Open AccessS876 GILTERITINIB SIGNIFICANTLY PROLONGS OVERALL SURVIVAL IN PATIENTS WITH FLT3‐MUTATED (FLT3MUT+) RELAPSED/REFRACTORY (R/R) ACUTE MYELOID LEUKEMIA (AML): RESULTS FROM THE PHASE 3 ADMIRAL TRIAL
Author(s) -
Perl A.,
Martinelli G.,
Cortes J.,
Neubauer A.,
Berman E.,
Paolini S.,
Montesinos P.,
Baer M.,
Larson R.,
Ustun C.,
Fabbiano F.,
Di Stasi A.,
Stuart R.,
Olin R.,
Kasner M.,
Ciceri F.,
Chou W.C.,
Podoltsev N.,
Recher C.,
Yokoyama H.,
Hosono N.,
Yoon S.S.,
Lee J.H.,
Pardee T.,
Fathi A.,
Liu C.,
Liu X.,
Bahceci E.,
Levis M.
Publication year - 2019
Publication title -
hemasphere
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.677
H-Index - 11
ISSN - 2572-9241
DOI - 10.1097/01.hs9.0000561784.84381.11
Subject(s) - medicine , daratumumab , al amyloidosis , renal function , gastroenterology , refractory (planetary science) , multiple myeloma , surgery , immunology , bortezomib , physics , antibody , astrobiology , immunoglobulin light chain
Background: Gilteritinib is a potent/selective oral inhibitor of fms‐ like tyrosine kinase 3 (FLT3). Based upon interim analysis response rates from the ADMIRAL phase 3 study of gilteritinib vs salvage chemotherapy (SC) in patients with R/R FLT3 mut+ AML (NCT02421939), gilteritinib became the first FLT3 inhibitor approved as single‐agent therapy in this population. Aims: We present the final results of the ADMIRAL trial. Methods: Adults with confirmed FLT3 mut+ AML ( FLT3 ‐ITD and/or FLT3 ‐TKD D835 or I836 mutations) refractory to induction chemotherapy or in untreated first relapse were randomized (2:1) to receive continuous 28‐day cycles of 120 mg/day gilteritinib or pre‐randomization selected SC: low‐dose cytarabine (LoDAC), azacitidine (AZA), mitoxantrone/etoposide/cytarabine (MEC), or fludarabine/cytarabine/granulocyte colony‐stimulating factor/idarubicin (FLAG‐IDA). Prior FLT3 inhibitor use, other than midostaurin or sorafenib, was excluded. Overall survival (OS) and the combined rate of complete remission/complete remission with partial hematologic recovery (CR/CRh) were co‐primary endpoints. Secondary endpoints were event‐free survival (EFS) and CR rate; safety/tolerability was also examined. Results: A total of 371 patients were randomized: 247 to gilteritinib and 124 to SC (MEC, 25.7%; FLAG‐IDA, 36.7%; LoDAC, 14.7%; AZA, 22.9%). Median age was 62 years (range, 19–85). Baseline FLT3 mutations were: FLT3‐ ITD, 88.4%; FLT3 ‐TKD, 8.4%; both FLT3 ‐ITD and FLT3 ‐TKD, 1.9%; unconfirmed, 1.3%. Overall, 39.4% of patients had refractory AML and 60.6% had relapsed AML. Patients randomized to gilteritinib had significantly longer OS (9.3 months) than SC (5.6 months; hazard ratio [HR] for death = 0.637; P = 0.0007); 1‐year survival rates were 37.1% and 16.7%, respectively. The CR/CRh rates for gilteritinib and SC were 34.0% and 15.3%, respectively ( P = 0.0001); CR rates were 21.1% and 10.5% (2‐sided P = 0.0106). Median EFS was 2.8 months and 0.7 months in the gilteritinib and SC arms, respectively (HR 0.793, P = 0.0830). Common adverse events (AEs) in all randomized patients were febrile neutropenia (43.7%), anemia (43.4%), and pyrexia (38.6%). Common grade ≥3 AEs related to gilteritinib were anemia (19.5%), febrile neutropenia (15.4%), thrombocytopenia (12.2%), and decreased platelet count (12.2%). Adjusted for exposure duration, serious treatment‐emergent AEs per patient year were less common with gilteritinib (7.1%) than SC (9.2%). Summary/Conclusion: In patients with R/R FLT3 mut+ AML, the potent, selective FLT3 inhibitor gilteritinib resulted in significantly longer overall survival and higher response rates compared with chemotherapy and had a favorable safety profile. These results change the treatment paradigm for salvage therapy of R/R FLT3 mut+ AML and establish gilteritinib as the new standard of care.