FLT3 Inhibitors Research Articles

Discovery and Chemical Exploration of Spiro[Benzofuran-3,3'-Pyrroles] Derivatives as Innovative FLT3 Inhibitors for Targeting Acute Myeloid Leukemia.

This study aimed at the synthesis of several spiro[benzofuran-3,3'-pyrroles] derivatives by a three-component reaction conducted by mixing DMAD, N-bridgehead het-erocycles, and benzofuran-2,3-diones in dichloromethane at room temperature for 24 h. Moreover, in vitro evaluation of their cytotoxicity affinities against FMS-like tyrosine kinase 3 was carried out. The objective of this study was to use a one-pot, three-component reaction to synthesize a novel set of spiro[benzofuran-3,3'-pyrroles] derivatives. A novel set of spiro[benzofuran-3,3'-pyrroles] ((11-13)a-e) was synthesized by a one-pot three-component reaction involving dimethyl acetylenedicarboxylate, N-bridgehead heterocycles and benzofuran-2,3-diones in dichloromethane at room temperature for 24 h. The compounds were analyzed using NMR 1H, 13C, 2D-NMR (COSY, HMQC, HMBC), and HRMS. Docking simulations were conducted to elucidate the anticancer activity of synthe-sized compounds on FLT3 protein, with Gilteritinib as a reference for comparison. This study demonstrated the successful design, synthesis, and biological evaluation of spiro[benzofuran-3,3'-pyrroles] derivatives as FLT3 inhibitors for AML treatment. The synthesized compounds demonstrated promising binding affinities and significant inhibitory activity against FLT3 kinase. The inhibitors (11a, 11b, 11c, 12d, and 12e) exhibited excellent selectivity profiles against FLT3. Particularly, compound 12e showed strong binding affinity and potent inhibitory activity (IC50 = 2.5 μM). Fifteen new synthetic spiro[benzofuran-3,3'-pyrroles] were prepared, character-ized, and evaluated for cytotoxicity affinities against FMS-like tyrosine kinase 3. Compound 12e showed strong binding affinity and potent inhibitory activity (IC50 = 2.5 μM), making it a promising candidate for further development as a therapeutic option for AML treatment. These findings lay the groundwork for further optimization and development of spiro[benzo-furan-3,3'-pyrroles] derivatives as potential therapeutics for AML treatment. Further studies are needed to explore their efficacy and safety profiles in preclinical and clinical settings.

Design, Synthesis, and Biological Activities Evaluation of Type I FLT3 Inhibitors for the Treatment of Acute Myeloid Leukemia.

The abnormal overexpression of FLT3 kinase is intimately associated with pathogenesis of acute myeloid leukemia (AML), positioning FLT3 inhibitors as pivotal therapeutic agents. Despite the availability of three FDA-approved FLT3 inhibitors, their clinical utility is hampered by resistance stemming from tyrosine kinase domain (TKD) mutations. Through an integrative analysis of case studies, we identified a potential advantage of type I FLT3 inhibitors in overcoming TKD mutation-induced resistance. Structure-activity relationships (SAR) analysis indicated that FW-1 exhibited over 50% inhibition against FLT3 at a concentration of 1 μM and demonstrated potent activity against AML cell lines MV4-11 (IC50 = 2.68 μM) and MOLM-13 (IC50 = 1.03 μM). In our cellular mechanistic studies, FW-1 also effectively induced apoptosis by arresting cell cycle progression in the G0/G1 phase. This study introduces FW-1 as a promising lead for type I FLT3 inhibitor, warranting further optimization.

The Dual PIM/FLT3 Inhibitor MEN1703 Combines Synergistically With Gilteritinib in FLT3-ITD-Mutant Acute Myeloid Leukaemia.

MEN1703 is a first-in-class, oral, Type I dual PIM/FMS-like tyrosine kinase 3 inhibitor (FLT3i) investigated in a Phase I/II DIAMOND-01 trial in patients with acute myeloid leukaemia (AML). Gilteritinib is a highly potent and selective oral FLT3i approved for the treatment of relapsed/refractory AML with FLT3 mutations. Although gilteritinib showed strong single-agent activity in FLT3-mutated AML, the development of gilteritinib resistance limits response durability, indicating the importance of novel combination strategies to improve disease outcome. PIM kinases govern FLT3-ITD signalling and increased PIM kinase expression is found in samples from AML patients relapsing on FLT3i. Here, we report that the simultaneous inhibition of PIM and FLT3, through the combination of MEN1703 and gilteritinib, can consistently improve the invitro/in vivo antitumor activity over the single agents, demonstrating the benefit of this combination. Moreover, we demonstrate that resistance to gilteritinib can be circumvented by combining MEN1703 with gilteritinib. MEN1703 interferes with FLT3 upregulation, Mcl-1 overexpression and PIM kinase signalling, which are all involved in FLT3i resistance. We also show that MEN1703 downregulates stromal cytokines that promote cytokine-mediated resistance of AML blast cells to FLT3 inhibition. These results demonstrate the importance of the combination approach to overcome microenvironment-mediated resistance to FLT3 inhibitors.

FLT3 mutation-related immune checkpoint molecule absent in melanoma 2 (AIM2) contributes to immune infiltration in pediatric and adult acute myeloid leukemia: evidence from bioinformatics analysis.

The use of FMS-like tyrosine kinase 3 (FLT3) as a crucial target for kinase inhibitors is well established, but its association with immune infiltration remains unclear. This study aimed to explore the relationship between FLT3 mutations and immune checkpoint molecules (ICMs) in patients with acute myeloid leukemia (AML). The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases were used to identify the ICMs associated with FLT3 mutations. A Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and gene set enrichment analysis (GSEA) were conducted to analyze the signaling pathways related to the ICMs. The single-sample GSEA (ssGSEA), Cibersort, and estimate algorithms were used to assess immune cell infiltration in AML. Absent in melanoma 2 (AIM2) exhibits elevated expression levels in AML patients harboring FLT3 mutation, contributing significantly to the progress of AML and establishing of an immunosuppressive microenvironment. AIM2 expression significantly correlated with sensitivity of clinically relevant drugs in ex vivo assays of AML. Additionally, AIM2 demonstrates substantial prognostic value and holds promise as a prospective immunotherapeutic target for AML. Our findings indicate a significant correlation between AIM2 and immune infiltration in AML cases, potentially affecting the presence of neutrophils, macrophages, effector memory T cells (Tem), and monocytes. Furthermore, AIM2 is closely linked to various signaling pathways, such as immune cytokine release, immune antigen presentation, and inflammasome signaling, which could play a role in immune cell enrichment in AML. Our study identified AMI2 as an ICM linked to FLT3 mutations. AMI2 may be involved in the activation of suppressive immune cell populations, such as macrophages, neutrophils, and monocytes. AIM2 could serve as a promising immunotherapeutic target for combination therapy with FLT3 inhibitors in AML.

Discovery of natural compounds as novel FMS-like tyrosine kinase-3 (FLT3) therapeutic inhibitors for the treatment of acute myeloid leukemia: An in-silico approach

FLT3 mutations, observed in approximately 30–35% of Acute Myeloid Leukemia (AML) cases, drive leukemic proliferation and survival pathways, presenting a significant challenge in clinical management. To address this therapeutic need, we employed a comprehensive computational approach integrating pharmacophore screening, molecular docking, ADMET analysis, and molecular dynamics simulations to identify potent inhibitors targeting FLT3. Utilizing ligand-based pharmacophore models generated from experimentally proven FLT3 inhibitors from BindingDB, we screened over 400,000 natural compounds from the COCONUT database. Hits identified through pharmacophore screening underwent further evaluation via Lipinski and Golden triangle criteria to ensure drug-like properties. Molecular docking against the FLT3 receptor, combined with ADMET analyses, facilitated the prioritization of lead compounds. Subsequently, three promising candidates were subjected to molecular dynamics simulations to assess binding stability. Our findings reveal three top-performing compounds, demonstrating robust and stable binding affinity and favorable ADMET characteristics. These compounds hold promise as potential scaffolds or leads for developing novel FLT3 inhibitors in AML therapy.

Central nervous system relapse after allogeneic HCT in FLT3-mutated AML.

Central nervous system (CNS) relapse in acute myeloid leukemia (AML) is rare, but prognostically extremely unfavorable and associated with very high mortality rates. Aim of our single-center study was to define risk factors for CNS relapse in patients with FLT3-mutated AML after allogeneic hematopoietic cell transplantation (HCT) and to determine the impact of pre-emptive or salvage therapy with FLT3-inhibitors (FLT3i) on occurrence of CNS relapse and overall prognosis. We analyzed 39 FLT3-mutated AML patients who were treated with intensive induction therapy and consecutively underwent HCT at our institution. We observed that the remission status before HCT was strongly associated with relapse probability. Notably, FLT3-mutated AML showed a high propensity for CNS relapse with a cumulative incidence of 50% (95% confidence interval [CI], 16-77) at 2 years in non-responders pre-HCT compared to 0% in responders (cause-specific hazard ratio, 24.5, 95% CI, 2.9-206.2; p = 0.003). This was not abrogated by pre-emptive or salvage therapy with FLT3i in first relapse. Targeted therapies prior to transplant, use of intrathecal chemoprophylaxis or closer monitoring may be considered in patients with FLT3-mutated AML with active disease prior to HCT in order to prevent CNS relapse.

Mutation- and MRD-informed treatments for transplant-ineligible patients.

The ongoing development of molecularly targeted therapies in addition to the new standard of care combination of azacitidine and venetoclax (AZA-VEN) has transformed the prognostic outlook for older, transplant-ineligible patients with acute myeloid leukemia (AML). While conventional treatments, such as standard anthracycline and cytarabine- based chemotherapy or hypomethylating agent (HMA) monotherapy, are associated with a generally poor prognosis in this patient population, the use of these novel regimens can result in long-lasting, durable remissions in select patient subgroups. Furthermore, the simultaneous discovery of resistance mechanisms to targeted therapies and AZA-VEN has enabled the identification of patient subgroups with inferior outcomes, leading to the development, of new risk-stratification models and clinical investigations incorporating targeted therapies using an HMA-VEN-based platform. Treatments inclusive of IDH1, IDH2, FLT3, and menin inhibitors combined with HMA-VEN have additionally demonstrated safety and high rates of efficacy in early-phase clinical trials, suggesting these regimens may further improve outcomes within select subgroups of patients with AML in the near future. Additional studies defining the prognostic role of measurable residual disease following VEN-based treatment have further advanced prognostication capabilities and increased the ability for close disease monitoring and early targeted intervention prior to morphologic relapse. This review summarizes these recent developments and their impact on the treatment and survival of transplant-ineligible patients living with AML.

A GIMEMA survey on therapeutic use and response rates of FLT3 inhibitors in acute myeloid leukemia: Insights from Italian real-world practice.

Given the limited data on the real-life therapeutic use of feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3) inhibitors in Italy, we surveyed investigators at 59 Italian hematology centers to gain insight into the proportion of acute myeloid leukemia (AML) patients receiving FLT3 inhibitors and we collected data on the efficacy and safety of these agents. The survey results showed that in the real-life setting the response rate of the 3/7 + midostaurin regimen in newly diagnosed FLT3-mutated AML and of gilteritinib in the relapsed/refractory AML were comparable to that reported in the registrative clinical trials. The 3/7 + midostaurin treatment resulted in a 63% of complete remission (CR) rates and gilteritinib in a 44% of CR rates. The discontinuation rate of gilteritinib for intolerance or toxicity was low (accounting for 4% of treated cases).

Cooperative blockade of FLT3 and ALK synergistically suppresses growth of osteosarcoma.

Osteosarcoma is a common primary malignant bone tumor in children and young adults, with limited progress in improving survival rates for metastatic or recurrent cases. Kinase inhibitors have emerged as potential treatments for osteosarcoma due to the critical role kinases play in regulating cellular networks. However, single-agent kinase inhibitors often face challenges due to the activation of compensatory oncogenic signaling pathways, which can undermine treatment efficacy. In this study, a combination screening of FDA-approved kinase inhibitors was conducted in osteosarcoma cells. We identified the combination of ALK inhibitor and FLT3 inhibitor as a potent kinase-based therapeutic strategy for osteosarcoma. Our results showed that the combinatorial treatment synergistically suppressed osteosarcoma in cell lines, patient-derived organoids, and xenograft models. Mechanistically, the inhibition of FLT3 significantly promoted the activation of ALK, which subsequently enhanced its downstream PI3K/Akt and MAPK signaling pathways. The combinatorial use of an ALK inhibitor could reverse this process. Thus, our study demonstrates that the cooperative blockade of FLT3 and ALK synergistically suppresses osteosarcoma, providing a potential alternative for its treatment.

Contemporary strategies and challenges in the management of acute Leukemia: An in-depth analysis

Abstract. This article provides a detailed overview of the current state of acute leukemia treatment, encompassing chemotherapy, molecular-targeted therapy, bone marrow transplantation, and the evolving role of personalized medicine. It delves into standard chemotherapy regimens, their efficacy, and adverse effects, highlighting the challenges posed by resistance and relapses. The significant impact of molecular-targeted therapy, including tyrosine kinase inhibitors and FLT3 inhibitors, is examined, along with their integration with traditional chemotherapy. The article also discusses bone marrow transplantation, comparing allogeneic and autologous transplants and conditioning regimens. Personalized medicine, driven by genetic profiling and the emergence of novel therapies like CAR-T and immunomodulatory drugs, is explored for its potential to revolutionize treatment approaches. The global trends in acute leukemia, including epidemiological shifts and disparities in access to care, are analyzed, alongside the economic aspects influencing treatment accessibility and policy decisions. This comprehensive review underscores the multifaceted nature of acute leukemia treatment and the ongoing efforts to enhance patient outcomes while addressing global disparities in care.

α-Triazolylboronic Acids: A Novel Scaffold to Target FLT3 in AML.

The treatment of acute myeloid leukemia (AML) presents a challenge to current therapies because of the development of drug resistance. Genetic mutation of FMS-like tyrosine kinase-3 (FLT3) is a target of interest for AML treatment, but the use of FLT3-targeting agents on AML patients has so far resulted in poor overall clinical outcomes.[1] The incorporation of the boronic group in a drug scaffold could enhance the bioavailability and pharmacokinetic profile of conventional anticancer chemotypes. Boronic acids represent an intriguing and unexplored class of compounds in the context of AML, and they are only scantly reported as inhibitors of protein kinases. We identified α-triazolylboronic acids as a novel chemotype for targeting FLT3 by screening a library of structurally heterogeneous in-house boronic acids. Selected compounds show low micromolar activities on enzymatic and cellular assays, selectivity against control cell lines and a recurring binding mode in in-silico studies. Furthermore, control analogues synthesized ad hoc and lacking the boronic acid are inactive, confirming that this group is essential for the activity of the series. All together, these results suggest α-triazolylboronic acids could be a promising novel chemotype for FLT3 inhibition, laying the ground for the design of further compounds.

The Role and Mechanism of NDUFS2 in FLT3-Mutated Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a common hematologic malignancy characterized by poor prognosis and high recurrence rates. Disease relapse and the lack of precise treatment tailored to each patient pose challenges in AML treatment. The mitochondria, crucial for cellular energy center and signaling, are essential for maintaining the metabolic flexibility of tumor cells. However, their complex and elusive functions in cancer pose challenges for targeted mitochondrial therapies. Therefore, there is an urgent need to discover new mitochondrial-targeted drugs and novel targeted therapeutic strategies for AML. In this study, we explored the expression of NDUFS2 in AML using real-time quantitative PCR and immunohistochemistry. Subsequently, we performed knockdown and overexpression experiments of NDUFS2 in MOLM-13 and MV4-11 cell lines and assessed its effects on AML cell proliferation, apoptosis, cell cycle, reactive oxygen species (ROS) levels, and mitochondrial membrane potential using flow cytometry. Additionally, we evaluated the impact of NDUFS2 on mitochondrial morphology using transmission electron microscopy and confocal microscopy. Seahorse energy metabolism assay kits were utilized to examine the influence of NDUFS2 on AML cell energy metabolism, while mitochondrial complex I and II assay kits were employed to assess its effect on mitochondrial enzyme activity. Furthermore, Western blot analysis was conducted to evaluate the effects of NDUFS2 knockdown on the AMPK pathway, endoplasmic reticulum stress pathway, and apoptosis pathway in AML cells, with reverse validation performed using AMPK and PERK inhibitors. Finally, we established xenograft models of FLT3-mutated AML tumor cells to investigate the impact of NDUFS2 on tumor growth and the synergistic effect of NDUFS2 with FLT3 inhibitor Gilteritinib against FLT3-mutated AML. Concurrently, we developed xenograft models of relapsed/refractory FLT3-mutated AML patients to explore the synergistic effect of mitochondrial complex I inhibitor IACS-010759 with Gilteritinib against relapsed/refractory FLT3-mutated AML. We validated that NDUFS2 exhibits the highest expression level in AML, especially in FLT3-mutated AML cells. Knockdown of NDUFS2 inhibited the proliferation of FLT3-mutated AML cell lines, caused cell cycle arrest, induced mitochondrial fission, decreased mitochondrial membrane potential, increased ROS levels, impaired the function of mitochondrial complex I, altered cellular energy metabolism by reducing oxidative phosphorylation (OXPHOS) levels, and activated the AMPK/PERK pathways, leading to apoptosis. Knockdown of NDUFS2 enhanced the cytotoxicity of Gilteritinib against FLT3-mutated AML cells, and the combination of NDUFS2 knockdown and Gilteritinib reduced mitochondrial membrane potential, increased ROS levels, and activated the AMPK/PERK pathways to induce cell apoptosis. In vivo experiments confirmed that knockdown of NDUFS2 enhanced the antitumor effect of Gilteritinib. Furthermore, IACS-010759 and Gilteritinib exhibited synergistic activity against FLT3-mutated AML by synergistically inducing cell apoptosis, inhibiting cell proliferation, affecting mitochondrial function, activating the AMPK/PERK pathways. In vivo experiments in mice also confirmed the synergistic killing effect on FLT3-mutated AML tumor cells without affecting normal hematopoiesis or the normal function of other organs. We found that NDUFS2 is associated with the prognosis of AML and is highly expressed in FLT3-mutated AML. Knockdown of NDUFS2 suppresses the proliferation of FLT3-mutated AML cells, induces excessive ROS production, disrupts mitochondrial membrane potential, inhibits the enzyme activity of mitochondrial complex I, thereby suppressing OXPHOS, decreasing ATP production, and activating the AMPK/PERK pathways, ultimately leading to cell apoptosis. Targeting NDUFS2 can exert synergistic anti-FLT3-mutated AML effects with FLT3 inhibitors by activating the AMPK/PERK pathways. Additionally, the inhibition of mitochondrial complex I by the inhibitor IACS-010759 can synergize with Gilteritinib to combat FLT3-mutated AML. This indicates that NDUFS2 may serve as a potential target for the treatment of FLT3-mutated AML and enhance the sensitivity of targeted drugs to FLT3-mutated AML.

EP0042, a Dual FLT3 and Aurora Kinase Inhibitor: Final Results of Dose Escalation and Optimization Cohorts from a Phase I/IIa Study in Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML), Chronic Myelomonocytic Leukemia (CMML) or Myelodysplastic Syndrome (MDS)

EP0042, a Dual FLT3 and Aurora Kinase Inhibitor: Final Results of Dose Escalation and Optimization Cohorts from a Phase I/IIa Study in Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML), Chronic Myelomonocytic Leukemia (CMML) or Myelodysplastic Syndrome (MDS)

Installment of Automation and Modernized Culture Methods Updates a Drug-Sensitivity Screening Platform and Paves the Way to Next-Generation of Precision Medicine

Since the field of drug discovery has seen a rise in the use of primary tumor specimens (PTS) derived from patients with hematological malignancies as live materials in ex vivo drug treatments in late 2010s, they have discovered many intriguing phenotypes of AML cells that can lead to therapeutic insights of this disease category. However, when we consider the fact that current methods in ex vivo drug screenings are not using the most updated culture and cell processing methodology, it is highly expected that modernization of cell processing and analyzing procedures will enable us to detect phenotypes of PTS at a higher resolution. Herein, we have installed our own updated methods in multimodal categories. Even though the number of primary tumor specimens in the screening cohort is not comparable to the ones in other studies using AML PTS, (24 cases of AML, 3 cases of CML, and 1 case of MPN, while we ongoingly recruit more cells), our approach is characterized by its full-automation both in cell processing and data acquisitions using multicolor flow cytometry, as well as updated ex vivo culture methods after optimization using different culture media. We harvested cells for flow cytometry as of day 0, 3, and 6. In a monotherapy section, 24 compounds (6 conventional chemotherapy drugs, 10 epigenetic inhibitors, 4 kinase inhibitors including a FLT3 inhibitor, 3 signal transduction inhibitors, and Venetoclax) were included, while 3 different combination therapies (IDR+ AraC, Ven + 5-Aza, and Ven + AraC) were performed using 6x6 matrix layouts. Drugs were prepared in 384-well plates using a computationally controlled drug dispenser. Using those updated systems, we could discover; 1) Those fully-automated high-throughput platform needs their own optimizations regarding seeding numbers, liquid handling methods, and optimal plastic vessels with low inherent variations of results. 2) PTS are well tolerable to up to 6 days of ex vivo culture 3) Choosing optimal time points for each of the drugs ensures more accurate representation of their drug activities. For example, epigenetic inhibitors have tendency to show better results on day 6 rather than day 3. 4) Multicolor flow cytometry provides previously unseen differences in drug activity profiles upon different clusters, which had not been visible from bulk-grade sensitivity profiling, such as colorimetric viability assay. Those specimens were genetically profiled by whole genome/ exome sequencing, as well as other multi-omics analyses (Bulk RNA seq, methylome analysis, and scRNA seq). 5) Optimizations of ex vivo culture methods not only ensure our better quality of these 6-day drug effects, but also extend the possibility of PTS for further applications by allowing leukemia stem cell fractions to be maintained in vitro for longer periods of time. They include long-term culture and ex vivo expansion of leukemic stem cells using the most updated serum-free liquid culture, and further gene modifications using various vectors. Collectively, our platform for DSS confers next-generation use of primary patient-derived biomaterials so that even a small- to middle-sized group can conduct these complexed assays to test their hypotheses based on primary specimens, which had been possible only in high-volume multi-institutional alliances.

T/NK Cell-Associated Transcriptomic Profile Informs Response to FLT3 Inhibitors in Acute Myeloid Leukemia

T/NK Cell-Associated Transcriptomic Profile Informs Response to FLT3 Inhibitors in Acute Myeloid Leukemia

Molecular Mechanisms Associated with Autophagy Inhibition to Overcome Resistance to FLT3 Inhibitors

Molecular Mechanisms Associated with Autophagy Inhibition to Overcome Resistance to FLT3 Inhibitors

The Immunomodulatory Effect of Different FLT3 Inhibitors on Dendritic Cells.

FMS-like tyrosine kinase 3 (FLT3) mutations or internal tandem duplication occur in 30% of acute myeloid leukemia (AML) cases. In these cases, FLT3 inhibitors (FLT3i) are approved for induction treatment and relapse. Allogeneic hematopoietic stem cell transplantation (alloHSCT) remains the recommended post-induction therapy for suitable patients. However, the role of FLT3i therapy after alloHSCT remains unclear. Therefore, we investigated the three currently available FLT3i, gilteritinib, midostaurin, and quizartinib, in terms of their immunosuppressive effect on dendritic cells (DCs). DCs are professional antigen-presenting cells inducing T-cell responses to infectious stimuli. Highly activated DCs can also cause complications after alloHSCT, such as triggering Graft versus Host disease, a serious and potentially life-threatening complication after alloHSCT. To study the immunomodulatory effects on DCs, we differentiated murine and human DCs in the presence of FLT3i and performed immunophenotyping by flow cytometry and cytokine measurements and investigated gene and protein expression. We detected a dose-dependent immunosuppressive effect of midostaurin, which decreased the expression of costimulatory markers like CD86, and found a reduced secretion of pro-inflammatory cytokines such as IL-12, TNFα, and IL-6. Mechanistically, we show that midostaurin inhibits TLR and TNF signaling and NFκB, PI3K, and MAPK pathways. The immunosuppressive effect of gilteritinib was less pronounced, while quizartinib did not show truncation of relevant signaling pathways. Our results suggest different immunosuppressive effects of these three FLT3i and may, therefore, provide an additional rationale for optimal maintenance therapy after alloHSCT of FLT3-positive AML patients to prevent infectious complications and GvHD mediated by DCs.

A Combinatorial Functional Precision Medicine Platform for Rapid Therapeutic Response Prediction in AML.

Despite advances made in targeted biomarker-based therapy for acute myeloid leukemia (AML) treatment, remission is often short and followed by relapse and acquired resistance. Functional precision medicine (FPM) efforts have been shown to improve therapy selection guidance by incorporating comprehensive biological data to tailor individual treatment. However, effectively managing complex biological data, while also ensuring rapid conversion of actionable insights into clinical utility remains challenging. We have evaluated the clinical applicability of quadratic phenotypic optimization platform (QPOP), to predict clinical response to combination therapies in AML and reveal patient-centric insights into combination therapy sensitivities. In this prospective study, 51 primary samples from newly diagnosed (ND) or refractory/relapsed (R/R) AML patients were evaluated by QPOP following exvivo drug testing. Individualized drug sensitivity reports were generated in 55/63 (87.3%) patient samples with a median turnaround time of 5 (4-10) days from sample collection to report generation. To evaluate clinical feasibility, QPOP-predicted response was compared to clinical treatment outcomes and indicated concordant results with 83.3% sensitivity and 90.9% specificity and an overall 86.2% accuracy. Serial QPOP analysis in a FLT3-mutant patient sample indicated decreased FLT3 inhibitor (FLT3i) sensitivity, which is concordant with increasing FLT3 allelic burden and drug resistance development. Forkhead box M1 (FOXM1)-AKT signaling was subsequently identified to contribute to resistance to FLT3i. Overall, this study demonstrates the feasibility of applying QPOP as a functional combinatorial precision medicine platform to predict therapeutic sensitivities in AML and provides the basis for prospective clinical trials evaluating exvivo-guided combination therapy.

FLT3 inhibitors potentially improve response rates in acute myeloid leukemia harboring t(6;9)(DEK::NUP214): the Mayo Clinic experience.

FLT3 inhibitors potentially improve response rates in acute myeloid leukemia harboring t(6;9)(DEK::NUP214): the Mayo Clinic experience.

Histamine dihydrochloride and low-dose interleukin-2 has anti-leukemic efficacy in NPM1-mutated and myelomonocytic/monocytic acute myeloid leukemia.

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