Clinical Trials Under Way to Improve Outcome in AML

Acute myeloid leukemia (AML) is a difficult disease to treat. Although 65 percent of patients achieve complete remission with chemotherapy, only 15 to 30 percent remain free of the disease for five years. New treatment medications and approaches are desperately needed.

The possibility of employing biological targeted therapies with or without chemotherapy in
the treatment of hematological malignancies has generated excitement over the last few
years. Members of the Taussig Cancer Institute Department of Hematologic Oncology and Blood
Disorders are among investigators evaluating these therapies in AML. A team led by Anjali Advani, MD, presented results of a Phase I trial of imatinib mesylate with daunorubicin and cytarabine for patients with c-kit positive relapsed AML at the 2008 ASH Annual Meeting.

“Although AML is not associated with one specific mutation, AML cells do share biological characteristics that may allow the application of molecular targeted therapies,” says Dr. Advani. C-kit, a tyrosine kinase receptor expressed on more than 90 percent of relapsed AMLs, mediates leukemic proliferation and anti-apoptotic effects. Signaling pathways including STAT3 and STAT5 may be activated downstream of c-kit. Higher c-kit expression is associated with a shorter time to relapse and shorter overall survival.

“Therefore, targeting the c-kit receptor in AML may improve the outcome for patients,” says Dr. Advani.

C-kit inhibitors are not active enough as single agents in AML. However, it is possible that c-kit
inhibitors may be effective when used in combination with other therapies, including chemotherapy.

“Imatinib mesylate is a potent c-kit inhibitor that has demonstrated some activity in relapsed/refractory AML,” says Dr. Advani. “In this trial, we combined imatinib mesylate with standard induction therapy for patients with c-kit+ relapsed AML.”

Twenty-one patients had enrolled at the time of the presentation. “Eleven of the 19 evaluable patients achieved complete remission (CR) or complete remission with incomplete platelet recovery (CRp), an encouraging result that merits evaluation in a larger Phase II study,” says Dr. Advani.

Dr. Advani and her colleagues continue to open clinical trials to improve the outcome for patients
with AML.