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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 93 No. 2 (January 15), 1999:
pp. 459-466
Myelodysplastic and Myeloproliferative Disorders of Childhood: A
Study of 167 Patients
By
Sandra Luna-Fineman,
Kevin M. Shannon,
Susan K. Atwater,
Jeffrey Davis,
Margaret Masterson,
Jorge Ortega,
Jean Sanders,
Peter Steinherz,
Vivian Weinberg, and
Beverly J. Lange
From the University of California, San Francisco, San Francisco, CA;
the British Columbia Children's Hospital, Vancouver, British Columbia,
Canada; the Children's Hospital Medical Center of Cincinnati,
Cincinnati, OH; the Children's Hospital of Los Angeles, Los Angeles,
CA; the Fred Hutchinson Cancer Research Center, Seattle, WA; the
Memorial Sloan-Kettering Cancer Center, New York, NY; and the
University of Pennsylvania and Children's Hospital of Philadelphia,
Philadelphia, PA.
 |
ABSTRACT |
Myelodysplastic syndromes (MDS) and myeloproliferative syndromes
(MPS) of childhood are a heterogeneous group of clonal disorders of
hematopoiesis with overlapping clinical features and inconsistent nomenclature. Although a number of genetic conditions have been associated with MDS and MPS, the overall contribution of inherited predispositions is uncertain. We report a retrospective study examining
clinical features, genetic associations, and outcomes in 167 children
with MDS and MPS. Of these patients, 48 had an associated
constitutional disorder. One hundred one patients had adult-type
myelodysplastic syndrome (A-MDS), 60 had juvenile myelomonocytic leukemia (JMML), and 6 infants with Down syndrome had a transient myeloproliferative syndrome (TMS). JMML was characterized by young age
at onset and prominent hepatosplenomegaly, whereas patients with A-MDS
were older and had little or no organomegaly. The most common
cytogenetic abnormalities were monosomy 7 or del(7q) (53 cases); this
was common both in patients with JMML and those with A-MDS. Leukemic
transformation was observed in 32% of patients, usually within 2 years
of diagnosis. Survival was 25% at 16 years. Favorable prognostic
features at diagnosis included age less than 2 years and a hemoglobin F
level of less than 10%. Older patients tended to present with an
adult-type MDS that is accommodated within the French-American-British
system. In contrast, infants and young children typically developed
unique disorders with overlapping features of MDS and MPS. Although the
type and intensity of therapy varied markedly in this study, the
overall outcome was poor except in patients with TMS.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
IN ADULTS, PRELEUKEMIC conditions have
been subdivided into myelodysplastic syndromes (MDS) and
myeloproliferative syndromes (MPS; Table
1).1,2 The French-American-British (FAB) group classifies
MDS into refractory anemia (RA), refractory anemia with ring
sideroblasts (RARS), refractory anemia with excess blasts (RAEB),
refractory anemia with excess blasts in transformation (RAEBt), and
chronic myelomonocytic leukemia (CMML).2 Myeloproliferative disorders are subdivided into chronic myeloid leukemia, polycythemia vera, primary thombasthenia, and myelofibrosis/agnogenic myeloid metaplasia.1 As the FAB system classification has gained
acceptance, several groups have attempted to apply these criteria to
pediatric disorders, usually by placing the disorder juvenile chronic
myeloid leukemia (JCML) within the FAB category of CMML.3-5
However, as emphasized by Wegelius,6 many children show
overlapping features of MPS and MDS, particularly patients with JCML
and infant monosomy 7 syndrome. This group of patients does not satisfy
criteria for the FAB CMML classification group, because most have white blood cell counts (WBC) greater than 13,000/µL,2,6-8 as
well as unique biologic characteristics.9 The
classification of pediatric MDS is complicated further by the fact that
some children develop MDS in the context of inherited predispositions
such as neurofibromatosis type 1 (NF1), Fanconi anemia, severe
congenital neutropenia, Down syndrome, or Noonan
syndrome.10-14 An International Working
Group15-17 recently proposed that the term juvenile
myelomonocytic leukemia (JMML) be added to the FAB MDS system to
accommodate children previously classified as having JCML or infant
monosomy 7 syndrome. We report here a retrospective analysis of a large unselected group of children with MPS and MDS in which we define clinical features, associated genetic conditions, and outcome.
| |
PATIENTS AND METHODS |
Patients.
Seven tertiary institutions with large pediatric hematology/oncology
referral bases participated in this study: University of California,
San Francisco (San Francisco, CA); Children's Hospital of Los Angeles
(Los Angeles, CA); Children's Hospital of Philadelphia (Philadelphia,
PA); Children's Hospital Medical Center of Cincinnati (Cincinnati,
OH); Memorial Sloan-Kettering Cancer Center (New York, NY); Fred
Hutchinson Cancer Research Center (Seattle, WA); and British Columbia
Children's Hospital (Vancouver, British Columbia, Canada). Some of these patients have been reported
previously.3,12 One investigator (S.L.-F.) reviewed the
medical records of all patients less than 21 years of age with the
diagnoses MDS, MPS, JCML, monosomy 7, and/or preleukemia who
presented between January 1975 and April 1995. Children with
Philadelphia chromosome-positive chronic myeloid leukemia were excluded
from the analysis. A computerized search using the terms
"preleukemia," "MDS," "JCML," and "monosomy 7"
identified 245 patients. Seventy-eight of these were excluded for the
following reasons: 30 had Fanconi anemia (FA) without evidence of MDS;
14 had acute myeloblastic leukemia (AML) with monosomy 7 without antecedent MDS; 5 had Blackfan-Diamond anemia without MDS; 8 had treatment-related leukemia; 1 had NF1 and AML; 1 had severe
congenital neutropenia and AML without preleukemia; 7 had aplastic
anemia followed by MDS or leukemia; and 12 had insufficient data for
analysis. MDS with clinical and marrow manifestations of the FAB MDS
subtypes were classified as adult-type MDS (A-MDS). In accordance with
the recent International Working Group
recommendations,15-17 children who fulfilled the diagnostic
criteria shown in Table 1 were classified as having JMML. This group
included patients previously diagnosed with JCML as well as most
children with monosomy 7 syndrome. Patients with a myeloproliferative
disorder that resolved spontaneously and did not fulfill the criteria
for either A-MDS or JMML were classified as having transient
myeloproliferative syndrome (TMS).
Records were reviewed to ascertain the history and
physical examination at diagnosis of MDS and MPS. Patients were
classified as having a constitutional predisposition if they had a
previously diagnosed genetic syndrome such as Down syndrome, NF1,
Fanconi anemia, and severe congenital neutropenia or a familial myeloid disorder (defined as a first degree relative with MDS, AML, or bone
marrow monosomy 7).
The complete blood count (CBC), differential, and hemoglobin F level
(HgF) at diagnosis were recorded. Available marrow aspirates and
biopsies were assessed blindly by S.K.A. for adequacy of material, percentage of blasts, and percentage of dysplastic cells in each lineage. Biopsy sections were evaluated for cellularity, morphology, blast percentage, myeloid:erythroid ratio, megakaryocyte number, and
fibrosis.2,18 Where there was discordance between S.K.A. and institutional marrow findings, the institutional diagnosis was used
provided that there were sufficient clinical, hematologic, and
cytogenetic data to support a diagnosis of MDS. Cytogenetic reports
were reviewed for number of mitoses, numerical and structural abnormalities, and complexity of karyotype. The clinical course was
examined for transformation into leukemia, treatment during the course
of the disease, and causes of death. The date of last follow-up was
used to compute outcome.
Statistical analysis.
Data were collected by S.L.-F. using a data capture tool adapted into
the relational database 4th-Dimension 3.0 (4D, San Jose, CA) and then
imported into Statistica (StatSoft, Tulsa, OK) for analysis. Descriptive statistics were calculated to
characterize the study population overall and within subsets based on
age, percentage of HgF, FAB MDS subset or JMML, karyotype, and therapy. Survival probabilities were estimated using the Kaplan-Meier product limit method19 and differences between survival
distributions were compared using the log-rank test.20 No
multiple comparison adjustment was performed due to the retrospective
design of the study.
| |
RESULTS |
Demographic and clinical features.
Table 2 shows the distribution of cases in
each diagnostic category. A-MDS was the most common diagnosis and
accounted for 101 patients (60%). Of 50 patients with A-MDS who were
classified by the institution according to the FAB system, 11 had RA,
27 had RAEB, and 12 had RAEBt. The other 43 were classified as MDS not
otherwise specified (NOS) at the referring institution based on
ineffective hematopoiesis, dysplasia, and exclusion of other diseases.
There were 60 patients with JMML (36%), including 48 initially
diagnosed with JCML and 12 classified as having monosomy 7 syndrome at
the referring institutions. Eight patients with monosomy 7 syndrome did
not fulfill the diagnostic criteria for JMML shown in Table 1 and were
assigned to the A-MDS group on the basis of marrow dysplasia, absence
of organomegaly, and peripheral cytopenias. Six patients with Down
syndrome had a TMS.
Overall, 125 patients (75%) were Caucasian, 14 (8.5%) were Hispanic,
12 (8%) were African-American, 6 (3.5%) were Asian, and for 8 (5%)
the background of origin was unknown. There was no significant racial
predilection. Although the number of African Americans was low, our
population approaches the racial population distribution of pediatric
malignancies in the United States.21
The 48 patients with a known constitutional predisposition to leukemia
are summarized in Table 2. Down syndrome (16 cases) was the most common
associated diagnosis, followed by Fanconi anemia (12 cases), familial
leukemia (11 cases), Kostmann's syndrome (1 case), and NF1 (8 cases).
The 11 patients with familial leukemia included 3 pairs of affected
siblings with bone marrow monosomy 7. All 12 patients with Fanconi
anemia and 10 of 16 with Down syndrome developed A-MDS, whereas 7 of 8 patients with NF1 had JMML. As shown in Table 2, children with A-MDS
were more likely to have an underlying genetic disorder than patients
with JMML (34% v 13%, P = .004).
Table 3 summarizes the clinical features of
our patients. The median age at diagnosis was 3.2 years; children with
JMML were significantly younger than those with diagnosis of A-MDS
(median age at diagnosis, 1.3 v 8 years; P = .001). A
male preponderance was seen in both groups, but was more pronounced in
JMML (male:female ratio = 1.7:1). Hepatomegaly and splenomegaly were
detected in the majority of patients with JMML (75% and 87%,
respectively). In contrast, only 22% and 26% of A-MDS cases had
either hepatomegaly or splenomegaly. Adenopathy and rashes were only
common in JMML.
Laboratory data.
The hematologic findings at diagnosis are shown in Table 3. Children
with JMML had prominent myeloproliferative features with a median WBC
of 32 × 109/µL. Although patients with A-MDS tended
to present with low or normal WBC counts, there was considerable
variability. Median hemoglobin values and platelet counts were reduced
in both groups but with a great deal of variability. HgF values were
available for 62 patients. Of 40 JMML patients tested, 20 (50%) had an
HgF greater than 10%. HgF values were measured in only 22 patients without JMML, 5 of whom had a value higher than 10%. As expected, monocytosis was most prominent in JMML.
Bone marrow preparations were available for review from 67 patients,
including 23 with both aspirate smears and biopsy sections, 39 with
aspirate smears only, 4 with biopsy sections only, and 1 with only a
biopsy touch preparation. Seventy-seven percent of the samples showed
bilineage or trilineage dysplasia, with the erythroid lineage affected
most often (61% of cases). Eighteen others (23%) appeared normal or
had insufficient material or information to establish a diagnosis based
on marrow findings alone. Twelve (18%) of the institutional diagnoses
were discordant with our central review, including 6 patients with
acute leukemia and 6 others with a different subtype of MDS. We
reviewed the clinical courses of patients in whom central review did
not confirm the institutional diagnoses and found that their outcomes
were generally consistent with the original diagnosis. Data from these
patients were therefore included in the overall analysis according to
the diagnosis established at the referring institution. Our experience with central review of bone marrow preparations emphasizes the difficulties in confirming the diagnosis of MDS using a single specimen.
Cytogenetics.
Table 4 summarizes the cytogenetic
findings. Original cytogenetics reports were available for review from
126 patients (75%). Of these, 25 (20%) were normal and 101 (80%)
were abnormal. Monosomy 7 and/or del(7q) was detected in 53 specimens (52%), including 34 (64%) in which monosomy 7/del(7q) was
the sole abnormality. Clonal cytogenetic abnormalities were seen in
bone marrow samples from 67 of 73 patients (93%) with A-MDS, including
37 that showed monosomy 7/del(7q). Of these, monosomy 7 was the only
abnormality present in 22 cases. Cytogenetic data were available from
48 of 60 patients with JMML. Abnormalities were identified in 29 specimens (60%), of which 16 showed isolated monosomy 7/del(7q).
Trisomy 21 was present in 16 specimens, including 9 patients who had
constitutional abnormalities due to Down syndrome. Importantly, the
translocations commonly associated with AML, such as t(8;21), t(15;17),
t(6;9), and inv(16), were absent.22 Monosomy 5 or del(5q)
were only detected in 3 specimens and 1 patient showed trisomy 8. Thirteen marrows were pseudodiploid, 4 were hyperdiploid, and 11 were
hypodiploid. No patients had t(5;12).23
Cytogenetic reports were available for 36 of the 48 patients with a
known genetic predisposition to myeloid leukemia and showed clonal
abnormalities in 25 cases (69%). Monosomy 7/del(7q) occurred in bone
marrows from 5 of 9 patients with familial leukemia, in 5 of 9 with
Fanconi anemia, in 2 of 14 with Down syndrome, and in 1 of 5 with NF1.
Outcome and treatment.
Outcome data were available in 154 patients with a median follow-up
from the time of diagnosis of 5.6 years.
Figure 1 shows the estimated survival among
all patients of 36% ± 5% (percentage of survival ± standard
error) at 10 years and 25% ± 9% at 16 years by Kaplan-Meier
analysis. The median survival was 6.3 years in A-MDS, 4.4 years in
JMML, and has not yet been reached for the 6 patients with TMS
(Fig 2). There were no significant
differences between the 3 groups or between each group by pairwise
comparison (P = .11, log-rank). Among children with
constitutional predispositions, only those with Down syndrome fared
relatively well (69% ± 19% survival at 6 years).
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| Fig 1.
Kaplan-Meier survival curve of patients with complete
follow-up data (n = 154). Survival at 10 years is 36% (confidence
interval [CI], 29% to 49%). Survival at 16 years is 25% (CI, 12%
to 44%).
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View larger version (11K):
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| Fig 2.
Kaplan-Meier survival curves of children with complete
follow-up who were diagnosed with TMS, JMML, or A-MDS. Ticks on the
lines represent censored cases.
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Fifty-four patients (32%) developed acute leukemia usually within 2 years of diagnosis (Table 5). Of these, 48 transformed to AML and 1 to ALL. In 2 of 4 patients with Fanconi
anemia, transformation occurred more than 5 years after diagnosis of
MDS. Forty-one of 101 children (41%) with A-MDS developed acute
leukemia compared with 8 of 60 (13%) of patients with JMML (P = .0001, log-rank). Within the A-MDS subgroups, 15 of 39 patients with
RAEB or RAEBt developed acute leukemia versus none of 11 with RA. All
myeloid leukemia subtypes occurred except promyelocytic leukemia.
Treatment varied among institutions and generally became more intensive
in later years. Fifty patients received low-dose chemotherapeutic regimens such as 6-mercaptopurine, hydroxyurea, busulfan, prednisone, or low-dose cytarabine; 22 patients received high-dose AML-like chemotherapy; and 12 received both low- and high-dose chemotherapy. Seven children with Fanconi anemia also received oxymethalone. There
was no apparent superiority of one approach over another (data not
shown).
One hundred sixteen patients also received a bone marrow transplant
(BMT); in 55 it was the first therapy. Of patients who received BMT, 86 were transplanted from an HLA-matched sibling, 23 from an unrelated
donor (URD), and 7 received an autologous marrow. Nineteen patients had
a second BMT after failure to engraft or relapse (18 of 19 of these
were HLA-matched). Survival data were available for 110 patients.
Survival for the patients with JMML at 10 years by Kaplan-Meier
analysis was similar with or without BMT (31% ± 9% and 34% ± 16%, respectively). Similarly, the actuarial survival for
children with A-MDS who received BMTs was not different from those who
did not (survival, 39% ± 7% v 43% ± 17% at 10 years, respectively).
Twenty-two patients initially received no cytotoxic therapy, of whom 17 had long-term follow-up. Four of these patients were infants with Down
syndrome and TMS. Nine had A-MDS and 4 had JMML. Ten patients were less
than 2 years old at diagnosis, and 13 of 14 had a WBC count less than
6.5 × 109/µL. Eleven progressed to AML within 3.5 years and then received intensive multiagent chemotherapy
and/or BMT. The other two children are surviving greater than 5 years from diagnosis without therapy or clinical progression. One child
presented with A-MDS at 11 years of age, had a WBC count of 2.9 × 109/µL, and hepatosplenomegaly. The other patient has
NF1; she presented at birth with neutropenia (WBC count, 3 × 109/µL) and anemia (Hg, 8.2 g/dL) but subsequently
developed a myeloproliferative disorder that fulfills diagnostic
criteria for JMML. She remains well with elevated neutrophil and
monocyte counts. Interestingly, molecular analysis showed loss of the
normal parental NF1 allele in her peripheral blood
leukocytes.24
Prognostic factors.
Age less than 2 years (P = .002, log-rank) and HgF less than
10% (P = .02, log-rank) were the only clinical or laboratory findings present at diagnosis found to be significantly favorable for
survival. When children with Down syndrome were excluded, the results
did not change (P = .002 and P = .02, respectively). The clinical diagnosis did not predict outcome (P = .18, log-rank). A low platelet count, the existence of chromosomal
abnormalities (none, single, or multiple), and the presence of monosomy
7/del(7q) did not impact negatively on survival. Similarly, the
presence of hepatosplenomegaly, lymphadenopathy, rash, initial low or
high WBC count, initial low Hg, initial high mean corpuscular volume (MCV), infections, or bleeding had no consistent effect on
outcome (data not shown).
Passmore et al14 analyzed clinical and laboratory findings
present at diagnosis in a series of children with MDS seen at a large
pediatric referral center and found that low platelet count, an HgF
greater than 10%, and the presence of complex cytogenetic abnormalities in the bone marrow correlated with a poor outcome. They
developed a cumulative scoring system based on these factors that we
applied to the 44 patients in our series who had all 3 studies
performed at diagnosis. This analysis did not confirm the prognostic
value of the Passmore score; however, the number of cases we were able
to analyze was relatively small.
| |
DISCUSSION |
We describe the largest cohort of pediatric MDS/MPS patients reported
to date. The retrospective methodology, absence of some clinical and
laboratory data, and the work-in-progress nature of classification
systems may weaken the study. However, the large number of cases and
the use of one reviewer who examined all primary data have provided a
number of new insights.
The 60% of children in this study with A-MDS had disorders that could
be accommodated within the standard FAB MDS classification system.
Sixty other patients (36%) had a disorder that meets the recent
International Working Group's definition of JMML,17 and 6 children (4%) had Down syndrome and TMS. Patients with A-MDS were more
likely to be older children whose disease was characterized by
trilineage dysplasia, functional and absolute cytopenias, and little or
no extramedullary disease. In contrast, the JMML patients were younger,
had extensive myeloid proliferation, had extramedullary hematopoiesis,
had a frequently elevated HgF, and showed less obvious morphologic
dysplasia. Children with JMML had unique clinical and biologic
characteristics that distinguished them from patients with CMML,
including young age and WBC counts greater than
13,000/µL.8 The (5;12) TEL/PDGFR  translocation and
variant translocation that exists in a subset of older children and
adults with CMML has not been observed in JMML.23,25,26
Finally, blood and bone marrow from JMML patients uniformly show
hypersensitivity to granulocyte-macrophage colony-stimulating factor
(GM-CSF) in in vitro culture assays9,15; this finding has
not been described in CMML. Deregulated Ras signaling is common in JMML
and may result from either oncogenic RAS mutations or
inactivation of the NF1 tumor-suppressor gene in the leukemic
clone.24,27-30
Although associations between childhood MDS and disorders such as Down
syndrome, NF1, Fanconi anemia, and severe congenital neutropenia are
known, the high prevalence of one of these underlying conditions among
children with MDS has only been appreciated recently. Bader-Meunier et
al31 reported constitutional disorders in 22 of 49 pediatric MDS patients. Similarly, 29% of our patients had a
constitutional predisposition to malignant myeloid disorders. This
probably represents a conservative estimate due to the combined effects
of underreporting and underdiagnosis. The latter possibility is
supported by a recent study that found NF1 mutations in bone marrows of 3 of 20 children with JMML without clinical stigmata of
NF1.32 Different constitutional disorders were associated with distinct types of MDS/MPS. For example, TMS and MDS in Down syndrome have an excellent outcome.33 In Fanconi anemia,
MDS is relatively indolent, but the long-term prognosis is
poor.34 In severe congenital neutropenia, somatic mutations
in the granulocyte colony-stimulating factor receptor,35,36
activating RAS mutations, and monosomy7/del(7q) have been
associated with progression to MDS or AML.37 Children with
inherited predispositions to MDS provide an extraordinary resource for
discovering genes and biochemical pathways that are involved in both
normal myelopoiesis and in leukemic transformation.
In this study, clonal cytogenetic abnormalities were identified in 80%
of the marrows analyzed, a percentage that is higher than reported in
most previous studies.5,10,16,31 Common nonrandom AML
translocations were absent and the high frequency of monosomy 5/del(5q)
and trisomy 8 seen in adults with MDS was not found in
children.38 Monosomy 7/del(7q) was the most common abnormality by far and was detected in 33% of JMML and 51% of A-MDS
patients. There was considerable overlap between the occurrence of
monosomy 7 and the constitutional disorders. Monosomy 7 has previously
been associated with myeloid disorders among patients with Fanconi
anemia,34 NF1,39 familial
leukemia,40,41 severe congenital neutropenia,42
and Down syndrome.33 We have previously proposed that
monosomy 7/del(7q) is a cytogenetic opportunist, ie, an abnormality
that occurs in patients who are already susceptible to myeloid leukemia
either because of a genetic predisposition or medical exposure to
mutagenic compounds.13 Molecular and cytogenetic analysis
of leukemic marrows with partial deletions of 7q have defined commonly
deleted segments, an important first step toward positional cloning of
putative myeloid leukemia tumor-suppressor genes on chromosome
7.43-46 The observation that activating RAS mutations (or inactivation of NF1) coexists with monosomy
7/del(7q) in the bone marrows of many children with MDS suggests that
these alterations cooperate in leukemogenesis (reviewed in Luna-Fineman et al13).
In addition to patients with Down syndrome and TMS, we identified 2 patients who are long-term survivors with supportive care only. The
other 11 children who received supportive care developed AML within a
few years of diagnosis. A French multicenter study recently describes
spontaneous remissions in a child with RA and another with
RAEB.31 More recently, Bader-Meunier et al11 described remissions with little or no therapy in three of four neonates with CMML and Noonan syndrome. They proposed that MDS in these
children may not be malignant disease. Our data from a large unselected
population of children with MDS indicate that prolonged survival
without therapy is uncommon except in infants with Down syndrome and
TMS. Further clinical and molecular investigation of children who do
well without therapy are required to elucidate the nature of these
unusual cases.
The outcome for children with MDS is poor in this series and in most
reports.5,14,16 We and others have found no differences between high-dose chemotherapy and low-dose chemotherapy.47 The optimal treatment of MDS in both children and adults has not been
defined.8 There is some evidence that patients with
monosomy 7 and MDS have outcomes similar to those with de novo AML if
they receive AML therapy while they have a low blast
count.48 In contrast, patients with monosomy 7 and AML have
a poor outcome.49 Recent studies in adults suggest that
patients with RAEBt may be more responsive to AML therapy than
others.48 However, it is not possible to argue strongly for
AML therapy in the majority of these patients. Therapeutic
recommendations await results of prospective trials, some of which are
now underway.
BMT has been proposed as the treatment of choice for children with
MDS.5,47,50-52 Our data and most published series show that
only about 30% of patients with JMML who receive allogeneic BMT will
become long-term survivors.5,52 However, the European Working Group on MDS in Children (EWOG-MDS) recently reported a 55%
5-year event-free survival (EFS) among 33 patients with MDS after BMT.50 Patients with A-MDS or JMML in our study
had a similar prognosis with or without marrow transplantation. Our transplant data must be interpreted with caution, because the patients
were treated over two decades of rapidly evolving transplantation technology. When to transplant children with MDS, the ideal preparative regimen, and the role of elective splenectomy in patients with massive
splenomegaly all remain controversial. These questions can only be
adequately addressed in a multicenter trial that uses a uniform
classification system and a consistent treatment plan. Two such trials
are anticipated, one in North America and another in Europe.
Data from this large series emphasize the importance of a uniform
classification system to assess the biology, prognosis, and therapy of
children with MDS and MPS. The presence or absence of a genetic
predisposition, the clinical findings, and the bone marrow morphology
and cytogenetic data should be considered together in evaluating
individual patients. Given our present incomplete state of knowledge,
we advocate the addition of JMML as a new subtype to the FAB MDS system
to encompass a group of young children with novel clinical and biologic
features. However, most children with MDS fulfill FAB criteria, and we
believe that these cases should be classified into one of the specific
FAB subsets. It is likely that the criteria used to classify children
with MDS and MPS will improve as molecular genetic basis of this
heterogeneous group of disorders is elucidated further.
| |
ACKNOWLEDGMENT |
The authors gratefully acknowledge the help provided by each
participating institution through their clinical research associates and research nurses.
| |
FOOTNOTES |
Submitted November 17, 1997;
accepted September 11, 1998.
Supported in part by National Institutes of Health (NIH) Grants No.
M01-RR01271 and R01-CA72614 and by the Frank A. Campini Foundation and
facilitated by a collaboration with the Children's Cancer Group (CCG).
CCG is supported by NIH Grant No. CA13539.
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. section
1734 solely to indicate this fact.
Address reprint requests to Sandra Luna-Fineman, MD, Department of
Pediatrics, Box 0106, University of California, San Francisco, San
Francisco, CA 94143.
| |
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Abstract
Introduction