^
7d
An Innovative Telomere-associated Prognosis Model in AML: Predicting Immune Infiltration and Treatment Responsiveness. (PubMed, Curr Med Chem)
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.
Journal
|
CD4 (CD4 Molecule) • RPA2 (Replication Protein A2)
|
erlotinib • Rydapt (midostaurin) • Vanflyta (quizartinib) • Zarnestra (tipifarnib)
24d
Develop a Novel Signature to Predict the Survival and Affect the Immune Microenvironment of Osteosarcoma Patients: Anoikis-Related Genes. (PubMed, J Immunol Res)
Notably, our study identified eight drugs-Bortezomib, Midostaurin, CHIR.99021, JNK.Inhibitor.VIII, Lenalidomide, Sunitinib, GDC0941, and GW.441756-as exhibiting sensitivity toward OS. The outcomes of this investigation present an opportunity to predict the survival outcomes among individuals diagnosed with OS. Furthermore, these findings hold promise for progressing research endeavors focused on prognostic evaluation and therapeutic interventions pertaining to this particular ailment.
Journal
|
CD8 (cluster of differentiation 8) • HAVCR2 (Hepatitis A Virus Cellular Receptor 2) • CD36 (thrombospondin receptor) • TNFRSF1A (TNF Receptor Superfamily Member 1A) • CD200R1 (CD200 Receptor 1) • HSP90AB1 (Heat Shock Protein 90 Alpha Family Class B Member 1) • LAIR1 (Leukocyte Associated Immunoglobulin Like Receptor 1) • MMP3 (Matrix metallopeptidase 3) • PIP5K1C (Phosphatidylinositol-4-Phosphate 5-Kinase Type 1 Gamma)
|
MYC expression
|
sunitinib • lenalidomide • bortezomib • Rydapt (midostaurin) • pictilisib (GDC-0941)
28d
Midostaurin shapes macroclonal and microclonal evolution of FLT3-mutated acute myeloid leukemia. (PubMed, Blood Adv)
Considering both treatment groups, if only 24% of FLT3-ITD microclones detected at diagnosis were retained at relapse, 43% of them became macroclones. Together, these results identify parameters influencing the fitness of FLT3-ITD clones and highlight the importance of using sensitive techniques for FLT3--ITD screening in clinical practice.
Clinical • Journal
|
FLT3 (Fms-related tyrosine kinase 3)
|
FLT3 mutation
|
Rydapt (midostaurin)
29d
Development and Validation of a Comprehensive Prognostic and Depression Risk Index for Gastric Adenocarcinoma. (PubMed, Int J Mol Sci)
With the Genomics of Drug Sensitivity in Cancer database, we found that the gastric adenocarcinoma patients with high risk-score may be sensitive to Pazopanib, XMD8.85, Midostaurin, HG.6.64.1, Elesclomol, Linifanib, AP.24534, Roscovitine, Cytarabine, and Axitinib. The gene signature consisting of the NDUFA4L2, ANKRD45, and AQP3 genes is a promising biomarker to distinguish the prognosis, the molecular and immune characteristics, the depressive risk, and the therapy candidates for gastric adenocarcinoma patients.
Journal
|
NDUFA4L2 (NDUFA4 Mitochondrial Complex Associated Like 2)
|
cytarabine • Iclusig (ponatinib) • pazopanib • Rydapt (midostaurin) • Inlyta (axitinib) • elesclomol (STA-4783) • linifanib (ABT-869) • seliciclib (CYC202)
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)
1m
Midostaurin added to 10-day decitabine, for patients unfit for intensive chemotherapy with AML and higher risk MDS, irrespective of FLT3 mutational status, does not improve outcome. (PubMed, Ann Hematol)
In the decitabine plus midostaurin arm 24% reached CR/CRi, the median OS was 4.8 months and 1-yrs OS was 31% which compared with 34% CR/CRi, median OS of 7.4 months and 1-yrs OS of 37% for the decitabine alone group (NS). Thus, while the addition of midostaurin appears safe, it does not enhance therapeutic efficacy of decitabine in unfit AML patients.
Clinical • Journal
|
FLT3 (Fms-related tyrosine kinase 3)
|
FLT3 mutation
|
Rydapt (midostaurin) • decitabine
2ms
Measurable Residual Disease Monitoring in AML With FLT3-ITD Treated With Intensive Chemotherapy Plus Midostaurin. (PubMed, Blood Adv)
NGS-based FLT3-ITD MRD monitoring allows for the identification of patients at high risk of relapse and death following intensive chemotherapy plus midostaurin. Using NGS-based technology, FLT3-ITD emerges as a novel, clinically highly relevant target for MRD monitoring.
Journal
|
FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1)
|
FLT3-ITD mutation • NPM1 mutation
|
Rydapt (midostaurin)
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
Prognosis and immunotherapeutic implications of molecular classification of cervical cancer based on immunophenoscore-related genes. (PubMed, J Biomol Struct Dyn)
cluster2 had higher immune cell infiltration levels and better prognosis, with greater sensitivity to Cyclopamine, Imatinib, MG-13, Paclitaxel, PHA-665752, Rapamycin, Sorafenib, Sunitinib, and VX-680. In contrast, cluster3 had higher TTN and PIK3CA mutations and greater sensitivity to AZ628, Dasatinib, Doxorubicin, HG-6-64-1, JQ12, Midostaurin, PF-562271, TAE684, and WH-4-023. In conclusion, we developed a feasible risk score model based on IPS-related genes for cervical cancer prognosis and identified potential drugs for different cervical cancer subtypes.
Journal • PD(L)-1 Biomarker • IO biomarker
|
PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PD-L2 (Programmed Cell Death 1 Ligand 2)
|
PIK3CA mutation
|
dasatinib • sorafenib • paclitaxel • imatinib • sunitinib • doxorubicin hydrochloride • Rydapt (midostaurin) • sirolimus • AZ 628 • TAE-684 • cyclopamine • RG6146 • benzesulfonate (PF-562271) • PHA665752 • tozasertib (MK-0457)
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
Phosphoproteomics predict response to midostaurin plus chemotherapy in independent cohorts of FLT3-mutated acute myeloid leukaemia. (PubMed, EBioMedicine)
In validation, MPhos outperformed the currently-used FLT3-based stratification method. Our findings have the potential to transform clinical decision-making, and highlight the important role that phosphoproteomics is destined to play in precision oncology.
Journal
|
FLT3 (Fms-related tyrosine kinase 3)
|
FLT3 mutation • FLT3 positive
|
Rydapt (midostaurin)
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
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
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)
2ms
Real-Life Management of FLT3-Mutated AML: Single-Centre Experience over 24 Years. (PubMed, Cancers (Basel))
Until 2018, 101 patients received chemotherapy; thereafter, 39 received 3+7+midostaurin...Post-transplant FLT3i was resumed in eight patients, all alive after a median of 65 months. Allogeneic transplantation is crucial in FLT3-mutated AML, but the next challenge will be to identify which patients can benefit from transplants in CR1 and in which to intensify post-transplant therapy.
Journal
|
FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1)
|
Rydapt (midostaurin)
3ms
Systemic Mastocytosis: State of the Art. (PubMed, Curr Hematol Malig Rep)
Avapritinib, the first licensed drug in SM capable of disease modification alongside the increasingly potent, oral and highly selective KIT tyrosine kinase inhibitors (TKIs) Bezuclastinib and now Elenestinib have enabled the prospect of long-term remissions...The importance of molecular profiling is being demonstrated in administering combination therapies for SM with an associated haematological neoplasm (AHN), allowing more personalised and streamlined treatment regimes. This review focuses on current management strategies of SM, focusing on state-of-the-art directed therapies, the evidence behind their use with presentation of two clinical cases to highlight key messages.
Review • Journal
|
KIT (KIT proto-oncogene, receptor tyrosine kinase)
|
Rydapt (midostaurin) • Ayvakit (avapritinib) • bezuclastinib (PLX9486) • elenestinib (BLU-263)
3ms
Real-world outcomes of intensive induction approaches in core binding factor acute myeloid leukemia. (PubMed, EJHaem)
The CD33-targeting antibody-drug conjugate, gemtuzumab ozogamicin (GO), is commonly added to intensive chemotherapy (IC) in CBF-AML...Induction treatment regimens were categorized as IC alone, IC with GO, or IC with KIT inhibitor (dasatinib or midostaurin)...Patients treated with IC with KIT inhibitor experienced a significantly improved 3-year EFS of 85% compared to those with IC with or without GO (p = 0.04). We find in our study that there is no survival benefit in patients treated with IC with the addition of GO; improved EFS was seen in patients with CBF-AML treated with IC plus KIT inhibitors, consistent with outcomes noted in prospective studies utilizing this approach.
Journal • Real-world evidence • Real-world
|
CD33 (CD33 Molecule)
|
dasatinib • Rydapt (midostaurin) • Mylotarg (gemtuzumab ozogamicin)
3ms
Concurrent versus sequential or no triazole anti-fungal therapy in patients undergoing 7 + 3 plus midostaurin induction for FLT-3 acute myelogenous leukemia. (PubMed, J Oncol Pharm Pract)
Azoles given concurrently or sequentially with midostaurin were found to be equally safe and effective in the treatment of newly diagnosed FLT3 AML. Additional confirmatory studies are needed due to our limited sample size.
Journal
|
FLT3 (Fms-related tyrosine kinase 3)
|
Rydapt (midostaurin) • Noxafil (posaconazole)
3ms
ROS1 kinase inhibition reimagined: identifying repurposed drug via virtual screening and molecular dynamics simulations for cancer therapeutics. (PubMed, Front Chem)
MD results showed that Midostaurin and Alectinib were stable with ROS1. Taken together, the study showed a rational framework for the selection of repurposed Midostaurin and Alectinib with ROS1 inhibitory potential for therapeutic management after further validation.
Journal
|
ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
Alecensa (alectinib) • Rydapt (midostaurin)
3ms
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)
3ms
Effect of midostaurin on the pharmacokinetics of P-gp, BCRP, and CYP2D6 substrates: assessing potential drug-drug interactions in healthy participants : Brief title: Drug-drug interaction of midostaurin. (PubMed, Cancer Chemother Pharmacol)
Midostaurin showed only a minor inhibitory effect on P-gp, a mild inhibitory effect on BCRP, and no inhibitory effect on CYP2D6. Study treatments were well tolerated in healthy adults.
PK/PD data • Journal
|
FLT3 (Fms-related tyrosine kinase 3)
|
Rydapt (midostaurin)
3ms
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
Improving Risk Assessment of AML With a Precision Genomic Strategy to Assess Mutation Clearance (clinicaltrials.gov)
P2, N=107, Active, not recruiting, Washington University School of Medicine | Trial completion date: Jul 2033 --> Jul 2029 | Trial primary completion date: Jul 2033 --> Jul 2029
Trial completion date • Trial primary completion date
|
FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • CEBPA (CCAAT Enhancer Binding Protein Alpha)
|
cytarabine • Rydapt (midostaurin)
4ms
The impact of different FLT3-inhibitors on overall survival of de novo acute myeloid leukemia: A network meta-analysis. (PubMed, Leuk Res)
Three relevant randomized controlled trials (RCTs), involving 1.358 patients treated with midostaurin, quizartinib, and sorafenib, were included in our analysis. This NMA, the first to explore this issue, found no OS differences among the different FLT3 inhibitors. In the absence of direct comparison trials, our findings provide practical insights for clinical decision-making.
Retrospective data • Journal
|
FLT3 (Fms-related tyrosine kinase 3)
|
sorafenib • Rydapt (midostaurin) • Vanflyta (quizartinib)
4ms
Enrollment open • Combination therapy
|
FLT3 (Fms-related tyrosine kinase 3) • CD33 (CD33 Molecule)
|
cytarabine • Rydapt (midostaurin) • Mylotarg (gemtuzumab ozogamicin) • daunorubicin • Starasid (cytarabine ocfosfate)
4ms
Sorafenib maintenance in FLT3-ITD mutated AML after allogeneic HCT: a real-world, single-center experience. (PubMed, Front Oncol)
Despite allogeneic hematopoietic stem cell transplant (allo-HCT) and the development of novel FLT3 inhibitors in both induction (midostaurin) and in the relapsed/refractory setting (gilteritinib), FLT3-ITD mutated leukemia (FLT3-ITD+ AML) still represents a challenge for modern hematology. No major long-term toxicity was reported at the last follow-up. Our real-world experience supports the use of sorafenib as a feasible and effective therapeutic option in post-HCT maintenance for FLT3-ITD+ AML.
Journal • Real-world evidence • Real-world
|
FLT3 (Fms-related tyrosine kinase 3)
|
sorafenib • Xospata (gilteritinib) • Rydapt (midostaurin)
4ms
Journal
|
FLT3 (Fms-related tyrosine kinase 3)
|
cytarabine • Rydapt (midostaurin) • idarubicin hydrochloride
5ms
Efficacy and safety of FLT3 inhibitors in monotherapy of hematological and solid malignancies: a systemic analysis of clinical trials. (PubMed, Front Pharmacol)
We searched and reviewed clinical trial reports on the monotherapy of 13 FLT3 inhibitors, including sorafenib, lestaurtinib, midostaurin, gilteritinib, quizartinib, sunitinib, crenolanib, tandutinib, cabozantinib, pexidartinib, pacritinib, famitinib, and TAK-659 in patients with hematological and solid malignancies before May 31, 2023...The ORRs of FLT3 inhibitors in hematologic malignancies and solid tumors were 40.8% and 18.8%, respectively, indicating FLT3 inhibitors were more effective for hematologic malignancies than for solid tumors. In addition, time to maximum plasma concentration (Tmax) in these FLT3 inhibitors ranged from 0.7-12.0 hours, but the elimination half-life (T1/2) range was highly variable, from 6.8 to 151.8 h. FLT3 inhibitors monotherapy has shown significant anti-tumor effect in clinic, and the effectiveness may be further improved through combination medication.
Review
|
FLT3 (Fms-related tyrosine kinase 3)
|
sorafenib • sunitinib • Xospata (gilteritinib) • Cabometyx (cabozantinib tablet) • Rydapt (midostaurin) • Vanflyta (quizartinib) • crenolanib (ARO-002) • tandutinib (MLN518) • Turalio (pexidartinib) • famitinib (SHR 1020) • mivavotinib (CB-659) • Vonjo (pacritinib) • lestaurtinib (CEP-701)
6ms
In vivo imaging system (IVIS) therapeutic assessment of tyrosine kinase inhibitor-loaded gold nanocarriers for acute myeloid leukemia: a pilot study. (PubMed, Front Pharmacol)
Midostaurin (MDS) is the first targeted therapy in FLT3-mutant AML, and its combination with chemotherapy showed good results...The herein study presents MDS-loaded gold nanoparticles and compares its efficacy with MDS alone, on both in vitro and in vivo models, using the FLT3-ITD-mutated AML cell line MV-4-11 Luc2 transfected to express luciferin. Our preclinical study suggests that MDS-loaded nanoparticles have a better tumor inhibitory effect than free drugs on in vivo models by controlling tumor growth in the first half of the treatment, while in the second part of the therapy, the tumor size was comparable to the cohort that was treatment-free.
Preclinical • Journal
|
FLT3 (Fms-related tyrosine kinase 3) • JAK2 (Janus kinase 2)
|
Rydapt (midostaurin)
6ms
Trial suspension
|
FLT3 (Fms-related tyrosine kinase 3) • CD33 (CD33 Molecule)
|
CD33 positive • CD33 expression
|
cytarabine • Rydapt (midostaurin) • Mylotarg (gemtuzumab ozogamicin) • daunorubicin • Starasid (cytarabine ocfosfate)
6ms
The potential of triplet combination therapies for patients with FLT3-ITD -mutated acute myeloid leukemia. (PubMed, Expert Rev Hematol)
In addition, the review discusses the emergence of drug resistance and the need for a nuanced approaches in treating patients who are ineligible for or resistant to intensive chemotherapy. Specifically, it explores the historical context of FLT3 inhibitors (FLT3Is) and their impact on treatment outcomes, emphasizing the pivotal role of midostaurin, as well as gilteritinib and quizartinib, and providing detailed insights into ongoing trials exploring the safety and efficacy of novel triplet combinations involving FLT3Is in different AML settings.
Review • Journal • Combination therapy
|
FLT3 (Fms-related tyrosine kinase 3)
|
FLT3-ITD mutation • FLT3 mutation
|
Xospata (gilteritinib) • Rydapt (midostaurin) • Vanflyta (quizartinib)
7ms
Emerging DNA Methylome Targets in FLT3-ITD-Positive Acute Myeloid Leukemia: Combination Therapy with Clinically Approved FLT3 Inhibitors. (PubMed, Curr Treat Options Oncol)
Hence, FLT3 is considered an attractive druggable target; selective small FLT3 inhibitors (FLT3Is), such as midostaurin and quizartinib, have been clinically approved. Therefore, understanding the role of different epigenetic alterations in FLT3-ITD AML pathogenesis and how they modulate FLT3I's activity is important to rationalize combinational treatment approaches including FLT3Is and modulators of methylation regulators or pathways. Data from ongoing pre-clinical and clinical studies will further precisely define the potential use of epigenetic therapy together with FLT3Is especially after characterized patients' mutational status in terms of FLT3 and DNA methlome regulators.
Review • Journal • Combination therapy
|
FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • DNMT3A (DNA methyltransferase 1) • TET2 (Tet Methylcytosine Dioxygenase 2)
|
FLT3-ITD mutation
|
Rydapt (midostaurin) • Vanflyta (quizartinib)
7ms
Correlation of miR-155 Expression with Drug Sensitivity of FLT3-ITD+ Acute Myeloid Leukemia Cell Line and Its Mechanism (PubMed, Zhongguo Shi Yan Xue Ye Xue Za Zhi)
Drug sensitivity of MV411 cells to doxorubicin, quizartinib and midostaurin can be enhanced significantly after miR-155 knockout, which is related to the inhibition of multiple signaling pathways including mTOR and Wnt signaling pathways.
Preclinical • Journal
|
FLT3 (Fms-related tyrosine kinase 3) • MIR155 (MicroRNA 155)
|
miR-155 expression
|
doxorubicin hydrochloride • Rydapt (midostaurin) • Vanflyta (quizartinib)
7ms
Gemtuzumab ozogamicin plus midostaurin in combination with standard '7 + 3' induction therapy in newly diagnosed AML: Results from the SAL-MODULE phase I study. (PubMed, Br J Haematol)
Three dose levels of midostaurin and one to three sequential doses of 3 mg/m2 GO in combination with '7 + 3' induction were evaluated. Based on safety findings in 12 patients, our results show that 3 mg/m2 GO on Days 1 + 4 and 100 mg midostaurin on Days 8-21 can be safely combined with IC in newly diagnosed AML.
P1 data • Journal • Combination therapy
|
FLT3 (Fms-related tyrosine kinase 3)
|
FLT3 mutation
|
Rydapt (midostaurin) • Mylotarg (gemtuzumab ozogamicin)
7ms
Day-21 bone marrow findings incorrectly designate residual leukaemia in FLT3-mutated acute myeloid leukaemia treated with intensive induction plus midostaurin: a morphology-focused study. (PubMed, Pathology)
In summary, based on morphology alone, D21-BM assessment following 7+3 intensive induction plus midostaurin for FLT3-AML incorrectly designates RL in some patients; thus correlating with associated flow and molecular results is essential before concluding RL following first induction. Where remission status is unclear, repeat D28-BMs should be performed.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3 mutation
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Rydapt (midostaurin)
8ms
Improving Risk Assessment of AML With a Precision Genomic Strategy to Assess Mutation Clearance (clinicaltrials.gov)
P2, N=107, Active, not recruiting, Washington University School of Medicine | Recruiting --> Active, not recruiting
Enrollment closed
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FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • CEBPA (CCAAT Enhancer Binding Protein Alpha)
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FLT3-ITD mutation • NPM1 mutation • CEBPA mutation
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cytarabine • Rydapt (midostaurin)
8ms
Macrophage migration inhibitory factor blockade reprograms macrophages and disrupts prosurvival signaling in acute myeloid leukemia. (PubMed, Cell Death Discov)
Furthermore, contact with reprogrammed MΦ relieves blast resistance to venetoclax and midostaurin acquired in contact with CD163+ protumoral MΦ. Using intravital imaging in mice, we also show that treatment with MIF inhibitor 4-IPP and GM-CSF profoundly affects the tumor microenvironment in vivo: it strikingly inhibits tumor vasculature, reduces protumoral MΦ, and slows down leukemia progression. Thus, our data demonstrate that MIF plays a crucial role in AML MΦ M2-like protumoral phenotype that can be reversed by inhibiting its activity and suggest the therapeutic targeting of MIF as an avenue towards improved AML treatment outcomes.
Journal
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CD163 (CD163 Molecule) • MIF (Macrophage Migration Inhibitory Factor)
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Venclexta (venetoclax) • Rydapt (midostaurin)
8ms
New P1 trial • Combination therapy
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Rydapt (midostaurin) • daunorubicin • revumenib (SNDX-5613)
9ms
Trial primary completion date • Combination therapy
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FLT3 (Fms-related tyrosine kinase 3) • CD33 (CD33 Molecule)
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CD33 positive • CD33 expression
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cytarabine • Rydapt (midostaurin) • Mylotarg (gemtuzumab ozogamicin) • daunorubicin • Starasid (cytarabine ocfosfate)
9ms
New P1 trial
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IFNG (Interferon, gamma)
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azacitidine • Rydapt (midostaurin)