Patients newly diagnosed with FLT3-ITD mutated AML who are unfit for intensive chemotherapy face poor clinical outcomes, even with current low-intensity regimens such as azacitidine plus venetoclax, which yield a median overall survival (OS) of just 9.9 months. Quizartinib, a selective FLT3 inhibitor, has demonstrated efficacy in FLT3-ITD+ AML and is being explored in combination with other agents to improve outcomes further. This Phase Ib trial investigated the safety, recommended Phase II dose (RP2D), and preliminary efficacy of a triplet regimen comprising decitabine (DAC), venetoclax (VEN), and quizartinib (Quiz) in both newly diagnosed patients ineligible for intensive chemotherapy and those with relapsed/refractory (R/R) FLT3-mutated AML.

Among 26 newly diagnosed patients (median age 70), the DAC+VEN+Quiz combination achieved a composite complete remission (CRc) rate of 92%, with high molecular clearance—71% FLT3-PCR and 67% MFC negativity. The 30-day mortality was low (4%), and the regimen enabled 35% of patients to proceed to allogeneic stem cell transplant, with median OS not reached after 17 months of follow-up. In the heavily pretreated R/R cohort (n=47), including patients with prior FLT3 inhibitor exposure, CRc and CR+CRi rates were 60% and 28%, respectively, with MRD negativity in ~30% and a median OS of 6.3 months. 

Quiz 30 mg/day was selected as the RP2D due to tolerability, as 40 mg/day was associated with hematologic dose-limiting toxicity. The triplet regimen was generally more tolerable in frontline patients compared to the R/R group, with fewer Grade ≥3 non-hematologic adverse events. These findings support further development of this combination in frontline FLT3-mutated AML settings.

KOL insights

“When choosing treatment for the newly diagnosed older patient, the first main decision point is whether we should start with an intensive induction treatment or with lower-intensity treatment. For older patients with newly diagnosed AML who are not appropriate candidates for intensive chemotherapy, the current standard of care is a hypomethylating agent (typically azacitidine or decitabine) plus venetoclax.”– Expert Opinion

Conclusion

Mutations in the FLT3 gene are commonly found in approximately 30% of patients diagnosed with AML. The detection of FLT3 mutations has been a subject of interest for over two decades, and the clinical application of FLT3 inhibitors has since become available for treating AML patients with such mutations. Despite overcoming several challenges in the development process of FLT3 inhibitors, it is imperative to conduct further in-depth investigations to identify the optimal treatment protocols for individual patients. 

FLT3 inhibitors are classified into two categories based on their receptor specificity: first-generation and second-generation agents. First-generation inhibitors—such as sunitinib, and sorafenib—lack high specificity for FLT3 and instead target multiple receptor tyrosine kinases and signaling pathways. This broader activity can offer therapeutic benefits but may also increase the risk of off-target effects. In contrast, second-generation FLT3 inhibitors like quizartinib and gilteritinib are more selective for the FLT3 receptor, which is expected to reduce therapy-related toxicities and improve tolerability.

The combination of decitabine, venetoclax, and quizartinib shows promising clinical activity and manageable safety in newly diagnosed FLT3-ITD mutated AML patients who are unfit for intensive chemotherapy. Ongoing clinical studies aim to expand the range of treatment options by tailoring therapies to patients’ specific vulnerability to FLT3-mutated AML and the stage of their disease. These efforts are expected to refine and personalize treatment strategies, ultimately improving patient outcomes.