News - FLT3-ITD mutation

Molecular measurable residual disease monitoring and transplant indications in NPM1 mutated acute myeloid leukemia. (PubMed, Bone Marrow Transplant)

In this review, we evaluate the prognostic role of MRD monitoring in NPM1 mutated AML and its use as a predictive biomarker to refine risk stratification and inform decision making regarding treatment. We explore the impact of pre-HCT MRD positivity on post-HCT outcomes in this AML subset, and how HCT-related factors such as conditioning intensity may influence this risk.

2 days ago

Review • Journal

FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1)

FLT3-ITD mutation • NPM1 mutation

Homoharringtonine Added to Venetoclax and Azacitidine Improves Outcome and Mitigates Genetic Impact in Relapsed/Refractory AML: A Multi-center Cohort Study. (PubMed, Clin Cancer Res)

Our findings suggest the addition of HHT to VA might enhance response and mitigate the negative impact of certain genetic patterns in RR-AML while being well tolerated.

4 days ago

Journal

KRAS (KRAS proto-oncogene GTPase) • FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • TET2 (Tet Methylcytosine Dioxygenase 2)

KRAS mutation • FLT3-ITD mutation • FLT3 mutation • DNMT3A mutation • TET2 mutation

Venclexta (venetoclax) • azacitidine • Synribo (omacetaxine mepesuccinate)

OXPHOS mediators in acute myeloid leukemia patients: Prognostic biomarkers and therapeutic targets for personalized medicine. (PubMed, World J Surg Oncol)

This study identifies NDUFA6 and SDHA as novel companion prognostic biomarkers which might present a rational strategy for personalized therapy of AML patients.

4 days ago

Journal

FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • NPM1 (Nucleophosmin 1) • SRSF2 (Serine and arginine rich splicing factor 2) • GPX4 (Glutathione Peroxidase 4) • CYB5A (Cytochrome B5 Type A) • CPT1A (Carnitine Palmitoyltransferase 1A) • SDHA (Succinate Dehydrogenase Complex Flavoprotein Subunit A)

FLT3-ITD mutation • IDH1 mutation • NPM1 mutation • SRSF2 mutation • NPM1 expression • NPM1 mutation + SRSF2 mutation

Evaluation of drug-drug interactions of a novel potent FLT3 inhibitor SKLB1028 in healthy subjects. (PubMed, Clin Transl Sci)

Based on the preclinical characterization of SKLB1028 metabolism, three drug-drug interaction clinical studies were performed to investigate the effects of itraconazole, rifampin (CYP3A4 inhibitor and inducer, respectively), and gemfibrozil (CYP2C8 inhibitor) on the metabolism of SKLB1028. Co-administration with rifampin reduced the AUC of SKLB1028 by ~30%, while the Cmax did not change significantly. All treatments were well tolerated in all three studies.

4 days ago

Journal

FLT3 (Fms-related tyrosine kinase 3)

FLT3-ITD mutation

itraconazole • rifampicin • ruserontinib (SKLB-1028)

Target-Capture Next-Generation Sequencing (NGS) for Use in Molecular-Based Research of Myeloid Measurable Residual Disease (MRD) (AMP 2024)

Target-capture NGS provides the opportunity to evaluate many genes in a single assay. Suitability for MRD requires highly uniform and sensitive target enrichment. Our study demonstrated reliable and accurate detection of variants down to 0.05% VAF, providing researchers with the capability to use capture-based NGS for myeloid MRD monitoring.

5 days ago

Next-generation sequencing

FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • JAK2 (Janus kinase 2)

FLT3-ITD mutation • NPM1 mutation • FLT3 D835Y • FLT3 D835 • IDH2 R172K • KIT D816V • IDH1 R132C • JAK2 V617F • IDH1 R132 • IDH2 R172

SureSeq™ Myeloid MRD Panel

DNA and RNA NGS for Myeloid Neoplasms Using Oncomine Myeloid Assay GX v2 on GeneXus: An Assessment of Clinical Utility (AMP 2024)

This DNA- and RNA-based 80-gene panel has proven to be a powerful tool for genomic profiling of myeloid neoplasms. The results were provided to hematopathologists/oncologists in timely fashion with the critical information for diagnosis confirmation, and disease classification, as well as assessment of patient response to treatment.

5 days ago

Clinical • Next-generation sequencing

KRAS (KRAS proto-oncogene GTPase) • 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) • JAK2 (Janus kinase 2) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • KMT2A (Lysine Methyltransferase 2A) • TET2 (Tet Methylcytosine Dioxygenase 2) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • SRSF2 (Serine and arginine rich splicing factor 2) • BCOR (BCL6 Corepressor) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • STAG2 (Stromal Antigen 2) • DDX41 (DEAD-Box Helicase 41) • CALR (Calreticulin) • ZRSR2 (Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2)

FLT3-ITD mutation • NPM1 mutation • U2AF1 mutation • CEBPA mutation • JAK2 V617F

Oncomine Myeloid Assay GX

11d

Characteristics and Outcome of FLT3-ITD-Positive Acute Myeloid Leukemia. (PubMed, Clin Lab)

Allo-HSCT immediately following complete remission could improve outcomes for young adults diagnosed with FLT3-ITD-positive AML. However, we found no statistical difference in the overall response rate (ORR) and clinical outcome between sorafenib combined with chemotherapy and chemotherapy alone.

11 days ago

Retrospective data • Journal

FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1)

FLT3-ITD mutation • NPM1 mutation

sorafenib

11d

Safety and Efficacy of Quizartinib in Children and Young Adults With Acute Myeloid Leukemia (AML), a Cancer of the Blood (clinicaltrials.gov)

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

11 days ago

Enrollment closed • Combination therapy

FLT3 (Fms-related tyrosine kinase 3)

FLT3-ITD mutation

cytarabine • etoposide IV • Vanflyta (quizartinib) • fludarabine IV

12d

Measurable residual mutated IDH1 before allogeneic transplant for acute myeloid leukemia. (PubMed, Bone Marrow Transplant)

For patients with IDH1 mutated AML co-mutated with NPM1 and/or FLT3-ITD, only detection of persistent mutated NPM1 and/or FLT3-ITD was associated with significantly higher rates of relapse (p = 0.01). These data, from the largest study to date, do not support the detection of IDH1 mutation in CR1 blood prior to alloHCT as evidence of AML MRD for increased post-transplant relapse risk.

12 days ago

Journal

FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • NPM1 (Nucleophosmin 1)

FLT3-ITD mutation • IDH1 mutation • FLT3 mutation • NPM1 mutation

12d

Prognostic Role of NGS-Based MRD Assessment in FLT3-TKD Mutated Patients with Acute Myeloid Leukemia (ASH 2024)

Only two patients in the MRD negative group received the FLT3 inhibitor midostaurin combined with chemotherapy...NGS-MRD was not prognostic in this cohort of FLT3-TKD mutated AML patients. Shared first authors: Isabell Arnhardt, Christian M Vonk Shared senior authorship: Michael Heuser, Peter J.M. Valk

12 days ago

Clinical • Next-generation sequencing

FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2)

FLT3-ITD mutation • NPM1 mutation • DNMT3A mutation • ASXL1 mutation • TET2 mutation • SF3B1 mutation • FLT3-TKD mutation

TruSight Myeloid Sequencing Panel

Rydapt (midostaurin)

12d

Measurable Residual Mutated NPM1 before Allogeneic Transplant for Acute Myeloid Leukemia (ASH 2024)

NPM1 MRD positive patients receiving nonmyeloablative conditioning or reduced-intensity conditioning (RIC) without melphalan (mel) had increased risk of relapse or death compared to patients receiving myeloablative conditioning or RIC with mel, regardless of FLT3-ITD co-mutational status (3yrs: relapse 87% vs 55%, P=0.006; OS 15% vs 42%, P=0.013). In patients with NPM1 mutated AML from the Pre-MEASURE study, we show that detection of residual NPM1 variants in pre-transplant blood during CR1 using a highly sensitive DNA-based assay is associated in a dose-dependent manner with a significantly increased risk of relapse and death after allo-HCT, which can be mitigated in part by conditioning regimen. In patients co-mutated for both FLT3-ITD and NPM1 at diagnosis, NPM1 should be prioritized as a target for NGS-MRD if only one test is available.

12 days ago

FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1)

FLT3-ITD mutation • FLT3 mutation • NPM1 mutation

FLT3 ITD MRD Assay • NPM1 Mutation Assay

melphalan

12d

Prognostic Significance of Low Copy Number FLT3 and NPM1 mrd As Detected By Ultra-Sensitive Next Generation Sequencing (ASH 2024)

To our knowledge, our study is the first to assess the clinical impact of MRD detected below the clinically-validated limit of detection by ultra-sensitive NGS. Findings from our retrospective study were consistent with previously published data suggesting the presence of “high level” MRD (i.e. above the current clinically-validated limit of detection) is associated with increased risk of AML relapse in both NPM1 and FLT3-ITD mutated AML.

12 days ago

Next-generation sequencing

FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1)

FLT3-ITD mutation • NPM1 mutation • FLT3‐ITD + NPM1 mutation

FLT3 ITD MRD Assay • NPM1 Mutation Assay

14d

PRDM16 Induces Methylation of FLT3 to Promote FLT3-ITD Signaling and Leukemia Progression. (PubMed, Cancer Res)

Altogether, these results suggest that PRDM16 boosts oncogenic FLT3 signaling in leukemic cells by prompting FLT3-ITD methylation. Therefore, PRDM16 may serve as a therapeutic target for AML.

14 days ago

Journal

FLT3 (Fms-related tyrosine kinase 3) • PRDM16 (PR/SET Domain 16)

FLT3-ITD mutation • FLT3 wild-type • FLT3 expression • FLT3-ITD expression

18d

Analysis of Morphologic Classification System for Acute Promyelocytic Leukemia and Its Correlation with Laboratory Tests and FLT3-ITD Mutation (PubMed, Zhongguo Shi Yan Xue Ye Xue Za Zhi)

The newly established morphologic classification system in this study can objectively characterize different types of APL blast cells, which helps to better assess the intra- and inter-individual heterogeneity of APL blast cells, and further use in accurately analyzing the correlation of morphological phenotypes with biological properties of APL.

18 days ago

Journal

FLT3 (Fms-related tyrosine kinase 3)

FLT3-ITD mutation • FLT3 mutation

20d

Exploring the Prevalence and Prognostic Impact of Wilms Tumor 1 Exon 7 Mutation Status with Combinations of FLT3-ITD and NPM1 Mutations as Potential Molecular Biomarkers in Acute Myeloid Leukemia Patients with Normal Cytogenetics. (PubMed, Asian Pac J Cancer Prev)

This study found a significant association between patient survival outcomes and NPM1 mutation status, as well as the combined FLT3-ITD and NPM1 status. Profiling both NPM1 and FLT3-ITD mutations at the time of diagnosis serves as a robust prognostic marker in AML treatment. WT1 mutation status did not show a significant association with patient outcomes. Larger population studies may provide more relevant insights.

20 days ago

Journal

FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • WT1 (WT1 Transcription Factor)

FLT3-ITD mutation • NPM1 mutation • WT1 mutation • FLT3‐ITD + NPM1 mutation • FLT3-ITD mutation + WT1 mutation • FLT3‐ITD + WT1 mutation

20d

The prognostic significance of genetics in acute myeloid leukemia under venetoclax-based treatment. (PubMed, Ann Hematol)

Its combination with HMA or low-dose cytarabine (LDAC) has been shown to enhance the response rates and prolong the survival outcomes of older or unfit patients with AML. Additionally, we examined the response rates and survival outcomes of CBF-AML when treated with a VEN-based regimen. Moving forward, it is imperative that risk stratification for LIT becomes more nuanced to better align with the requirements of personalized diagnosis and treatment strategies.

20 days ago

Review • Journal • IO biomarker

FLT3 (Fms-related tyrosine kinase 3) • BCL2 (B-cell CLL/lymphoma 2) • NPM1 (Nucleophosmin 1)

FLT3-ITD mutation • NPM1 mutation

Venclexta (venetoclax) • cytarabine

23d

Measurable residual mutated IDH2 before allogeneic transplant for acute myeloid leukemia. (PubMed, Bone Marrow Transplant)

Patients testing negative for IDH2m prior to transplant had low relapse-related death, regardless of conditioning intensity. Post-transplant relapse rates for those with persistently detectable IDH2m in pre-transplant remission were lower after the FDA approval of enasidenib in August 2017.

23 days ago

Journal

FLT3 (Fms-related tyrosine kinase 3) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1)

FLT3-ITD mutation • IDH2 mutation • NPM1 mutation

Idhifa (enasidenib)

23d

Quizartinib with donor lymphocyte infusion for post-transplant relapse of FLT3-ITD-positive acute myeloid leukemia. (PubMed, Int J Hematol)

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.

23 days ago

Journal • Post-transplantation

FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1)

FLT3-ITD mutation • NPM1 mutation • DNMT3A mutation • DNMT3A mutation + NPM1 mutation • DNMT3A R882

Vanflyta (quizartinib)

28d

Identification of furo[2,3-d]pyrimidin-4-ylsulfanyl-1,3,4-thiadiazole derivatives as novel FLT3-ITD inhibitors. (PubMed, Eur J Med Chem)

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.

28 days ago

Journal

FLT3 (Fms-related tyrosine kinase 3)

FLT3-ITD mutation • FLT3 F691L • FLT3 expression • FLT3-ITD expression • FLT3-ITD mutation + FLT3 F691L

sorafenib • Vanflyta (quizartinib)

Anti-leukemic effects of Vernonia amygdalina extract. (PubMed, Braz J Biol)

The potential of alkaloid fractions on MOLM-13 cells was indicated by the robust cytotoxic effect of the alkaloid fractions, which resulted in over 50% cell mortality at 30 µg/ml. Our results suggest that VAE-96 may be a beneficial agent for the prevention and treatment of AML with FLT3-ITD mutation.

1 month ago

Journal

FLT3 (Fms-related tyrosine kinase 3)

FLT3-ITD mutation • FLT3 expression

CLAG±DAC regimen in the treatment of refractory/relapsed acute myeloid leukemia (PubMed, Zhonghua Xue Ye Xue Za Zhi)

Objective: To investigate the efficacy and prognosis of CLAG±DAC (Clofarabine, Cytarabine, G-CSF±Decitabine) chemotherapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML) . The remission rate was relatively higher in patients with R/R AML combined with FLT3-ITD mutation by applying the DAC+CLAG regimen (OR=10.84, 95%CI 1.48-288.50, P=0.04) . The CLAG±DAC regimen is considered effective in patients with R/R AML, whereas decitabine combined with the CLAG regimen is more suitable for patients with R/R AML combined with FLT3-ITD mutation.

1 month ago

Retrospective data • Journal

FLT3 (Fms-related tyrosine kinase 3) • DNMT3A (DNA methyltransferase 1)

FLT3-ITD mutation • DNMT3A mutation

cytarabine • decitabine • clofarabine

A Study of ASP2215 in Combination With Induction and Consolidation Chemotherapy in Patients With Newly Diagnosed Acute Myeloid Leukemia. (clinicaltrials.gov)

P1/2, N=97, Completed, Astellas Pharma Inc | Active, not recruiting --> Completed

1 month ago

Trial completion • Combination therapy

FLT3 (Fms-related tyrosine kinase 3)

FLT3-ITD mutation

cytarabine • Xospata (gilteritinib) • idarubicin hydrochloride

Tarlock K, Gerbing RB, Ries RE, et al. Prognostic impact of cooccurring mutations in FLT3-ITD pediatric acute myeloid leukemia. Blood Adv. 2024;8(9):2094-2103. (PubMed, Blood Adv)

No abstract available

1 month ago

Journal

FLT3 (Fms-related tyrosine kinase 3)

FLT3-ITD mutation • FLT3 mutation

Targeting rapid TKI-induced AXL upregulation overcomes adaptive ERK reactivation and exerts antileukemic effects in FLT3/ITD acute myeloid leukemia. (PubMed, Mol Oncol)

Finally, we observed that TKI-induced AXL upregulation occurs in patient samples, and combined inhibition of both AXL and FLT3 increased efficacy in our in vivo models. Taken together, these data suggest that AXL plays a role in adaptive resistance in FLT3/ITD AML and that combined AXL and FLT3 inhibition might improve FLT3/ITD AML patient outcomes.

1 month ago

Journal

FLT3 (Fms-related tyrosine kinase 3) • AXL (AXL Receptor Tyrosine Kinase)

FLT3-ITD mutation

Clinical features and long-term outcomes of pediatric patients with de novo acute myeloid leukemia in China with or without specific gene abnormalities: a cohort study of patients treated with BCH-AML 2005. (PubMed, Hematology)

Not achieving complete remission after induction 2 was found to be an independent prognostic factor for OS and EFS. These findings indicate that genetic abnormalities could be considered stratification factors, predict patient outcomes, and imply the application of targeted therapy.

1 month ago

Journal

FLT3 (Fms-related tyrosine kinase 3) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A) • RUNX1T1 (RUNX1 Partner Transcriptional Co-Repressor 1) • NUP214 (Nucleoporin 214) • CBFB (Core-Binding Factor Subunit Beta 2) • DEK (DEK Proto-Oncogene)

FLT3-ITD mutation • KIT mutation • KMT2A rearrangement • MLL rearrangement • DEK-NUP214 rearrangement

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.

2 months ago

Journal

FLT3 (Fms-related tyrosine kinase 3)

FLT3-ITD mutation • FLT3 mutation

Xospata (gilteritinib) • Vanflyta (quizartinib)

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.

2 months ago

Journal

FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1)

FLT3-ITD mutation • NPM1 mutation

Rydapt (midostaurin)

2ms

Quizartinib: a new hope in acute myeloid leukemia, an applied comprehensive review. (PubMed, Future Oncol)

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.

2 months ago

Review • Journal

FLT3 (Fms-related tyrosine kinase 3)

FLT3-ITD mutation • FLT3 mutation

Vanflyta (quizartinib)

2ms

Selective degradation of mutant FMS-like tyrosine kinase-3 requires BIM-dependent depletion of heat shock proteins. (PubMed, Leukemia)

The expression levels of HSP90 and HSP110 correlate with reduced AML patient survival (p < 0.1) and HSP90, HSP110, and BIM are linked to the expression of FLT3 in primary AML cells (p < 0.01). HSP90 suppresses degrader-induced FLT3-ITD elimination and thereby establishes a mechanistically defined feed-back circuit.

2 months ago

Journal

FLT3 (Fms-related tyrosine kinase 3) • BCL2L11 (BCL2 Like 11) • HSPH1 (Heat Shock Protein Family H (Hsp110) Member 1) • HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1Heat Shock Protein 90 Alpha Family Class A Member 1)

FLT3-ITD mutation • FLT3 mutation • FLT3 wild-type • FLT3 expression

2ms

Trial Evaluating MGTA-456 in Patients With High-Risk Malignancy (clinicaltrials.gov)

P2, N=22, Active, not recruiting, Masonic Cancer Center, University of Minnesota | Trial completion date: Jun 2024 --> Jun 2025

2 months ago

Trial completion date

FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • HLA-DRB1 (Major Histocompatibility Complex, Class II, DR Beta 1) • CEBPA (CCAAT Enhancer Binding Protein Alpha)

FLT3-ITD mutation • NPM1 mutation • MLL rearrangement • MLL rearrangement • CEBPA mutation • FLT3 wild-type

cyclophosphamide • melphalan • fludarabine IV • busulfan • spanlecortemlocel (MGTA-456)

2ms

MKIA-088-001: Study of NMS-03592088 in Patients With Relapsed or Refractory AML or CMML (clinicaltrials.gov)

P1/2, N=63, Terminated, Nerviano Medical Sciences | N=200 --> 63 | Trial completion date: Feb 2026 --> Aug 2024 | Recruiting --> Terminated | Trial primary completion date: Dec 2025 --> Aug 2024; Study stopped due to strategic reasons. The decision is not based on specific safety findings as the safety observed in the phase II part of the study is in line with what was reported in the phase I part.

2 months ago

Enrollment change • Trial completion date • Trial termination • Trial primary completion date

FLT3 (Fms-related tyrosine kinase 3)

FLT3-ITD mutation

NMS-088

2ms

Only FLT3-ITD co-mutation did not have a deleterious effect on acute myeloid leukemia patients with NPM1 mutation, but concomitant with DNMT3A co-mutation or a < 3log reduction of MRD2 predicted poor survival. (PubMed, Ann Hematol)

In AML patients with NPM1 mutation, the detrimental impact of FLT3-ITD mutation was exacerbated by DNMT3A co-mutation. Poor-risk younger patients identified by FLT3-ITD and DNMT3A co-mutations or MRD2 < 3 log reduction benefit from allo-HSCT.

2 months ago

Journal

FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1)

FLT3-ITD mutation • NPM1 mutation • DNMT3A mutation

2ms

Synergistic effect of FMS-like tyrosine kinase-3 (FLT3) inhibitors combined with a CDK7 inhibitor in FLT3-ITD-mutated acute myeloid leukemia. (PubMed, Blood Cancer J)

No abstract available

2 months ago

Journal

FLT3 (Fms-related tyrosine kinase 3)

FLT3-ITD mutation

2ms

A Clinical Trial to Evaluate Clifutinib in Patients with Relapsed or Refractory Acute Myeloid Leukemia(AML) (clinicaltrials.gov)

P1, N=75, Completed, Sunshine Lake Pharma Co., Ltd. | Recruiting --> Completed

2 months ago

Trial completion

FLT3 (Fms-related tyrosine kinase 3)

FLT3-ITD mutation

clifutinib (HEC73543)

2ms

Venetoclax and Quizartinib in Treating Patients With FLT3-mutated Recurrent or Refractory Acute Myeloid Leukemia (clinicaltrials.gov)

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.

2 months ago

Trial termination • Combination therapy

FLT3 (Fms-related tyrosine kinase 3) • BCL2 (B-cell CLL/lymphoma 2)

FLT3-ITD mutation

Venclexta (venetoclax) • Vanflyta (quizartinib)

2ms

ADMIRAL: A Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation (clinicaltrials.gov)

P3, N=371, Active, not recruiting, Astellas Pharma Global Development, Inc. | Trial completion date: Aug 2024 --> Dec 2024

2 months ago

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

CXCR4 as a therapeutic target in acute myeloid leukemia. (PubMed, Leukemia)

Additionally, we explore clinical implications, including prognosis, correlation with WBC count, blast count in the bone marrow and peripheral blood, as well as its association with FLT3-ITD, NPM1 mutations, and FAB classification. Finally, this paper extensively discusses drugs that specifically target the CXCL12-CXCR4 axis, including plerixafor/AMD3100, ulocuplumab, peptide E5, and motixafortide, shedding light on their potential therapeutic value in the treatment of AML.

2 months ago

Review • Journal

FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • CXCL12 (C-X-C Motif Chemokine Ligand 12)

FLT3-ITD mutation • NPM1 mutation

ulocuplumab (BMS-936564) • Aphexda (motixafortide) • plerixafor

2ms

Discovery of SILA-123 as a Highly Potent FLT3 Inhibitor for the Treatment of Acute Myeloid Leukemia with Various FLT3 Mutations. (PubMed, J Med Chem)

In in vivo studies, SILA-123 significantly suppressed the tumor growth in MV4-11 (50 mg/kg/d, TGI = 87.3%) and BaF3-FLT3-ITD-G697R (50 mg/kg/d, TGI = 60.0%) cell-inoculated allograft models. Our data suggested that SILA-123 might be a promising drug candidate for FLT3-ITD-positive AML.

2 months ago

Journal

FLT3 (Fms-related tyrosine kinase 3)

FLT3-ITD mutation • FLT3 mutation • FLT3 G697R

2ms

Relapse and resistance in acute myeloid leukemia post venetoclax: improving second lines therapy and combinations. (PubMed, Expert Rev Hematol)

The combined use of the BCL-2 inhibitor venetoclax with azacitidine now is the standard of care for patients with acute myeloid leukemia (AML) unfit for intensive chemotherapy with outcomes exceeding those achieved with hypomethylating agents alone. Further, strategies to overcome resistance including combinatorial regimens of hypomethylating agent (HMA) + venetoclax + inhibitors targeting actionable mutations like IDH1/2 or FLT3-ITD and the introduction of novel agents like menin-inhibitors are addressed. Although venetoclax is reshaping the treatment of unfit and fit AML patients, prognosis of patients after HMA/VEN failure remains dismal and strategies to abrogate primary and secondary resistance are an unmet clinical need.

2 months ago

Review • Journal • IO biomarker

FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)

FLT3-ITD mutation • IDH1 mutation

Venclexta (venetoclax) • azacitidine

3ms

Targeted gene sequencing and transcriptome sequencing reveal characteristics of NUP98 rearrangement in pediatric acute myeloid leukemia. (PubMed, Eur J Med Res)

These investigations contribute to the understanding of the molecular characteristics, risk stratification, and prognostic evaluation of pediatric AML patients.

3 months ago

Journal

FLT3 (Fms-related tyrosine kinase 3) • WT1 (WT1 Transcription Factor) • NUP98 (Nucleoporin 98 And 96 Precursor 2)

FLT3-ITD mutation • WT1 mutation • NUP93 mutation • NUP98 rearrangement

6ms

FLT3-ITD regulation of the endoplasmic reticulum functions in acute myeloid leukemia. (PubMed, Hematol Oncol)

Overexpression of ERO1α resulted essential for ITD mutant cells survival and chemoresistance and also played a crucial role in shaping the type of glucose metabolism in AML cells, being the mitochondrial pathway the predominant one in those with a higher ER stress (non-mutated cells) and the glycolytic pathway the predominant one in those with lower ER stress (mutated cells). Our data indicate that FLT3 mutational status dictates the route for glucose metabolism in an ERO1α depending on manner and this provides a survival advantage to tumors carrying these ITD mutations.

6 months ago

Journal

ER (Estrogen receptor) • FLT3 (Fms-related tyrosine kinase 3) • ERO1A (Endoplasmic Reticulum Oxidoreductase 1 Alpha)

FLT3-ITD mutation • FLT3 mutation

6ms

Comprehensive insights into AML relapse: genetic mutations, clonal evolution, and clinical outcomes. (PubMed, Cancer Cell Int)

Our study integrates karyotype, gene rearrangements, and gene mutation results to provide a further understanding of AML heterogeneity and evolution. We demonstrate the clinical relevance of specific mutations and clonal evolution patterns, emphasizing the need for personalized therapies and measurable residual disease monitoring in AML management. By bridging the gap between genetics and clinical outcome, we move closer to tailored AML therapies and improved patient prognoses.

6 months ago

Clinical data • Journal

TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • WT1 (WT1 Transcription Factor)

FLT3-ITD mutation • NPM1 mutation • DNMT3A mutation • RUNX1 mutation • WT1 mutation