midostaurin

In this review, we summarize the human myeloid leukemia cell lines that express mutated FLT3 and the effect of several drugs on these cell lines. Our aim in this review is to provide clinicians with a basic science understanding of human myeloid leukemia cell lines and to provide scientific researchers with the clinical implications of FLT3 signaling inhibition.

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.

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.

The subsequent generation of potent and selective inhibitors has transformed outcomes, culminating in FDA approvals of midostaurin, quizartinib, and gilteritinib. These pathways sustain measurable residual disease (MRD), the key predictor of relapse. Rational combination strategies and MRD-directed approaches are therefore essential to fully realize the curative potential of FLT3 inhibition.

P2, N=22, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Oct 2030 --> Sep 2029

CAFs exhibited broad sensitivity to multikinase inhibitors, with dasatinib, midostaurin, and FGFR inhibitors (AZD4547, erdafitinib) emerging as top stromal-directed candidates. These findings underscore the plasticity of prostate CAFs and reveal actionable vulnerabilities, supporting the development of targeted stromal therapies to disrupt tumor-stroma interactions in PCa.

P1, N=21, Completed, Uma Borate | Active, not recruiting --> Completed

Molecular analyses confirmed the KIT mutation in multiple non-infiltrated tissues, demonstrating the germline nature of the mutation. Despite targeted treatment with pharmacokinetically monitored midostaurin and adjunct therapies, the disease progressed rapidly, resulting in fatal multiorgan failure.

P=N/A, N=5000, Recruiting, Acute Leukemia French Association | N=2500 --> 5000

First-generation multi-kinase inhibitors like midostaurin and second-generation agents such as gilteritinib and quizartinib have shown success. It discusses how these agents, including small-molecule like STI-8591, compounds 36 and 80 and novel therapeutic strategies such as CLN-049, and SENTI-202, are designed to combat resistance. The goal is to provide a medicinal chemistry perspective to provide insights for the design of novel small-molecule FLT3i.

Although this study did not focus on outcomes, no significant differences in post-alloHCT relapse by PDC were found. Discontinuation risk was higher for midostaurin (HR = 2.79, p = .0005) and sorafenib (HR = 1.74, p = .046) versus gilteritinib in patients with Commercial insurance vs Medicare/Medicaid (HR = 1.68, p = .019).

We evaluated the safety and efficacy of the combination of daunorubicin, cytarabine (DA), gemtuzumab ozogamicin (GO) and midostaurin (DAGO+m) for younger patients with newly diagnosed FLT3mut AML in the UK NCRI AML19 trial...DAGO2+m will now be evaluated in a randomised study (OPTIMISE-FLT3, ISRCTN 34016918). Trial: ISRCTN78449203.