Volumen: 12 # Number : 3
Publication Date : Septiembre - Diciembre Year: 2008
Authors: John M. Bennett, MD
Abstract: In order to understand the pathobiology of event
associated MDS one most appreciate what primary
or “idiopathic” MDS represent. These are a group
of malignant hematopoietic marrow disorders that
share an ineffective production of one or more myeloid
cell lines (accelerated apoptosis) with a variable
percent of leukemic blasts (ranging from <5%
to 20%). The net result is a discrepancy between a
cellular marrow and peripheral cytopenias (marrow
failure). The median age is 70 years and 30%
progress to Acute Myeloid Leukemia within 5 years.
In the USA approximately 15,000 cases are diagnosed
annually.
The vast majority of Event Related. MDS are the
results of chemotherapy and (or) radiation intervention
in patients with a known malignancy that requires
treatment. Another cause is the increasing use
of immunosuppression in transplantation medicine
(alloBMT; cardiac; liver, etc.). Very few proven cases
have been associated with environmental toxins. The
two major classes of mutagenic agents are alkylators,
ionizing radiation and topoisomerase-2 inhibitors.
The identification of pharmacogenomic polymorphisms
(e.g. NQ01; GSTq 1-null) are an increasing
important aspect of exposure reactions.
Alkylating agents are associated with a long latency
(4 + years) and a high frequency of chromosomal
deletions (-5; -7) whereas Topo-II targeting
agents (etoposides, anthracyclines) have a short latency
(1 year) and specific chromosomal translocations
with t(3;21); t(8;21); t(15;17),inv.16, as well as
11 q 23 rearrangements.
One example of the over expression of methylation
of genes involved in marrow regulation of cellular
growth is seen in the higher % of p15-ink in
secondary AML and the association with 7q- and
very short survival. Another example involves the
mutation of the AML1 transcription factor (16% in patients with t-MDS/AML). Further evidence of involvement
is noted with complex arrangements with
CBF and AMP1.
Secondary AML/MDS represents about 15% of
the total number of MDS/AML diagnosed each year.
Antecedent malignancies vary with institutional referral
patterns but solid tumors (breast, lung) and
hematologic malignancy accounts for about 80% of
all reported cases.
Overall survival is short, usually <1 year with longer
survival for patients with balanced translocations.
A well studied series of over 1,000 patients with
NHL exposed to a radionuclide indicates an overall
incidence of 2.2%, all exposed to other alkyating
agents as well.
In addition a small number of cases of ALL secondary
to topo-II inhibitors have been noted often
with [ t(4;11)] representing about 10% of all of the
secondary leukemias reported to date.
Key words:
Pages : 74
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