FLT3-mutated acute myeloid leukaemia: a new opportunity

Acute myeloid leukaemia (AML) is a heterogeneous, aggressive malignancy of immature myeloid progenitors with poor survival.1 Approximately 30% of patients with newly diagnosed AML have fms-related tyrosine kinase 3 (FLT3) mutations, most of which are internal tandem duplications (ITD).2 Historically, FLT3-positive AML, particularly FLT3-ITD-positive AML, has been associated with relapse and poor survival.1,2 Since 2017, routine referral for allogeneic stem-cell transplant (ASCT) and regulatory approval of the multikinase inhibitor midostaurin in combination with standard chemotherapy (on the basis of data from the RATIFY study)2 for both FLT3-ITD-positive and FLT3-tyrosine-kinase-domain-positive newly diagnosed AML have improved outcomes.2,3 Midostaurin plus chemotherapy improves median overall survival (74 months vs 26 months) and event-free survival (8 months vs 3 months), and is now the standard of care for chemotherapy-eligible patients with FLT3-positive AML.2 Quizartinib, an FLT3-ITD-specific type 2 inhibitor, has shown safety and activity in combination with chemotherapy for newly diagnosed AML.4,5 In The Lancet, Harry P Erba and colleagues report results from a randomised, double-blind, placebo-controlled, phase 3 trial (QuANTUM-First) conducted at 193 hospitals and clinics across 26 countries in Europe, Asia, and North America of quizartinib in combination with standard induction and consolidation chemotherapy with or without ASCT allogeneic haematopoietic cell transplantation (allo-HCT).6 Eligible patients were aged 18–75 years and had FLT3-ITD-positive AML. 539 patients aged 20–75 years were randomly assigned (1:1) to the quizartinib group (n=268) or the placebo group (n=271); patients who had allo-HCT could continue up to 3 years of quizartinib maintenance. The secondary efficacy outcomes included event-free survival (defined by the US Food and Drug Administration as not having complete remission within 42 days from the start of the last induction cycle) and composite complete remission (defined as complete remission or complete remission with incomplete neutrophil or platelet recovery) with or without FLT3-ITD measurable residual disease (MRD) negativity. Most troublesome is the lack of a comparator group containing an active FLT3 inhibitor—midostaurin was approved in both the USA and Europe in 2017.2 The maximum age of enrolled patients was 75 years and 40% of those enrolled were aged between 60 years and 75 years, endorsing the value of addi