H e m a t o lo g y E d u c a t io n - European Hematology Association

16 th Congress of the European Hematology Association
mon cytogenetic abnormality in childhood MDS, seen
in 25% of all patients. 27 Trisomy 8 and trisomy 21 are
the most common numerical abnormalities after monosomy
7. Constitu tional trisomy 21 is clinically obvious
when present, whereas constitu tional trisomy 8
mosaicism may be clinically silent and should be tested
for when trisomy 8 is found in the BM. 28
Monosomy 7, as the only cytogenetic aberration, is
not an unfavorable feature in childhood MDS, 3,29-31
whereas structural complex abnormalities are associated
with a very poor outcome. 27 Monosomy 7 is associated
with a shorter time to progression in children with
RCC. 4 Favorable cytogenetic aberrations, identified in
adults as -Y, 20q- and 5q-, are so infrequent in children
that they are of no practical importance. 5
AML specific trans loca tions, e.g., t(8;21)(q22;q22),
t(15;17)(q22;q12), or inv(16) (p13q22), should be considered
as AML regardless of the blast count. 10
Immunophenotype
Flow cytometry immunophenotyping does not have
the same diagnostic yield in MDS as in acute leukemia.
Few data on immunophenotype characteristics of MDS
in children have been reported. 32 No consensus is available
on standard protocols and techniques of flow
cytometry in childhood MDS.
Refractory cytopenia versus aplastic anemia
A trephine biopsy is fundamental for the evaluation
of a child with suspected aplastic anemia or MDS.
Careful sequential morpholog ic studies are necessary
to establish the correct diagnosis. The typical biopsy in
MDS shows hypoplasia, scarcely scattered granulopoiesis,
patchy islands of immature erythropoiesis,
and micro megakaryocytes. 2 Immunohistochemical
studies may be helpful in demonstrating a high expression
of p53 and a low expression of survivin in MDS,
compared with patients with non-clonal BM failures. 33
Separating MDS from AML
AML is the major differential diagnosis of advanced
MDS. There are significant differences in clinical features,
cytogenetics and response to therapy between
MDS and AML, 34 reflecting fundamental biologic differences,
35 thus making the morphologically based classification
a surrogate marker for the distinction between
biological entities. Blast count in a single specimen is
insufficient to differentiate MDS from AML. Biological
features rather than any arbitrary cut-off in blast count
may be more important in distinguishing MDS from
(chemosensitive) AML. 36
Prognosis and natural course
Children with RCC and RAEB or even RAEB-T may
show a long and stable clinical course without treatment.
Blood transfusions may only be required infrequently
and severe infections are rarely seen. The condition
may smolder with unchanged cytopenia for
months or even years. In a series of 67 children with
primary RCC, four died from complications of pancytopenia
prior to therapy or progression and 20 progressed
to more advanced MDS at a median of 1.7
years from presentation. 4 RCC with monosomy 7 is
associated with a higher risk of progression, and once
progression has occurred, the outcome is inferior even
after HSCT. 4
The International Prognostic Scoring System (IPSS)
for MDS weighed data on BM blast count, cytopenia
and cytogenetics and separated patients into four prognostic
groups. Children show more poor risk features
than adults, but only thrombocytopenia and BM blasts
>5% correlate with poor survival in children. 5 Overall
the IPSS provides little diagnostic information in children
but identifies a very small group (7%) of the
patients with low-risk disease and a very favorable outcome.
5 Adolescence and complex cytogenetics are associated
with a poorer outcome. 27
Treatment
Myeloablative therapy is the only treatment option
with a realistic curative potential. Immunosuppressive
therapy with antithymocyte globulin and cyclosporine
in children with hypoplastic RCC results in complete or
partial response in 70%, with overall and failure-free
survival rates at 3 years of 90% and 60%, respectively.
37-38 The long-term outcome of immunosuppressive
therapy in MDS is not known.
AML type chemotherapy
Conventional intensive chemotherapy without
HSCT is unlikely to eradicate the primitive pluripotent
cells involved in MDS and associated with a complete
remission rate of less than 60%, treatment-related mortality
rate between 10 and 30%, many relapses, and an
overall survival rate of less than 30%. 14,31,34,39 However, a
few studies have reported outcomes in MDS patients
not significantly different from those in AML, especially
in patients with RAEB-T or AML following
MDS. 31,39,40 Children with monosomy 7 diagnosed as
AML have a poor response to induction chemotherapy,
as in MDS patients, but in contrast to MDS those who
responded well to chemotherapy had an outcome similar
to other AML patients. 41
Hematopoietic allogeneic stem cell transplantation
HSCT is the therapy of choice for virtually all forms
of MDS in childhood. Myeloablative therapy with
busulfan, cyclophosphamide, and melphalan has cured
more than half of children with MDS both after
matched family donor (MFD) and matched unrelated
donor (MUD) HSCT. 42-43
Stage of disease has a significant effect on relapse and
outcome following HSCT, with a very low relapse rate
in RCC. In children with RCC and absence of profound
cytopenia, postponement of HSCT with a watch–andwait
strategy may be justified, especially in patients
with a normal karyotype. 4 A fludarabine based
reduced-intensity conditioning regimen in 19 children
with RCC and normal karyotype resulted in an overall
survival and DFS at 3 years of 84% and 74%, respectively,
comparable to those of patients treated with
myeloablative HSCT. 44
It remains unknown whether AML-type induction
chemotherapy prior to HSCT for advanced MDS can
reduce relapse and thus improve DFS. Data from
EWOG-MDS on children with primary advanced MDS
showed no benefit of intensive AML-type therapy preceding
HSCT. 43 Small series of patients transplanted as
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