Key questions in FLT3-mutated AML, and ongoing research to address these

The AML Hub was pleased to speak with Charles Craddock, Queen Elizabeth Hospital Birmingham, Birmingham, UK. We asked, What are the key ongoing questions in FLT3-mutated AML, and how are ongoing trials addressing these?  

Craddock begins by highlighting the progress made in the treatment of FLT3-mutated (FLT3m) acute myeloid leukemia (AML) over the past decade with two large randomized clinical trials: the phase III RATIFY (NCT00651261) trial, investigating the addition of midostaurin to standard chemotherapy in patients with newly diagnosed (ND) FLT3m AML;¹ and the phase III QuANTUM-First (NCT02668653) trial, assessing the addition of quizartinib to standard chemotherapy in patients with ND FLT3-internal tandem duplication (FLT3-ITD) AML.² He discusses data from trials aiming to further improve outcomes for patients with FLT3m AML and considers whether similar benefit can be demonstrated in patients requiring less intensive regimens. 

Key points 

• In the RATIFY trial, at a median follow-up of 59 months, the median overall survival (mOS) in patients with ND FLT3m AML was longer with midostaurin (n = 360; mOS, 74.7 months) vs placebo (n = 357; mOS, 25.6 months; hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.63–0.96; p = 0.009).¹ 
• The survival benefit was observed primarily in patients who proceeded to allogeneic hematopoietic stem cell transplant (allo-HSCT) in first remission.¹ 
• In the QuANTUM-First trial, at a median follow-up of 39.2 months, mOS was longer in patients with ND FLT3-ITD AML treated with quizartinib (n = 268; mOS, 31.9 months) vs placebo (n = 271; mOS, 15.1 months; HR, 0.78; 95% CI, 0.62–0.98; p = 0.032).² 
• An overall survival benefit was demonstrated with quizartinib, regardless of transplant status.² 
• There is growing interest in the use of FLT3 inhibitors in less-intensive triplet regimens with venetoclax (Ven) and a hypomethylating agent, for unfit or older patients with mutated FLT3. 
• In a phase I/II trial (NCT03661307) investigating quizartinib + Ven + decitabine, the composite complete response (CRc) rates were 61% in patients with R/R FLT3m AML (n = 46), and 94% in patients with ND FLT3m AML (n = 30).³ 
• In the phase I/II VICEROY (NCT05520567) trial, the combination of Ven + azacitidine (Aza) + gilteritinib demonstrated CRc rates of up to 91% in patients aged ≥75 years with ND FLT3m AML who were ineligible for intensive chemotherapy (N = 43).⁴ 
• Allo-HSCT remains a cornerstone of treatment for patients with FLT3m AML, with ongoing studies evaluating the role of FLT3 inhibitor maintenance therapy post-transplant. 
• In the phase III MORPHO (NCT02997202) trial, post-transplant maintenance with gilteritinib improved relapse-free survival in patients with FLT3-ITD AML and measurable residual disease positivity pre- or post-transplant.⁵ 
• The treatment landscape for patients with FLT3m AML is rapidly evolving, with investigation of tailored strategies including intensification of therapy in younger, fit patients, and the use of Ven-based triplet regimens in older or unfit patients. 

This educational resource is independently supported by Daiichi Sankyo. All content was developed by SES in collaboration with an expert steering committee. Funders were allowed no influence.