CLINICAL NEWS
Literature Scan
New and noteworthy research from the
medical literature landscape
New Hope in High-Risk Leukemia Subtype
Philadelphia chromosome-like
acute lymphocytic leukemia
(Ph-like ALL) is a precursor
of B-cell ALL. Unfortunately,
pediatric patients with Ph-like
ALL face worse outcomes. Adding
tyrosine kinase inhibitors (TKIs)
to the treatment protocol, however,
may turn things around for them,
according to new research.
In a genomic profiling analysis,
Kathryn Roberts, PhD, from St.
Jude Children’s Research Hospital
in in Memphis, Tennessee,
identified genetic alternations
in Ph-like ALL that may be
“amenable” to inhibition with TKIs,
such as dasatinib and imatininb.
Their findings, published in the
New England Journal of Medicine,
lay the groundwork for clinical
trials to assess whether adding TKIs
to current Ph-like ALL therapy
improves survival odds for these
patients, explained co-author
Charles Mullighan, MD.
“Our study has shown that
the prevalence of Ph-like ALL
increases with age, and it is
associated with poor outcome,” Dr.
Mullighan told ASH Clinical News.
“We defined the genetic basis
of Ph-like ALL and identified a
range of genetic changes activating
kinase signaling pathways.” The
“ e can now
W
revisit the
entire blood
cell hierarchy
and see how
the current
knowledge
holds true.”
—JIANLONG SUN, PhD
majority of these pathways,
he noted, are targetable with
approved TKIs.
In the current study, Roberts et
al. identified 264 cases of Ph-like
ALL among more than 1,000 cases
of standard or high-risk precursor
B-cell ALL. A total of 154 patients
(age range, 1 to 39 years) with
Ph-like ALL underwent nextgeneration genome sequencing.
The investigators also looked at the
associations between Ph-like ALL
status, event-free survival, and
overall survival.
In their analysis, kinaseactivating alterations were
pinpointed in 91percent of Ph-like
ALL patients, with rearrangements
involving 11 genes, including
CRLF2 and JAK2. They also noted
sequence mutations involving
FLT3, IL7R, and SH2B3. Across
the whole cohort, the authors
identified rearrangements
activating kinase signaling in 96
of 154 patients (62%). All kinase
fusions retained an intact TKI.
Dr. Mullighan said many of
the underlying genetic changes
in these patients can be identified
with standard assays, such as PCR
and FISH. “We have developed
simple screening tests for Ph-like
ALL that are being implemented in
clinical trials, and several centers,
including St. Jude, will use genome
sequencing at diagnosis to detect
Ph-like ALL and the underlying
genetic alterations.”
In other findings, Ph-like ALL
was more common among males
than females. Also, prevalence
of Ph-like ALL significantly
increased with age: 10 percent
and 21 percent of children and
adolescents, respectively, with
standard-risk ALL; 13 percent and
27 percent among children and
adolescents with high-risk ALL.
Among high-risk Ph-like ALL
patients, the median five-year
event-free survival was reached in:
• 58.2 percent of children
• 41 percent of adolescents
• 24.1 percent of young adults
Rates of five-year overall survival
ranged from a high of nearly 73
percent for children to almost 26
percent for young adults.
Finally, using a mouse model,
Dr. Roberts and colleagues noted
that ABL1, ABL2, and CSF1R
fusions were sensitive to imatinib
and dasatinib – two ABL-class
inhibitors. They also found that
there was a high frequency of
rearrangements activating JAK2
in young adult patients, making
ruxolitinib a potential treatment
option in these patients.
Among a dozen patients in the
cohort who received TKI therapy,
all but one showed “rapid and
sustained responses” to treatment,
the authors stated.
“Cases of refractory Ph-like
ALL showed a dramatic response
to TKI therapy,” Dr. Mullighan
added, “providing the justification
and rationale for prospective trials
of TKI therapy in Ph-like ALL.”
In terms of future research, Dr.
Mullighan said that the Children’s
Oncology Group will commence a
national trial in 2015 to screen for
Ph-like ALL, with an eye toward
identifying the underlying genetic
alterations. The trial also will
incorporate ABL-class inhibitors
into treatment in patients with
targetable alterations.
St. Jude will perform genome
sequencing of all patients at
diagnosis and TKI therapy will
be incorporated in the next
front-line study of ALL. The
trial, called Total XVII, will open
in 2015, he said. ●
Reference
• Roberts KG, Li Y, Payne-Turner D, et al. Targetable kinaseactivating lesions in Ph-like acute lymphoblastic leukemia.
N Engl J Med. 2014;371:1005-1015.
Barcoding Stem Cells Add to
Understanding of Hematopoietic Disease
A barcoding and tracking system for
tissue stem cells has revealed previously unrecognized features of normal
blood production: Surprisingly, the
billions of blood cells produced in the
body each day are not made by blood
stem cells, but by their less pluripotent
descendants – progenitor cells.
Based on these findings,
published in Nature, the, the
researcher s hypothesize that blood
comes from stable populations of
different long-lived progenitor cells
that are responsible for giving rise
to specific blood cell types. Blood
stem cells, meanwhile, likely act
as reserves. This means that these
progenitor cells could potentially be
just as valuable as blood stem cells
for blood regeneration therapies.
This look into the origins of
blood cells was made possible by the
new “barcoding” tool developed at
the Boston Children’s Hospital. The
tool generates a unique barcode in
the DNA of all blood stem cells and
their progenitor cells in a mouse.
When a tagged cell divides, all of its
descendant cells possess the same
barcode. This biologic inventory
system makes it possible to determine
the number and lifetime of stem
cells/progenitors being used to make
blood, and to answer fundamental
questions about where individual
blood cells come from.
“There’s never been such a robust
experimental method that could al-
low people to look at lineage relationships between mature cell types in the
body without doing transplantation,”
study author Jianlong Sun, PhD, of
Boston Children’s Hospital, said. “We
can now revisit the entire blood cell
hierarchy and see how the current
knowledge holds true when we use
this internal labeling system.”
The researchers are now planning
to explore many more applications
for their barcode tool, such as tumor
progression and identifying the precise origins of circulating cancer cells
that have broken off from a tumor. ●
Reference:
• Sun J, Ramos A, Chapman B, et al. Clonal dynamics of
native haematopoiesis. Nature. 2014;514:322-7.
Continued on page 51
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ASH Clinical News
December 2014