Quizartinib Data Encouraging in Phase II Investigations of FLT3 Mutation–positive Acute Myeloid Leukemia

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The investigational oral FLT3 inhibitor quizartinib appears to be a safe and effective treatment for patients with relapsed or refractory acute myeloid leukemia (AML), according to results of a phase II trial presented at the 54th Annual Meeting of the American Society of Hematology (ASH) in Atlanta.1,2 Quizartinib achieved high response rates in a difficult-to-treat cohort of patients, and some of the responses were durable. Quizartinib treatment enabled more than one-third to go on to stem cell transplant. Phase III studies of this compound are in the planning stages.

Potent and Selective Agent

Acute myeloid leukemia is a rapidly proliferating cancer. Internal tandem duplication of the FLT3 gene occurs in up to one-third of patients with AML and is associated with more aggressive disease and failure of standard treatment. Stem cell transplant can be used, but only in patients who achieve remission. Therefore, effective treatments are needed if patients require transplant.

“Quizartinib is a potent and selective FLT3 inhibitor, and is the first drug designed as a selective FLT3 inhibitor. It is 10 to 50 times more potent in humans than other FLT3 inhibitors that have been studied. We have been trying to attack this enzyme for the last 10 years,” stated lead author Mark J. Levis, MD, Associate Professor at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine in Baltimore.

The phase II trial enrolled two cohorts of patients (N = 271). Cohort 1 included patients aged 60 or older with the FLT3 mutation who had a recent first relapse or for whom standard chemotherapy had failed. Cohort 2 included patients over age 18 who presented with relapsed or refractory AML and had been given salvage chemotherapy after failure of prior treatment or relapse after a stem cell transplant. The majority of patients in both cohorts had the FLT3 mutation.

Cohort 2 Results

At the ASH meeting, Dr. Levis reported results in cohort 2 in 137 patients (99 with FLT3 mutations and 38 without).1 Cohort 1 results were presented in a separate session (see below).

“The FLT3-positive cohort 2 was a rough group, the essential equivalent of being on death row. They were running out of options,” Dr. Levis said.

Quizartinib was given once daily at a starting dose of 90 mg/d in women and 135 mg/d in men in 28-day cycles until disease progression or unacceptable toxicity. In cohort 2, the complete response rate was 46% in 100 patients with FLT3 mutation–positive disease and 32% in FLT3 mutation–negative patients.

“Seventy-five percent of cohort 2 had a reasonable, dramatic response—all cleared from the blood and mostly cleared the marrow,” he said.

Survival Data

Median overall survival was 22.9 weeks for FLT3 mutation–positive patients and 25.6 weeks for FLT3 mutation–negative patients. Quizartinib enabled 37% of all patients to go on to stem cell transplant. Among all transplanted patients, median overall survival was 33.3 weeks, vs 17.7 weeks for those who did not undergo transplant. Among the group with FLT3 mutation–negative AML who underwent stem cell transplant, median overall survival had not yet been reached at the time of the ASH meeting, whereas median overall survival was 20.8 weeks in those without stem cell transplant.

“In patients with of FLT3 mutations who were bridged to an allogeneic transplant, the survival is extremely encouraging,” Dr. Levis noted.

In this small study, quizartinib appeared to be well tolerated with manageable toxicity, he added. The most common treatment-emergent adverse events were nausea (53%), vomiting (41%), febrile neutropenia (38%), diarrhea (37%), anemia (34%), QT-interval prolongation (27%), and fatigue (24%). The QT-interval prolongations were asymptomatic and transient, and there were no grade 4 events or deaths associated with this abnormality, Dr. Levis said. Progressive disease was the most common event leading to treatment discontinuations among the 18% who stopped taking quizartinib.

Cohort 1 Results

Results in the older cohort 1, presented by Jorge Cortes, MD, Deputy Chair and Professor of Medicine in the Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, showed that complete responses were achieved in more than 50% of elderly patients with FLT3 mutation–positive disease.2 These results were considered clinically meaningful and allowed some patients to be bridged to stem cell transplant. Slightly less than one-third of FLT3 mutation–negative patients achieved a complete response. The side-effect profile of quizartinib was similar to that in cohort 2. The investigators concluded that quizartinib may be an option for elderly AML patients who require further therapy, but additional studies are needed.

Commenting on this trial, Aaron Schimmer, MD, Princess Margaret Cancer Center University Health Toronto, Canada, was enthusiastic about these preliminary results with a targeted therapy. “We see that what we have learned about genetic abnormalities in hematologic cancers is paying off in terms of therapy. Quizartinib is a drug that works on patients with a specific mutation who no longer respond to other therapies.” ■

Disclosure: Drs. Levis and Schimmer reported no potential conflicts of interest. Dr. Cortes receives research support from Ambit, Astellas, Ariad, Novartis, and Arog, and he is a consultant for Ariad.


1. Levis MJ, Perl AE, Dombret H, et al: Final results of a phase 2 open-label monotherapy efficacy and safety study of quizartinib (AC220) in patients with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia after second-line chemotherapy or hematopoietic stem cell transplantation. 2012 ASH Annual Meeting. Abstract 673. Presented December 10, 2012.

2. Cortes J, Perl AE, Dombret H, et al: Final results of a phase 2 open-label monotherapy efficacy and safety study of quizartinib (AC220) in patients ≥ 60 years old with FLT3 ITD positive or negative relapsed/refractory acute myeloid leukemia. 2012 Annual Meeting of ASH. Abstract 48. Presented December 9, 2012.