ASH News Daily 2017 - Issue 2 - A-27

Sunday, December 10, 2017

DNA

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treatments. NGS is thus having to
nudge its way into this crowd and
prove how it adds value.
In the scientific session "NextGeneration Sequencing (NGS) in
Routine Diagnostics: Are We There
Yet?" Dr. Elaine Lyon addressed the
topic "Understanding the Genome:
Professional Guidelines in Clinical
Genomic Testing and Interpretation." A major issue is how to generate a uniform "product" across labs,
specifically how to rein in interlaboratory variation to yield a consistent
set of results and interpretation. The
standards of precision and accuracy
for genetic testing are extremely
high and have set similarly high
expectations for genomic testing.
She described the recently adopted
National Institute of Standards and
Technology (NIST) genome reference standard known familiarly as
Genome in a Bottle, which is then
used by sequencing laboratories to
assess the accuracy and precision
(reproducibility) of their data as well
as to derive quality metrics. Dr. Lyon
described how professional societies
such as the Association of Molecular
Pathology and the American College of Medical Genetics could provide a "taming influence" on what
has been described as a "wild west"
of genomic testing. The hope is that
these professional societies will also
undertake the constant but obligatory updating of guidelines that
will benefit the end-user of genomic
data, the clinicians, and the end beneficiaries - the patients.
Dr. J.D. Watson quipped that the

Myeloma
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get in this disease for more than 15
years, but direct targeting has been
elusive. Now we have three drugs
in the clinic that target MCL1 directly and several other drugs that
take advantage of its short half-life
as a means to deplete it from cells."
Dr. Florian Bassermann of Technical University of Munich discussed the multiple personalities
of cereblon (CRBN), a major target
for the IMiDs. Originally thought of
as a pathway toward antiproliferation, it is now known that binding
to CRBN can alter patterns of angiogenesis, cell invasion, and cellular metabolism. Dr. Bassermann's
presentation highlighted the importance of persistent research into
the mechanism of action of therapies, even after they have already
been declared "a success!"
Dr. Basserman gave several examples of these discovery efforts.
He described CD147 and MCT1,
which are downstream of CRBN
and are likely the secondary targets
of IMiDs. These proteins are overexpressed in multiple myeloma

ASH NEWS DAILY

Page A-27
®

secret of life is written in three letter
words. He must have been referring
only to the exome. Dr. Torsten Heferlach of Munich Leukemia Laboratory will discuss "Whole Exome
Sequencing (WES) in Patients with
Hematologic Malignancies: Ready
for Real-Time Precision Medicine?"
Touching on some familiar themes,
Dr. Heferlach spoke about the uses
of WES and the extension of that
technology to RNA sequencing to
identify specific patterns of expression that define a cellular phenotype
in clinical samples. The differences
in the genetic coverage and the sensitivity of gene panel, whole exome
and whole genome sequencing
(WGS) is, however, counterpoised
by the turn-around time, cost, and
most importantly interpretation
and utility. He demonstrated these
points with several case studies contrasting what knowledge is gained
by a conventional medical work-up
of myelodysplastic syndrome employing morphology, cytogenetics,
and the sequence of a limited gene
panel versus what whole exome
sequencing and mRNA sequence
would further reveal. Whole-genome sequence provided even more
detailed characterization of the patient's genetic status but the added bioinformatics challenge is too
daunting now for routine use. While
he makes clear that WES and WGS
are research tools today, the implementation into practice is not far off.
Dr. Heferlach finished with a
flourish, predicting that artificial intelligence will ride to the rescue of
mortals faced with overwhelming
amounts of data with unimaginable
complexity. He did not predict that
and may contribute to angiogenesis
and proliferation, thus explaining
the antiangiogenic and teratogenic
properties of IMiDs. Even more
interestingly, Dr. Basserman explained that IMids require CRBN
to increase oxidative stress and,
subsequently, ER stress to work on
myeloma cells. This may finally explain the synergy between IMiDs
and proteasome inhibitors. Further
understanding of the downstream
targets of CRBN will likely uncover
additional targets that may be synergistic with our familiar IMiDs.
These intriguing lectures only
scratch the surface in terms of the
scientific research being conducted
in this field. Though myeloma has
enjoyed the fortune of several agents
being approved during the past three
years, any hematologist will tell you
that our patients are already progressing, even on these. The efforts of
these and other investigators to study
intracellular and microenvironment
signaling presents an opportunity for
parsimony: doing more with what
we already have.
Dr. Shah indicated no relevant conflicts of interest.

Watson, the IBM supercomputer,
will replace physicians as some
have prophesized, but Watson or his
computational kin will certainly be
in the examination room.
Dr. Kojo Elenitoba-Johnson from

the University of Pennsylvania was
prevented from presenting due to
weather-complicated travel.
Dr. Rienhoff indicated no relevant
conflicts of interest.

MDS

My Low Down on Myelodysplasia
By hugh young rienhoFF, Jr., Md

number of sequencing studies
have
circumscribed
the spectrum of mutations
found in hematopoietic stem cells
of patients with myelodysplastic
syndromes (MDS). These recurrent
mutations occur in genes that participate in a limited number of cellular
functions including RNA splicing,
genomic stress, DNA damage, epigenetic regulation of chromatin, and
growth factor signaling. The evolution of clinical disease is thought to
depend on the successive accumulation of mutations that at first confer
a growth advantage on the affected
stem cell clone and eventually manifest as cytopenias and dysplastic
bone marrow cell morphology.
Dr. Colman Lindsley opened the
session tackling the "Uncoding [of]
the Genetic Heterogeneity of MDS."
Dr. Lindsley began with a discussion of the context-dependent biology of MDS driver mutations. This
was illustrated by the patterns of
association, viz., their co-occurrence
or their mutual exclusivity as is
seen with mutations in the splicing factors. Likewise, somatic mutations associated with MDS arise
in a rough order from early-stage
to late-stage disease. Though the
combinatorial diversity of mutations and their temporal appearance
is great, clearly it is not random. In
treatment-related MDS (tMDS), mutations in TP53 and PPM1D cluster
in this sub-type and account for
the more ominous clinical course
of tMDS. Dr. Lindsley finished describing the role of germline mutations focusing on mutations in SBDS
that cause Shwachman-Diamond
syndrome. He noted that adults presenting with MDS can have known
pathogenic mutations in this gene.
Dr. Aristoteles Giagounidis presented the "Current Treatment Algorithm for the Management of
MDS." He conceded perhaps that
the precision an algorithm implies
is not feasible in a clinical setting
with such a heterogeneous patient
population with overlapping hematologic problems and a variety of
genetic and cytogenetic abnormalities. But in the end, he threaded that
needle. He first asked, "What are
the goals of therapy?" and crafted
his algorithm based on the answer:
improvement of the hematologic
profile and well-being of the patient
and, more ambitiously, altering the
natural history of the disease, perhaps even avoiding transformation.

To achieve the first, he described the
subcategories of MDS patients using
as an initial filter the IPSS-R categories and the sub-groups with similar hematologic profiles that dictate
specific treatments. Dr. Giagounidis
systematically stepped through the
clinical characteristics of low-risk
MDS patients providing a useful
flow diagram tantamount to a treatment algorithm with treatment recommendations for erythropoietin,
darbopoietin, lenolidamide, the
experimental agent luspateracept,
the thrombopoietin agonists romiplostim and eltrombopag, the hypomethylators, and the immunosuppressive agents.
The chairman of the session, Dr.
Olatoyosi Odenike finished the
session with her views on "Incorporating Novel Approaches in the
Management of MDS Beyond Hypomethylating Agents." A critical
milestone in the treatment of MDS
was the approval of hypomethylating agents beginning in 2004; they
have had an important impact on
the management of MDS, most importantly, in the overall survival. But
the complete response rate average
among studies at 20 percent or less
suggesting that there is a great deal
of room for improvement. This poor
response may be in part owing to
the hypermethylator phenotype of
MDS and the numerous genes that
contribute to this phenotype and
resistant to hypomethylator agents.
She reviewed the rationale for more
prolonged exposure to azanucleotides, which has focused on efforts
to improve the bioavailability of
these agents including the concomitant use of inhibitors of intestinal epithelial cytidine deaminases as well
as the pro-drug approach of linking
decitabine to deoxyguansoine. She
also summarized the drugs in early
clinical development including inhibitors of epigenetic enzymes such
as LSD1, neddylation, BET, IDH1/2,
immune checkpoints, Bcl2, and
PI3K, all of which could yield alone
or in combination significant clinical
benefit.
"We need to move away from
the one-size-fits-all approach in
MDS and move towards subset specific therapy," Dr. Odenike said in
closing, noting that our increasing
knowledge of the molecular pathobiology these diseases, plus the development of targeted therapies is
laying the foundation for the future.
Dr. Rienhoff indicated no relevant
conflicts of interest.

Table of Contents for the Digital Edition of ASH News Daily 2017 - Issue 2