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Gilteritinib new standard of care for relapsed, refractory FLT3-mutated acute myeloid leukemia
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Gilteritinib significantly extended OS and demonstrated higher rates of complete response compared with standard salvage chemotherapy among patients with relapsed or refractory FLT3-mutated acute myeloid leukemia, according to results of the randomized phase 3 ADMIRAL trial published in The New England Journal of Medicine.
“FLT3-mutated AML is a clinically aggressive subtype with high rates of front-line treatment failure, most often from relapse but also from lack of initial remission. Relapsed and refractory patients with FLT3 mutations show low response rates to traditional salvage chemotherapy, which frequently is toxic and requires prolonged hospitalization for supportive care,” Alexander E. Perl, MD, associate professor in the division of hematology oncology at Perelman School of Medicine at University of Pennsylvania, and member of the leukemia program at Abramson Cancer Center, told HemOnc Today. “Remissions with traditional cytotoxic agents for these patients are often of short duration, which limits the feasibility of bridging responding patients to hematopoietic stem cell transplant, their only potentially curative therapy.”
For this reason, Perl and colleagues sought to evaluate the FLT3 inhibitor gilteritinib (Xospata, Astellas) among 371 adults (median age, 62 years; range, 19-85; 54.2% women) with AML and known FLT3 mutations. Eligible patients had disease that was refractory to induction chemotherapy or were in an untreated initial relapse. Fewer than half of patients (39.4%) had refractory disease and 60.6% had relapsed AML.
The researchers randomly assigned patients 2:1 to uninterrupted, 28-day cycles of 120 mg once-daily gilteritinib (n = 247) or standard salvage chemotherapy (n = 124). Investigator-chosen salvage chemotherapy consisted of four options: low-dose cytarabine or azacytidine until disease progression or intolerance, or high-intensity (one to two cycles) mitoxantrone, etoposide and cytarabine, or fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin.
OS and the proportion of patients with complete remission with full or partial hematologic recovery served as the study’s primary endpoints. Secondary endpoints included EFS and complete response rate. Researchers also assessed the safety and tolerability of gilteritinib.
Median follow-up was 17.8 months.
Researchers observed significantly longer OS among patients treated with gilteritinib compared with salvage chemotherapy (9.3 months vs. 5.6 months; HR = 0.64; 95% CI, 0.49-0.83). One-year survival rates were 37.1% with gilteritinib and 16.7% with salvage chemotherapy.
The OS benefit with gilteritinib appeared consistent across several subgroups, including the high- and low-intensity chemotherapy groups.
Median OS among patients with primary refractory AML was 10.4 months with gilteritinib vs. 6.9 months with salvage chemotherapy (HR = 0.99; 95% CI, 0.63-1.55).
Thirty-four percent of patients treated with gilteritinib achieved complete remission with full or partial hematologic recovery, compared with 15.3% of those treated with salvage chemotherapy (risk difference [RD], 18.6 percentage points; 95% CI, 9.8-27.4). Moreover, results showed complete response rates of 21.1% (n = 52) with gilteritinib vs. 10.5% (n = 13) with salvage chemotherapy (RD, 10.6 percentage points; 95% CI, 2.8-18.4).
Researchers also observed a median EFS of 2.8 months with gilteritinib vs. 0.7 months with salvage chemotherapy (HR = 0.79; 95% CI, 0.58-1.09).
An analysis adjusted for duration of therapy exposure showed fewer grade 3 or higher adverse events per patient year in the gilteritinib group vs. the chemotherapy group (19.34 vs. 42.44). The most prevalent grade 3 or higher adverse events among patients treated with gilteritinib included febrile neutropenia (45.9%), anemia (40.7%) and thrombocytopenia (22.8%).
Researchers acknowledged that the design of the trial provided an imperfect estimate of response duration among the chemotherapy cohort for EFS comparison, which served as a study limitation.
“In addition, enrollment occurred before widespread use of midostaurin [Rydapt, Novartis] in first-line chemotherapy, which could plausibly generate resistance to FLT3-targeted therapy and subsequently alter gilteritinib activity,” they wrote.
Based on these data, gilteritinib received approval for patients with FLT3-mutated AML by the FDA and by regulatory agencies in Japan and Europe, Perl told HemOnc Today.
“The clinical availability of gilteritinib has established a new standard of care for treatment of relapsed and refractory FLT3-mutated AML,” he said. “Although response and survival were clearly superior with gilteritinib than with traditional chemotherapy, long-term survival on the ADMIRAL trial ultimately was poor on both arms, confirming an ongoing, unmet need to achieve sustained disease control for this highly aggressive subtype after relapse or lack of response to front-line chemotherapy.” – by Jennifer Southall
For more information:
Alexander E. Perl, MD , can be reached at Perelman School of Medicine at University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104; email: alexander.perl@uphs.upenn.edu.
Disclosures: Astellas funded this study. Perl reports honoraria from AbbVie, Actinium Pharmaceuticals, Agios, Astellas, Daiichi Sankyo, Jazz Pharmaceuticals, New Link Genetics, Novartis and Takeda; consultant fees from AbbVie, Arog, Astellas and Daiichi Sankyo; and research funding to his institution from Actinium Pharmaceuticals, Astellas, Bayer, BioMed Valley Discoveries, Daiichi Sankyo, Fujifilm and Novartis. Please see the study for all other authors’ relevant financial disclosures.
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