The emergence of FLT3 inhibitors has reshaped the management of patients with acute myeloid leukaemia (AML) with FLT3-internal tandem duplication (ITD) mutations. At an industry-sponsored symposium during The Second Asia Pacific Myeloid Forum (APMF 2026), Professor Adriano Venditti of the University of Rome Tor Vergata in Rome, Italy, discussed the evolving treatment landscape for AML, detailing pivotal results of the QuANTUM-First trial and the potential of the oral, second-generation, type 2 FLT3 inhibitor, quizartinib, to extend survival benefits across all phases of AML therapy and beyond the FLT3-ITD mutation into the wild-type (WT) setting.
From RATIFY to QuANTUM-First: Advancing frontline and maintenance FLT3 inhibition
FLT3-ITD mutations are associated with high relapse rates and poor prognosis in AML. FLT3 inhibitors have substantially improved outcomes in this population. [N Engl J Med 2017;377:454-464; Lancet 2023;401:1571-1583]
The phase III RATIFY trial showed overall survival (OS) and event-free survival (EFS) benefits when midostaurin, a multitargeted protein kinase inhibitor, was added to standard chemotherapy in adults aged <60 years with newly diagnosed FLT3-mutated AML. [N Engl J Med 2017;377:454-464]
“While RATIFY demonstrated the value of FLT3 inhibition in frontline therapy, the trial did not definitively establish the role of FLT3 inhibition during maintenance after consolidation. It was not designed to definitively determine midostaurin’s contribution to the maintenance treatment phase, and patients who underwent allogeneic haematopoietic stem cell transplantation [allo-HSCT] did not receive midostaurin as maintenance therapy,” commented Venditti. [N Engl J Med 2017;377:454-464; Leukemia 2021;35:2539-2551]
“The subsequent global phase III randomized QuANTUM-First trial aimed to address several of these limitations using the selective, type 2, second-generation FLT3 inhibitor, quizartinib,” he continued. [Lancet 2023;401:1571-1583; Erba H, et al, EHA 2022, abstract S100]
The trial included 539 adults aged 18–75 years with newly diagnosed FLT3-ITD–positive AML who received either quizartinib or placebo plus standard induction and consolidation chemotherapy ± allo-HSCT, followed by quizartinib or placebo single-agent maintenance. Maintenance was delivered after either consolidation or allo-HSCT.
“Unlike RATIFY, QuANTUM-First enrolled only patients with FLT3-ITD– positive AML, included patients up to 75 years of age, and incorporated quizartinib throughout induction, consolidation and maintenance therapy for up to 36 cycles,” highlighted Venditti. [N Engl J Med 2017;377:454-464]
The trial met its primary endpoint, demonstrating a statistically significant 22.4 percent reduction in risk of death vs placebo (median OS, 31.9 vs 15.1 months; hazard ratio [HR], 0.776; p=0.0324).
“This OS benefit was observed across most prespecified subgroups, including patients aged >60 years,” said Venditti. “Importantly, this OS advantage was accompanied by improvements in relapse-related outcomes, including relapse-free survival and cumulative incidence of relapse.”
Quizartinib had a generally manageable safety profile. Grade ≥3 adverse events occurred in 92 percent of patients on quizartinib vs 90 percent of those on placebo. Key toxicities were myelosuppression, infections and QT prolongation, with no new safety signals. Grade ≥3 neutropoenia was more frequent with quizartinib (18.1 vs 8.6 percent), whereas rate of serious infections was similar between groups. Most QT prolongations were asymptomatic and manageable with dose modification and electrolyte monitoring.
Maintenance therapy and MRD: Deepening responses, improving outcomes
“Another critical component of quizartinib’s clinical profile is its use throughout all phases of treatment [ie, induction, consolidation, and maintenance],” stressed Venditti. [Vanflyta Hong Kong Prescribing Information] “This ‘total therapy’ approach sets quizartinib apart from other inhibitors, which failed to show a definitive maintenance benefit.” [Lancet 2023;401:1571-1583; N Engl J Med 2017;377:454-464; Leukemia 2021;35:2539-2551]
“Quizartinib appears to act synergistically across different phases of treatment,” he remarked. “For instance, QuANTUM-First’s post-hoc analyses showed that quizartinib synergized with allo-HSCT, resulting in longer OS in patients achieving first complete remission [CR1] and composite CR1.” [J Clin Oncol 2020;38:2993-3002; Lancet Oncol 2020;21:1201-1212; Haematologica 2025;110:2024-2039; Blood Adv 2026;doi:10.1182/bloodadvances.2025017738]
In the post-remission setting, QuANTUM-First’s exploratory analyses showed a 60 percent reduction in risk of death with quizartinib maintenance vs placebo for patients who did not undergo allo-HSCT (HR, 0.401; 95 percent confidence interval [CI], 0.192–0.838), with median OS not reached with quizartinib vs 42.5 months with placebo. A benefit was observed in patients who were measurable residual disease (MRD)–negative at the start of maintenance (HR, 0.194; 95 percent CI, 0.056–0.676). Importantly, for patients who remained MRD-negative after consolidation and received quizartinib maintenance without allo-HSCT, the estimated 3-year survival rate was 89.1 percent. [Blood Adv 2026:doi:10.1182/bloodadvances.2025017738]
“This suggests that for patients who achieve deep molecular responses, quizartinib maintenance may provide survival benefit and potentially eliminate the need for allo-HSCT,” said Venditti.
A post-hoc analysis of QuANTUM-First used ultra-high-sensitivity next-generation sequencing to further describe the relationship between quizartinib and MRD. Results showed that adding quizartinib to intensive induction chemotherapy significantly deepened molecular responses. During the first induction cycle, quizartinib treatment was associated with a nearly three-fold lower median best FLT3-ITD MRD variant allele frequency vs placebo (0.0086 vs 0.0242 percent; p=0.0439). (Figure 1A) [Blood Adv 2026;10:917-928]
These deeper remissions translated into improved survival outcomes. Using a 10-4 cut-off, MRD negativity at the end of induction was associated with superior OS compared with MRD positivity (HR, 0.627; 95 percent CI, 0.427-0.922), supporting use of FLT3-ITD MRD monitoring for prognostication. (Figure 1B) However, quizartinib maintained an OS benefit vs placebo regardless of MRD status. (Figures 1C and 1D)
Expanding into FLT3- WT AML: QUIWI and QuANTUM-Wild
FLT3 signalling is believed to remain biologically relevant beyond FLT3-ITD– positive disease. This was the rationale for the phase II QUIWI trial, which evaluated quizartinib in 273 patients aged 18–70 years with newly diagnosed FLT3-ITD–negative (mutant-to-WT allelic ratio <0.03) AML. [J Clin Oncol 2026;44:42-53]
Patients were randomly assigned (2:1) to receive either quizartinib or placebo with standard chemotherapy, followed by single-agent maintenance. Results showed that quizartinib significantly prolonged EFS (20.4 vs 9.9 months; HR, 0.72; 95 percent CI, 0.53-1.00; p=0.046) and median OS vs placebo (not reached vs 29.3 months; HR, 0.63; 95 percent CI, 0.44-0.91; p=0.012). The 3-year OS rates were also in favour of the quizartinib group (60.8 vs 45.7 percent).
“These results suggest that FLT3 signalling may remain clinically relevant even in patients who are classified as FLT3-ITD–negative,” said Venditti.
Building on these findings, the ongoing phase III QuANTUM-Wild trial is evaluating quizartinib combined with intensive chemotherapy and as maintenance monotherapy in patients with newly diagnosed FLT3-ITD–negative AML. The study aims to determine whether the survival benefits observed in QUIWI can be confirmed in a larger global population of approximately 700 patients. [Montesinos P, et al, ASCO 2025, poster TPS6580]
Conclusions
Clinical evidence supports the use of quizartinib across the treatment continuum for FLT3-ITD– positive AML, delivering significant survival gains and deeper molecular remissions. As randomized trials remain the mainstay for drug approval, results of the ongoing QuANTUM-Wild trial are eagerly anticipated to determine if this benefit extends to the majority of AML patients who lack FLT3-ITD mutations.