Vanflyta (quizartinib)

Functionally, MV4-11QR cells showed broad cross-resistance to clinically relevant agents, including midostaurin, venetoclax, and cytarabine. Importantly, pharmacological targeting of mutant p53 with eprenetapopt or MAPK signaling with trametinib restored sensitivity to quizartinib, inducing synergistic or additive cytotoxic effects and increased apoptosis. Together, these findings define a multilayered resistance program involving genetic, signaling, and metabolic adaptations and support rational combination strategies to overcome FLT3 inhibitor resistance in AML.

First-generation inhibitors, such as midostaurin, provided the foundation for targeted therapy, while recently developed agents such as gilteritinib and quizartinib have shown more selectivity and demonstrated superior clinical efficiency and improved tolerability. This review discusses the significance of FLT-3 mutations, the evolution of targeted therapies, current treatment guidelines, and ongoing challenges such as resistance and high relapse rates. We also discuss the emerging combinations of therapies and novel agents currently in clinical trials that aim to overcome resistance and improve long-term outcomes for patients with FLT-3-mutated AML.

PLD1-inhibitor remodeled phospholipid metabolism, induced ferroptosis and restored QUIZOM response in LSC. Our findings provided the therapeutic and resistant mechanisms of QUIZOM and paved the way for targeted interventions in this AML subtype.

P1, N=12, Recruiting, Daiichi Sankyo | Trial completion date: Mar 2026 --> Oct 2026 | Trial primary completion date: Mar 2026 --> Oct 2026

P3, N=700, Recruiting, Daiichi Sankyo | N=283 --> 700

Here, we detail the current targeted therapies available for AML: specifically, those targeting the BCL2 family (venetoclax), FLT3 (midostaurin, gilteritinib, quizartinib), IDH1/2 (enasidenib, ivosidenib), and MENIN (revumenib, ziftomenib). In addition, we outline potential mechanisms of resistance against these therapies, as well as efforts being taken to prevent or bypass them.

In patient-derived xenograft models, co-treatment with FLT3i (quizartinib) and CD276-targeting agents led to 72.9%-80.4% tumor burden reduction and enhanced CD8+ T cell function, outperforming quizartinib monotherapy. These findings define a scaffolded PKCι-pS727-STAT1 signaling axis that promotes immune evasion in FLT3-ITD AML, supporting combined FLT3 and CD276 targeting as a promising translational strategy in this aggressive leukemia subtype.

In FLT3-ITD AML cell lines (MOLM13 and MV4-11), treatment with first- and second-generation FLT3i (midostaurin and quizartinib, respectively) induced autophagy. The combination of quizartinib and chloroquine demonstrated a synergistic effect in MV4-11QR cells and this effect was associated with greater inhibition of the FLT3 receptor compared to the monotherapies. Therefore, combining FLT3i with autophagy inhibition enhances the FLT3i antileukemic efficacy and overcomes pharmacological resistance.

Polθ inhibitors enhance the anti-leukemic effects of standard drugs such as FLT3 kinase inhibitor quizartinib, cytarabine ± doxorubicin, and etoposide in vitro and in mice with DNMT3Amut leukemia. Altogether, Polθ is an attractive target in DNMT3Amut hematological malignancies.

P3, N=376, Not yet recruiting, PETHEMA Foundation

All fit patients with FLT3m-AML must receive intensive chemotherapy plus a FLT3i (midostaurin or quizartinib) and be evaluated for allo-HSCT. For unfit patients, the current standard of HMA + venetoclax is considered suboptimal, making the search for alternative strategies imperative...In the R/R setting, retesting the FLT3 status is mandatory, and gilteritinib is the standard treatment, serving as a bridge-to-transplant and for post-HSCT maintenance. The integration of FLT3i has shifted FLT3m-AML into a more favorable intermediate prognostic category, enhancing the role of curative strategies like allo-HSCT. This consensus paper provides a structured evidence-based comprehensive guide, translating complex data into clear actionable clinical recommendations that minimize practice variability and ultimately optimize management for this high-risk population.

P4, N=289, Recruiting, Medizinische Hochschule Hannover | N=128 --> 289