&lt;p&gt;Midostaurin In Acute Myeloid Leukemia: An Evidence-Based Review And Patient Selection&lt;/p&gt;

Abbas, Hussein A.; Alfayez, Mansour; Kadia, Tapan M.; Ravandi‐Kashani, Farhad; Daver, Naval

doi:10.2147/cmar.s177894

Cited by 24 publications

(15 citation statements)

References 72 publications

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“…While not standard of care, use of single-agent maintenance FLT3 inhibitors, either in remission for patients not going to HCT or in post-HCT remission can be considered. This would ideally be done in a clinical trial setting, although off-label use of sorafenib or midostaurin maintenance is routinely practiced in the US ( 156 , 157 ). We await the results of ongoing clinical trials to help determine in which settings FLT3 inhibitor maintenance is most useful.…”

Section: Treating Flt3 -Mutated Aml Todaymentioning

confidence: 99%

FLT3 Mutations in Acute Myeloid Leukemia: Key Concepts and Emerging Controversies

2020

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The FLT3 receptor is overexpressed on the majority of acute myeloid leukemia (AML) blasts. Mutations in FLT3 are the most common genetic alteration in AML, identified in approximately one third of newly diagnosed patients. FLT3 internal tandem duplication mutations (FLT3-ITD) are associated with increased relapse and inferior overall survival. Multiple small molecule inhibitors of FLT3 signaling have been identified, two of which (midostaurin and gilteritinib) are currently approved in the United States, and many more of which are in clinical trials. Despite significant advances, resistance to FLT3 inhibitors through secondary FLT3 mutations, upregulation of parallel pathways, and extracellular signaling remains an ongoing challenge. Novel therapeutic strategies to overcome resistance, including combining FLT3 inhibitors with other antileukemic agents, development of new FLT3 inhibitors, and FLT3-directed immunotherapy are in active clinical development. Multiple questions regarding FLT3-mutated AML remain. In this review, we highlight several of the current most intriguing controversies in the field including the role of FLT3 inhibitors in maintenance therapy, the role of hematopoietic cell transplantation in FLT3-mutated AML, use of FLT3 inhibitors in FLT3 wild-type disease, significance of non-canonical FLT3 mutations, and finally, emerging concerns regarding clonal evolution.

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Section: Treating Flt3 -Mutated Aml Todaymentioning

confidence: 99%

FLT3 Mutations in Acute Myeloid Leukemia: Key Concepts and Emerging Controversies

2020

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“…Thus, while patients with FLT3 mutations have improved outcomes, both primary and secondary resistance remains unfortunately still common. Factors predictive of the development of resistance include the initial presence of multiple leukemic clones, low FLT3-mutant allelic ratio, or additional primary mutations in the FLT3 kinase domain [ 5 , 8 , 11 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Genomic markers of midostaurin drug sensitivity in FLT3 mutated and FLT3 wild-type acute myeloid leukemia patients

et al. 2020

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Acute myeloid leukemia (AML) is a heterogeneous malignancy with the most common genomic alterations in NPM1, DNMT3A, and FLT3. Midostaurin was the first FLT3 inhibitor FDA approved for AML and is standard of care for FLT3 mutant patients undergoing induction chemotherapy [1, 2]. As there is a spectrum of response, we hypothesized that biological factors beyond FLT3 could play a role in drug sensitivity and that select FLT3-ITD negative samples may also demonstrate sensitivity. Thus, we aimed to identify features that would predict response to midostaurin in FLT3 mutant and wild-type samples. We performed an ex vivo drug sensitivity screen on primary and relapsed AML samples with corresponding targeted sequencing and RNA sequencing. We observed a correlation between FLT3-ITD mutations and midostaurin sensitivity as expected and observed KRAS and TP53 mutations correlating with midostaurin resistance in FLT3-ITD negative samples. Further, we identified genes differentially expressed in sensitive vs. resistant samples independent of FLT3-ITD status. Within FLT3-ITD mutant samples, over-expression of RGL4, oncogene and regulator of the Ras-Raf-MEK-ERK cascade, distinguished resistant from sensitive samples. Overall, this study highlights the complexity underlying midostaurin response. And, our results suggest that therapies that target both FLT3 and MAPK/ERK signaling may help circumvent some cases of resistance.

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“…Indeed, many recently discovered kinase inhibitors are classified as BCS II compounds. [ 53–63 ] Another advantage is that, depending on the size of the particles and locations, subcutaneously administered micro‐ and nanoparticles tend to drain into the lymphatics, thus resulting in unpredictable local drug concentrations at the intended site of action and potential absorption into the systemic vasculature. Therefore, clEAK is a potential platform for delivering drug‐loaded particles and cells in vivo for sustained release.…”

Section: Discussionmentioning

confidence: 99%

Chemically‐Induced Cross‐Linking of Peptidic Fibrils for Scaffolding Polymeric Particles and Macrophages

Armen

Schueller

Velankar

et al. 2021

Macromolecular Bioscience

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EAK16‐II (EAK) is a self‐assembling peptide (SAP) that forms β‐sheets and β‐fibrils through ionic‐complementary interactions at physiological ionic strengths. The soft materials can be injected in vivo, creating depots of drugs and cells for rendering pharmacological and biological actions. The scope of the applications of EAK is sought to extend to tissues through which the flow of extracellular fluid tends to be limited. In such anatomical locales the rate and extent of the fibrilization are limited insofar as drug delivery and cellular scaffolding would be impeded. A method is generated utilizing a carbodiimide cross‐linker by which EAK fibrils are pre‐assembled yet remain injectable soft materials. It is hypothesized that the resulting de novo covalent linkages enhance the stacking of the β‐sheet bilayers, thereby increasing the lengths of the fibrils and the extent of their cross‐linking, as evidenced in Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, scanning electron microscopy, and atomic force microscopy analyses. The cross‐linked EAK (clEAK) retains polymeric microspheres with an average diameter of 1 µm. Macrophages admixed with clEAK remain viable and do not produce the inflammatory mediator interleukin‐1β. These results indicate that clEAK should be investigated further as a platform for delivering particles and cells in vivo.

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<p>Midostaurin In Acute Myeloid Leukemia: An Evidence-Based Review And Patient Selection</p>

Cited by 24 publications

References 72 publications

FLT3 Mutations in Acute Myeloid Leukemia: Key Concepts and Emerging Controversies

FLT3 Mutations in Acute Myeloid Leukemia: Key Concepts and Emerging Controversies

Genomic markers of midostaurin drug sensitivity in FLT3 mutated and FLT3 wild-type acute myeloid leukemia patients

Chemically‐Induced Cross‐Linking of Peptidic Fibrils for Scaffolding Polymeric Particles and Macrophages

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