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Blood, Vol. 96 No. 2 (July 15), 2000:
pp. 429-436
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Myelodysplasia syndrome and acute myeloid leukemia in patients
with congenital neutropenia receiving G-CSF therapy
Melvin H. Freedman,
Mary Ann Bonilla,
Carol Fier,
Audrey Anna Bolyard,
Debra Scarlata,
Laurence A. Boxer,
Sherri Brown,
Bonnie Cham,
George Kannourakis,
Sally E. Kinsey,
Pier Georgio Mori,
Tammy Cottle,
Karl Welte, and
David C. Dale
From the Severe Chronic Neutropenia International
Registry, University of Washington, and the University of Washington
Department of Medicine, Seattle, WA; the University of Michigan Medical
Center, Ann Arbor, MI; St Barnabas Medical Center, West Orange, NJ; the
Clinical Safety Department, Amgen, Inc, Boulder, CO, and Thousand Oaks,
CA; The Hospital for Sick Children and the University of Toronto
Faculty of Medicine, Toronto, Ontario, Canada; the Manitoba Cancer
Treatment and Research Foundation, Winnipeg, Manitoba,
Canada; the Cancer Research Center, University of Ballarat; St James's
University Hospital, Leeds, England; the Istituto Giannina Gaslini,
Genova, Italy; and the Medizinische Hochschule, Hannover, Germany.
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Abstract |
Granulocyte colony-stimulating factor (G-CSF) has had a
major impact on management of "severe chronic neutropenia," a
collective term referring to congenital, idiopathic, or cyclic
neutropenia. Almost all patients respond to G-CSF with increased
neutrophils, reduced infections, and improved survival. Some responders
with congenital neutropenia have developed myelodysplastic syndrome and
acute myeloblastic leukemia (MDS/AML), which raises the question of the
role of G-CSF in pathogenesis. The Severe Chronic Neutropenia International Registry (SCNIR), Seattle, WA, has data on 696 neutropenic patients, including 352 patients with congenital
neutropenia, treated with G-CSF from 1987 to present. Treatment and
patient demographic data were analyzed. The 352 congenital patients
were observed for a mean of 6 years (range, 0.1-11 years) while being treated. Of these patients, 31 developed MDS/AML, for a crude rate of
malignant transformation of nearly 9%. None of the 344 patients with
idiopathic or cyclic neutropenia developed MDS/AML. Transformation was
associated with acquired marrow cytogenetic clonal changes: 18 patients
developed a partial or complete loss of chromosome 7, and 9 patients
manifested abnormalities of chromosome 21 (usually trisomy 21).
For each yearly treatment interval, the annual rate of
MDS/AML development was less than 2%. No significant relationships
between age at onset of MDS/AML and patient gender, G-CSF dose, or
treatment duration were found (P > .15). In addition to the
31 patients who developed MDS/AML, the SCNIR also has data on 9 additional neutropenic patients whose bone marrow studies show
cytogenetic clonal changes but the patients are without transformation to MDS/AML. Although our data does not support a cause-and-effect relationship between development of MDS/AML and G-CSF therapy or other
patient demographics, we cannot exclude a direct contribution of G-CSF
in the pathogenesis of MDS/AML. This issue is unclear because MDS/AML
was not seen in cyclic or idiopathic neutropenia. Improved survival of
congenital neutropenia patients receiving G-CSF therapy may allow time
for the expression of the leukemic predisposition that characterizes
the natural history of these disorders. However, other factors related
to G-CSF may also be operative in the setting of congenital neutropenia.
(Blood. 2000;96:429-436)
© 2000 by The American Society of Hematology.
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Introduction |
Severe chronic neutropenia (SCN) and recurrent serious infections
are features of a heterogeneous group of disorders of myelopoiesis including congenital neutropenia, cyclic neutropenia, and idiopathic neutropenia. In keeping with the definition of SCN, these disorders are
all characterized by absolute neutrophil counts of less than 0.5 × 109 counts per L on 3 separate occasions during 6 months of observation. Kostmann's syndrome, a subtype of congenital
neutropenia inherited in an autosomal recessive manner, is
characterized by early childhood onset of profound neutropenia,
recurrent life-threatening infections, and a maturation arrest of bone
marrow myeloid precursors at the promyelocyte-myelocyte stage of
differentiation.1,2
Severe congenital neutropenia described herein has the same hematologic
phenotype and clinical presentation as Kostmann's syndrome.
Neutropenia is profound, with usually less than
0.2 × 109 neutrophil counts per L, and often absolute.
The recessive inheritance of Kostmann's syndrome is deduced by
inference when there is more than 1 affected child in a family.
Congenital neutropenia is the more appropriate designation used for a
single "sporadic" case in a family, and hence, may or may not be
inherited in an autosomal recessive manner as is Kostmann's syndrome.
Because at least one of the causes of SCN has only recently been
discovered, and molecular diagnostic methods have not yet been readily
available to distinguish between the disorders termed Kostmann's
syndrome, the option to "lump" or "split" the 2 disorders
remains a subject of argument. For this report, the terms Kostmann's
syndrome and congenital neutropenia are used interchangeably.
Shwachman-Diamond syndrome (SDS), an additional but discrete subtype of
congenital neutropenia, is inherited in an autosomal recessive manner
and consists basically of exocrine pancreatic insufficiency and varying
degrees of neutropenia, usually with growth failure.3
Prior to the availability of recombinant human granulocyte
colony-stimulating factor (G-CSF), it was recognized that leukemic transformation occurred in patients with these congenital forms of
neutropenia.4-7 In the subgroup with SDS, the
predisposition to spontaneous leukemic transformation is inordinately
high, possibly up to 30%.8,9 However, in the precytokine
era, many congenital neutropenia patients died in the first years of
life from other causes. According to published cases of Kostmann's
syndrome, for example, 42% of patients died, secondary to sepsis or
pneumonia, at a mean age of 2 years.10 Thus, the true risk
of congenital neutropenia patients developing myelodysplasia syndrome
and/or acute myeloblastic leukemia (MDS/AML) has never been defined.
With G-CSF therapy, more than 90% of patients have responded with
increased neutrophil numbers, have not developed life-threatening infections, and have survived well beyond 2 years of age. However, it
is not known if increased survival will allow for the natural expression of leukemogenesis in this population. Moreover, because the
long-term effects of G-CSF are not known beyond 11 years of observation, it is still unclear whether MDS or AML will occur with
increased frequency in patients who receive G-CSF on a chronic life-long basis.
To address these issues, the largest currently available database of
chronic neutropenia patients treated with G-CSF was used to determine
the incidence of malignant myeloid transformation and its relationship
to treatment and to other patient demographics that may be operative.
The following hypothesis was also addressed: If the risk of
transformation is directly dependent on G-CSF therapy, there should be
a relationship to the duration of G-CSF treatment or to the dosage given.
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Patients, materials, and methods |
The Severe Chronic Neutropenia International Registry
In 1987, Amgen, Inc (Boulder, CO, and Thousand Oaks, CA) initiated
clinical trials to test G-CSF therapy for SCN; 335 patients were
enrolled and followed prospectively until 1994. The Severe Chronic
Neutropenia International Registry (SCNIR), Seattle, WA, was
established in 1994 to continue monitoring the clinical course, treatment, and disease outcomes of patients with SCN.11-21
Clinical trial data from 1987-1994 were retrospectively transferred to the Registry and were added to the data of newly diagnosed SCN patients
from 1994 onward. SCNIR is a unique resource that continues to collect
clinical data on large numbers of patients worldwide. Patient data are
submitted internationally to the data coordinating centers at the
University of Washington, Seattle, and the Medizinische Hochschule,
Hannover, Germany.
The Registry's administrative and operational structure
consists of 5 components: (1) an international Scientific Advisory Board of 10 physicians/hematologists; (2) a panel of European local
liaison physicians who treat neutropenic patients; (3) the Registry
data coordinating offices, which are responsible for data collection;
(4) Amgen's International Clinical Safety Department; and (5) a Safety
Monitoring Committee, which comprises 3 physicians and 2 scientists who
address the risks and benefits of G-CSF therapy with regard to the
hazard of MDS/AML arising during treatment.
For this report, all data received as of December 31, 1998, were
available for analysis. Patients who met the eligibility criteria with
documented persistent severe neutropenia (less than 0.5 × 109 absolute neutrophil counts per L), a
confirmed diagnosis of SCN, and signed release of medical information
were eligible for enrollment in the SCNIR.
Criteria for diagnosis and classification
Entry criteria for enrollment in the SCNIR required documentation of
severe neutropenia, defined as an absolute neutrophil count of less
than 0.5 × 109 counts per L on 3 separate occasions
during at least a 6-month period. Severe congenital neutropenia
patients in the SCNIR have the identical hematologic phenotype and
clinical presentation as Kostmann's syndrome and, hence, the terms are
used interchangeably. The diagnostic criteria for congenital
neutropenia and for SDS are detailed in the "Introduction."
Patients with cyclic neutropenia were required to demonstrate 5 consecutive days per cycle of absolute neutrophil counts of less than
0.5 × 109 counts per L for each of 3 regularly
spaced cycles during a 6-month period. The term idiopathic neutropenia
refers to the onset of absolute neutrophil counts of less than
0.5 × 109 counts per L from months to years after
birth without apparent cause. Excluded from the idiopathic group are
patients with marrow clonal cytogenetic abnormalities at diagnosis or
with MDS, aplastic anemia, collagen vascular and autoimmune disease
including Felty's syndrome, and drug-induced neutropenia. The SCNIR
does not have data on the incidence of antineutrophil antibodies in
idiopathic neutropenia patients.
Clinical monitoring
Bone marrow aspirations for morphology and cytogenetic studies were
performed at local institutions prior to G-CSF therapy and were
required at 12-month intervals thereafter for all enrolled patients who
were receiving treatment through 1996. After October 1996, when the
data indicated that only patients with congenital neutropenia were at
risk of MDS/AML, the annual requirement for marrow testing was dropped
for patients with cyclic and idiopathic neutropenia. Patients were seen
at varying intervals for assessment of hematological and clinical
parameters. For the patients enrolled in the SCNIR, data assessment
forms were requested from the treating physicians every 6 months. For
patients enrolled in clinical trials from 1987 to 1994, hematological
studies were collected at least monthly. The discovery of a cytogenetic
clonal abnormality of marrow cells or marrow morphologic changes of MDS
or AML were reported immediately.
Statistical analysis and study design
The protocol design used to analyze the Registry data can be
described as nonrandomized, noncontrolled, multicentered, and observational. All patients in the SCNIR were followed through December
31, 1998. Univariate descriptive statistics were generated on all
demographic, hematologic, and dosing parameters. The
Kaplan-Meier21 method was used to estimate hazard rates and
probability of conversion to MDS/AML for years of treatment with G-CSF
and for age. The Cox proportional hazards model22 was used
to assess both the univariate and multivariate effects G-CSF dosage,
years of treatment with G-CSF, and demographic factors on the age
of MDS/AML conversion. All statistical analyses were performed
using SAS.23
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Results |
Patient demographics
By the end of 1998, we had received information dating back to 1987 on a total of 648 patients submitted by 358 treating physicians from 13 countries (Table 1). Of this total, 304 patients were classified as having congenital neutropenia (including
Kostmann's syndrome and SDS). Of the other patients, 132 had cyclic
neutropenia, and 212 patients had idiopathic neutropenia.
In addition to the 304 patients with congenital neutropenia (Table 1),
the SCNIR compiled data on 48 congenital patients who were enrolled in
industry-sponsored G-CSF clinical trials from 1987 to 1994. These
patients were not prospectively enrolled in the SCNIR for a variety of
reasons; most commonly, death occurred prior to enrollment. Thus, a
total of 352 patients (304 plus 48 patients) with congenital
neutropenia who were treated with G-CSF were available for analysis.
Efficacy of G-CSF therapy
Previous clinical trials of G-CSF therapy in patients with
congenital neutropenia were conducted for up to 6 years. In more than
90% of these patients, the cytokine selectively increased and
sustained blood neutrophil numbers with little effect on other blood
counts.24 From a subset of 238 patients in the SCNIR
database, only 8 patients (3%) failed to experience a sustained
increase in neutrophil counts, even when they were given large daily
doses (greater than 100 µg/kg) of G-CSF.16 Responders
have sustained a mean absolute neutrophil count of more than
2.0 × 109 counts per L for up to 10 years of
observation. As of December 1998, SCNIR patients with congenital
neutropenia were receiving a mean daily G-CSF subcutaneous dose of 13.8 µg/kg (range, 0.1-240 µg/kg), with a mean therapy duration of 6 years (range, 0.1-11 years). For patients with cyclic neutropenia and
idiopathic neutropenia, G-CSF induced identical neutrophil responses in
more than 90% of the patients in each diagnostic category. The mean
daily G-CSF dose for both groups was lower than the mean dose for the
congenital neutropenia patients (for cyclic neutropenia, 2.64 µg/kg;
for idiopathic neutropenia, 2.4 µg/kg).
Malignant myeloid transformation
Of the 352 patients with congenital neutropenia who were treated
with G-CSF, 31 patients developed MDS/AML from 1987 to
December 1998. Thus, the overall incidence or crude rate of malignant
transformation is 8.8%, with an average follow-up rate of 6 years. Of
these 31 patients, 29 were diagnosed with a type of Kostmann's
syndrome congenital neutropenia, and 2 patients were classified as
having SDS. It is noteworthy that to date, there have been no cases of MDS/AML reported in patients with glycogen storage disease type 1b (the
other subgroup of congenital neutropenia). There also have been no
reported cases of MDS/AML in any SCNIR patients with cyclic or
idiopathic neutropenia who have been treated with G-CSF for up to 11 years.
In Table 2, summary demographic and dosing
information of the patients who converted to MDS/AML are compared with
those who did not convert, and Table 3
provides individual details of all 31 patients with MDS/AML. The ages
of the patients varied widely. There was a preponderance of male
patients (n = 18, 58%), but this was not statistically significant
compared with patients who did not convert to MDS/AML (51% of total).
The patients who converted to MDS/AML received a broad range of G-CSF
daily doses (from 1-58 µg/kg/d), and there was no consistent pattern
of prescribed dosage. To answer the question of whether there was a
difference between the G-CSF doses given to MDS/AML patients versus
those without MDS/AML, an analysis of variance was performed and failed to show a significant trend (P = .83). The Cox proportional
hazards model was used to determine if there was a relationship between the G-CSF dose and patient age when MDS/AML developed, and none was
demonstrated (P = .15).
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Table 2.
Comparison of demographics and G-CSF dosing among
patients who converted to MDS/AML and those who did not convert
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Table 3.
Data on 31 patients with congenital neutropenia who
developed malignant myeloid transformation while receiving G-CSF
therapy
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Of the 21 patients who could be classified by the
French-American-British morphology guidelines for MDS and AML, 1 patient was classified as MDS refractory anemia with
excess blasts (RAEB); 1 patient, MDS RAEB in transformation (T); 4 patients, AML M1; 3 patients, AML M2; 9 patients, AML M4; 2 patients,
AML M7; and 1 patient, "basophilic leukemia."
Conversion to MDS/AML was associated with diverse marrow cell
cytogenetic abnormalities reflecting the malignant clonal disease (Table 3). Of the 30 patients who were studied, 28 had abnormal chromosomal changes: A partial or complete loss of chromosome 7 (7q or monosomy 7) was noted in 18 patients. Abnormalities of
chromosome 21 (usually trisomy 21 [n = 6]) were noted in 9 patients. This was often detected in conjunction with the aberrant chromosome 7 alterations. None of the patients who were tested prior to
G-CSF therapy showed abnormal marrow cytogenetic changes.
Cytogenetic abnormalities without MDS/AML
In addition to the 31 patients with MDS/AML, the SCNIR also
has data on 9 patients with severe chronic neutropenia whose bone marrow shows cytogenetic clonal changes, but the patients appear to be
without transformation to MDS/AML (Table
4). Of these 9 patients, 5 have congenital
neutropenia including 2 with SDS, 2 patients have idiopathic
neutropenia, and 2 patients have cyclic neutropenia or a variant.
Although 3 of these 9 patients have abnormalities in chromosome 7, the
other cytogenetic changes are variable and show no consistent pattern.
None of the patients had abnormal cytogenetic studies prior to G-CSF
therapy. These patients were observed for 2.5-86 months after the
initial abnormal cytogenetic finding without further evidence of
MDS/AML. There is no apparent relationship between onset of clonal
changes, patient age, gender, or dose and duration of G-CSF therapy.
The 2 patients with SDS and monosomy 7 received a bone marrow
transplantation.
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Table 4.
Nine patients with severe chronic
neutropenia receiving G-CSF therapy with clonal cytogenetic
abnormalities but not malignant myeloid transformation
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Transformation risk versus duration of therapy
A crucial issue is whether long-term administration of G-CSF therapy
for congenital neutropenia increases the risk of transformation to
MDS/AML. To address this issue, we performed a life table analysis of
the malignant conversions and analyzed, year to year, 31 patients who
received G-CSF therapy (Table 5).
Table 5 shows the total number of patients who received
G-CSF therapy at the start of each time interval (for example n = 352
for the first yearly interval), the "effective" number of
patients at risk of MDS/AML for each interval (after adjusting for
those patients who did not complete the interval for reasons other than
leukemia), and the number of patients developing MDS/AML in that
interval. This information allows generation of the statistical
parameters shown in Table 5 including the hazard rate or percent of
MDS/AML patients as determined by numerator (n, the number of patients
with MDS/AML) over the denominator ("effective" n at risk)
times 100.
As shown in Table 5, the number of patients with MDS/AML and the
resultant hazard rates are fairly uniform for each time span, less than
2% per year, except for an apparent increase in year 4 to 5 (hazard
rate, 2.7%), in year 6 to 7 (hazard rate, 4.4%), and in year 8 to 9 (hazard rate, 8.4%). The meaning of these 3 increases is not clear
because the pattern was not reproduced in the yearly interval
immediately following the designated year. The hazard rates may give
the appearance of increasing with time, and as a result, we conducted a
review of the 95% confidence intervals for each yearly time span. The
results show that each estimate either includes zero or was
sufficiently close to zero. These results support the conclusion that
the increases observed were seemingly apparent, but they were not real
and were most likely due to the changes in sample size.
Transformation risk versus patient age
To determine if improved patient survival allows more time for
expression of an underlying propensity for MDS/AML, a graphic plot was
prepared showing the duration of G-CSF therapy versus the age of
patients who did and did not develop malignant transformation (Figure
1). The proportion of patients with MDS/AML
within each 10-year age increment and 2-year period of G-CSF exposure
is shown. The distribution of malignant events was random and without
clustering during the years of therapy with G-CSF. Life table analyses
of the time to MDS/AML conversion compared with patient ages showed that the 10- to 20-year-old patients had a greater proportion of
malignant transformation (16 patients) than either the 0- to 9-year-old
group (11 patients) or the 20- to 29-year-old group (2 patients). In
the 40- to 49-year-old group, we observed 2 patients, but there were no
patients found in the 30- to 39-year-old group. Among the 10- to
20-year-old group, 3 of 4 patients developing MDS/AML did so during
clinical trials and were retrospectively found to have documented
evidence of leukemic conversion prior to G-CSF initiation. These cases
have been considered part of the natural background rate of leukemic
conversion among patients with congenital neutropenia.
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| Fig 1.
The duration of treatment with G-CSF pictured in a
graphic plot and sectioned into yearly intervals versus patients' ages
in 10-year intervals.
The 31 patients with MDS/AML are represented by red circles, and those
who did not transform to MDS/AML are represented by yellow circles.
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Finally, a Cox proportional hazards model analysis was used to assess
the univariate impact of years of G-CSF treatment on patient ages at
the time of MDS/AML conversion. The effect of years of G-CSF treatment
was not significant when the model was assessed with all 352 congenital
neutropenia patients (P = .57).
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Discussion |
G-CSF has had a major impact on the management of severe chronic
neutropenia and has established itself as the first choice of treatment
for this heterogeneous group of disorders. After 10 years of clinical
use, it is clear that more than 90% of patients have benefited
substantially in terms of a well-documented improved quality of life
with less infection, inflammation, and oropharyngeal ulcers; less
antibiotic use and hospitalization; and improved survival.25-27
The beneficial effect of G-CSF therapy has been most evident in the
management of severe congenital forms of neutropenia, especially the
subgroup of Kostmann's syndrome. In these congenital neutropenias,
defective marrow granulopoiesis can be profound and can predispose a
patient to life-threatening bacterial sepsis. A review of published
cases, for example, showed that 42% of the patients died in the
precytokine era, at an average age of 2 years, due to overwhelming
pneumonia or septicemia.10 The SCNIR data on 352 patients
with congenital neutropenia shows that severe bacterial complications
have been almost completely eliminated in more than 90% of patients
with G-CSF therapy, and death from sepsis is now a very unusual, if not
rare, event. Thus, the natural history of congenital neutropenia has
been sharply altered by G-CSF therapy. These patients have a vastly
improved survival and are living longer.
The phenomenon of malignant myeloid transformation in some patients
with congenital neutropenia has understandably dampened the euphoria of
the therapeutic success. Through the efforts of the SCNIR Scientific
Advisory Board, the evolution from neutropenia to MDS/AML in patients
with congenital disease has been catalogued carefully and brought to
the attention of treating physicians, patients, and families by way of
newsletters, booth exhibits at pertinent meetings, and oral
presentations.17 Predictably, there is dismay and concern
about the malignant conversion and its relationship, if any, to G-CSF
therapy. This issue has prompted us at the SCNIR to meticulously
examine possible factors that may be operative in the development of
MDS/AML.
First, conversion to MDS/AML must be considered in light of the
underlying primary problem. It is well known that many of the inherited bone marrow failure syndromes have a propensity to evolve
into MDS and/or AML,28 and this background of malignant predisposition in patients with congenital neutropenia has been well
documented in a few cases.4-7 However, prior to the
availability of G-CSF therapy, the true risk of patients with
congenital neutropenia developing MDS/AML was never defined. A clearer
understanding of the natural history and incidence of MDS/AML in SDS is
known because many patients have milder forms of neutropenia and
survive the disease long-term without the need for G-CSF treatment.
Recent information suggests that the incidence of malignant
transformation in these patients with SDS may be as high as
30%.8,9 Thus, any analysis of factors that may play a role
in malignant conversion must be weighed against this historical
background for leukemic predisposition.
In the analysis described herein, the evolution to MDS/AML was
associated with a fairly distinctive clinical and laboratory profile.
After starting G-CSF therapy and remaining on treatment for varying
durations, a subgroup of patients developed malignant myeloid
transformation in association with one or more cellular genetic
changes. Many of these changes were repetitive and somewhat predictable. Of the 31 patients who developed transformations, 18 patients acquired a partial or complete loss of chromosome 7 in marrow
cells, and 9 patients showed abnormalities of chromosome 21; often,
both of these situations occurred together in the same patient. We
showed previously that none of the patients tested prior to starting
G-CSF therapy had chromosome 7 alterations.29 After
development of MDS/AML, activating ras oncogene mutations were
also identified retrospectively, but not at baseline, in 5 of 10 patients from our series.29 Of the 5 patients, 4 had monosomy 7. The ras mutations were all similar, with GGT
(glycine) to GAT (aspartic acid) substitutions at codon 12. Marrow
cells from the 5 patients with MDS/AML also showed point mutations in the gene for the G-CSF receptor, therefore resulting in a truncated C-terminal cytoplasmic region of the receptor, which is crucial for
maturation signaling.30-32 There were 20 patients without
receptor mutations who showed no evidence of progression to MDS/AML,
and 4 additional patients were identified with mutations but without MDS/AML.33 The receptor mutations are acquired and are not
the cause of congenital neutropenia.31 These patients and
the ones with clonal cytogenetic changes but without MDS/AML (Table 4) are currently being monitored closely for early signs of
transformation. The chromosome and molecular abnormalities must be
operative in the pathogenesis of MDS/AML because they are so
repetitive, but this requires further study.
The acquired marrow cytogenetic clonal abnormalities shown in Table 4
are of great interest, but they are puzzling. None of the patients had
these alterations prior to starting G-CSF therapy, and, therefore, the
change was acquired and detected between 19 months and 7.5 years after
being on therapy. Clonal changes usually signify malignant
transformation, yet none of these patients have developed MDS/AML. One
of the patients with trisomy 8 has been monitored for more than 6 years
and has remained in good health. Note also that not all of these
patients have congenital neutropenia, the only diagnostic category thus
far in which MDS/AML has been observed.
What is the role of G-CSF in the conversion of congenital neutropenia
to MDS/AML? Can G-CSF be considered leukemogenic? Does it accelerate
the overt development of an underlying preleukemic or leukemic
predisposition? From the data presented herein, there was no definitive
evidence that either the dose of G-CSF or the duration of G-CSF therapy
were directly related to the malignant transformation. Similarly, there
was no apparent relationship to age, gender, or any other demographic
factors that could be linked to the development of MDS/AML. However,
these data do not completely "exonerate" G-CSF as a direct
contributor in the pathogenesis. The data thus far are unclear about
this, and further monitoring is needed to clarify the issue.
Regarding G-CSF as a carcinogen, it would be unexpected for G-CSF to
break molecular bonds and cause DNA damage. In well-defined, treatment-related cases of secondary MDS/AML due to chemotherapy for a
primary disorder, there is also always a lag phase between the drug
exposure and the malignant event. For example, the risk of alkylating
agent-related leukemia begins to increase 2 years after the start of
chemotherapy and peaks in the 5-10 year follow-up. Similarly,
etoposide-related AML has a median 2- to 3-year lag phase
following its therapeutic use. In the 0- to 1-year interval of G-CSF
therapy, there were 3 conversions to MDS/AML at varying times within
the first 12 months of treatment (Table 5). Thus, the customary lag
phase expected for treatment-induced MDS/AML is not apparent; however,
it is unknown if longer follow-up will disclose a pattern similar to
chemo-induced MDS/AML. Thus far, the hazard rate appears flat, but this
could change, and it requires careful long-term surveillance. It seems
highly unlikely at this point, though, that G-CSF is directly
leukemogenic. It may be operative in facilitating transformation in
other ways yet to be defined.
It is notable that MDS/AML has not been diagnosed in any of the other
patients with cyclic neutropenia or idiopathic neutropenia who are
enrolled in the SCNIR and have been treated with G-CSF for the same
duration of time. If the cytokines were contributing to the development
of MDS/AML, one might expect to see cases in these other diagnostic
categories, as well. However, it must be acknowledged that these
disorders are heterogeneous and have varying leukemogenic potential.
Thus, it is not clear from our data that the potential, if any, for
G-CSF therapy to exacerbate a leukemic predisposition would be the same
for each of these types of neutropenias.
Patients with congenital neutropenia who respond well to G-CSF therapy
have been observed to develop MDS/AML associated with recurrent
acquired patterns of cellular genetic changes, singly or in
combination. Although the exact sequence of events is unclear, the
change seemingly begins with a genetic lesion that causes the
congenital neutropenia, which then evolves into G-CSF-receptor mutations, monosomy 7, ras oncogene mutations, and finally
overt malignant disease. We could not identify any specific factors that could be implicated in promoting MDS/AML. We conclude that G-CSF
improves survival of patients with congenital neutropenia, and with
improved survival, the underlying leukemic propensity that
characterizes this disorder becomes unmasked. On the other hand, our
data have not excluded a direct contribution of G-CSF in the
pathogenesis. In this regard, it is possible that G-CSF allows abnormal
malignant cellular clones to proliferate excessively and survive. In
addition, G-CSF may confer a growth advantage on these cells,
especially after the myeloid cells acquire mutations of the G-CSF
receptor.34,35 Currently, G-CSF is still deemed specific
therapy for all forms of severe chronic neutropenia and still offers a
high margin of safety. It should be the initial treatment for this
family of disorders. However, careful surveillance and serial
monitoring of clinical, hematological, and cytogenetic parameters are urged.
Note added in proof. The data presented in this manuscript
were analyzed up to a cut-off date of December 31, 1998. Between January 1, 1999, and December 31, 1999, 36 additional patients with
congenital neutropenia were enrolled in the Registry, thereby increasing the total number to 388. During the same time interval, there were 4 new cases of MDS/AML. Thus. the new, overall incidence or
crude rate of MDS/AML conversion is 9.0% (35 cases among 388 patients
taking G-CSF). This new crude rate is not statistically different than
that of 8.8% quoted in the manuscript. Furthermore, when the new data
were added to Tables 1, 2, and 5 and reanalyzed statistically, there
were no significant differences compared to the analysis in the
manuscript. Therefore, the data interpretation and conclusions based on
the new information are virtually identical to those presented in the paper.
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Acknowledgments |
We thank all of our colleagues and friends associated with the Data
Collection Centers of the Severe Chronic Neutropenia International Registry at the University of Washington, Seattle, WA, and the Medizinische Hochschule, Hannover, Germany. We are also grateful to the
many physicians worldwide who have faithfully and generously submitted
data on their patients.
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Footnotes |
Submitted January 6, 2000; accepted March 7, 2000.
The Severe Chronic Neutropenia International Registry, Seattle, WA, is
funded by Amgen Inc, Boulder, CO, and Thousand Oaks, CA.
Reprints: Melvin H. Freedman, Division of
Hematology/Oncology, The Hospital for Sick Children, 555 University
Ave, Toronto, Ontario, Canada M5G 1X8; e-mail:
melvin.freedman{at}sickkids.on.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.
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Abstract
Introduction