allows a dramatic improvement in quality of life and
survival, the prolonged use of G-CSF in children with SCN has been
associated with adverse side effects that vary in
severity.18 In some cases, it is difficult to determine
whether the complications are associated with the underlying
pathophysiology of the disease, are induced by G-CSF, or are related to
a combination of both.
The greatest concern is the risk for hematopoietic malignancies. In
these patients, treatment is difficult and most patients die within a
few months despite the use of aggressive
chemotherapy.19-22 The latest report from the Severe
Chronic Neutropenia International Registry indicates that the incidence
of myelodysplastic syndrome and AML is almost 9% in patients with SCN
receiving G-CSF.23 Malignant myeloid disorders have not
been reported11,18 in patients with idiopathic or cyclic
neutropenia maintained on long-term treatment with G-CSF and followed
up or the same period, indicating that the risk for leukemic
transformation is probably a function of the underlying myelopoietic
defect rather than a direct effect of growth-factor treatment.
The case we present here is the first to demonstrate a direct relation
between G-CSF administration and blast count in a patient with SCN. In
this patient, who has had SCN since infancy and who manifests the
recently reported mutation of the gene for neutrophil elastase, AML
developed in association with a clonal cytogenetic abnormality after 9 years of treatment with G-CSF. The patient had morphologic and
cytogenetic remission on discontinuation of G-CSF, but a mutation of
G-CSF-R was detectable in 2 samples from the 3-month remission period
(Table 1).
G-CSF is known to mediate its effect by G-CSF-R. On ligand binding, the
G-CSF-R is dimerized and stimulates cell proliferation or
differentiation by activating various signaling
pathways.24 Current evidence25 indicates that
mutations in G-CSF-R lead to hypersensitivity to G-CSF with robust
proliferation of the host cells. In this patient, we examined bone
marrow by PCR and RT-PCR using G-CSF-R-specific primers. Sequencing of
the corresponding PCR-amplified fragments revealed a point mutation in
G-CSF-R coding region (manuscript in preparation). The same G-CSF-R
mutation was detected at 2 different time points when the patient
was off G-CSF (Table 1). Examination of PCR-amplified bone
marrow-derived genomic DNA from this patient also revealed a point
mutation in the coding region of neutrophil elastase17
(Table 1).
Overt leukemia recurred 7 weeks after G-CSF treatment was resumed. Cell
surface markers were identical to those at diagnosis, and cytogenetic
test results confirmed the reappearance of the old abnormal clone in
addition to the emergence of a new clone (Table 1). A second
morphologic remission was achieved 14 days after G-CSF was again
stopped, and it lasted until the patient underwent bone marrow
transplantation 6 weeks later. After transplantation, both the elastase
and the G-CSF-R mutations were no longer detectable (Table1).
The G-CSF expansion of the blast count in this patient is consistent
with models in which selection and maturation of individual hematopoietic lineages are stimulated by hematopoietic growth factors.
The mechanism that allowed this patient's leukemia to remain quiescent
when pharmacologic doses of G-CSF were withdrawn deserves further
study. The G-CSF-R mutation persisted despite the variations in blast
count. Additional studies may clarify the relation between this
mutation and the underlying mutation of the gene for neutrophil
elastase in the pathophysiology of SCN. This patient did not have
monosomy 7, a frequent marker of AML in patients with SCN. We recommend
that in patients with congenital neutropenia and AML, G-CSF be
withheld, if the clinical condition allows, so that they may be
observed off G-CSF before chemotherapy is begun.
| |
Footnotes |
Submitted April 20, 2000; accepted July 13, 2000.
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: Sima Jeha, Department of Pediatrics, University of
Texas M.D. Anderson Cancer Center, Box 87, 1515 Holcombe Boulevard,
Houston, TX 77030; e-mail: sjeha{at}mdanderson.org.
| |
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Abstract
Introduction
