A randomized phase 2 study combining midostaurin, low-dose cytarabine and venetoclax in newly diagnosed AML ≥60 years

In randomized studies, addition of FLT3 inhibitors failed to improve survival in older patients with FLT3-ITD AML unfit for intensive chemotherapy. Although hypomethylating agents or low-dose cytarabine combined with venetoclax is standard, FLT3-ITD is an important mechanism of resistance and a barrier to improved survival. Recent studies show promise for the addition of gilteritinib or quizartinib to less intensive venetoclax-based therapy, however resulting marrow toxicity requires substantial reductions to administered treatment. The INTERVENE study (Investigating Novel Triplets to Extend Remission with VENetoclax in Elderly AML) (ACTRN12619001655134) examined the role of midostaurin (M) administered sequentially after low-dose cytarabine (L) combined with venetoclax (V) in patients with newly diagnosed AML ≥60 years with non-adverse karyotype. After a run-in phase (n=18) established that LDAC combined with venetoclax from days 1-28 and midostaurin from days 11-28 was tolerable, 120 patients were randomized 2:1 to receive either LVM or LV. For the primary endpoint, LVM did not improve composite complete remission (CRc), compared to LV (72% vs 68%). Combining midostaurin with LV enhanced CRc among the sub-group of patients (n=29) with FLT3-ITD (82% vs 57%, difference = 25%, 0.85 posterior probability true difference > 5%, 95% CrI: -10 to 59%) and improved FLT3-ITD clearance as measured by ultrasensitive NGS (65% vs 0%), resulting in longer OS (median 24.2 vs 8.8 months, HR=0.34, 95% CrI: 0.071 to 0.960), compared to LV. In conclusion, midostaurin combined with low-dose cytarabine and venetoclax is well-tolerated and may have a role in newly diagnosed FLT3-ITD AML unfit for intensive chemotherapy.