The impact of FLT3 mutation clearance and treatment response after gilteritinib therapy on overall survival in patients with FLT3 mutation-positive relapsed/refractory acute myeloid leukemia.

The FLT3 inhibitor gilteritinib has clinical activity in patients with FLT3-mutated (FLT3mut+ ) relapsed/refractory (R/R) acute myeloid leukemia (AML). The impact of FLT3 mutation clearance and the achievement of composite complete remission (CRc) and complete remission/complete remission with partial hematologic recovery (CR/CRh) on overall survival (OS) in patients with FLT3mut+ R/R AML treated with single-agent gilteritinib in a phase 1/2 trial were evaluated. Using next-generation sequencing, a FLT3-ITD variant allele frequency of ≤10-4 was used to define FLT3-ITD clearance in patients with no morphologic leukemia (ie, CRc). A total of 108 patients with FLT3-ITD-positive (FLT3-ITD+) R/R AML were analyzed; 95 of these patients had received ≥80-mg/day gilteritinib. Ten of the 95 patients had FLT3-ITD clearance; eight of these 10 patients achieved CRc and were considered negative for measurable residual disease. There was a trend toward longer OS in patients who attained CRc with FLT3-ITD clearance (131.4 weeks) versus those who achieved CRc and did not have FLT3-ITD clearance (n = 41; 43.3 weeks; HR = 0.416; p = 0.066). Among patients treated with ≥80-mg/day gilteritinib who achieved CR/CRh (n = 24), seven had FLT3-ITD clearance. Among patients who received 120-mg/day gilteritinib, those who achieved CR/CRh had a longer median OS (70.6 weeks) and higher 52-week survival probability (66.7%) than patients who did not achieve CR/CRh (n = 71; median OS, 41.7 weeks; 52-week survival probability, 20.2%). Overall, these data suggest that gilteritinib can induce deep molecular responses in patients with FLT3-ITD+ R/R AML, and in the setting of CRc or CR/CRh, these responses may be associated with prolonged survival.

Altman JK ，Perl AE ，Hill JE ，Rosales M ，Bahceci E ，Levis MJ ... -  《Cancer Medicine》

[Efficacy and safety of gilteritinib-based combination therapy bridging allo-HSCT in relapsed or refractory acute myeloid leukemia patients with positive FLT3-ITD mutation].

Xu Y ，Zhang J ，Xue SL ，Miao M ，Wang Y ，Chen SN ，Qiu HY ，Wu DP ... -  《-》

Azacitidine, Venetoclax, and Gilteritinib in Newly Diagnosed and Relapsed or Refractory FLT3-Mutated AML.

Short NJ ，Daver N ，Dinardo CD ，Kadia T ，Nasr LF ，Macaron W ，Yilmaz M ，Borthakur G ，Montalban-Bravo G ，Garcia-Manero G ，Issa GC ，Chien KS ，Jabbour E ，Nasnas C ，Huang X ，Qiao W ，Matthews J ，Stojanik CJ ，Patel KP ，Abramova R ，Thankachan J ，Konopleva M ，Kantarjian H ，Ravandi F ... -  《-》

Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML.

Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene (FLT3) infrequently have a response to salvage chemotherapy. Gilteritinib is an oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory FLT3-mutated AML. In a phase 3 trial, we randomly assigned adults with relapsed or refractory FLT3-mutated AML in a 2:1 ratio to receive either gilteritinib (at a dose of 120 mg per day) or salvage chemotherapy. The two primary end points were overall survival and the percentage of patients who had complete remission with full or partial hematologic recovery. Secondary end points included event-free survival (freedom from treatment failure [i.e., relapse or lack of remission] or death) and the percentage of patients who had complete remission. Of 371 eligible patients, 247 were randomly assigned to the gilteritinib group and 124 to the salvage chemotherapy group. The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P<0.001). The median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI, 0.58 to 1.09). The percentage of patients who had complete remission with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group (risk difference, 18.6 percentage points; 95% CI, 9.8 to 27.4); the percentages with complete remission were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8 to 18.4). In an analysis that was adjusted for therapy duration, adverse events of grade 3 or higher and serious adverse events occurred less frequently in the gilteritinib group than in the chemotherapy group; the most common adverse events of grade 3 or higher in the gilteritinib group were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%). Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated AML. (Funded by Astellas Pharma; ADMIRAL ClinicalTrials.gov number, NCT02421939.).

Perl AE ，Martinelli G ，Cortes JE ，Neubauer A ，Berman E ，Paolini S ，Montesinos P ，Baer MR ，Larson RA ，Ustun C ，Fabbiano F ，Erba HP ，Di Stasi A ，Stuart R ，Olin R ，Kasner M ，Ciceri F ，Chou WC ，Podoltsev N ，Recher C ，Yokoyama H ，Hosono N ，Yoon SS ，Lee JH ，Pardee T ，Fathi AT ，Liu C ，Hasabou N ，Liu X ，Bahceci E ，Levis MJ ... -  《-》

Myelomonocytic differentiation of leukemic blasts accompanied by differentiation syndrome in a case of FLT3-ITD-positive AML treated with gilteritinib.

Kondo T ，Onozawa M ，Fujisawa S ，Harada S ，Ogasawara R ，Izumiyama K ，Saito M ，Morioka M ，Mori A ，Teshima T ... -  《-》