Effects of quizartinib: A Synthesis of Findings from 22 Studies

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Original Abstract of the Article

Major findings

Quizartinib is an effective treatment for patients with FLT3-ITD acute myeloid leukemia (AML). 16 . Quizartinib inhibits the activity of the FLT3 gene, leading to tumor cell death. 16 . Quizartinib has been shown to be effective in treating patients with relapsed or refractory AML with an FLT3-ITD mutation. 16 . Quizartinib has received US Food and Drug Administration breakthrough therapy designation for patients with relapsed/refractory FLT3-ITD AML. 16 . Quizartinib has potential to be a promising treatment option for AML patients, especially those with FLT3-ITD mutations. 16 . The FLT3/ITD mutation can lead to constitutive autophosphorylation of FLT3 and activation of downstream effectors, including RAS/RAF/MEK, MAPK/ERK, PI3K/AKT/mTOR and JAK/STAT5 signaling pathways. 16 . Quizartinib can specifically inhibit these downstream pathways by inhibiting FLT3. 16 . Quizartinib exhibits high selectivity for FLT3 compared to other kinase inhibitors. 13 . Quizartinib is highly active against mutant FLT3 such as FLT3-ITD and FLT3-D835Y compared to other kinase inhibitors. 13 . Quizartinib inhibits the proliferation of FLT3-ITD positive AML cells. 14 . Quizartinib induces apoptosis in FLT3-ITD positive AML cells. 14 . Quizartinib is attracting attention as a new treatment option for AML. 9 . Quizartinib may enhance the efficacy of AML treatment when combined with existing chemotherapy drugs. 2 . Quizartinib is expected to be used in combination with chemotherapy in the treatment of newly diagnosed AML patients. 2 . Quizartinib shows strong growth inhibitory effects on FLT3-ITD positive AML cells. 8 . Quizartinib demonstrates sustained FLT3 inhibition in FLT3-ITD positive AML cells. 8 . Quizartinib is expected to be a promising agent for the treatment of patients with AML with FLT3 mutations. 8 . Quizartinib induces cell cycle arrest at G0/G1 phase, and induces apoptosis and necrosis. 22 . Quizartinib demonstrates selective antiproliferative activity against FLT3-ITD positive AML cell lines. 22 . Quizartinib has no cytotoxic effects on normal cells. 22 . Quizartinib could be an effective and safe drug for the treatment of AML. 22 . Quizartinib is effective in treating AML with FLT3 mutations, but resistance mutations have been reported. 8 . Quizartinib may overcome resistance when combined with other agents. 20 . Quizartinib may enhance the efficacy of AML treatment when combined with other agents. 3 . Quizartinib may enhance the efficacy of AML treatment when combined with CXCR4 inhibitors. 3 . Quizartinib is being investigated for use in combination with other agents to overcome resistance in the bone marrow microenvironment. 20 . Quizartinib may enhance the efficacy of AML treatment when combined with other agents. 17 . Quizartinib may enhance the efficacy of AML treatment when combined with other agents. 7 . Quizartinib may enhance the efficacy of AML treatment when combined with autophagy inhibitors. 7 .

Benefits and risks

Benefit summary

Quizartinib has been shown to be an effective treatment for patients with FLT3-ITD mutated AML by inhibiting tumor cell growth and inducing apoptosis in multiple clinical trials. 16 . Quizartinib exhibits strong growth inhibitory effects on FLT3-ITD positive AML cells. 8 . Quizartinib may enhance the efficacy of AML treatment when combined with existing chemotherapy drugs. 2 . Quizartinib may enhance the efficacy of AML treatment when combined with other agents. 3 . Quizartinib may enhance the efficacy of AML treatment when combined with autophagy inhibitors. 7 . Quizartinib has no cytotoxic effects on normal cells. 22 . Quizartinib could be an effective and safe drug for the treatment of AML. 22 . Quizartinib is effective in treating AML with FLT3 mutations, but resistance mutations have been reported. 8 . Quizartinib may overcome resistance when combined with other agents. 20 . Quizartinib may enhance the efficacy of AML treatment when combined with other agents. 3 . Quizartinib is being investigated for use in combination with other agents to overcome resistance in the bone marrow microenvironment. 20 . Quizartinib may enhance the efficacy of AML treatment when combined with other agents. 17 . Quizartinib may enhance the efficacy of AML treatment when combined with autophagy inhibitors. 7 .

Risk summary

Quizartinib is effective in treating AML with FLT3 mutations, but side effects have been reported. 4 . Quizartinib may cause skin cancer, so caution is needed when using it. 4 . Quizartinib should be used at the appropriate dose, paying attention to the occurrence of side effects. 13 . Quizartinib is effective in treating AML with FLT3 mutations, but side effects have been reported. 18 . Quizartinib may prolong the QT interval. 2 . Quizartinib should be used with caution when combined with CYP3A4 inhibitors. 1 . Resistance mutations have been reported. 8 .

Comparison between studies

Commonalities between studies

Multiple studies have shown that Quizartinib is an effective treatment for patients with FLT3-ITD mutated AML. 16 . Quizartinib has been shown to inhibit the growth of FLT3-ITD positive AML cells and to induce apoptosis. 14 . Quizartinib exhibits high selectivity for FLT3 compared to other kinase inhibitors. 13 . Quizartinib may enhance the efficacy of AML treatment when combined with existing chemotherapy drugs. 2 . Quizartinib may enhance the efficacy of AML treatment when combined with other agents. 3 . Quizartinib may enhance the efficacy of AML treatment when combined with autophagy inhibitors. 7 .

Differences between studies

The administration method and dosage of Quizartinib vary across studies. 2 . The side effects of Quizartinib also vary across studies. 4 . Different studies report different results regarding the mechanism of resistance to Quizartinib. 8 .

Consistency and inconsistency of results

Multiple studies have shown that Quizartinib is an effective treatment for patients with FLT3-ITD mutated AML. 16 . However, different studies have reported different results regarding the side effects and mechanism of resistance to Quizartinib. 4 , 8 . Further research is needed to address these inconsistencies.

Considerations for application in real life

Quizartinib has been shown to be an effective treatment for patients with FLT3-ITD mutated AML. 16 . However, Quizartinib carries the risk of side effects and resistance mutations, so it is important to use it at the appropriate dose and under the guidance of a physician. 4 , 8 . Consult your physician about the side effects and resistance mutations associated with Quizartinib before using it.

Limitations of current research

Research on the side effects and mechanism of resistance to Quizartinib is still insufficient. 4 , 8 . Further research is needed to determine the optimal administration method and dosage of Quizartinib. 2 .

Future research directions

Further research on the side effects and mechanism of resistance to Quizartinib is needed. 4 , 8 . Research is needed to optimize the administration method and dosage of Quizartinib. 2 . Further research should investigate whether Quizartinib can enhance the efficacy of AML treatment when combined with other agents. 3 .

Conclusion

Quizartinib has been shown to be an effective treatment for patients with FLT3-ITD mutated AML in multiple clinical trials. 16 . However, Quizartinib carries the risk of side effects and resistance mutations, so it is important to use it at the appropriate dose and under the guidance of a physician. 4 , 8 . Consult your physician about the side effects and resistance mutations associated with Quizartinib before using it.

Literature analysis of 22 papers
Positive Content
22
Neutral Content
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Negative Content
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22
1.

Drug-drug interactions of newly approved small molecule inhibitors for acute myeloid leukemia.

Author: Megías-VericatJuan Eduardo, Solana-AltabellaAntonio, Ballesta-LópezOctavio, Martínez-CuadrónDavid, MontesinosPau

Drug-drug interactions
QTc prolongation

This systematic review analyzes drug-drug interactions (DDIs) of small molecule inhibitors (SMIs) recently approved for treating acute myeloid leukemia (AML). The review highlights the importance of managing DDIs due to the frequent use of multiple medications in AML patients. The most concerning interactions involve CYP3A4 inhibitors, which can increase SMI exposure and toxicity, and CYP3A4 inducers, which can decrease SMI efficacy.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

2.

Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia.

Author: AltmanJessica K, ForanJames M, PratzKeith W, TroneDenise, CortesJorge E, TallmanMartin S

AML treatment
QT prolongation

This study evaluated the safety and tolerability of quizartinib, a FLT3 inhibitor, in combination with standard of care chemotherapy in patients with newly diagnosed acute myeloid leukemia (AML).

Clinical Trial, Phase IThe first stage of clinical trials in humans. Evaluates the safety, tolerability, and pharmacokinetics of a new drug/treatment.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

4.

Eruption of squamous cell carcinomas after beginning nilotinib therapy.

Author: CrainCaroline B, WinsettFrank T, WoolridgeKatelyn F, WilsonJanice M, GoodwinBrandon P

CML treatment
SCC development

This case report describes a patient with chronic myelogenous leukemia who developed multiple squamous cell carcinomas (SCCs) after beginning treatment with nilotinib, a tyrosine kinase inhibitor. The authors highlight the potential for nilotinib to cause eruptive SCCs and recommend close monitoring by a dermatologist.

Case ReportsIn the medical field, a report that describes in detail a unique case, an unusual medical condition, or the effect of a treatment. Provides new insights and possibilities for treatment through individual patient cases.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

5.

Quizartinib inhibits necroptosis by targeting receptor-interacting serine/threonine protein kinase 1.

Author: LiMin, WeiJun, ZhuGuofeng, FuShufang, HeXiaoyan, HuXinqian, YuYajie, MouYan, WangJia, YouXiaoling, XiaoXin, GuTanrong, YeZhi, ZhaYunhong

Necroptosis inhibition
SIRS treatment

This study identified quizartinib, an FDA-approved drug, as an effective inhibitor of necroptosis, a form of cell death contributing to systemic inflammatory response syndrome (SIRS). Quizartinib directly inhibits RIPK1 kinase activity and protects mice against TNFα-induced SIRS, suggesting its potential for repurposing as a treatment for RIPK1-dependent inflammatory diseases.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

6.

FMS-Like Tyrosine Kinase 3 Inhibitors for the Treatment of Acute Myeloid Leukemia.

Author: NovatchevaElli D, AnoutyYasmine, SaundersIla, ManganJames K, GoodmanAaron M

AML treatment
FLT3 inhibitors
Clinical toxicities
Drug interactions

This review summarizes the clinical evidence for five FLT3 inhibitors (midostaurin, sorafenib, gilteritinib, crenolanib, and quizartinib) used to treat FLT3-positive acute myeloid leukemia (AML). The review discusses the clinical trials, similarities and differences between the drugs, clinical toxicities, and drug interactions relevant to treating clinicians.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

7.

Selective Inhibitors of Autophagy Reveal New Link between the Cell Cycle and Autophagy and Lead to Discovery of Novel Synergistic Drug Combinations.

Author: SungKisa, KurowskiAgata, LansiquotCarisse, WanKanny K, PatnaikSamarjit, WalshMartin J, LazarusMichael B

Cancer treatment
Unknown

This study investigates the inhibition of autophagy in pancreatic cancer cells using selective small molecule inhibitors. The findings reveal that blocking autophagy inhibits cell replication and activates other metabolic pathways to compensate. The study also identifies drug combinations that may be effective in treating pancreatic cancer, such as quizartinib and THZ1.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, N.I.H., ExtramuralResearch funding provided by the NIH to external research institutions and researchers.

Language : English

8.

A novel irreversible FLT3 inhibitor, FF-10101, shows excellent efficacy against AML cells with <i>FLT3</i> mutations.

Author: YamauraTakeshi, NakataniToshiyuki, UdaKen, OguraHayato, ShinWigyon, KurokawaNaoya, SaitoKoichi, FujikawaNorie, DateTomomi, TakasakiMasaru, TeradaDaisuke, HiraiAtsushi, AkashiAkimi, ChenFangli, AdachiYoshiya, IshikawaYuichi, HayakawaFumihiko, HagiwaraShinji, NaoeTomoki, KiyoiHitoshi

Selective and irreversible FLT3 inhibition

FLT3 mutations are associated with poor prognosis in acute myeloid leukemia (AML). This study developed a novel FLT3 inhibitor, FF-10101, designed to possess selective and irreversible FLT3 inhibition. FF-10101 showed potent growth inhibitory effects on AML cell lines harboring FLT3 mutations, including those resistant to quizartinib.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

9.

Quizartinib for the treatment of acute myeloid leukemia.

Author: Garcia-HortonAlejandro, YeeKaren Wl

Improved OS
Improved remission rates

Acute myeloid leukemia (AML) is a type of blood cancer. FLT3 mutations are present in about 30% of patients with AML. Targeted therapies, such as FLT3 inhibitors, are changing the way AML is treated and improving patient outcomes, including survival rates and remission rates.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

10.

FLT3 Inhibition in Acute Myeloid Leukaemia - Current Knowledge and Future Prospects.

Author: HoganFrancesca L, WilliamsVictoria, KnapperSteven

FLT3 inhibition
FLT3-mutated AML treatment
Drug resistance

FLT3 mutations are found in 30% of acute myeloid leukemia patients and lead to a worse prognosis. Several drugs targeting FLT3 have been developed, with two recently approved for treatment. These drugs show promise but face challenges like resistance development. This review discusses the biology of FLT3, the challenges of treating FLT3-mutated AML, and the future outlook for FLT3-inhibiting drugs.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

11.

Antifungal prophylaxis in adult patients with acute myeloid leukaemia treated with novel targeted therapies: a systematic review and expert consensus recommendation from the European Hematology Association.

Author: StemlerJannik, de JongeNick, SkoetzNicole, SinkóJános, BrüggemannRoger J, BuscaAlessandro, Ben-AmiRonen, RáčilZdeněk, PiechottaVanessa, LewisRussell, CornelyOliver A

Invasive fungal disease prevention
Survival improvement
Adverse effects

Antifungal prophylaxis during remission induction chemotherapy is recommended for patients with acute myeloid leukemia. Many novel targeted agents are metabolized by cytochrome P450, leading to uncertainty about potential drug-drug interactions (DDIs) and their risk-benefit ratio. This study provides recommendations on the role of antifungal prophylaxis and the management of pharmacokinetic DDIs with triazole antifungals, based on a systematic literature review. Antifungal prophylaxis is moderately recommended in most settings and strongly recommended if the novel acute myeloid leukemia agent is administered in combination with intensive induction chemotherapy. For ivosidenib, lestaurtinib, quizartinib, and venetoclax, we moderately recommend adjusting the dose of the antileukaemic agent during administration of triazoles. Future studies are needed to determine the role of dosage adjustment of novel antileukaemic drugs during concomitant administration of CYP3A4-inhibiting antifungals.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.
Systematic ReviewA review that systematically collects, evaluates, and integrates relevant research to answer a specific research question.

Language : English

12.

Advancing treatment of acute myeloid leukemia: the future of FLT3 inhibitors.

Author: ElshouryAmro, PrzespolewskiAmanda, BaronJeffrey, WangEunice S

AML treatment

FLT3 mutations are a common and negative prognostic factor in acute myeloid leukemia (AML). While first-generation FLT3 inhibitors had limited success, second-generation inhibitors, such as quizartinib, crenolinib, and gilteritinib, have shown high potency and specificity for mutant FLT3 kinases. These newer inhibitors offer diverse kinase inhibitory properties, toxicity profiles, and pharmacokinetics, which must be considered when developing treatment plans. The integration of FLT3 inhibitors into AML treatment promises to significantly improve outcomes.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, N.I.H., ExtramuralResearch funding provided by the NIH to external research institutions and researchers.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

13.

Comparison of effects of midostaurin, crenolanib, quizartinib, gilteritinib, sorafenib and BLU-285 on oncogenic mutants of KIT, CBL and FLT3 in haematological malignancies.

Author: WeisbergEllen, MengChengcheng, CaseAbigail E, SattlerMartin, TivHong L, GokhalePrafulla C, BuhrlageSara J, LiuXiaoxi, YangJing, WangJinhua, GrayNathanael, StoneRichard M, AdamiaSophia, DubreuilPatrice, LetardSebastien, GriffinJames D

AML treatment
SM treatment

This article compares the in vitro activities of clinically available FLT3 and KIT inhibitors against cells expressing a variety of oncogenic FLT3 or KIT receptors, including wild-type (wt) FLT3, FLT3-internal tandem duplication (ITD), FLT3 D835Y, the resistance mutant FLT3-ITD+ F691L, KIT D816V, and KIT N822K. The results show a wide spectrum of activity of these various mutations to these clinically available TKIs.

Comparative StudyResearch that compares multiple groups/interventions to determine differences/similarities in outcomes/characteristics.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

15.

Discovery and development of extreme selective inhibitors of the ITD and D835Y mutant FLT3 kinases.

Author: BaskaFerenc, SiposAnna, ŐrfiZoltán, NemesZoltán, DobosJudit, Szántai-KisCsaba, SzabóEszter, SzénásiGábor, DézsiLászló, HamarPéter, CserepesMihály T, TóváriJózsef, GaramvölgyiRita, KrekóMarcell, ŐrfiLászló

FLT3 inhibition
apoptosis induction
drug resistance

This study identified a novel family of (phenylethenyl)quinazoline compounds as potent and selective inhibitors of FLT3-ITD and FLT3-D835Y kinases. These compounds showed significant anti-leukemic activity in FLT3-ITD AML cells and may be effective against drug-resistant AML.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

16.

Quizartinib (AC220): a promising option for acute myeloid leukemia.

Author: ZhouFang, GeZheng, ChenBaoan

AML treatment

Quizartinib is an effective therapy for patients with FLT3-ITD acute myeloid leukemia (AML) by inhibiting the activity of the FLT3 gene. This review summarizes the characteristics of FLT3/ITD mutations, the mechanism and pharmacokinetics of quizartinib, and the mechanisms of resistance to the drug. The review also discusses clinical experiences and adverse effects associated with quizartinib.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

17.

The magnitude of CXCR4 signaling regulates resistance to quizartinib in FLT3/ITD<sup>+</sup> cells via RUNX1.

Author: FukudaSeiji, MatsudaNozomi, ShojiTsukimi, OnishiChie, HiradeTomohiro, TaketaniTakeshi, PelusLouis M

FLT3 inhibitor sensitivity
Apoptosis in AML cells

CXCR4 antagonists sensitize FLT3/ITD<sup>+</sup> AML cells to FLT3 inhibitors, but CXCR4 signaling can also induce apoptosis in AML cells. This study investigates the paradoxical function of CXCR4 in resistance to FLT3 inhibitors. The findings suggest that CXCR4 signaling of different magnitudes paradoxically regulates resistance to quizartinib in FLT3/ITD<sup>+</sup> cells via RUNX1.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

18.

The safety profile of FLT3 inhibitors in the treatment of newly diagnosed or relapsed/refractory acute myeloid leukemia.

Author: MarconiGiovanni, GianniniMaria Benedetta, BagnatoGianmarco, SimonettiGiorgia, CerchioneClaudio, Mosquera OrgueiraAdrián, MusuracaGerardo, MartinelliGiovanni

Effective for FLT3-positive AML

FLT3 inhibitors are essential drugs in the treatment of FLT3-positive acute myeloid leukemia (AML). This review discusses the approved FLT3 inhibitors, midostaurin, gilteritinib, and quizartinib, and the promising FLT3 inhibitors currently in clinical research.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

20.

Dasatinib overcomes stroma-based resistance to the FLT3 inhibitor quizartinib using multiple mechanisms.

Author: PatelAmi B, PomicterAnthony D, YanDongqing, EiringAnna M, AntelopeOrlando, SchumacherJonathan A, KelleyTodd W, TantravahiSrinivas K, KovacsovicsTibor J, ShamiPaul J, O'HareThomas, DeiningerMichael W

Combination therapy
FLT3 inhibition

FLT3-ITD mutations are associated with aggressive AML and can lead to resistance to FLT3 inhibitors. This study found that bone marrow microenvironment contributes to resistance and that combining quizartinib with dasatinib might overcome this resistance.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, N.I.H., ExtramuralResearch funding provided by the NIH to external research institutions and researchers.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

21.

Acute myeloid leukemia transformed to a targetable disease.

Author: SalehKhalil, Khalifeh-SalehNadine, KourieHampig Raphael

AML treatment
Targeted therapies

Acute myeloid leukemia (AML) is now considered a targetable disease with several new drugs approved. Gemtuzumab ozogamicin targets CD33+ AML, while midostaurin, gilteritinib, and crenolanib inhibit FLT3-positive AML. Ivosidenib and enasidenib are effective against IDH-mutated AML. These drugs have significantly changed the landscape of AML treatment.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

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