Background: Activating mutations of FLT3 occur in roughly 30% of adults with AML and are associated with an increased relapse rate and reduced survival. Lestaurtinib (CEP-701), an oral FLT3 kinase inhibitor, has activity as monotherapy in relapsed/refractory AML patients with FLT3 mutations. In vitro studies have demonstrated synergistic cytotoxic effects when FLT3 mutant AML cells were exposed to chemotherapy followed by lestaurtinib.

Methods: Patients with AML in first relapse were randomized 1:1 to receive chemotherapy alone or chemotherapy followed by treatment with lestaurtinib. Eligible patients were required to have a FLT3 activating mutation (ITD or Asp835) at first relapse. Chemotherapy was determined by duration of initial remission: 1–6 months, MEC (mitoxantrone, etoposide, cytarabine); 6–24 months, HiDAC (high-dose cytarabine). Both regimens consisted of 5 days of chemotherapy, and, for those patients randomized to receive lestaurtinib (80 mg bid), treatment was started two days after the final dose of chemotherapy. The primary endpoint was complete remission (CR), determined within 42 days of study entry. Prior to initiation of chemotherapy, leukemia cells of the patients randomized to lestaurtinib were tested for in vitro sensitivity to lestaurtinib using a cytotoxicity assay. Plasma samples were obtained at baseline and Days 15 and 42 to determine FLT3 inhibitory activity.

Results: To date, 42 patients have been enrolled and 34 have completed the primary endpoint assessment (12 male and 22 female, median age 58, range 26–72). In general, lestaurtinib was well tolerated, with mild to moderate gastrointestinal symptoms and fatigue attributed to the drug. Of the pretreatment leukemia samples available for cytotoxicity analysis, 78% were sensitive to lestaurtinib in vitro. Thirteen of 17 (76%) patients achieved a plasma FLT3 inhibitory activity of greater than 85%. All patients who achieved this degree of plasma FLT3 inhibitory activity and whose pretreatment leukemia cells were sensitive in vitro to lestaurtinib achieved a clinical response. Conversely, patients with insensitive cells or low drug plasma levels did not respond. Ten of 17 patients randomized to lestaurtinib showed evidence of response (CR or partial response [PR]), with 5 achieving CR, 3 CR with incomplete blood count recovery (CRi), and 2 PR. Four of 17 patients randomized to receive chemotherapy alone had achieved a response (2 CR, 2 CRi). Accrual is ongoing, and updated clinical and correlative data will be presented.

Conclusions: These results demonstrate that real-time correlative studies are able to accurately predict response to lestaurtinib, and the clinical benefit achieved for these patients provides important evidence that targeting FLT3 remains a valid therapeutic approach for AML with FLT3 activating mutations.

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