ASH News Daily 2017 - Issue 4 - A-4

Page A-4

ASH News Daily

Tuesday, December 12, 2017

®

E. Donnall Thomas
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Dr. Sidney Farber in 1948. Several
landmark advances have occurred
in the evolution of treatment of
pediatric acute lymphoblastic
leukemia (ALL) - the most common form of childhood leukemia,
transforming a once-fatal disease
to one with a cure rate of approximately 90 percent. This may just
be the greatest success story in the
history of cancer.
Recognizing his impressive
body of work related to hematopathology and childhood leukemia, particularly ALL, Dr. James
R. Downing of St. Jude Children's
Research Hospital was awarded
the E. Donnall Thomas Lecture
and Prize on Monday. His lecture
focused on the progress made in
advancing our understanding of
pediatric acute leukemia during
the past 15 years and its impact
on our ability to further increase
cure rates. Highlighting the importance of how the careful examination of chromosomal analysis provided the major insights into the
pathogenesis of acute leukemia, he
talked about some of the seminal
works done by his lab.
The AML1 gene (also known
as RUNX1) is frequently affected

Late-Breaking
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therapy armamentarium, especially for patients with severe or refractory disease." Whether it will have
a broader role in all patients with
acquired TTP remains to be seen.
The second abstract, presented by
Dr. John Seymour, sets the stage to
influence the standard of care for patients with chronic lymphocytic leukemia (CLL). The phase III Murano
study evaluated the efficacy and
safety of the novel targeted combination of venetoclax and rituximab
(VR) versus standard immunochemotherapy with bendamustine and
rituximab in patients with relapsed/
refractory CLL. The study was prematurely unblinded following an
interim analysis due to the demonstrated superiority of VR, which resulted in a profound improvement
in progression-free survival (PFS;
24-month PFS, 84.9% vs. 36.3%, respectively; HR, 0.19) and a benefit in
overall survival (HR, 0.48; 95% CI,
0.25-0.90). "This trial will undoubtedly influence standard practice in
CLL and will guide sequencing of
therapy in the relapsed/refractory
setting," said Dr. Sehn.
Congenital neutropenia is a
heterogenous group of disorders
characterized by frequent bacterial infections and risk for leukemic
transformation, with the majority

in acute myelogenous leukemia
(AML) and t(8:21) translocation
(involving AML1/ETO fusion
oncoprotein) is among the most
common rearrangements found
in AML. Dr. Downing's lab explored the leukemic potential of
translocation-encoded AML1 chimeric genes, with an AML1/ETO
fusion gene by knocking ETO
into the AML1 genomic locus
in a series of mice experiments.
Further, his work also showed
how the AML1/ETO fusion transcripts can be consistently detected by RNA-based PCR in AML
with t(8:21). A second area of investigation that his lab focused
on was the analysis of the expression profiles of primary human
leukemia samples with an aim
to provide important insights
into the molecular mechanisms
of leukemogenesis. The analysis
of these databases demonstrated
specific gene expression profiles
for each of the known prognostically and therapeutically relevant
subgroups of childhood ALL and
AML. Given the high accuracy,
his work suggested that microarray-based
gene
expression
profiling may provide a viable
approach for the front-line diagnostic work-up of patients with
acute leukemia. Further, his team
of cases having no attributable genetic link. Dr. Christine BellannéChantelot and colleagues embarked
on an exploratory study to unravel
the mystery and will be presenting
data from whole genome sequencing studies in eight sporadic cases,
six families with multiple affected
members, and 66 other patients
from the French congenital neutropenia registry. After discovering mutations in the SRP54 gene in
23 cases, including an autosomal
dominant family, functional and
structural studies were conducted
on primary hematopoietic and fibroblast cells taken from these patients confirming the pathogenic
nature of the mutations in causing
promyelocytic maturation arrest.
Just when the VMP regimen was
taking its last breath in multiple
myeloma (MM) care, along comes a
study to breathe new life in to it. Dr.
Maria-Victoria Mateos will be presenting efficacy data on the Alcyone
trial, the first phase III study to explore the utility of daratumumab, an
anti-CD38 monoclonal antibody in
the front-line therapy of MM (n=706
subjects). When combined with
bortezomib, melphalan, and prednisone (D-VMP) in newly diagnosed
transplant-ineligible patients, this
novel combination doubled the PFS
(median PFS not reached vs. 18.1
months; HR, 0.5) compared with
VMP alone. The overall response

Attendees listen to Dr. James R. Downing give the E. Donnall Thomas Lecture.

went on to perform the wholegenome sequencing of pediatric
cancers, including leukemias,
providing fundamental discovery
in the landscape of mutations. Dr.
Downing eloquently summarized
these contributions in his talk.
The recent development of sequencing technologies has enhanced our ability to sequence
leukemias at both population and
single cell level. Diverse mechanisms that lead to disease evolution, disease response, and
refractoriness are slowly being un-

derstood. These advancements, we
hope, will translate to more targeted therapies with better outcomes
in patients with leukemia in the
future. With the recent approval
of two targeted therapies in AML
by the U.S. Food and Drug Administration, precision medicine may
be on the horizon in the leukemia
world, and we owe this in large
part to Dr. Downing's contributions!

rate (90.9% vs. 73.9%) and various
depth of response measures including minimal residual disease (MRD)
negativity rate seem to be higher
for the D-based combination and
will be reported in detail during the
presentation. "Based on the compilation of data in both the front-line
and relapsed/refractory settings,
daratumumab appears to be emerging as the 'rituximab' of MM," Dr.
Cuker said.
Detection of MRD in acute myeloid leukemia (AML) has been
recognized as a predictor of relapse
and survival outcomes since the
1990s, but the methodologies have
varied from polymerase chain reaction to flow-based technologies.
Dr. Mojca Jongen-Lavrencic will be
presenting data on the independent
prognostic implications of MRD
using next-generation sequencing (NGS) in 482 newly diagnosed
AML patients (<65 years) treated
on HOVON-SAKK clinical trials.
The MRD-NGS panel of 54 known
genes was performed at diagnosis
(present in 89% of subjects) and
repeated postinduction in bone
marrow biopsies in morphological

chain reaction. The presenter will
be discussing the prognostic implication of the different mutations
detected in 51 percent of the postinduction samples. Do we need to
act on all or some of them? Find out
in the LBA session.
The final presentation will be
given by Dr. Gary Raskob on the efficacy results of the Hokusai Venous
Thromboembolism (VTE) Cancer
Study. The study randomized 1,050
cancer patients with a VTE event to
receive either five days of low-molecular-weight heparin (LMWH)
followed by direct oral anticoagulant edoxaban, or dalteparin for
up to 12 months. The primary endpoint was a composite of recurrent
VTE or a major bleeding event. This
is the first trial to show that an oral
anticoagulant (edoxaban) is noninferior to LMWH for treatment of
cancer-associated VTE. "Cancer patients and their physicians will rejoice at being able to choose an oral
over an injectable anticoagulant
without compromising on efficacy
and safety," said Dr. Sehn.
Dr. Usmani indicated no relevant
conflicts of interest.

Dr. Dhakal and Dr. Hamadani indicated no relevant conflicts of interest.

The Daily Needs New Blood!
Want to get involved with the 2018 ASH News Daily as an Editor or
Author? Email Managing Editor jllorens@hematology.org to learn how!



Table of Contents for the Digital Edition of ASH News Daily 2017 - Issue 4

ASH News Daily 2017 - Issue 4 - A-1
ASH News Daily 2017 - Issue 4 - A-2
ASH News Daily 2017 - Issue 4 - A-3
ASH News Daily 2017 - Issue 4 - A-4
ASH News Daily 2017 - Issue 4 - A-5
ASH News Daily 2017 - Issue 4 - A-6
ASH News Daily 2017 - Issue 4 - A-7
ASH News Daily 2017 - Issue 4 - A-8
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