Selective Inhibitor of FLT3 Allows High-Risk AML Patients to Bridge to Stem Cell Transplant

A unique targeted therapy, quizartinib, was able to clear leukemia cells from the bone marrow in more than 33% of patients with an aggressive form of acute myeloid leukemia (AML) marked by a mutation in the FLT3 gene.

Of 47 patients in an open-label study who had a complete response to quizartinib and were then bridged to potentially curative bone marrow transplant, 18 are long-term survivors, said Mark Levis, MD, PhD, lead investigator of the study. He presented his data at the 54th Annual Meeting of the American Society of Hematology.

Quizartinib is a potent and selective inhibitor of FLT3, a gene that produces an enzyme that signals bone marrow stem cells to divide and replenish. In AML, an FLT3-ITD (internal tandem duplication) mutation occurs in approximately one-third of patients, and constitutively activates FLT3. This mutation is associated with high blast counts, frequent and rapid relapse, and a reduced overall survival, explained Dr Levis, Associate Professor of Oncology and Medicine, Johns Hopkins Kimmel Cancer Center, Baltimore, MD.

“We have been trying to inhibit this enzyme for the past 10 years,” he said. “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 II trial included 271 patients with AML who were divided into 2 cohorts. Cohort 1 consisted of patients 60 years and older who failed to achieve remission with standard chemotherapy or who had a first relapse within the past year. Cohort 2 consisted of patients 18 years and older who had relapsed after or were refractory to second-line treatment or stem cell transplant.

The data he presented here were from cohort 2 (n = 138), 100 of whom 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.”

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

The median overall survival time 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,” said Dr Levis. In both cohorts, 34% were successfully bridged to transplantation. Patients who were FLT3-ITD—positive who were bridged to transplantation had a median overall survival time of 33.3 weeks compared with 17.7 weeks among those patients that did not receive a stem cell transplant. In those in whom the FLT3-ITD mutation was not detectable, the median overall survival time has not yet been reached in those patients bridged to transplantation, whereas median overall survival time was 20.8 weeks in those without stem cell transplant.