New Targeted Agent Shows Significant Success in Treating Refractory Form of AML

Complete response seen in patients with FLT3 mutation
February 2013 Vol 6, No 1, Special Issue - Leukemia
Wayne Kuznar

A new selective inhibitor of the FLT3 gene, quizartinib, produced complete remission in more than 33% of patients with an aggressive form of acute myeloid leukemia (AML). The treatment allowed these patients to bridge to potential­ly curative allogeneic stem-cell transplant, said principal investigator, Mark Levis, MD, PhD, Associate Professor of Oncology and Medicine, Johns Hopkins Kimmel Can­­­cer Center, Baltimore, MD, at ASH 2012.

Quizartinib is a potent and selective inhibitor of FLT3, a gene that produces an enzyme that signals bone marrow stem cells to re­populate after chemotherapy. In pa­tients with AML, an FLT3-ITD (internal tandem duplication) mutation occurs in approximately 33% of patients, and constitutively activates FLT3. The FLT3 mutation is associated with high blast counts, frequent and rapid relapse, and reduced overall survival (OS), said Dr Levis.

“We have been trying to inhibit this enzyme for the last 10 years,” he stated. “Quizartinib is the first drug designed as a FLT3 inhibitor. It’s extremely selective; it tends to just hit FLT3 and a few others. It’s 10 to 50 times more potent in humans than any of the other FLT3 inhibitors.”

The phase 2 open-label trial included 271 patients with AML who were divided into 2 cohorts. Cohort 1 consisted of patients aged ≥60 years who failed to achieve remission with standard chemotherapy or who had recently relapsed for the first time. Cohort 2 consisted of patients aged ≥18 years who presented with relapsed or refractory AML and were administered salvage chemotherapy after failing to respond to prior treatment, or had relapsed after a stem-cell transplant.

Dr Levis presented data from the 138 patients in cohort 2, of whom 100 had the FLT3-ITD mutation. “These patients are essentially the equivalent of those on death row,” said Dr Levis. “We don’t have a cure rate to even report in this group.”

Patients were treated with 28-day cycles of quizartinib monotherapy. In the 100 patients with the confirmed FLT3-ITD mutation, 46% had a complete response (CR)—6% had a CR with or without full platelet recovery, and 40% had a CR without full hematologic recovery. In the group with a CR, the median duration of response was 12.1 weeks.

A composite complete remission oc­-curred in 46% of patients with the FLT3-ITD mutation and in 32% of patients in whom the mutation was not detectable. Of the patients with the FLT3-ITD mutation who were refractory to their most recent therapy, 79% had at least a partial response to quizartinib.

Of the patients who had a CR to quizartinib and were then bridged to potentially curative bone marrow transplant, 18 have survived at least 60 weeks, Dr Levis noted.

The median OS was 22.9 weeks and 25.6 weeks in patients with the FLT3-ITD mutation and in whom the mutation was not detectable, respectively.
“Our focus with this drug is to clear the leukemia out of the patient’s bone marrow to a sufficient degree to allow them to go to transplant,” Dr Levis explained. Overall, 34% of patients were successfully bridged to transplantation.

The median OS was 33.3 weeks in the patients who were FLT3-ITD positive and were bridged to transplantation compared with 17.7 weeks among those who did not receive a stem-cell transplant. In patients in whom the FLT3-ITD mutation was not detectable, the median OS has not yet been reached in the patients who were bridged to transplantation, whereas the median OS was 20.8 weeks in those without stem-cell transplant.

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Last modified: March 4, 2013
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