Due to its aggressive nature, high relapse rates, and poor survival outcomes, acute myeloid leukaemia (AML) with FMS-like tyrosine kinase 3 (FLT3) gene mutation continues to present significant treatment challenges despite use of targeted therapy. At an industry-sponsored meeting, Dr Richard Dillon from Guy’s Hospital, King’s College London, London, UK, reviewed evolving management practices for patients with FLT3-mutated AML, including unmet needs in the first-line and relapsed/refractory (R/R) settings, and discussed the role of measurable residual disease (MRD)–guided intervention.
FLT3-mutated AML
FLT3-activating mutations are present in approximately 30 percent of patients with AML, typically as in-frame internal tandem duplications (ITDs) or missense point mutations in the tyrosine kinase domain (TKD). [Leuk Res 2010;34:752-756; Blood 2022;140:1345-1377]
Front-line management with earlier-generation FLT3 inhibitors
“Despite improvements with FLT3 inhibitors in the frontline setting, relapse remains frequent in patients with FLT3-mutated AML,” said Dillon. “Reported 4-year overall survival [OS] rates remain modest with earlier generation FLT3 inhibitors, at 51 percent with midostaurin and 48 percent with quizartinib.” [N Engl J Med 2017;377:454-464; Lancet 2023;401:1571-1583]
The UK National Cancer Research Institute (NCRI) AML19 trial demonstrated a higher 4-year OS rate of 68 percent with a regimen of fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin (FLAG-Ida) plus gemtuzumab. [J Clin Oncol 2024;42:1158-1168] The randomized NCRI AML19 v2/MIDOTARG pilot trial showed that adding a FLT3 inhibitor to intensive chemotherapy further improves survival outcomes. Daunorubicin, cytarabine and gemtuzumab (DA-GO) in combination with midostaurin yielded an 18-month OS rate of 82 percent, which compares favourably to the 18-month OS rate of 72 percent in patients treated with DA-GO alone in AML19 v1. [Russel N, et al, ASH 2023, abstract P484]
FLT3-mutated R/R AML: Gilteritinib reshapes salvage therapy
“FLT3 mutations are associated with high relapse rates of up to 40 percent, despite use of [earlier-generation] FLT3 inhibitors, and poor prognosis,” Dillon noted. [Leukemia 2023;37:2066- 2072; Blood Adv 2022;6:5345-5355] “This underscores the need for more effective salvage strategies.”
Improved OS with gilteritinib monotherapy
The phase III ADMIRAL trial compared single-agent gilteritinib, an oral, potent and selective FLT3 inhibitor vs salvage chemotherapy in patients with FLT3-mutated R/R AML (n=371). Compared with salvage chemotherapy, gilteritinib monotherapy was associated with a significantly higher complete remission (CR) rate (21.1 vs 10.5 percent; risk difference, 10.6 percent; 95 percent confidence interval [CI], 2.8–18.4) and improved median OS (9.3 vs 5.6 months; hazard ratio [HR], 0.64; 95 percent CI, 0.49–0.83; p<0.001). Results were similar among patients with FLT3-TKD mutations alone and FLT3- ITD mutations alone. Notably, more patients receiving gilteritinib proceeded to haematopoietic stem cell transplantation (HSCT) vs those on salvage chemotherapy (25.5 vs 15.3 percent). [N Engl J Med 2019;381:1728-1740]
COMMODORE: Focus on a predominantly Asian population
“The phase III COMMODORE trial validated the results of ADMIRAL in a predominantly Asian [85.9 percent] cohort with FLT3-mutated R/R AML,” Dillon said. [Leukemia 2024;38:2410-2418]
In COMMODORE, median OS was significantly longer in the gilteritinib vs salvage chemotherapy arm (9.6 vs 5.0 months; HR, 0.566; 95 percent CI, 0.392–0.818; p=0.00211) after a median follow-up of 10.3 months. (Figure 1) The 1-year OS rates were 35.1 vs 25.1 percent.
“Although CR rates were modest [16.4 vs 10.2 percent; composite CR rates (CRc), 50.0 vs 20.3 percent], the consistency of benefit across populations confirmed the efficacy of gilteritinib vs salvage chemotherapy in patients with R/R FLT3-mutated AML,” stressed Dillon.
Timing of response to gilteritinib
“It is important to allow sufficient time for response to gilteritinib monotherapy in the salvage setting, as there is a significant number of late responders [LRs], and LRs may not necessarily fare worse than the whole population [of responders],” noted Dillon.
A post hoc pooled analysis of the gilteritinib arms of ADMIRAL and COMMODORE provided critical insights into response kinetics. Patients were categorized as early responders (ERs; CRc by end of cycle 2) or LRs (CRc after cycle 3 initiation). “Although nearly 90 percent of CRc responders achieved remission within six cycles, only about one-third of overall CRc responders achieved CRc by the end of cycle 2, with the proportion steadily increasing from cycle 3 right up till cycle 6,” said Dillon. The median duration of CRc was 2.7 months for ERs and 3.5 months for LRs, while median OS was comparable, at 9 and 10 months, respectively. [Blood 2024;144:2889-2890]
Real-world evidence: Consistent survival benefits with gilteritinib
“A UK real-world cohort study demonstrated consistent survival outcomes with gilteritinib as those seen in clinical trials,” he continued.
The study involved 152 patients with FLT3-mutated R/R AML receiving single-agent gilteritinib in 38 hospitals in the UK. CR was achieved in 21 percent of patients, and an additional 9 percent of patients had CR with incomplete recovery. Median OS was 9.5 months, which is similar to previously reported clinical trial results. (Figure 2) Patients previously treated with FLT3 inhibitors had slightly lower CR rates, but those with prior transplants or who acquired FLT3 mutations at relapse responded better. [Blood Adv 2024;8:5590-5597]
“Although gilteritinib has reshaped salvage therapy, long-term survival remains limited, with approximately 20 percent of patients surviving beyond 2 years,” noted Dillon. “This underlines the need for more effective interventions.” [N Engl J Med 2019;381:1728- 1740; Leukemia 2024;38:2410-2418; Blood Adv 2024;8:5590-5597]
Role of MRD monitoring in preventing relapse
MRD relapse and pre-emptive therapy
“MRD monitoring offers prognostic and predictive value in AML, which can help guide therapeutic interventions and potentially improve patient outcomes,” said Dillon. [Lancet Haematol 2025;12:e346-e356]
The phase III randomized UK NCRI AML17 and AML19 trials aimed to determine whether sequential MRD monitoring coupled with MRD-guided therapy at treating physicians’ discretion can improve survival. Although no OS benefit was shown in the entire study population, a clear survival advantage for sequential molecular MRD monitoring coupled with MRD-guided treatment vs no monitoring was observed in patients with both NPM1 and FLT3-ITD mutations at baseline (3-year OS rates: 69 vs 58 percent; HR, 0.53; 95 percent CI, 0.31–0.91; p=0.021). In contrast, there was no difference in survival between the monitoring and no monitoring groups in patients with NPM1 mutations without FLT3-ITD or those with fusion gene transcripts. [Lancet Haematol 2025;12:e346-e356]
“Comprehensive molecular diagnostics, including fluorescence in situ hybridization and RNA sequencing, are important strategies to help identify MRD targets,” Dillon stated. [Lancet Haematol 2025;12:e346-e356] “For instance, in the UK NCRI AML17 and AML19 cohorts, RNA sequencing uncovered cryptic fusions in >25 percent of patients with apparently isolated FLT3-ITD–mutated AML lacking conventional MRD markers.” [Potter N, et al, EHA 2024, abstract P449]
Analysis also showed that patients with FLT3-ITD AML harbouring cryptic fusions had a trend of poorer survival vs those without cryptic fusions (median survival, 15.62 vs 24.36 months; HR, 0.68–1.47; p=0.0871), which may have direct implications for treatment and disease monitoring.
Beyond FLT3-ITD–positive disease, MRD relapse in patients with AML can also be detected through other aberrations, such as NPM1 mutations, underscoring the benefit of early intervention based on MRD surveillance, independent of FLT3 status. [J Clin Oncol 2024;42:2161-2173; Blood Adv 2024;8:343-352]
“MRD monitoring and pre-emptive therapy [ie, at time of MRD vs frank relapse] offers several theoretical benefits,” Dillon suggested. “These include patients remaining clinically well with preserved blood counts, facilitating optimal treatment planning with improved tolerability and avoiding the need for emergency salvage therapy, and allowing early initiation of targeted and immune therapies [eg, donor lymphocyte infusion], which may be more effective during low-disease states.” [J Clin Oncol 2024;42:2161-2173; Blood Adv 2024;8:343-352; Leukemia 2023;37:2066-2072]
FLT3-ITD MRD: Marker for pre-emptive FLT3 inhibitor therapy
Studies show that even low levels of FLT3-ITD MRD detected before HSCT are associated with poor outcomes, regardless of conditioning intensity. This underscores the potential of FLT3-ITD MRD detection, particularly through high-sensitivity polymerase chain reaction (PCR)–next-generation sequencing (NGS) assays, in MRD-based pre-emptive intervention to improve outcomes and bridge patients to allogeneic transplant. [Rücker FG, et al, EHA 2023, abstract S135; Leukemia 2019;33:2535- 2539; Blood 2022;140:2407-2411; Leukemia 2023;37:2066-2072]
A retrospective study suggested that FLT3-ITD assessment at the time of molecular failure may help identify patients with FLT3-mutated AML who are most likely to benefit from FLT3 inhibitor therapy. Retrospective analysis for FLT3-ITD MRD of available stored pretreatment bone marrow aspirate samples from patients with molecular failure found that 78 percent had these mutations detectable by NGS. Patients with detectable FLT3-ITD MRD showed higher molecular response rates to FLT3 inhibitor therapy than those with undetectable FLT3-ITD MRD (68 vs 25 percent). These findings further support integration of NGS-based FLT3- ITD assessment into clinical practice to guide pre-emptive interventions (eg, with FLT3 inhibitors) and improve outcomes in patients with FLT3- mutated AML. [Leukemia 2023;37:2066-2072]
Conclusions
The treatment landscape of FLT3-mutated AML is dynamic and continues to evolve, with improved outcomes driven by upfront FLT3 inhibition, effective salvage therapy with gilteritinib monotherapy, and MRD-guided strategies. Ongoing research into novel agents and molecular monitoring will be critical in further improving long-term patient outcomes.
