ASH News Daily 2017 - Issue 3 - A-27

Monday, December 11, 2017

ASH News Daily

Page A-27
®

TPO

«« From Page A-1

conclusions at first seem simple:
eltrombopag binds c-MPL downstream of the natural TPO binding
site, thereby evading the inhibitory
steric effect of IFNγ. However, the
implications of this are more far
reaching.
"I think these data are spectacular," said Dr. Janis Abkowitz, who
introduced the abstract. These results suggest that "small molecules
that target a cytokine receptor
downstream of the receptor-ligand

ASM

«« From Page A-2

to the safety, pharmacokinetics, and
preliminary efficacy of Blu-285, patients also underwent evaluation
for clonal hematopoiesis. Thirtytwo patients were treated with
varying doses of Blu-285, 28 patients had KIT D816V mutation, two
patients had KIT D816Y mutation,
one patient had KIT polymorphism
M541L, and three patients had no
detectable KIT alteration. Twenty-four patients had at least one
co-occurring mutation(s) in bone
marrow, most frequently TET2
(17 patients), DNMT3A (9 patients), ASXL1 (7 patients), SRSF2 (6
patients), and GATA2 (6 patients).
Patients had a median of one prior
therapy, and four patients had received prior midostaurin. Blu-285
demonstrated significant clinical
activity across all dose levels and in
all measured parameters, including
tryptase reduction and spleen volume reduction. In the 18 patients
who were evaluable for response,
the overall response rate was 72
percent, with an 11 percent complete response rate and 17 of the 18
patients continuing on treatment

Symposium
«« From Page A-1

disease.
Dr. Margaret A. Goodell will discuss epigenetic regulation in normal
and malignant hematopoiesis. The
consistent finding among hematologic malignancies of mutations in
genes encoding proteins involved in
the regulation of epigenetic phenomena such as the chemical adornment
of DNA, RNA, or histones strongly
implies a role these modifications
must play in normal hematopoiesis.
More often than not these activities
are methyltransferases or demethylases whose substrates are DNA, histones, and, in some cases, transcription factors and RNA. Thus, there is
now strong evidence that dynamic
methylation is fundamental to stem
cell biology and normal hematopoietic differentiation. That there is

binding domain can be powerful
reagents because they can bypass
physiologic control mechanisms."
This is not only important for this
particular drug and disease but
possibly for similar small molecules in a variety of clinical settings. Indeed, the abstract's senior
author Dr. Andre Larochelle is already looking toward the next step.
"We will be able to do a screen for
small molecules that could target
the erythropoeitin receptor - similar to what eltrombopag is doing
with the TPO receptor - so that we
could use this as a model for devel(median duration, 9 months). Only
one patient had progressive disease
with acute myelogenous leukemia.
Interestingly, all patients who had
received prior midostaurin remain
on study, and this included two patients with MCL and two patients
who were intolerant to midostaurin.
Blu-285 also seemed to be well tolerated and the most common grade ≥ 3
treatment related adverse events included neutropenia (13%), anemia,
fatigue, and periorbital edema (6%
each). Only one dose-limiting toxicity was observed (grade 3 alkaline
phosphatase elevation) at 60 mg, but
the maximally tolerated dose was
not reached. Based on safety profile,
pharmacokinetics, and anti-tumor
activity, 300 mg was selected as the
recommended phase II dose.
This report is extremely important not only because it provides
preliminary data for the utility of
Blu-285 in patients with AdvSM.
However, according to Dr Angelo,
how this therapy will result in longterm sustained disease control rates
still remains to be seen and would
require longer follow-up.
Dr. Awan indicated no relevant conflicts of interest.
no single pattern of aberrant methylation strongly suggests that these
epigenetic regulators perform a variety of functions depending on the
cell type, its stage of maturation, and
the physiologic environment. In the
words of Dr. Goodell, "What is now
emerging is an understanding that
epigenetics affects more than transcription rates and probably touches
on every aspect of gene expression
from chromatin structure to the fate
of mRNA." Dr. James Bradner will
discuss the therapeutic targeting of
chromatin. Nucleotide analogues
for the treatment of neoplastic and
viral disorders more than 50 years
ago were re-purposed as "epigenetic" therapies when abnormal DNA
methylation patterns were observed
in cancer and a more detailed molecular understanding of their enzymatic targets came to light. However, the world has moved on to a

oping new therapies for other diseases of chronic inflammation, such
as anemia of inflammation."
This work is a culmination of an
effort that started out with a perplexing clinical observation. As Dr.
Larochelle recalled, "I noted that
patients with aplastic anemia had
very high levels of TPO in their
blood and that didn't make sense
because we were giving them more
TPO in the form of eltrombopag
and they seemed to have a clinical
response. So this was sort of a paradox that started this project."
From that clinical observation
came a variety of functional experiments to confirm the activity
of eltromobag in an inflammatory
milieu. Thereafter, the investigating team embarked on cell signaling studies and finally focused their
efforts on protein-protein binding.
Serendipitously, Dr. Alvarado began working in the lab. He brought
with him a unique experience in
biophysics that allowed for the

Lymphoma
«« From Page A-2

received G-CSF primary prophylaxis, according to Independent
Data Monitoring Committee
recommendations, febrile neutropenia rates decreased from
19 percent to 11 percent. Not
surprisingly, severe neuropathy
as seen in the patient above was
more commonly seen in the BV +
AVD group.
Should we now consider
BV+AVD as the new standard of
care in advanced classical Hodgkin lymphoma? "Not so quick!"
said abstract introducer Dr.
Canellos; he added, "It is much
too early to say this is practice
much deeper understanding of the
chromatin-associated protein players influencing both malignant and
normal patterns of gene expression.
As understanding of the activity and
function of these proteins improves,
they invariably suggest themselves
as targets for therapeutics. So how
can we better understand the multiple functions of these proteins and
further validate their various domains as potential drug targets?
One approach is the in vivo chemical modification of specific regions
of these proteins as probes to dissect their contribution to normal
and pathologic functions. Active
sites aren't always where the action is. Borrowing from the classic
paradigm in genetics to identify hypomorphic, neomorphic, and null
alleles, the field of chemical biology
is elaborating "incisive chemical
probes of chromatin-associated pro-

characterization of the interaction
between TPO and IFNγ and eventual confirmation that this was not
the case for eltrombopag.
This arc of discovery, from patient
observations to a granular mechanism of action, has been an almost
three-year journey for Dr. Larochelle
and his team. He credits his PhD
mentor Dr. John Dick, and Dr. Cindy
Dunbar, now at NIH, for giving him
the motivation and the supportive
environment to follow this line of scientific questioning. What other molecules will work in a similar manner
to overcome the deleterious effect of
chronic inflammation? According to
Dr. Abkowitz, "the obvious ones are
ligands that also signal through the
JAK-STAT pathway." Perhaps the
telltale sign of this abstract's impact
is not that a conclusion was reached,
but that more questions have been
raised.
Dr. Shah indicated no relevant conflicts of interest.
changing with only (a) small PFS
difference and short duration
(of follow up)." He further cautioned that the addition of BV
and routine use of growth factor
will lead to significant escalation
of ABVD administration costs.
While lung toxicity was lower
in the BV+AVD arm, however,
omission of bleomycin after cycle 2 of ABVD (at least in PET
patients) can arguably provide
similar results. It remains to be
seen if these results will lead to
the U.S. Food and Drug Administration granting brentuximab
vedotin approval for upfront
therapy of advanced HL.
Dr. Hamadani indicated no relevant conflicts of interest.
teins which confer a refined kinetic
understanding of gene control in
mammalian biology," according to
Dr. Bradner. Of high interest will be
his introduction to the development
of a chemical strategy to target chromatin-associated proteins such as the
BRD family and histone methyl and
acetyltransferases for degradation.
Together, these talks from leaders in
the field cover the basic biology and
the experimental tools that are providing the insights into how both
normal and diseased states are influenced by epigenetic mechanisms
and how genetic changes including
chromosomal alterations as well as
point mutations dictate new epigenetic states that favor the evolution of
disease. As one president (not Ken
Anderson) said, this stuff is "bigly."
Dr. Rienhoff indicated no relevant
conflicts of interest.

Table of Contents for the Digital Edition of ASH News Daily 2017 - Issue 3