CLINICAL NEWS
Written in
Featured research from recent issues of Blood
PAPER SPOTLIGHT
Acute Myeloid Leukemia:
Time for New Research
Paradigms
Although molecular and
immunological cancer
therapies have made
great strides across the
clinical landscape in
recent years, their use in
treating acute myeloid
leukemia (AML) has met
with only modest success. In a recent report
published in Blood, a
group of experts, led by
Elihu Estey, MD, examined the state of AML
treatment research and
offered six changes to
current therapeutic development methods that
may yield better results.
“Discovering effective
new therapies in AML is
often inefficient, with
many drugs eventually
proven ineffective after
considerable expenditure
of time and resources,”
wrote Dr. Estey, of the
University of Washington School of Medicine
and the Fred Hutchinson
Cancer Research Center in
Seattle, and colleagues.
Strengths and Weaknesses of AML Studies
The authors first looked
at preclinical studies. In
examining their limitations, Dr. Estey and coauthors pointed out one
important obstacle: “the
genomic complexity of
AML and the presence of
multiple coexisting molecularly defined clones or
subclones.”
Using xenograft assays
may be more clinically
relevant than testing cell
lines, they observed. “Assays done in the presence
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ASH Clinical News
of supporting stroma
might, in principle,
provide a more realistic
replica of the in vivo situation.”
“The limitations to preclinical studies are probably the biggest obstacle,
but those limitations
are not susceptible to
immediate remediation”
in bringing about change
in AML therapy development, Dr. Estey told ASH
Clinical News. “I think the
quicker use of combined
therapies (multiple targeted agents and agents
+ chemotherapy) would
have the most immediate
potential clinical benefit.”
Given the complex
genetic landscape of
AML, there is also a need
for clinical trials that use
more than one targeted
agent. For example, the
authors pointed out,
there is often more than
a single driver mutation
in AML, with an average
of 13 coding mutations
reported in de novo AML.
They argued for testing
combinations of several
agents that modulate
distinct pathways or
targets, which could be
administered simultaneously or sequentially in
early drug development.
What Needs to
Change?
In addition to testing
combinations of targeted
therapies, the authors
strongly supported:
• Early study of combining targeted agents
with chemotherapy
(although that could
require a more extensive financial outlay on
behalf of the agency
developing therapies)
• Inclusion of newly
diagnosed patients in
targeted therapy trials
(rather than the current
standard of relapsed/
refractory AML patients
or those considered
unfit for conventional
chemotherapy)
• Early trials of targeted
therapies in specific,
genotypically defined
populations, followed
by studies in the broader AML population
• A reevaluation of commonly used endpoints
to assess efficacy
“While truly effective
drugs might work even
in very advanced disease
(as is true with all-trans
retinoic acid in acute
promyelocytic leukemia)
it also seems plausible
that conclusions about
the value of a targeted
therapy based solely
on testing in relapsed/
refractory patients may
be falsely negative,” the
authors wrote.
“Likewise, restricting
testing to newly
diagnosed, unfit patients
impedes introduction
of combinations of
targeted agents with
chemotherapy, despite
the possible merit of this
approach noted above.”
In terms of reassessing efficacy endpoints,
Dr. Estey and colleagues
advocated for replacing
overall survival (OS) with
event-free survival. Not
only does EFS takes less
time to evaluate than OS,
but it is a less confounded indicator of a new
therapy or new combination’s value than OS.
“I hope that our paper
increases awareness that
the way we go about
studying targeted therapies leaves much to be
desired,” Dr. Estey said.
“Some of the problem is
simple lack of knowledge,
as with preclinical studies
– that is understandable.
Less understandable are
the problems raised in
the other issues.”
So, what are the biggest barriers to adoption
of the changes advocated
in this paper? The common culprits with any
major change, Dr. Estey
said: “Cost and lack of
time.”
Unique Complications
of AML
Asked to comment on
the paper by Dr. Estey’s
group, Farhad Ravandi,
MD, of the University
of Texas MD Anderson
Cancer Center in Houston,
said he agreed with their
assessments.
“The biggest problem
in AML research is the
heterogeneity of the AML
population. The treatment is complicated,” he
told ASH Clinical News.
“Also, the question of
transplant will always
affect therapies.”
For example, he explained, if you are assessing a drug in solid tumors,
you give the drug to
some patients and not to
others; then you assess
the response and survival
for each group at the end
of therapy. In leukemia,
though, the drug is given
and patients are then
sent for transplan B