On Location
Conference Coverage
NEW COMBINATIONS, NEW TREATMENTS
FOR HEMATOLOGIC DISORDERS
his year, the European Hematology Association’s 20th Congress, taking place in
Vienna, Austria, featured innovative research
in hematologic disorders, including inotuzumab
ozogamicin in poor-prognosis acute lymphocytic
leukemia, uncovering a key to overcoming chemoresistance in acute myeloid leukemia, and a review of the
PI3K inhibitors under investigation for the treatment of
chronic lymphocytic leukemia.
Attendees of the EHA Congress walk the hall
of the convention center in Vienna, Austria.
The DNMT3A R882 Mutation’s Impaired
DNA-Damage Sensing: A Key to Overcoming
Chemoresistance in AML
A study presented at the 2015
European Hematology Association
Congress suggests an important
role for DNMT3A R882 mutations in chemoresistance in acute
myeloid leukemia (AML).
“Unfortunately, apart from some
exceptional sub-types, the prognosis [for AML] hasn’t really changed
for the last 30 years,” said lead study
author Olga Guryanova, MD,
PhD, from the Memorial Sloan
Kettering Cancer Center in New
York City. “Although the majority
of patients respond to standard
chemotherapy initially, it is believed
that a small set of chemoresistantcells will persist in the body, later
giving rise to relapse.”
While low-level residual AML
is seen in many patients even at
clinical remission, the mechanisms
underlying persistence of AML
cells after chemotherapy are not
fully understood. In a multivariate
analysis of 398 patients with AML
from the ECOG E1900 study, Dr.
Guryanova and colleagues sought
to determine which mutations, if
any, were predictive of minimal residual disease (MRD) followed by
relapse, and how such mutations
promote resistance to chemotherapy.
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ASH Clinical News
Patients were younger than 60
years old and had received induction chemotherapy with cytarabine
plus high-dose or standard-dose
daunorubicin for the treatment of
AML. MRD was assessed by flow
cytometry at day 28 in patients
with complete pathologic remission. In the trial, patients were
followed for a median of 47.4
months.
“There was only one particular
mutation that robustly correlated
with the presence of MRD: a very
specific mutation on the gene DNMT3A,” Dr. Guryanova reported.
Presence of the DNMT3A R882
mutation was associated with a
non-significant increased risk
of MRD at the time of complete
remission (p=0.07). By contrast,
non-R882 mutations in DNMT3A
did not predict for MRD followed
by relapse – nor did any other
recurrent AML genetic mutations.
After identifying the DNMT3A
R882 mutation as a predictor of
MRD followed by relapse, Dr.
Guryanova and researchers then
developed a novel mouse model to
study its role in the pathogenesis
and chemoresistance of AML.
By introducing DNMT3Amutant hematopoietic stem cells
into mice and treating them with
daunorubicin, the researchers
observed a survival advantage for
DNMT3A-mutant cells compared
with wild-type controls, with preserved potential for proliferation
after in vitro and in vivo exposure
to daunorubicin. Treating cells
with chemotherapy induces DNA
damage. In the case of DNMT3A
R882 mutant cells, Dr. Guryanova
explained, “The damage persists
because the cell doesn’t know that
those [DNA breaks] are there and
is unable to repair them.” Because
the mutant cells fail to survey their
DNA for the signs of damage,
the damaged cells survive and
accumulate additional mutations
after chemotherapy, but are not
eliminated by apoptosis.
Introducing DNMT3A did not
cause leukemia in mice; however,
when combined with other mutations that are commonly present in
AML (FLT3-ITD and NPM1), the
disease was much more aggressive
than with these mutations alone.
“Maybe this particular mutation doesn’t cause leukemia, but it
makes really good stem cells that
can outcompete all other stem cells
in the body,” Dr. Guryanova said.
This was particularly true under
stress conditions, including when
mice were exposed to chemotherapy.
“This defect in DNA damage
repair means that maybe we can
find novel ways to target this specific vulnerability,” Dr. Guryanova
concluded. In the E1900 trial, she
noted, patients with the DNMT3A
R882 mutation who were resistant
to standard-dose daunorubucin
benefitted from the increased dose,
while patients without this mutation saw increased toxicity but no
additional benefit with the higher
dose. “Now, we have a mechanistic
basis for understanding why increased doses of chemotherapy in
these patients would be beneficial.”
Dr. Guryanova also mentioned
other therapeutic implications for
this finding, including targeting
other components of the DNA
damage machinery or combining chemotherapy with BCL-2
inhibitors to promote apoptosis of
damaged cells. ●
REFERENCE
Guryanova O, Shank K, Garrett-Bakelman F, et al.
DNMT3A R882 mutation promotes chemoresistance
and therapeutic relapse through impaired DNA-damage
sensing. Abstract #S473. Presented at the 2015 European
Hematology Association, Vienna, Austria, June 12, 2015.
July 2015