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Novel drugs help solve Gleevec resistance
December 4-7, 2004. San Diego, California.
The American Society of Hematology is the world's largest professional society concerned with the
management of blood disorders.
SAN DIEGO - Two different novel targeted therapies can produce
strong responses in patients who have become resistant to Gleevec(tm),
the standard therapy for chronic myeloid leukemia (CML), researchers
at The University of Texas M. D. Anderson Cancer Center are reporting.
Researchers say the benefits offered by these drugs, BMS-354825
and AMN107, appear to be promising for treatment of relapsed CML
and offer an immediate effective option for the minority of patients
who do not achieve an optimal response to Gleevec therapy.
M. D. Anderson Cancer Center, the only institution to have tested
both of these novel compounds, undertook independent Phase I clinical
trials of both agents. It conducted the study of BMS-354825 in conjunction
with the University of California, Los Angeles, and the study of
AMN107 with the University of Frankfurt, in Germany. The M. D. Anderson
researchers will discuss their experiences using these agents in
patients with leukemia at the American Society of Hematology (ASH)
BMS-354825 "shows remarkable activity"
In the study conducted at M. D. Anderson and at UCLA School of
Medicine, the majority of patients with advanced, Gleevec-resistant
CML have responded to the drug BMS-354825, says Moshe Talpaz, M.D.,
a professor in the Department of Experimental Therapeutics at M.
Of 11 patients with advanced "blast phase" CML, seven have had
a hematologic response from the drug (defined as control of white
blood cell counts). Of these, three patients experienced a complete
hematologic response (disappearance of all findings consistent with
advanced stage CML, and return of blood counts to normal), while
two patients showed no evidence of leukemia. Two other patients
had their CML downgraded to "chronic." Additionally, of the 11 patients,
four have had a major "cytogenetic response" (defined as elimination
of cells with the cancer-causing defect), and two had minor cytogenetic
Of six patients with advanced accelerated phase of the disease,
three had a hematologic response: two were complete, and one patient
showed no remaining evidence of leukemia.
One patient demonstrated resistance to BMS-354825, Talpaz reports.
Side effects, which included reduced red and white blood cells and
platelets, have been well tolerated, he says. Talpaz expects the
efficacy of BMS-354825 to increase as more patients are enrolled
and tested. "We haven't reached anything close to the maximum tolerated
dose, yet we still are showing some remarkable activity," he says.
"Very encouraging responses continue to be seen in the new cohort
of patients recently enrolled."
Talpaz is co-principal investigator with Charles Sawyers, M.D.,
professor of medicine at UCLA, of a study that tested 29 patients
with early-stage CML who are either resistant to Gleevec or who
could not tolerate the drug's side effects. Their study is being
presented by Dr. Sawyers in the first presentation at the meeting's
The investigators found that in these patients, 73 percent experienced
a complete hematologic response "and they have shown that the drug
is capable of overcoming Gleevec resistance in the vast majority
of cases which resistance is caused by a mutation in the BCR-ABL
gene," Talpaz says.
"This is a remarkably high response rate," he says. "Also exciting
is the fact that clinical responses matched very well to preclinical
testing in animal models. A specific mutation that was resistant
to BMS-354825 in the test tube and the animal model was associated
with resistance in patients, whereas the other mutations did not
induce resistance in the test tube or the patient.
This suggests that we may be able to 'tailor' therapy according
to the molecular profile of the disease," Talpaz says. "That means
different treatments may be proposed for different patient subsets
based on molecular and biochemical screening."
Bristol-Myers Squibb, which manufactures BMS-354825, paid for
AMN107 is effective in patients with Gleevec-resistant ALL
Francis Giles, M.D., professor of medicine in the Department
of Leukemia, presented results of the second study, which found
that the novel oral targeted therapy, AMN107, can produce responses
not only in advanced and Gleevec-resistant CML patients, but also
in patients with acute lymphocytic leukemia (ALL) associated with
the "Philadelphia chromosome."
The AMN107 Phase I study has accrued 65 patients since opening
in May 2004. Even though an optimal dose has yet to be established
as no significant toxicities have yet been encountered, more than
50 percent of patients with Gleevec-resistant CML have responded,
including cytogenetic and molecular responses in some patients so
far, Giles says.
"While more study needs to be done to define a reasonable regimen
for this drug, it has, so far, produced very important responses
in patients who were desperately ill," he says. "Despite the response
rate, we still have not seen any consistent severe side effects,
so clearly AMN107 will have a different tolerability profile than
Gleevec, a drug which is, in general, very well tolerated," he adds.
"Gleevec changed everything in CML. It has led to marked improvement
in survival in all three phases of the disease, and it also has
shown benefit in treating the 20 percent of ALL that shares the
same genetic abnormality as CML, the Philadelphia chromosome," Giles
says. "But a drug that can cope with resistance to Gleevec might
do even better across the board, although it must be remembered
that we are still learning how to optimally use Gleevec itself,
a drug which we have only had available for a few years."
The clinical trial reported by Giles is unusual in that it allows
for a rapid "intrapatient" dose escalation. Within the trial, patients
are allowed to move to higher doses as they prove to be safe, and
the study can move seamlessly from Phase I into Phase II. "No patient
is ever 'stuck' at a lower, potentially ineffective dose," says
Giles, who helped design the protocol. "Everyone keeps moving up
until we find the best dose that is both safe and active." Doses
from 50 milligrams to 1,200 milligrams have been tested so far.
"This kind of study is in the best interest of patients because
it gives us the power and the numbers to quickly find the dose that
can work best," he says.
The study is funded by Novartis, which manufacturers both AMN107
Both drugs have "tight" mechanism of action
Gleevec, as well as its two new companions, reduces the activity
of an abnormal tyrosine kinase enzyme that leads to uncontrolled
cell growth. Both CML and Philadelphia-positive ALL is caused by
the swapping of genetic material in bone marrow stem cells between
chromosome 9 and 22, producing an abnormality called the Philadelphia
chromosome (named for the city from where the first patient in whom
it was seen resided).
Specifically, a fusing of a piece of chromosome 9 that contains
part of the ABL gene with a piece of chromosome 22 that contains
part of the BCR gene forms the new cancer causing gene, BCR-ABL.
This oncogene produces a tyrosine kinase that turns on multiple
signals that tell the cells to grow and divide in an uncontrolled
manner leading to overt leukemia. Gleevec binds to the abnormal
enzyme (Bcr-Abl) and shuts down its activity, often leading to the
death of the leukemia cell.
AMN107 is up to 30 times more potent than Gleevec because it
was designed to more efficiently bind to the enzyme, Giles says.
"Through molecular, chemical and crystallography studies, we now
know the detailed structure of the enzyme, which allowed the development
of the better-fitting drug AMN107," he says. "This both increases
the effectiveness of the agent and perhaps reduces the potential
of developing resistance."
BMS-354825 has a dual mechanism of action, which gives it a 100-fold
greater potency to inhibit BCR-ABL, based on preclinical tests that
compared it to Gleevec, Talpaz says. Such experiments also have
shown that it can treat 14 of 15 mutations that arise in Gleevec-resistant
tumors, he says. Giles adds that this appears to be similar to the
activity profile of AMN107.
Like AMN107, BMS-354825 binds to the active form of Bcr-Abl.
It is less specific than AMN107, however, and therefore has a broader
spectrum of action because it inhibits a family of tyrosine kinases
known as Src, Talpaz says.
"This is an engineered drug so we know exactly how it works,
but we cannot say at this point whether there are clinically meaningful
differences between BMS-354825 and AMN107," he says. "Many more
studies are needed to see how these drugs will perform."
The bottom line, says Giles, is that "rational drug design is
a reality and effective targeted therapies will rapidly increase
in number, which means that options for patients are expanding,"
he says. "Prognosis of diseases that were, until very recently,
rapidly fatal is getting better at an unprecedented rate. Science
Copyright ? 2004 The University of Texas M. D. Anderson
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