Vanflyta (quizartinib)

These findings highlight the potent efficacy of gilteritinib against a wide range of FLT3 mutations, including TKD-PM and JMD-PM, as well as those associated with resistance to quizartinib or midostaurin. This comparative analysis underscores the need for tailored therapeutic strategies in AML treatment, emphasizing the clinical significance of gilteritinib in overcoming drug resistance.

P1/2, N=58, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2025 --> Dec 2027 | Trial primary completion date: Dec 2025 --> Dec 2027

Importantly, in vitro transcription of circTADA2A and in vivo delivery via lipid nanoparticles (LNPs) significantly enhance the elimination of FLT3-ITD leukemia cells in combination with quizartinib treatment. In conclusion, our work uncovers the crucial functions of circTADA2A in the maintenance of FLT3-ITD AML and highlights a translationally important circTADA2A-based therapeutic approach for FLT3-ITD AML treatment.

Specifically, inhibition of PINK1 by AC220 or knockout of PINK1 impairs mitophagy and enhances ROS production, leading to oxidation and oligomerization of TOMM20, followed by mitochondrial recruitment and activation of BAX. Furthermore, inhibition or deficiency of PINK1 potentiates the anti-tumor effects of the clinical ROS-inducing drug ethacrynic acid (EA) to inhibit neuroblastoma progression in vivo. Therefore, our study provides a promising intervention strategy for neuroblastoma through the induction of pyroptosis.

We further evaluated the drug sensitivity of FLT3-mutant patients to 3 FDA-approved FLT3i, gilteritinib, midostaurin, and quizartinib, and observed heightened sensitivity in FLT3-mutant cohorts, accompanied by the activation of immune-related pathways in treatment-responsive groups. These biomarkers were consistently upregulated in favorable prognostic subgroups and demonstrated strong correlations with immune activation pathways. The identification of CD36, SASH1, and NIBAN2 as predictive biomarkers offers a novel toolset for stratifying FLT3i response and prognosis.

Patients who underwent protocol-specified allo-HCT in CR1/CRc1 experienced post-allo-HCTQrelated complications, mostly grade ≥2 graft-versus-host disease, as expected. This posthoc analysis further supports quizartinib and allo-HCT in CR1/CRc1 as an efficacious and well-tolerated treatment strategy for newly diagnosed FLT3-ITDQpositive AML patients fit for intensive chemotherapy.

P1, N=7, Completed, Daiichi Sankyo Co., Ltd. | Phase classification: P1b --> P1

Additional studies are required to determine the optimal FLT3I-based combinations, reduce resistance emergence, and improve outcomes. This review highlights the current state of FLT3I therapy, ongoing challenges with resistance, and future directions in optimizing treatment for FLT3-mutated AML, focusing on quizartinib.

Notably, targeting STING showed inhibited acute myeloid leukemia (AML) development in a Dnmt3a-KO; Flt3-ITD AML model, comparable to AC220, an FDA-approved FLT3-ITD inhibitor. A patient-derived xenograft (PDX) model further demonstrated that targeting STING effectively alleviates the leukemic burden of DNMT3A-mutant AML. Collectively, our findings highlight a critical role for STING in hematopoietic disorders induced by DNMT3A mutations and propose STING as a potential therapeutic target for preventing the progression of DNMT3A mutation-associated leukemia.

Our study shows that IHCH9033, a novel class I HDACi with a desirable pharmacological profile, is a promising drug candidate for FLT3-ITD AML, and suggests a strategy of combining class I HDACis and FLT3is in AML clinical trials to increase efficacy and overcome resistance, thus potentially providing a curative treatment option.

P2, N=130, Not yet recruiting, Daiichi Sankyo

Targeting p300/CBP with A485 or CCS1477 retained the efficacy of quizartinib, suggesting marked synergy when combined with p300/CBP inhibitors in quizartinib-resistant AML models, as well as primary FLT3-ITD+ AML samples. These results demonstrate a potential therapeutic strategy of combining p300/CBP and FLT3 inhibitors to treat FLT3-ITD and FLT3-TKD AML.

P1, N=70, Recruiting, Daiichi Sankyo

P1, N=44, Not yet recruiting, M.D. Anderson Cancer Center

P1, N=12, Recruiting, Daiichi Sankyo

P1, N=32, Completed, Daiichi Sankyo

Gilter/quizar monotherapy are effective and tolerable options for patients with R/R FLT3mut AML in a real-world setting. Response and toxicity rates are similar to those reported in the phase 3 trials, despite the more heterogeneous nature of the study population.

All-trans retinoic acid (ATRA) is well known for its effectiveness in acute promyelocytic leukemia (APL) treatment and has already been shown to have synergistic effects combined with another TKI, sorafenib. Finally, in a xenotransplantation model ATRA plus AC220 was more efficient to reduce the leukemic burden than monotherapy with ATRA or AC220. Taken together, our results are a proof of the concept that ATRA and AC220 have synergistic anti-leukemic effects.

Since 2017, a turning point in AML research, 12 agents have received regulatory approval for AML in the United States: venetoclax (BCL2 inhibitor); gemtuzumab ozogamicin (CD33 antibody-drug conjugate); midostaurin, gilteritinib, and quizartinib (fms-like tyrosine kinase 3 inhibitors); ivosidenib, olutasidenib, and enasidenib (isocitrate dehydrogenase 1 and 2 inhibitors); oral azacitidine (a partially absorbable formulation); CPX351 (liposomal encapsulation of cytarabine:daunorubicin at a molar ratio of 5:1); glasdegib (hedgehog inhibitor); and recently revumenib (menin inhibitor; approved November 2024). Oral decitabine-cedazuridine, which is approved as a bioequivalent alternative to parenteral hypomethylating agents in myelodysplastic syndrome, can be used for the same purpose in AML. Menin inhibitors, CD123 antibody-drug conjugates, and other antibodies targeting CD123, CD33, and other surface markers are showing promising results. Herein, the authors review the frontline and later line therapies in AML and discuss important research directions.

P3, N=700, Recruiting, Daiichi Sankyo | Not yet recruiting --> Recruiting

Finally, we highlight some of the ongoing studies that test quizartinib in patients with FLT3-ITD-positive AML, patients with FLT3-ITD-negative AML, in both the first-line and R/R settings, in patients fit or unfit for intensive chemotherapy, including studies for quizartinib-based combination with other compounds such as decitabine and venetoclax. Future research should aim to further optimize the clinical value of quizartinib and explore its use in additional clinical settings, which could be achieved by testing quizartinib with other drugs, better characterization of the mechanisms of resistance, identification of the role of quizartinib as a maintenance therapy after allo-HCT, and investigating quizartinib in patients with FLT3-ITD-negative AML.

Our results suggest different immunosuppressive effects of these three FLT3i and may, therefore, provide an additional rationale for optimal maintenance therapy after alloHSCT of FLT3-positive AML patients to prevent infectious complications and GvHD mediated by DCs.

This innovative TRG scoring model demonstrates considerable predictive value for AML patient prognosis, offering valuable insights for optimizing treatment strategies and personalized medicine approaches. The identified TRGs and associated scoring models could aid in risk stratification and guide tailored therapeutic interventions in AML patients.

P1/2, N=65, Active, not recruiting, Daiichi Sankyo | Recruiting --> Active, not recruiting

P1/2, N=84, Ongoing, Fundación Pethema

Therefore, quizartinib and gilteritinib are second-generation FLT3 inhibitors that are frequently applied for treating patients with AML. In conclusion, these findings suggest that second-generation FLT3 inhibitors can improve the overall survival of patients with AML. However, QTc prolongation is a potential adverse effect that should be monitored.

The patient achieved hematological CR on day 163 and remained in molecular CR 3 years after allo-HCT without adverse effects. Quizartinib combined with DLI may be a feasible treatment for early relapse of FLT3-ITD-positive AML after allo-HCT, even with concurrent DNMT3A and NPM1 mutations.

Notably, compound 49 demonstrated cytotoxic effects in Ba/F3 cells expressing FLT3-ITD or FLT3-ITD-F691L mutant, exceeding the potency of both sorafenib and quizartinib. The study suggests that substituted furo[2,3-d]pyrimidines could be useful additions to the growing field of FLT3-targeted therapy for AML. These compounds have the potential to serve as novel FLT3-ITD inhibitors and may offer insights for developing future therapeutic strategies in AML.

Polθ inhibitors enhanced the anti-leukemic effects of mainstream drugs such as FLT3 kinase inhibitor quizartinib, cytarabine and etoposide in vitro and in mice with FLT3(ITD);DNMT3Amut leukemia. Altogether, Polθ is an attractive target in DNMT3Amut hematological malignancies.

Inflammasome activation was also shown to strongly increase the likelihood of a poor ex vivo response to the FLT3 inhibitors quizartinib and sorafenib. These findings reveal a distinct molecular pattern within FLT3-ITD AML samples that underscores the necessity for further exploration into how approaching these supportive parallel yet altered pathways could improve therapeutic strategies.

The present study aimed to gain insights into the molecular interactions and affinity forces of four TKI drugs (sorafenib, midostaurin, gilteritinib and quizartinib) with the wild‑type (WT)‑FLT3 and ITD‑mutated (ITD‑FLT3) structural models of FLT3, in its inactive aspartic acid‑phenylalanine‑glycine motif (DFG‑out) and active aspartic acid‑phenylalanine‑glycine motif (DFG‑in) conformations. Thus, the current study presented novel information about molecular interactions between the FLT3 receptors (WT or ITD‑mutated) and some of their inhibitors. It also paves the way for the search for novel inhibitory molecules with potential use against AML.

"Invivoscribe is excited to announce that their CE-2797 IVD certified LeukoStrat CDx FLT3 Mutation Assay has been approved by BSI (Netherlands) and the EMA to aid in the selection of individuals in the European Union and European Economic Area with newly diagnosed FLT3-ITD positive acute myeloid leukemia (AML) who may be eligible to receive treatment with Daiichi Sankyo’s VANFLYTA (quizartinib)...In regions where XOSPATA (gilteritinib fumarate) is available, the LeukoStrat CDx FLT3 Mutation Assay is used as an aid in the assessment of patients with AML for whom XOSPATA (gilteritinib fumarate) treatment is being considered...In regions where VANFLYTA (quizartinib hydrochloride) is available, the LeukoStrat CDx FLT3 Mutation Assay is used as an aid in the assessment of patients with FLT3-ITD+ AML for whom VANFLYTA (quizartinib hydrochloride) treatment is being considered."

In Japan, alongside monotherapy with gilteritinib or quizartinib for relapsed/refractory patients, combination of quizartinib with intensive chemotherapy was approved in 2023 for untreated FLT3-ITD mutation-positive AML. Thus, FLT3 mutations are utilized not only as a prognostic factor in AML but also as a target for treatment and for response assessment. Furthermore, the development of new treatment strategies involving FLT3 inhibitors is highly anticipated to improve clinical outcomes for patients with FLT3 mutation-positive AML.

It has shown promise in clinical studies since 2013 due to its excellent oral absorption and potent activity on FLT3. This review explores Quizartinib's mechanism of action, efficacy in monotherapy or combination with chemotherapy, drug interactions, adverse events, resistance mechanisms and future research directions.

Since 2017, twelve agents have been approved for the treatment of AML subsets: the BCL2 inhibitor venetoclax; the CD33 antibody drug conjugate gemtuzumab ozogamicin; three FLT3 inhibitors (midostaurin, gilteritinib, quizartinib); three IDH inhibitors (ivosidenib and olutasidenib targeting IDH1 mutations; enasidenib targeting IDH2 mutations); two oral hypomethylating agents (oral poorly absorbable azacitidine; fully absorbable decitabine-cedazuridine [latter approved as an alternative to parenteral hypomethylating agents in myelodysplastic syndrome and chronic myelomonocytic leukemia but commonly used in AML]); and CPX-351 (encapsulated liposomal 5:1 molar ratio of cytarabine and daunorubicin), and glasdegib (hedgehog inhibitor)...To achieve optimal results in such a rare and heterogeneous entity as AML requires expertise, familiarity with this rare cancer, and the access to, and delivery of disparate therapies under rigorous supportive care conditions. In this review, we update the standard-of-care and investigational therapies and outline promising current and future research directions.

P1/2, N=8, Terminated, M.D. Anderson Cancer Center | Completed --> Terminated; This study was terminated early due to other competing trials, therefore did not go on to the Phase II portion of the study.

Hypomethylating agents like azacitidine and decitabine have shown promise in improving relapse-free and overall survival, particularly in older patients with AML ineligible for transplantation. Combination regimens involving azacitidine and venetoclax have demonstrated encouraging outcomes post-hematopoietic stem cell transplantation. Targeted therapies, particularly FLT3 inhibitors like midostaurin and quizartinib, have shown significant benefits in improving survival outcomes, especially in FLT3-mutated AML cases. Gilteritinib and sorafenib also exhibit the potential to reduce relapse rates post-transplant. Isocitrate dehydrogenase inhibitors, including ivosidenib and enasidenib, present novel options for postchemotherapy and posttransplantation maintenance...The approval of oral azacitidine represents a significant advancement, emphasizing the need for further investigation into personalized maintenance approaches. In conclusion, the evolving landscape of maintenance therapy and integrating targeted therapies in AML offers promising avenues for improving patient outcomes.

P3, N=700, Not yet recruiting, Daiichi Sankyo

Dobutamine as a monotherapy can inhibit theproliferation of FLT3-ITD mutated AML cells, inducing apoptosis. Additionally, the combination of quizartinib enhances the targeted inhibitory effect on FLT3-ITD mutated AML. The mechanism may involve the inhibition of YAP1 protein expression in AML cells of this type, leading to an increase in ROS levels and exerting its anti-tumor effects.

Since then, the understanding of the molecular pathogenesis of AML has expanded, allowing the identification of additional potential targets for drug therapy, treatment incorporation of molecularly targeted therapies (midostaurin, gilteritinib, and quizartinib targeting FLT3 variants; ivosidenib and olutasidenib targeting IDH1 variants, and enasidenib targeting IDH2), and identification of rational combination regimens. The approval of hypomethylating agents combined with venetoclax has revolutionized the therapy of AML in older adults, extending survival over monotherapy. Additionally, patients are now referred for hematopoietic cell transplant on a more rational basis. In the era of genomic medicine, AML treatment is customized to the patient's comorbidities and AML genomic profile.

These findings establish the sphingolipid metabolic enzyme SPHK1 as a regulator of TKI sensitivity and suggest that combining SPHK1 inhibition with TKIs could be an effective approach for treating FLT3-mutated AML.

In Japan, the combination of quizartinib and intensive chemotherapy for untreated FLT3-ITD-positive AML was approved in 2023...Meanwhile, various resistance mechanisms to FLT3 inhibitors have been identified, including the emergence of resistance-associated mutations, and attenuated inhibitory effects of FLT3 inhibitors involving the bone marrow microenvironment surrounding AML cells. Thus, future efforts should aim to optimize combination therapy based on the characteristics of each FLT3 inhibitor, develop biomarkers that could inform treatment selection, and to better understand these resistance mechanisms and develop methods for overcoming them.