ASH News Daily - Monday, December 12, 2011 - (Page A-6)
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AML
Find Cancer Early – Really Early
By Michael roSenzweiG, Md
T
he progressive development
of malignancy involves the
clonal evolution from a normal
cell to a malignant one. The sequential
acquisition of genetic mutations
has been well described in some
solid tumors including colon cancer.
Our understanding of AML genomics
has also progressed significantly
in recent years. While the majority
of patients have a normal karyotype
among this group, patients with internal
tandem duplications in the
FLT3 tyrosine kinase (FLT3-ITD)
have a worse prognosis, whereas pa-
MDS
«« From Page A-1
mutations in patients with RARS.
They identified 62 point mutations
in eight patients, with a predominance
of transitions. In six
out of eight patients they found
recurrent somatic mutations in the
SF3B1 gene, a gene encoding a core
component of RNA splicing machinery.
In order to evaluate the
frequency of SF3B1 mutations in
various myeloid malignancies and
other neoplasms, they went on to
perform targeted re-sequencing of
the gene. They were able to show
that mutations are present with
higher frequency in patients with
MDS (28.1%) when compared
with patients with myelodysplastic/myeloproliferative
neoplasms
(19.3%) and patients with acute
myeloid leukemia (5.3%). The gene
was found to be mutated in lower
percentage (1-5%) in other tumor
types.
There was a significant relation-
ship between SF3B1 mutation status
and/or mutant allele burden and
the presence and proportion of bone
marrow ring sideroblasts — nearly
100 percent.
Patients carrying an SF3B1 muta-
tion showed a significantly better
overall survival and had a lower
risk of progression to AML; this better
prognosis was retained in multivariate
analysis. Dr. Malcovati suggested
that, based on these findings,
we may have a better understanding
of the underlying mechanisms
of this disease, and we may be able
to “implicate abnormalities in RNA
splicing in the pathogenesis of myelodysplastic
syndromes.”
The MDS puzzle is still nowhere
near being completed, but we have
just seen another piece added.
Dr. Pro indicated no relevant conflicts
of interest.
ASH NEWS DAILY
Monday, December 12, 2011
tients with mutations in NPM1 fare
better. Identification of these genomic
features in patients with active
AML help us to prognosticate and
guide our treatment approaches. On
the other hand, our understanding
of the genomics behind leukemogenesis
is less developed, and founding
mutations for the development of
leukemia from a non-leukemic stem
cell are largely unknown.
In the Plenary Scientific abstract,
“Clonal Evolution of Pre-Leukemic
Hematopoietic Stem Cells Precedes
Human Acute Myeloid Leukemia,”
Dr. Ravindra Majeti from Stanford
University described work done that
will help us better understand the
nature of mutations in pre-leukemic
stem cells through comparative, genomic
analysis of de novo AML cells
with patient-matched residual nonleukemic
hematopoietic stem cells
(HSCs). Through this elegant work,
Dr. Majeti separated residual hematopoetic
stem cells from patients with
AML. He then identified specific
mutations within the AML cells and
then went back to the HSCs to search
for those same mutations. While the
majority of mutations present in leukemic
cells were absent in the HSCs,
Dr. Vavindra Majeti presents during plenary scientific session.
specific mutations including SKP2
and TET2 mutations were sometimes
present in these presumed to be normal
cells. These so-called “early”
mutations separate normal HSCs
from pre-leukemic stem cells and
may prove to be founder mutations
that later evolve through sequential
acquisition of further mutations into
AML genomes.
The clinical significance of this
finding is yet to be seen; however,
if a pre-leukemic HSC clone can
be found within a pool of residual
HSCs, targeting that reservoir may
lead to specific anti-leukemic treatment
options and more durable remissions.
The ability to separate re-
sidual HSCs from pre-leukemia stem
cells is exciting and provides context
for a targeted approach to prevent
the most common cause of mortality
in our treatment for AML, relapsed
disease. In addition, identification
of the pre-leukemic stem cell raises
the possibility of new, effective treatments
including purged autologous
hematopoietic cell transplants as
part of AML therapy. In summary,
this provocative work by Dr. Majeti
may identify leukemic cells earlier in
their development and provide better,
less toxic treatment options.
Dr. Rosenzweig indicated no relevant
conflicts of interest.
Highlights from Sunday’s Sickle Cell Disease Press Briefing
By aManda Brandow, do, MS
D
uring yesterday’s sickle
cell disease (SCD) press
briefing moderated by
Dr. Susan Shurin, acting director
of the National Heart, Lung, and
Blood Institute, three investigators
presented results of recently
completed SCD clinical trials that
have addressed important clinical
questions regarding the care of
children with SCD. Dr. Zora Rogers
presented results of the Pediatric
Hydroxyurea Phase III Clinical
Trial (BABY HUG) and followup
trial that showed significant
clinical benefit of hydroxyurea in
young infants nine to 18 months
of age. Hydroxyurea decreased
pain events, episodes of chest syndrome,
hospitalizations, and episodic
transfusions.
Dr. Patrick McGann also dis-
cussed data from the BABY HUG
trial that supported the low risk
of genotoxicity of hydroxyurea
in infants, providing further support
and encouragement that hydroxyurea
is safe.
Dr. Jo Howard concluded the
briefing by discussing data from
the Transfusion Alternatives Preoperatively
in Sickle Cell Disease
Trial (TAPS) conducted in the
Panelists Drs. Zora R. Rogers, left, Patrick T. McGann, and Jo Howard
answer questions during the press briefing “Assessing Therapeutic Strategies
and Improving Quality of Life for Patients with Sickle Cell Disease.”
United Kingdom, Netherlands, and
Canada that evaluated the need for
pre-operative transfusion in patients
with HbSS/HbSβ0
thalassemia un-
dergoing low- to medium-risk surgeries.
Children were randomized to
either receive or not receive a routine
preoperative transfusion, and the trial
was closed early because of a significant
increase in serious adverse
events, including marked increase in
acute chest syndrome, in the nontransfused
arm. “This trial shows
a significant increase in significant
complications in those not transfused
before surgery and affirms
that children with homozygous
SCD should be given a transfusion
before surgery,” Dr. Howard
stated. Additional findings of
these studies were presented in
oral presentations on Sunday.
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