AMLSG 16-10: long-term benefits of midostaurin for FLT3-ITD-mutated AML

The final results of the phase 2 AMLSG 16-10 trial showed that younger and older patients with FLT3-ITD-mutated AML benefitted from adding midostaurin to intensive chemotherapy.

Induction therapy response rate was higher in the midostaurin cohort

Midostaurin is a first-generation, type I kinase inhibitor targeting FLT3-ITD and FLT3-TKD mutations2. The single-arm, phase 2 AMLSG 16-10 trial (NCT01477606) included patients with newly diagnosed, FLT3-ITD-mutated AML up to 70 years of age (n=440) to investigate midostaurin plus induction chemotherapy, followed by allogeneic haematopoietic cell transplantation (HCT) and 1-year midostaurin maintenance therapy.

A cohort of historical AMLSG trial participants (n=415) was used as control group. Dr Hartmut Döhner (Universitätsklinikum Ulm, Germany) mentioned that patients in the historical cohort had received their treatment approximately a decade earlier than patients in the AMLSG 16-10 trial. The primary endpoint was event-free survival. The key secondary endpoint was overall survival.

Dr Döhner presented the final results of the trial. The response rate to induction therapy was higher in the midostaurin cohort (CR/CRi 74.9%) than in the control cohort (64.6%). Moreover, the proportion of patients undergoing HCT in CR/CRi was higher in patients receiving midostaurin (45.2%) compared with control subjects (22.6%). The 5-year event-free survival and overall survival rates were significantly improved in the AMLSG 16-10 trial compared with the historical cohort.

NPM1 mutations had a favourable impact on event-free survival

Patients <60 years of age treated with midostaurin had a 5-year overall survival rate of 49% versus 33% in controls. Patients between 61 and 70 years of age receiving midostaurin therapy showed a 5-year overall survival rate of 33%. Patients in the control group in this age category demonstrated an overall survival rate of 8% after 5 years.

Furthermore, NPM1 mutations had a favourable impact on event-free survival (HR 0.48; P<0.001), whereas older age (HR 1.17), higher WBC count (HR 1.21), and high FLT3-ITD allelic ratios (HR 1.19; P=0.072) were associated with an unfavourable effect on event-free survival. The therapy effect of midostaurin remained significant when allogeneic HCT was considered as a time-dependent variable.

Midostaurin was generally well tolerated. Respiratory, metabolic, and vascular adverse events were more frequently reported in older patients. However, Dr Döhner argued that underlying comorbidities may be the explanation for this outcome. 

1. Döhner H, et al. Midostaurin plus intensive chemotherapy for younger and older patients with acute myeloid leukemia and FLT3 internal tandem duplications – Final analysis of the AMLSG 16-10 Trial. O615, ASH 2021 Scientific Sessions, 11-14 December
2. Weisberg E, et al. Cancer Cell. 2002;1(5):433-443