ASH News Daily 2012 - Tuesday, December 11, 2012 - (Page A-2)
Page A–2
®
ASH News Daily
2012 Editorial Board
Editor
Michael R. Bishop, MD
University of Chicago
Authors
Jose A. Bufill, MD
Michiana
Hematology
Oncology, PC
Jenna D. Goldberg, MD
Memorial SloanKettering
Cancer
Center
Matthew Hsieh, MD
National Institutes
of Health
Marc Kahn, MD,
MBA
Tulane University
School of Medicine
Andrew D. Leavitt, MD
University of
California,
San Francisco
The information contained in ASH
News Daily is provided solely for
educational purposes. A diversity
of opinions exists in the field of
hematology, and the articles in this
publication are often intended to
inform readers about more than one
point of view. These articles are not
comprehensive and should not be
used as a substitute for traditional
sources of hematology information,
traditional diagnostic and treatment
information, or the individual
judgment of health-care providers.
The views expressed in ASH News
Daily do not necessarily represent
ASH’s views, and their inclusion
in this publication should not be
interpreted as an endorsement by
ASH. ASH is not responsible for any
inaccurate or inappropriate use of the
information, publications, products,
or services discussed or advertised
within.
©2012 by the American Society of
Hematology
All materials contained in this
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reproduced, or otherwise exploited in
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permission of ASH News Daily.
Contributing authors have declared
any financial interest in a product or
in potentially competing products,
regardless of the dollar amount. Any
such financial interest is noted with
the author byline.
LEUKEMIA
The Beginning of AML Genomics – Not the End
BY MATTHEW HSIEH, MD
Y
esterday Timothy J. Ley, MD,
from Washington University
School of Medicine, St. Lou-
is, MO, delivered the E. Donnall
Thomas Lecture for his research
in acute myeloid leukemia (AML).
AML, a rare but highly aggressive
form of malignancy, is currently
classified based on pathology and
chromosomal analysis. This classification
is helpful but inadequate
in a substantial proportion of AML
that has typical morphology with
normal cytogenetics. Targeted investigations
have identified mutations
among candidate genes
in this group of AML, but critical
questions relative to the initiating
event/mutation and more efficient
ways to study AML with “normal”
chromosomes remained unanswered.
Dr. Ley began the lecture with
his work in the early 1980s using
low-dose azacitadine in patients
with AML and MDS. He shared
that while the low response rate
was disappointing, he distinctly
remembered his conversation with
Dr. Thomas and his challenge: “You
should define the genetic determinants
of response.” Dr. Ley dedicated
the remainder of the lecture to
describing his response to this challenge.
He and his team at Washington
University used whole-genome
sequencing in paired samples (skin
and AML cells), and reported the
initial results from one patient with
AML with normal cytogenetics.
They uncovered previously known
mutations (e.g., NPM1 and FLT3),
but also several new ones. After sequencing
more patients, they were
able to classify which mutations are
founding or initiating, and which
ones are cooperating.
Dr. Ley’s team then applied
this same approach to 24 paired
AML samples, half from M3 and
half from M1, and compared them
with seven healthy samples. As
Efficacy
«« From Page A-1
showed a statistically higher rate of
depression among survivors of TTP
when compared with the general
population (abstract 366).
Lara N. Roberts from King’s College
in the United Kingdom presented
data on the National VTE Prevention
Programme (abstract 363). She
and her colleagues were able to demonstrate
a significant reduction in
patient harm with the introduction
of a comprehensive risk assessment,
thromboprophylaxis, and root-cause
analysis program instituted on a na-
expected, they found PML-RARA
mutations in the M3 samples, but
mutations in NPM1, DNMT3A,
and IDH all occurred together in
the M1 samples. These divergent
sets of mutations were mutually
exclusive, strongly suggesting that
these are the leukemia-initiating
lesion(s). There were also mutations
that were present in both
AML sample sets, with FLT3 being
the most common – suggesting that
FLT3 mutations (and others) are cooperating
lesions in leukemogenesis.
They also found that both sets
of AML samples had an average of
one to five events, fitting with the
pattern of one initiating and one or
more cooperating lesions.
They next tried to identify what
happens to the founding clones at
the time of relapse. At diagnosis,
some patients have one, while others
have more clones. It appears that
when patients with multiple clones
relapse and go through chemotherapy,
treatment eliminates only some
of the clones. The remaining clones
not only retain their founding mu-
tation, but acquire additional mutations
with proliferation advantage.
It is now clear that as we all get
older, the more mutations we accumulate.
Dr. Ley has convincingly
shown us that to develop AML
there is one initiating mutation,
followed by one or two cooperating
lesions. He also has demonstrated
the progression of these
clones through AML treatment
and how the genetics do determine
treatment response. I think he has
clearly answered Dr. Thomas’ challenge.
Now it is time for us to answer
his challenge, “To understand
AML, it is not enough to know the
disease, but it is necessary to know
the clones.”
Dr. Hsieh indicated no relevant conflicts
of interest.
Look for an article about the
late E. Donnall Thomas in the
January/February 2013 issue
of The Hematologist by
Frederick Appelbaum, MD.
ASH NEWS DAILY
Tuesday, December 11, 2012
Dr. Daniela Zackova, University Hospital Brno, Brno, Czech Republic, takes
advantage of a Wi-Fi Hot Spot sponsored by Incyte and Seattle Genetics.
tional level. A meta-analysis presented
by Siavash Piran, MD, MSc, from
the University of Ottawa on the outpatient
treatment of pulmonary embolism
suggested that most patients
with uncomplicated pulmonary embolism
can be treated as outpatients
without excess adverse events (abstract
361).
Deena Khamees, BS, MLS, from
The Ohio State University presented
a paper (abstract 477) on the effectiveness
of population screening for
bleeding disorders among adolescents
with heavy menstrual bleeding.
Despite available recommendations
from the American College
of Obstetricians and Gynecologists,
these authors found that very few
adolescents were actually screened,
suggesting that our estimates of the
frequency of bleeding disorders in
this population are severely underestimated.
These papers, as an aggregate,
will help the clinician decide what
to do in an individual practice and
help to show outcomes of diseases
over time. Moving the laboratory
into the office is the inevitable result
of well-designed studies.
Dr. Kahn indicated no relevant conflicts
of interest.
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ASH News Daily 2012 - Tuesday, December 11, 2012
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