Moonshot Progress
SIDEBAR 2
ASH Task Force on
Precision Medicine
As part of its efforts to advance hematol-
ogy research, the American Society of
Hematology (ASH) established the Task
Force on Precision Medicine to lead ef-
forts in increasing the understanding of
germline and somatic mutations in hema-
tologic disorders. 1 A separate Task Force
on Immunotherapy – a key focus of the
Moonshot Initiative – was formed to ad-
dress specific scientific and clinical issues
related to this area of precision medicine.
“When discussing germline mutations,
the first challenge is knowing what genes
have variants that lead to hematologic
disease,” explained Task Force Co-Chair
Benjamin L. Ebert, MD, PhD, chair of
medical oncology at Dana-Farber Cancer
Institute. “The second challenge is, once
you sequence those genes, determining
which variants are pathogenic and which
don’t have an impact on the likelihood of
developing disease.”
The Task Force is approaching these
challenges through the publication of
a series of review articles designed to
educate clinicians about the implications
of sequencing studies and through the la-
borious task of annotating all variants that
clinicians might find in these hematologic
disorders as benign or pathologic, Dr. Ebert
explained.
As part of that effort, ASH has
partnered with the National Institutes of
Health Clinical Genome Resource (ClinGen)
to develop a broad and accessible compen-
dium of genomic data aimed at improving
the diagnosis of hematologic disorders.
ASH is supporting two expert review panels
to analyze the clinical significance of
variants and mutations understood to be
associated with myeloid malignancies and
platelet disoders. 2
The Task Force also is eager to expand
research about somatic mutations. Certain
hematologic diseases have been very
well-studied in terms of finding pathogenic
mutations, Dr. Ebert said. However, this
research is far from complete.
“The Task Force is looking for op-
portunities to support research about
under-studied disease states,” Dr. Ebert
said. “We also want to aggregate all of
the complex somatic data that have been
collected and make these easily accessible
by researchers and clinicians.”
REFERENCES
1. Mullighan CG. The ASH Agenda for Hematology Research:
a roadmap for advancing scientific discovery and cures for
hematologic diseases. Blood Advances. 2018;2:2430-2.
2. American Society of Hematology. ASH announces
partnership with the University of North Carolina, a
ClinGen grantee, to curate genomic data for blood disease
research. April 5, 2018. Accessed November 2, 2018,
from http://www.hematology.org/Newsroom/Press-
Releases/2018/8460.aspx.
146
ASH Clinical News
tailoring the treatment to an individ-
ual. That is something hematologist/
oncologists have been doing for a
long time,” said Dr. Mullighan, who
also is chair of the ASH Committee
on Scientific Affairs and co-chair
of ASH’s Task Force on Precision
Medicine.
Equipped with more precise
tools for understanding and treating
disease, clinicians can predict which
patients will be susceptible to certain
disease and which patients are more
likely respond to specific treatments.
“Within the past decade – with
greater access to large-scale tumor
sequencing and the identification of
potentially actionable genetic changes
– the idea of precision medicine has
become much more fashionable,” Dr.
Mullighan added.
Fashionable, yes, but maybe not
accessible. The reality is that preci-
sion medicine is not yet considered
part of the routine care of most
patients with cancer, explained Louis
M. Staudt, MD, PhD, director of the
Center for Cancer Genomics at the
National Cancer Institute (NCI).
That is because cancer is “an
incredibly complex set of diseases
that are essentially the result of a
‘Darwinian evolution’ of individual
malignant cells within a patient that
occurs typically over decades,” he
said.
“The challenge in bringing preci-
sion medicine to every patient is
to truly understand which genetic
changes in cancer are important
drivers of the malignant process and
which are nonfunctional passenger
mutations,” Dr. Staudt said. “In the
future, I can envision and hope
for a time when we can not only
sequence a patient’s tumor but also
point to evidence that shows which
mutations are important to pay at-
tention to and which will respond to
a particular drug.”
But, in most cases, the science is
not there yet, Dr. Staudt said.
Precision Medicine
Progress
In some cases, though, a focus on
understanding the genomic land-
scape of a disease has improved the
diagnosis and treatment of certain
blood cancers in recent years, Dr.
Mullighan said.
In the pediatric arena, clini-
cians now have a better grasp of
the drivers that classify subtypes of
acute lymphocytic leukemia (ALL),
which have helped them better select
treatments. He offered the follow-
ing example: About 10 percent of
patients with childhood ALL have
Philadelphia chromosome–like
disease. About 10 percent of these
cases will have ABL-class fusions
that respond to ABL1 tyrosine kinase
inhibitors, and another 30 percent
will have mutations that activate the
JAK-STAT pathway that may respond
to JAK inhibitors. 4
“Precision
medicine is
more than
matching
a drug to a
mutation; it is
tailoring the
treatment to
an individual.”
—CHARLES G. MULLIGHAN, MBBS
(Hons.), MSc, MD
Increased use of sequencing
also has revealed a large number of
inherited polymorphisms and muta-
tions that are associated with drug
response, resistance, and toxicity and
the risk of leukemic transformation.
He noted, though, that these discov-
eries are a culmination of a decade’s
worth of work, not just on research
done since the Moonshot launched.
“At St. Jude, we sequence all
patients with this diagnosis now,” Dr.
Mullighan said. “We don’t wait until
they relapse.”
The U.S. Food and Drug Admin-
istration (FDA) also has approved
targeted therapies for acute my-
eloid leukemia (AML), noted Lucy
Godley, MD, PhD, professor in the
department of medicine, section of
hematology/oncology at The Univer-
sity of Chicago.
For her day-to-day practice, the
biggest precision medicine success
story is the approval of midostaurin.
The FLT3 inhibitor, in combination
with chemotherapy, is indicated for
the treatment of patients with newly
diagnosed, FLT3-positive AML –
approximately one-third of the adult
AML population, generally consid-
ered to be a poor-risk mutation. 5
“I now consider midostaurin
standard therapy,” Dr. Godley said.
She added that investigators are
looking into whether midostaurin
can be given more broadly, “because
evidence has suggested that other
leukemias could have FLT3 activated
by other mechanisms.”
She also applauded the approv-
als of the IDH inhibitors ivosidenib
and enasidenib, which are indicated
for adult patients with relapsed or
refractory IDH1- or IDH2-mutated
AML. The FDA based its approval of
ivosidenib on results from a single-
arm study of 174 adults in which ap-
proximately 33 percent experienced
complete response or complete
response with partial hematologic
recovery. 6 Enasidenib was approved
based on results from a single-arm
study of 199 patients, in which 23
percent had complete remission
or complete remission with partial
hematologic recovery. 7 Both drugs
are approved with a companion
diagnostic.
“In leukemia, it is common to
have point mutations of IDH1 or
IDH2 genes,” Dr. Godley explained.
“There are many older people who
have AML who wouldn’t be candi-
dates for induction chemotherapy
because of age or comorbidities who
are now able to be treated with a pill.
That is pretty remarkable.”
Precision medicine also has
enabled researchers to identify
powerfully prognostic mutations in
myelodysplastic syndromes (MDS),
according to Benjamin L. Ebert,
MD, PhD, chair of medical oncology
at Dana-Farber Cancer Institute in
Boston.
“Given that MDS is a heterog-
enous disease and patient prognosis
varies widely, these mutations are
useful in helping to predict progno-
sis,” Dr. Ebert said.
In a recent New England Journal
of Medicine paper, for example,
researchers found that patients
with MDS who harbored at least
one persistent disease-associated
mutation 30 days after undergo-
ing allogeneic hematopoietic cell
transplantation had higher rates of
progressive disease and lower rates
of progression-free survival at one
year, compared with patients who
had mutation clearance. 8 “Knowing
this information may provide an
opportunity for earlier intervention
to delay or prevent progression and
also may [help] identify patients
who can be recommended for more
aggressive monitoring,” study co-
author Meagan Jacoby, MD, PhD,
from the Washington University
School of Medicine in St. Louis, told
ASH Clinical News. 9
Missing in Actionable
Precision medicine efforts have made
next-generation sequencing easier,
faster, and cheaper to perform –
exponentially increasing the amount
of information clinicians have about
December 2018