AACR 2019: Gilteritinib in Patients With FLT3-Mutated Acute Myeloid Leukemia
Treatment with the FLT3-targeted therapeutic gilteritinib improved survival for patients with relapsed or refractory acute myeloid leukemia (AML) harboring an FLT3 mutation compared with standard chemotherapy regimens, according to results from the phase III ADMIRAL trial presented by Perl et al at the American Assocation for Cancer Research (AACR) Annual Meeting 2019 (Abstract CT184).
Gilteritinib was approved by the U.S. Food and Drug Administration (FDA) in November 2018, for the treatment of adult patients who have relapsed or refractory AML that tests positive for an FLT3 mutation.
“The FDA approval of gilteritinib was based on safety data and an interim analysis of the rate of response to gilteritinib in the ADMIRAL trial; it was not based on a comparison of the efficacy of gilteritinib relative to standard chemotherapy,” said study author Alexander E. Perl, MD, Associate Professor in the Division of Hematology/Oncology at the Perelman School of Medicine at the University of Pennsylvania and a member of the Abramson Cancer Center. “We are now presenting the final analysis of the results from the ADMIRAL trial, including data showing that gilteritinib is superior to standard chemotherapy, as measured by improved overall survival.”
He continued, “These survival data combined with gilteritinib’s relatively low toxicity establish gilteritinib monotherapy as the new standard of care for patients with relapsed or refractory FLT3-mutated AML. In addition, the relatively low toxicity of gilteritinib and the fact that it is an oral therapy means physicians can manage patients in the outpatient setting, which is a paradigm shift for the treatment of this disease.”
Dr. Perl explained that the FLT3 gene is mutated in about one-third of the AML cases diagnosed in the United States. Patients with relapsed or refractory FLT3-mutated AML have a particularly poor prognosis, with standard chemotherapy regimens yielding low remission rates and any remissions achieved lasting a short duration, he said.
ADMIRAL Trial
ADMIRAL was a randomized, phase III clinical trial designed to determine whether gilteritinib improved survival for patients with relapsed or refractory FLT3-mutated AML compared with standard chemotherapy regimens, which included investigator’s choice of low-dose cytarabine; azacitidine; mitoxantrone, etoposide, and cytarabine; and fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin. Of the 371 patients enrolled in the clinical trial, 247 were randomly assigned to gilteritinib and 124 to standard chemotherapy.
At the final analysis, patients assigned gilteritinib were found to have a 36% reduction in risk of death compared with those assigned standard chemotherapy. Median overall survival was 9.3 months for those assigned gilteritinib vs 5.6 months for those assigned standard chemotherapy. The 1-year survival rate was 37.1% in the gilteritinib-treated group compared with 16.7% among those receiving standard chemotherapy.
The combined rate of complete remission and complete remission with partial hematologic recovery was 34.0% for those assigned gilteritinib and 15.3% for those assigned standard chemotherapy.
“The longest survival in the gilteritinib arm was seen among patients who proceeded to transplant and then resumed gilteritinib thereafter to prevent relapse, but unfortunately, long-term survival was very uncommon on either treatment arm,” said Dr. Perl. “In an effort to further improve long-term outcomes, clinical trials testing gilteritinib in combination with other therapies for relapsed or refractory FLT3-mutated AML and testing gilteritinib as frontline therapy for newly diagnosed patients have already been launched.”
According to Dr. Perl, the main limitation of the study is that the standard front-line treatment for FLT3-mutated AML changed during enrollment to the ADMIRAL trial, because the FDA approved the FLT3-targeted therapeutic midostaurin for this indication in April 2017. Thus, a small minority of patients in both arms received prior FLT3-targeted therapy. It is possible that leukemias that relapsed after or were refractory to front-line treatment that included midostaurin were less dependent on FLT3 for their growth and therefore had less likelihood of responding to gilteritinib, he explained.
Disclosure: This study was funded by Astellas Pharma US Inc. The study authors’ full disclosures can be found at abstractsonline.com.
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