FLT3-ITD mutation

OS was additionally negatively affected when the ten genes were unmutated. Notably, outcomes were excellent for SAR mutations (2-year LFS 76%, OS 84%), indicating allo-HCT in CR1 can overcome their adverse risk at diagnosis.

Moreover, FTY720 co-treatment resensitized G12D NRAS -mutated M14(R)701 cells to gilteritinib in vivo. Co-treatment inactivated ERK, transcriptionally downregulated SPHK1, and inactivated downstream AKT, p70S6K and BAD, with inactivation abrogated by constitutive SPHK1 expression. The clinically applicable S1PR modulators fingolimod and mocravimod resensitize NRAS -mutated FLT3-ITD AML cells to FLT3 inhibitors, supporting potential clinical efficacy of these combinations.

Better responses were observed in patients treated with the venetoclax in combination with hypomethylating agent (VEN + HMA) regimen compared to those receiving the '3 + 7' regimens (composite complete remission [CRc], 53.8% vs. 30.2%; p = 0.018)...In conclusion, molecular factors matter in influencing the prognosis of TP53-mutant AML patients. Among them, TP53 mutation sites merit particular attention.

This study confirmed well-known gene-disease associations in myeloid malignancies but found no significant link between parvovirus B19 infection and specific somatic mutations or disease subtypes. These findings suggest that B19 infection may be incidental, underscoring the need for larger-scale studies to clarify its clinical relevance in patients with myeloid malignancies.

This study delineated the genetic landscape of pAML in Southwest China and explored the prognostic value of gene fusions and mutations in early and long-term outcomes. These findings provide a foundation for understanding the genetic heterogeneity of pAML and offer evidence for the development of precision medicine approaches.

Resistance mechanisms, particularly following venetoclax, remain a therapeutic challenge. These data support the continued use of gilteritinib beyond second-line and highlight the need for prospective studies to optimize sequencing strategies.

Here, we applied our recently developed single-cell lineage tracing method ReSisTrace to identify cells that are intrinsically resistant or sensitive to the FLT3 inhibitors midostaurin and quizartinib in AML with FLT3-ITD mutations...In addition, in an FLT3-ITD-positive AML patient-derived xenograft (PDX) mouse model, the CC-90009 and quizartinib combination showed significantly higher anti-tumor efficacy and prolonged overall survival compared to either treatment alone...Vistusertib (mTOR inhibitor), linsitinib (IGF1R and insulin receptor inhibitor), and meisoindigo (IGF1R and Src family kinase inhibitor), all inhibiting pathways parallel to or downstream of oncogenic FLT3 signaling, were predicted and validated to sensitize FLT3-mutated cell lines and primary cells to FLT3 inhibitors. Collectively, these findings demonstrate the ability of ReSisTrace to unveil pre-existing transcriptional features of treatment vulnerability in hematological cancers and elucidate strategies for enhancing FLT3 inhibitor treatment efficacy in FLT3-ITD-mutated AML.

Although the European LeukemiaNet (ELN) classifications (2017, 2022) for AML have been used to stratify outcomes for patients receiving intensive chemotherapy, application to patients receiving less intensive therapy, like azacitidine plus venetoclax, has been less satisfactory. Overall, these data support the importance of molecular sub-classification in defining treatment outcomes to venetoclax-based therapies. NCT02287233; NCT03069352.

PSP-0119 is metabolically stable, retaining 71% of parent compound at 60 minutes in human liver microsomes. In summary, IRAK4 degradation via PSP-0119 as a promising therapeutic strategy for treatment of FLT3-mutant AML.

P2, N=22, Active, not recruiting, Masonic Cancer Center, University of Minnesota | Completed --> Active, not recruiting | Trial completion date: Dec 2023 --> Dec 2026

WT1 overexpression and KIT mutations (in selected cytogenetic contexts) are validated as adverse prognostic indicators in pediatric AML. Conversely, FLT3-ITD and CEBPA mutations require nuanced interpretation due to variable effects and methodological heterogeneity. These findings support the integration of molecular profiling into pediatric AML risk stratification and underscore the need for harmonized, prospective studies to refine prognostic models in this population.

Our study confirms NPM1 mutations independently predict improved survival in pediatric AML, though outcomes remain inferior to those reported from high income countries. Larger studies are needed in pediatric AML due to its rare occurrence.