College of American Pathologists
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Acute myeloid leukemia and FLT3

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May 2003
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 chemotherapy.