Acute myeloid leukemia and FLT3
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William Check, PhD
As in the case of chronic myeloid leukemia, elucidation of an oncogenic
mutation in acute myeloid leukemia, or AML, has led to potential
targeted molecular therapy in this cancer as well.
Donald Small, MD, PhD, associate professor of oncology, pediatrics,
and cellular and molecular medicine at Johns Hopkins Medical Institutions,
found that a protein with tyrosine kinase activity, called FLT3,
is overexpressed in many AML patients.
After Japanese researchers demonstrated that the FLT3 gene in AML
often contains an internal tandem duplication, or ITD, Dr. Small
and others showed a much lower cure rate with standard chemotherapy
in AML patients whose leukemic cells contain the ITD. In one study,
eight-year survival was six percent in AML patients whose leukemic
cells contained the ITD, compared with 44 percent in patients whose
cells did not have this mutation. Survival differences were independent
of chemotherapy regimens.
Dr. Small and others have screened libraries of compounds to identify
potential inhibitors of FLT3. Clinical trials are being conducted
now with four promising chemicals. Dr. Small is working with one
called CEP-701, which induces a cytotoxic effect on AML cells in
a dose-responsive fashion that parallels inhibition of FLT3 (Blood.
2002;99:3885-3891). In phase two studies, Dr. Small says, CEP-701
“has been well tolerated by patients.” Only patients
who have an FLT3 gene containing the ITD are enrolled. “This
selection may or may not be necessary,” Dr. Small says. “Perhaps
patients without the duplication will also respond.”
Even if one or more of these drugs proves effective, Dr. Small doesn’t
see them having as great an impact on their own as imatinib in CML.
Thirty percent to 40 percent of AML patients have an FLT3 gene with
an ITD. Also, at relapse, 20 percent of patients who initially had
the ITD mutation no longer harbor it, suggesting that AML cells
can become independent of FLT3 activity. Alternatively, the FLT3
ITD can be a late hit in a stem cell that was already leukemic.
Nonetheless, Dr. Small says, “There is great excitement about
this approach, especially for those patients who have a bad prognosis.
Targeted molecular therapy may increase their chance for cure.”
He expresses “guarded optimism” that specific molecular
therapy can be developed against other mutations in AML cells, leading
to specific combination regimens. For now, any agent that emerges
from clinical trials is likely to be combined with conventional