^
1d
Discovery of IRAK1/4/pan-FLT3 Kinase Inhibitors as Treatments for Acute Myeloid Leukemia. (PubMed, ACS Med Chem Lett)
Optimization of this series has produced compound 31 which displays potent and selective inhibition of IRAK1, IRAK4, FLT3, and all mutant forms of FLT3, as well as good in vitro ADME and pharmacokinetic properties. In a mouse xenograft model of AML, 31 produces survival prolongation equal to that of Gilteritinib, the leading marketed FLT3 inhibitor currently used to treat AML.
Journal
|
FLT3 (Fms-related tyrosine kinase 3) • IRAK1 (Interleukin 1 Receptor Associated Kinase 1) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
|
FLT3 mutation
|
Xospata (gilteritinib)
1d
New P2 trial • Combination therapy
|
Venclexta (venetoclax) • Xospata (gilteritinib) • azacitidine
4d
A Study to Assess the Safety of Xospata in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-Like Tyrosine Kinase 3 (FLT3) Mutation (clinicaltrials.gov)
P=N/A, N=33, Active, not recruiting, Astellas Pharma Korea, Inc. | Recruiting --> Active, not recruiting | N=20 --> 33
Enrollment closed • Enrollment change
|
Xospata (gilteritinib)
7d
The Immunomodulatory Effect of Different FLT3 Inhibitors on Dendritic Cells. (PubMed, Cancers (Basel))
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.
Journal • Immunomodulating
|
FLT3 (Fms-related tyrosine kinase 3) • IL6 (Interleukin 6) • TNFA (Tumor Necrosis Factor-Alpha) • CD86 (CD86 Molecule)
|
FLT3 mutation • FLT3 positive
|
Xospata (gilteritinib) • Rydapt (midostaurin) • Vanflyta (quizartinib)
15d
A phase 1/2 study of gilteritinib in combination with chemotherapy in newly diagnosed patients with AML in Asia. (PubMed, Int J Hematol)
In this interim analysis, gilteritinib 120 mg/day in combination with chemotherapy was well tolerated, with similar CRc rates to previous studies.
P1/2 data • Journal • Combination therapy
|
FLT3 (Fms-related tyrosine kinase 3)
|
FLT3 mutation
|
cytarabine • Xospata (gilteritinib) • idarubicin hydrochloride
16d
T/NK Cell-Associated Transcriptomic Profile Informs Response to FLT3 Inhibitors in Acute Myeloid Leukemia (ASH 2024)
We then profiled a wet-lab cohort of 37 FLT3-mut AML patients treated either with Midostaurin plus chemotherapy (M) or Gilteritinib (G) at Bologna Hematology Institute by using the PanCancer IO 360 Panel (NanoString Technologies, San Diego, CA). This study provides evidence that FLT3 mutational status is associated with a unique T-cell activation profile and AML maturation state, and that T/NK cell-associated genes correlate with response to FLT3i. Our RNA metric of FLT3 mutational status could be utilized to refine patient stratification in future clinical trials. S.R.
FLT3 (Fms-related tyrosine kinase 3) • CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule) • GLI2 (GLI Family Zinc Finger 2)
|
FLT3 mutation
|
nCounter® PanCancer IO 360™ Panel
|
Xospata (gilteritinib) • Rydapt (midostaurin)
22d
New P2 trial • Combination therapy
|
cytarabine • Xospata (gilteritinib) • idarubicin hydrochloride • fludarabine IV
22d
Efficacy and safety of second‑generation FLT3 inhibitors in acute myeloid leukemia: A systematic review and meta‑analysis of randomized controlled trials. (PubMed, Mol Clin Oncol)
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.
Retrospective data • Review • Journal
|
FLT3 (Fms-related tyrosine kinase 3)
|
Xospata (gilteritinib) • Vanflyta (quizartinib)
23d
Gilteritinib-Induced Hypopituitarism: A Case Report. (PubMed, Cureus)
After 10 months of gilteritinib withdrawal, the levels of anterior pituitary hormones returned to normal values. When nonspecific symptoms such as fatigue in patients treated with gilteritinib are coupled with electrolyte abnormalities, a close checkup for hypopituitarism is recommended.
Journal
|
FLT3 (Fms-related tyrosine kinase 3)
|
Xospata (gilteritinib)
23d
Gilteritinib reverses ABCB1-mediated multidrug resistance: Preclinical in vitro and animal investigations. (PubMed, Biomed Pharmacother)
In vivo studies have shown that gilteritinib improves the antitumor efficacy of paclitaxel in nude mice without obvious toxic effects. In conclusion, our preclinical investigations show that gilteritinib has the potential to successfully overcome ABCB1-mediated MDR in a clinical environment when combined with substrate medicines.
Preclinical • Journal
|
FLT3 (Fms-related tyrosine kinase 3) • ABCB1 (ATP Binding Cassette Subfamily B Member 1)
|
ABCB1 overexpression • ABCB1 expression
|
paclitaxel • Xospata (gilteritinib)
1m
Trial completion • Combination therapy
|
FLT3 (Fms-related tyrosine kinase 3)
|
FLT3-ITD mutation
|
cytarabine • Xospata (gilteritinib) • idarubicin hydrochloride
1m
In silico and in vitro study of FLT3 inhibitors and their application in acute myeloid leukemia. (PubMed, Mol Med Rep)
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.
Preclinical • Journal
|
FLT3 (Fms-related tyrosine kinase 3)
|
FLT3 mutation • FLT3 wild-type
|
sorafenib • Xospata (gilteritinib) • Rydapt (midostaurin) • Vanflyta (quizartinib)
2ms
EU Notified Body (BSI Netherlands) and the EMA Grant Approval of the LeukoStrat CDx FLT3 Mutation Assay for VANFLYTA Therapy in the EU and EEA (Businesswire)
"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."
European regulatory
|
LeukoStrat® CDx FLT3 Mutation Assay
|
Xospata (gilteritinib) • Vanflyta (quizartinib)
2ms
Enrollment open
|
FLT3 (Fms-related tyrosine kinase 3)
|
FLT3 mutation • CBL mutation
|
Venclexta (venetoclax) • Xospata (gilteritinib)
2ms
Pathogenesis and treatment of acute myeloid leukemia with FLT3 mutations (PubMed, Rinsho Ketsueki)
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.
Journal
|
FLT3 (Fms-related tyrosine kinase 3)
|
FLT3-ITD mutation • FLT3 mutation
|
Xospata (gilteritinib) • Vanflyta (quizartinib)
2ms
Phosphoproteomic subtyping of gastric cancer reveals dynamic transformation with chemotherapy and guides targeted cancer treatment. (PubMed, Cell Rep)
We present our investigation of intracellular signaling related to the EMT in gastric cancer and propose therapeutic approaches targeting AXL. This study also provides a wealth of resources for the future development of treatments and biomarkers for AGC.
Journal
|
AXL (AXL Receptor Tyrosine Kinase)
|
Xospata (gilteritinib)
2ms
Cholesterol inhibition enhances antitumor response of gilteritinib in lung cancer cells. (PubMed, Cell Death Dis)
In a xenograft model, the combination of gilteritinib and 25HC showed significantly better efficacy than either monotherapy in suppressing lung cancer growth, without obvious general toxicity. Thus, our findings identify an increase in cholesterol induced by gilteritinib as a mechanism for LCC survival, and highlight the potential of combining gilteritinib with cholesterol-lowering drugs to treat lung cancer.
Journal
|
FLT3 (Fms-related tyrosine kinase 3)
|
FLT3 mutation
|
Xospata (gilteritinib)
2ms
Tracking Response and Resistance in Acute Myeloid Leukemia through Single-Cell DNA Sequencing Helps Uncover New Therapeutic Targets. (PubMed, Int J Mol Sci)
For Pt #1, disease resistance was associated with clonal expansion of minor clones, and 2nd line TKI therapy with gilteritinib provided a proliferative advantage to the clones carrying NRAS and KIT mutations, thereby responsible for relapse. In Pt #2, clonal architecture was less complex, and 1st line TKI therapy with midostaurin was able to eradicate the leukemic clones. Our results corroborate previous findings about clonal selection driven by TKIs, highlighting the importance of a deeper characterization of individual clonal architectures for choosing the best treatment plan for personalized approaches aimed at optimizing outcomes.
Journal
|
FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • KIT (KIT proto-oncogene, receptor tyrosine kinase)
|
NRAS mutation • FLT3 mutation • KIT mutation
|
Xospata (gilteritinib) • Rydapt (midostaurin)
2ms
Current status and research directions in acute myeloid leukemia. (PubMed, Blood Cancer J)
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.
Review • Journal • IO biomarker
|
FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • CD123 (Interleukin 3 Receptor Subunit Alpha) • CD33 (CD33 Molecule) • IL3RA (Interleukin 3 Receptor Subunit Alpha)
|
IDH1 mutation • IDH2 mutation
|
Venclexta (venetoclax) • Xospata (gilteritinib) • azacitidine • Rydapt (midostaurin) • Vanflyta (quizartinib) • Tibsovo (ivosidenib) • Mylotarg (gemtuzumab ozogamicin) • Vyxeos (cytarabine/daunorubicin liposomal formulation) • Idhifa (enasidenib) • Inqovi (decitabine/cedazuridine) • Rezlidhia (olutasidenib) • Daurismo (glasdegib)
2ms
Trial completion date
|
FLT3 (Fms-related tyrosine kinase 3)
|
FLT3-ITD mutation • FLT3 mutation • FLT3 D835 • FLT3 I836
|
cytarabine • Xospata (gilteritinib) • azacitidine • etoposide IV • idarubicin hydrochloride • mitoxantrone • fludarabine IV
2ms
FLT3 MUTATIONAL STATUS IS ASSOCIATED WITH DIFFERENCES IN ACUTE MYELOID LEUKEMIA IMMUNE TRANSCRIPTOMIC PROFILE IMPACTING ON RESPONSE TO FLT3 INHIBITORS (SIE 2024)
We then screened a cohort of FLT3-mut AML patients treated either with Midostaurin plus chemotherapy (M) or Gilteritinib (G) at Bologna Hematology Institute by using the PanCancer IO 360 Panel (NanoS-tring GEA). This study highlights how FLT3 mutational status is associated with T-Cell activation and AML maturation state. Differences in immune transcriptomic profile impact on FLT3i response.
FLT3 (Fms-related tyrosine kinase 3) • CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule) • GLI2 (GLI Family Zinc Finger 2)
|
FLT3 mutation • CD8 expression
|
nCounter® PanCancer IO 360™ Panel
|
Xospata (gilteritinib) • Rydapt (midostaurin)
2ms
Enhancing Therapeutic Efficacy of FLT3 Inhibitors with Combination Therapy for Treatment of Acute Myeloid Leukemia. (PubMed, Int J Mol Sci)
The advent of FLT3 tyrosine kinase inhibitors (TKIs), such as midostaurin and gilteritinib, has shown promise in achieving complete remission. Specifically, we provide evidence for integrating gilteritinib with mammalian targets of rapamycin (mTOR) inhibitors and interleukin-15 (IL-15) complexes. The combination of gilteritinib, mTOR inhibitors, and IL-15 complexes presents a compelling strategy to enhance the eradication of AML blasts and enhance NK cell killing, offering a potential for improved patient outcomes.
Review • Journal • Combination therapy
|
FLT3 (Fms-related tyrosine kinase 3) • IL15 (Interleukin 15)
|
FLT3 mutation
|
Xospata (gilteritinib) • Rydapt (midostaurin) • sirolimus
2ms
Simultaneous inhibition of FLT3 and HDAC by novel 6-ethylpyrazine-2-Carboxamide derivatives provides therapeutic advantages in acute myelocytic leukemia. (PubMed, Eur J Med Chem)
In this study, we first observed that the combined use of FLT3 inhibitor gilteritinib and HDAC inhibitor vorinostat increased the survival rate of leukemia xenograft mouse model. Furthermore, compound 25h demonstrated superior anti-tumor efficacy in the MOLM-13 xenograft model compared to combination therapy, along with reduced in vivo toxicity. To conclude, we have identified a novel FLT3/HDAC dual inhibitor that could serve as a potential candidate for the treatment of AML.
Journal
|
FLT3 (Fms-related tyrosine kinase 3)
|
FLT3 mutation
|
Xospata (gilteritinib) • Zolinza (vorinostat)
2ms
Outcomes with single-agent gilteritinib for relapsed or refractory FLT3-mutant AML after contemporary induction therapy. (PubMed, Blood Adv)
Gilteritinib is the current standard of care for relapsed or refractory FLT3-mutated AML in many countries, however outcomes for patients relapsing after contemporary first-line therapies (intensive chemotherapy with midostaurin, or non-intensive chemotherapy with venetoclax) are uncertain. Twenty patients received gilteritinib as first salvage having progressed following first-line therapy with venetoclax, with CR/CRi achieved in 25% and median survival 4.5 months. Real-world results with gilteritinib mirror those seen in the clinical trials but outcomes remain suboptimal, with more effective strategies needed.
Journal
|
FLT3 (Fms-related tyrosine kinase 3) • RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A)
|
FLT3 mutation • RUNX1 mutation • KMT2A rearrangement • MLL rearrangement
|
Venclexta (venetoclax) • Xospata (gilteritinib) • Rydapt (midostaurin)
2ms
Long-term remissions with Gilteritinib in early relapse after allogeneic stem cell transplantation of FLT3/NPM1 mutated acute myeloid leukemia. (PubMed, Blood Cell Ther)
Thus, FLT-3 inhibitors may be viable treatment options in this setting. Here, we report three patients with FLT3 and NPM1 mutated AML who relapsed early after allo-HSCT and were treated with gilteritinib (associated with donor lymphocyte Infusion in two patients) to achieve long-term remission without a second transplantation.
Journal
|
FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1)
|
NPM1 mutation • FLT3 mutation + NPM1 mutation
|
Xospata (gilteritinib)
2ms
Complete morphologic response to gilteritinib in ALK-rearranged acute myeloid leukemia. (PubMed, NPJ Precis Oncol)
Additionally, this demonstrates that gilteritinib is clinically active as an ALK inhibitor, and could be considered for use in any AML patient presenting with an inv(2(p23q13)) translocation. Finally, it is an example of using a disease-agnostic, precision medicine approach to arrive at a beneficial treatment.
Journal
|
ALK (Anaplastic lymphoma kinase) • FLT3 (Fms-related tyrosine kinase 3) • RANBP2 (RAN Binding Protein 2) • DDX41 (DEAD-Box Helicase 41)
|
ALK positive • ALK rearrangement • ALK fusion • DDX41 mutation
|
Xospata (gilteritinib)
3ms
Maintenance Therapy in Acute Myeloid Leukemia. (PubMed, Am J Clin Oncol)
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.
Journal • IO biomarker
|
FLT3 (Fms-related tyrosine kinase 3) • WT1 (WT1 Transcription Factor)
|
FLT3 mutation
|
Venclexta (venetoclax) • sorafenib • Xospata (gilteritinib) • Rydapt (midostaurin) • Vanflyta (quizartinib) • decitabine • Tibsovo (ivosidenib) • Idhifa (enasidenib) • Onureg (azacitidine oral)
3ms
Phase 3 study of gilteritinib versus salvage chemotherapy in predominantly Asian patients with relapsed/refractory FLT3-mutated acute myeloid leukemia. (PubMed, Leukemia)
Gilteritinib plasma concentration peaked ~4 h postdose; ~3-fold accumulation occurred with multiple dosing. The COMMODORE trial demonstrated that gilteritinib significantly improved OS and EFS in predominantly Asian patients, validating the outcomes of gilteritinib from the ADMIRAL trial in R/R FLT3mut+ AML.
P3 data • Journal
|
FLT3 (Fms-related tyrosine kinase 3)
|
FLT3 mutation
|
Xospata (gilteritinib)
3ms
Lipopolymer/siRNA Complexes Engineered for Optimal Molecular and Functional Response with Chemotherapy in FLT3-Mutated Acute Myeloid Leukemia. (PubMed, Acta Biomater)
The effect of combining lipopolymer/siFLT3 complexes with daunorubucin and FLT3 targeting TKI gilteritinib led to a significant augmentation of anti-leukemic activity...Cellular and molecular responses to siRNA treatment have been characterized in cell models, including leukemia patient-derived cells. The use of the siRNA therapy with clinically used chemotherapy was demonstrated.
Journal
|
FLT3 (Fms-related tyrosine kinase 3)
|
FLT3 mutation
|
Xospata (gilteritinib)
3ms
Concentration of gilteritinib in the cerebrospinal fluid of a patient with relapsed FLT3-ITD positive acute myeloid leukemia with optic nerve involvement (PubMed, Rinsho Ketsueki)
In this patient, pharmacokinetic (low CNS penetration of gilteritinib) and pharmacodynamic (acquisition of a drug resistance mutation) mechanisms were thought to be responsible for the CNS relapse and hematologic PD, respectively. We believe this is a valuable case to report considering the scarcity of data on CNS penetration of FLT3 inhibitors and their effects on CNS disease in the literature.
Journal
|
FLT3 (Fms-related tyrosine kinase 3)
|
FLT3 F691L
|
Xospata (gilteritinib)
3ms
A Study of Venetoclax in Combination With Conventional Chemotherapy in Pediatric Patients With Acute Myeloid Leukemia (clinicaltrials.gov)
P2, N=70, Recruiting, St. Jude Children's Research Hospital | Trial primary completion date: Mar 2025 --> Dec 2026
Trial primary completion date • Combination therapy
|
Venclexta (venetoclax) • cytarabine • Xospata (gilteritinib) • azacitidine • etoposide IV • Mylotarg (gemtuzumab ozogamicin) • daunorubicin • idarubicin hydrochloride • mitoxantrone • fludarabine IV
3ms
Triplet therapy with gilteritinib, venetoclax, and azacitidine for relapsed/refractory FLT3mut acute myeloid leukemia. (PubMed, Leuk Res)
The estimated 2-year OS was 62 % in 19 (65.5 %) patients who received allo-HSCT after triplet therapy and 37 % in 10 patients who did not receive allo-HSCT (P=0.03). In conclusion, triplet therapy with gilteritinib, VEN, and AZA is effective and safe and an excellent frontline option for R/R FLT3mut AML.
Journal
|
FLT3 (Fms-related tyrosine kinase 3)
|
Venclexta (venetoclax) • Xospata (gilteritinib) • azacitidine
3ms
FLT3AML-2024: The Efficacy of Triple Regimen in Newly Diagnosed AML Patients With FLT3 Mutation (clinicaltrials.gov)
P1/2, N=36, Not yet recruiting, Institute of Hematology & Blood Diseases Hospital, China
New P1/2 trial
|
Venclexta (venetoclax) • cytarabine • Xospata (gilteritinib) • azacitidine
3ms
Overcoming post-transplant graft failure and adenovirus infection in a patient with FLT3-TKD-mutated mixed-phenotype acute leukemia: A case report. (PubMed, EJHaem)
A 31-year-old man with FLT3-TKD-mutated MPAL achieved hematological remission through the JALSG ALL202-O protocol and gilteritinib, followed by cord blood transplantation (CBT). Post-transplant complications included adenovirus-induced hemorrhagic cystitis, managed with bladder irrigation and ribavirin, and engraftment failure, necessitating a second CBT on Day 35...The patient achieved neutrophil engraftment by Day 76 and was discharged on Day 173 without relapse. This case highlights the importance of vigilant supportive care and tailored therapy in managing MPAL with FLT3 mutations, especially in the context of post-transplant complications.
Journal • Post-transplantation
|
FLT3 (Fms-related tyrosine kinase 3)
|
Xospata (gilteritinib)
3ms
RR-AML-2023: Multicenter, Platform-type Clinical Study of Refractory/Recurrent Acute Myeloid Leukemia (clinicaltrials.gov)
P=N/A, N=120, Recruiting, Institute of Hematology & Blood Diseases Hospital, China | Not yet recruiting --> Recruiting
Enrollment open
|
Venclexta (venetoclax) • cytarabine • Xospata (gilteritinib) • azacitidine • Xpovio (selinexor) • Tibsovo (ivosidenib)
3ms
Discovery of NFκB2-Coordinated Dual Regulation of Mitochondrial and Nuclear Genomes Leads to an Effective Therapy for Acute Myeloid Leukemia. (PubMed, Int J Mol Sci)
Based on our discovery of NFκB2's novel function of regulating mitochondrial-nuclear dual genomes, we explored a novel triplet therapy including inhibitors of NFκB2, tyrosine kinase, and mitochondrial ATP synthase that effectively eliminated primary AML blasts with mutations of the FMS-related receptor tyrosine kinase 3 (FLT3) and displayed minimum toxicity to control cells ex vivo. As such, effective treatments for AML must include strong inhibitory actions on the dual genomes mediating metabolic plasticity to improve leukemia prognosis.
Journal
|
FLT3 (Fms-related tyrosine kinase 3) • TFAM (Transcription Factor A, Mitochondrial)
|
Xospata (gilteritinib)
3ms
TKI type switching overcomes ROS1 L2086F in ROS1 fusion-positive cancers. (PubMed, NPJ Precis Oncol)
Using Ba/F3 and NIH3T3 cell models, CRISPR/Cas9-edited isogenic wildtype and mutant patient-derived cell lines, and in vivo tumor growth studies, we compared type I TKIs (crizotinib, entrectinib, taletrectinib, lorlatinib, and repotrectinib) to type II TKIs (cabozantinib and merestinib) and the type I FLT3 inhibitor gilteritinib...While cabozantinib effectively inhibits ROS1 L2086F, its multi-kinase inhibitor nature highlights the need for more selective and better-tolerated TKIs to overcome kinase-intrinsic resistance. Gilteritinib may offer an alternative for targeting ROS1 L2086F with distinct off-target toxicities, but further studies are required to fully evaluate its potential in this setting.
Journal
|
FLT3 (Fms-related tyrosine kinase 3) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
Xalkori (crizotinib) • Rozlytrek (entrectinib) • Lorbrena (lorlatinib) • Xospata (gilteritinib) • Cabometyx (cabozantinib tablet) • Augtyro (repotrectinib) • merestinib (LY2801653) • taletrectinib (AB-106)
4ms
Contemporary Management of Acute Myeloid Leukemia: A Review. (PubMed, JAMA Oncol)
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.
Review • Journal
|
TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • TET2 (Tet Methylcytosine Dioxygenase 2)
|
Venclexta (venetoclax) • Xospata (gilteritinib) • Rydapt (midostaurin) • Vanflyta (quizartinib) • Tibsovo (ivosidenib) • Idhifa (enasidenib) • Rezlidhia (olutasidenib)
4ms
FLT3-PROTACs for combating AML resistance: Analytical overview on chimeric agents developed, challenges, and future perspectives. (PubMed, Eur J Med Chem)
Next, we explored the latest FLT3-targeting PROTACs developed in the past few years such as quizartinib-based PROTACs, dovitinib-based PROTACs, gilteritinib-based PROTACs, and others. Then, we followed with a deep analysis of their advantages regarding potency improvement and overcoming AML drug resistance. Finally, we discussed the challenges facing these chimeric molecules with proposed future solutions to circumvent them.
Review • Journal
|
FLT3 (Fms-related tyrosine kinase 3)
|
Xospata (gilteritinib) • Vanflyta (quizartinib) • dovitinib (TKI258)
4ms
Gilteritinib Reduces FLT3 Expression in Acute Myeloid Leukemia Cells. (PubMed, Biomol Ther (Seoul))
Other FLT3 inhibitors, midostaurin, crenolanib, and quizartinib, also reduced FLT3 expression, consistent with the effect of gilteritinib. These findings hold great promise for optimizing gilteritinib treatment in AML patients. However, it is important to recognize that further research is warranted to gain a full understanding of these mechanisms and their clinical implications in the context of FLT3 reduction.
Journal
|
FLT3 (Fms-related tyrosine kinase 3)
|
Xospata (gilteritinib) • Rydapt (midostaurin) • Vanflyta (quizartinib) • crenolanib (ARO-002)
4ms
Enrollment open • Enrollment change
|
FLT3 (Fms-related tyrosine kinase 3)
|
Venclexta (venetoclax) • Xospata (gilteritinib)
4ms
Journal
|
FLT3 (Fms-related tyrosine kinase 3)
|
Xospata (gilteritinib)