OncoLog, Volume 50, Number 2/3, February/March 2005 Page: 4
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Novel Drugs Address
Gleevec Resistance
in ongoing Phase I clinical trials at M. D. Anderson,
two different molecularly targeted therapies are showing
promise as the 'next-generation' agents for treating
Gleevec-resistant chronic myeloid leukemia.Five years ago, imatinib
(Gleevec) ushered in the
age of the smart drug-drugs
targeted to fight specific
cancer cells while leaving normal cells
unharmed. Relatively nontoxic and
easy to administer, Gleevec led to a
marked improvement in survival for a
majority of patients with chronic
myeloid leukemia (CML), producing
unprecedented clinical remissions and
becoming the new standard of care.
Still, some patients were unaffected
by the drug and others eventually
developed resistance to it.
Now, two new targeted therapies
in early clinical trials show significant
promise for treating Gleevec-resistant
CML. After testing the novel com-
pounds in laboratory studies, M. D.
Anderson undertook two independent
Phase I clinical trials, one of BMS-
354825 in conjunction with the
University of California, Los Angeles,
and the other of AMN 107 with the
University of Frankfurt in Germany.
Encouraging response
in Phase I trials
BMS-354825 has shown an impres-
sive response rate, said Moshe Talpaz,
M.D., a professor in the Department
of Experimental Therapeutics at M. D.
Anderson. "The majority of patients
with advanced, Gleevec-resistant CML
responded to the drug."
Of 22 patients with advanced, blast
phase or accelerated phase CML, five
had complete hematologic responses,
while three additional patients showed
no evidence of leukemia. Furthermore,
of 29 patients with early-stage CML
who were either resistant to Gleevec
or could not tolerate the drug's side
effects, 73% experienced a complete
hematologic response.Dr. Talpaz expects
the response rates
to rise as the study
progresses. "We
haven't reached
anything close to the
maximum tolerated
dose, yet we still are
seeing very encour-
aging responses,"
he said.
"Also exciting is
the fact that clinical
responses matched
very well to preclini-
cal testing in animal
models. A specific
mutation that was
resistant to BMS-
354825 in the test('
Dr. Moshe Talpaz (1), a professor in the Department of
Experimental Therapeutics, and Dr. Francis Giles, a professor
in the Department of Leukemia, are optimistic about the new
drugs being studied for use in CML. "We may be on the road
toward developing treatment tailored to the molecular profile
of the disease in different patient subsets," said Dr. Talpaz.tube and animal
model was also associated with resistance
in patients. This suggests that we may be
on the road toward developing treatment
tailored to the molecular profile of the
disease in different patient subsets."
Another new agent, AMN 107, has
shown promise not only in CML but
also in patients with acute lymphocytic
leukemia (ALL) associated with the
Philadelphia chromosome.
More than half of 65 patients with
Gleevec-resistant CML who have
joined the study since it began in
May 2004 have had responses-includ-
ing cytogenetic and molecular responses
in some patients, said Francis Giles,
M.D., a professor in the Department of
Leukemia. "And we have not yet seen
any consistent severe side effects.
"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% of ALL that shares
the same genetic abnormality as CML,"The bottom line 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."
- Francis Giles, M.D.
the Philadelphia chromosome," Dr.
Giles said. "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."4 OncoLog " February/March 2005
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University of Texas M.D. Anderson Cancer Center. OncoLog, Volume 50, Number 2/3, February/March 2005, periodical, February 2005; Houston, Texas. (https://texashistory.unt.edu/ark:/67531/metapth903216/m1/4/: accessed June 17, 2024), University of North Texas Libraries, The Portal to Texas History, https://texashistory.unt.edu; crediting UNT Libraries Government Documents Department.