Treatment Of Acute Myeloid Leukemia Research Articles

Clinical efficacy and immune response of BCL-2 inhibitors combined with hypomethylating agents in the treatment of acute myeloid leukemia

ObjectiveAcute myeloid leukemia (AML) is a malignant clonal proliferative disease with a high mortality rate. The combination therapy of BCL-2 inhibitor Venetoclax (VEN) and hypomethylating agents (HMAs) has significant anti-leukemia activity.MethodsWe analyzed the efficacy, safety and immune response characteristics of AML patients who were unfit for high-dose chemotherapy and accepted the medication of VEN + HMAs.ResultsAfter VEN + HMAs treatment, 31 newly diagnosed AML patients had the morphologic leukemia-free state rate (MLFS%) of 80.6% (25/31), complete response rate (CR%) of 54.8% (17/31), the minimal residual disease negative rate (MRD-%) of 51.6% (16/31), and the median progression-free survival (PFS) of 14 months. After treatment, the proportion of bone marrow primitive cells, the MRD level, white blood cell (WBC) count, fibrinogen (FIB) level and the proportion of B cells were significantly decreased. The red blood cell (RBC) count, hemoglobin (HGB) level, platelet count (PLT) count, activated partial thromboplastin time (APTT), the proportion of total T cells, CD8 + T cells and the IFN-γ level were significantly increased. After VEN + HMAs treatment, 12 relapsed AML patients had a MLFS% of 50% (6/12), CR% of 33.3% (4/12), MRD-% of 25% (3/12), and a median PFS of 7 months. After treatment, the proportion of bone marrow primitive cells and MRD level were slightly decreased, the proportions of CD8 + T cells and NK cells were significantly increased, the proportion of B cells and IL-10 level were significantly decreased. 12 AML patients who receive microtransplantation (MST) treatment using VEN + HMAs as a pretreatment regimen had a PFS of 20.5 months, which was much greater than VEN + HMAs group alone. Hematological recovery was better in the MST group with significantly increased RBC count, HGB level and PLT count. The most common adverse events were myelosuppression, agranulocytosis, infection and cardiovascular toxicity. No fatal adverse events were reported.ConclusionThe combination of BCL-2 inhibitors and HMAs had good efficacy and safety in AML patients who were unfit for high-dose chemotherapy, which may improve the immune microenvironment and enhance anti-leukemia immune response.

Bone Marrow Stromal Cells Enhance Differentiation of Acute Myeloid Leukemia Induced by Pyrimidine Synthesis Inhibitors.

Acute myeloid leukemia (AML) is a heterogeneous group of hematologic malignancies characterized by differentiation arrest, high relapse rates, and poor survival. The bone marrow (BM) microenvironment is recognized as a critical mediator of drug resistance and a primary site responsible for AML relapse. Our previous study reported that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr) induces AML cell differentiation by inhibiting pyrimidine synthesis and activating Checkpoint kinase 1. While the protective effect of BM stroma on leukemia cells in response to cytotoxic drugs is well-documented, its effect on AML differentiation remains less explored. In this study, we investigated the impact of stromal cell lines and primary mesenchymal stromal cells (MSCs) on AML cell line differentiation triggered by AICAr and brequinar, a known dihydroorotate dehydrogenase (DHODH) inhibitor. Our findings indicate that the mouse MS-5 stromal cell line, known for its cytoprotective effects, does not inhibit AML cell differentiation induced by pyrimidine synthesis inhibitors. Interestingly, AICAr caused morphological changes and growth arrest in MS-5 stromal cells via an AMPK-dependent pathway. Human stromal cell lines HS-5 and HS-27, as well as primary MSCs isolated from patient bone marrow, were superior in promoting AML differentiation compared to mouse cells in response to AICAr and brequinar, with the inhibitors not significantly affecting the stromal cells themselves. In conclusion, our study highlights the supportive role of human BM MSCs in enhancing the differentiation effects of pyrimidine synthesis inhibitors on AML cells, suggesting that AML treatment strategies focusing on differentiation rather than cell killing may be successful in clinical settings.

Nanotechnology-assisted combination drug delivery: a progressive approach for the treatment of acute myeloid leukemia.

Acute myeloid leukemia (AML), a heterogeneous hematopoietic cancer prevalent in adults, has been a leading cause of leukemia-associated deaths for decades. Despite advancements in understanding its pathology and pharmacological targets, therapeutic strategies have seen minimal change. The standard treatment, combining cytarabine and anthracycline, has persisted, accompanied by challenges such as pharmacokinetic issues and non-specific drug delivery, leading to severe side effects. Nanotechnology offers a promising solution through combination drug delivery. FDA-approved CPX351 (VYXEOS™) a liposomal formulation delivering doxorubicin and cytarabine, exemplifies enhanced therapeutic efficacy. Ongoing research explores various nanocarriers for delivering multiple bioactives, addressing drug targeting, pharmacokinetics and chemoresistance. This review highlights nanotechnology-based combination therapies for the effective management of AML, presenting a potential breakthrough in leukemia.

The role of long noncoding RNAs in the diagnosis, prognosis and therapeutic biomarkers of acute myeloid leukemia.

Acute myeloid leukemia (AML) is the abnormal proliferation of immature myeloid blast cells in the bone marrow. Currently, there are no universally recognized biomarkers for the early diagnosis, prognosis and effective treatment of AML to improve the overall survival of patients. Recent studies, however, have demonstrated that long noncoding RNAs (lncRNAs) are promising targets for the early diagnosis, prognosis and treatment of AML. A critical review of available data would be important to identify study gaps and provide perspectives. In this review, we explored comprehensive information on the potential use of lncRNAs as targets for the diagnosis, prognosis, and treatment of AML. LncRNAs are nonprotein-coding RNAs that are approximately 200 nucleotides long and play important roles in the regulation, metabolism and differentiation of tissues. In addition, they play important roles in the diagnosis, prognosis and treatment of different cancers, including AML. LncRNAs play multifaceted roles as oncogenes or tumor suppressor genes. Recently, deregulated lncRNAs were identified as novel players in the development of AML, making them promising prognostic indicators. Given that lncRNAs could have potential diagnostic marker roles, the lack of sufficient evidence identifying specific lncRNAs expressed in specific cancers hampers the use of lncRNAs as diagnostic markers of AML. The complex roles of lncRNAs in the pathophysiology of AML require further scrutiny to identify specific lncRNAs. This review, despite the lack of sufficient literature, discusses the therapeutic, diagnostic and prognostic roles of lncRNAs in AML and provides future insights that will contribute to studies targeting lncRNAs in the diagnosis, treatment, and management of AML.

Licochalcone A decreases cancer cell proliferation and enhances ferroptosis in acute myeloid leukemia through suppressing the IGF2BP3/MDM2 cascade.

Licochalcone A (Lico A), a naturally bioactive flavonoid, has shown antitumor activity in several types of cancers. However, few studies have focused on its effect on acute myeloid leukemia (AML). Cell viability and colony formation potential were detected by CCK-8 assay and colony formation assay, respectively. Cell cycle distribution and apoptosis were assessed by flow cytometry. Ferroptosis was assessed by measuring reactive oxygen species (ROS), lipid ROS, malondialdehyde (MDA), and glutathione (GSH). Protein expression levels were determined by immunoblotting and immunohistochemistry (IHC), and mRNA expression was detected by real-time qPCR. The m6A modification of MDM2 mRNA was verified by methylated RNA immunoprecipitation (MeRIP) assay, and the interaction of IGF2BP3 and MDM2 mRNA was analyzed by RIP assay. Actinomycin D was used to evaluate mRNA stability. The efficacy of Lico A in vivo was examined by a murine xenograft model. Lico A suppressed cell proliferation and induced ferroptosis in MOLM-13 and U-937 in vitro, and slowed the growth of xenograft tumors in vivo. IGF2BP3 was highly expressed in human AML specimens and cells, and Lico A suppressed IGF2BP3 expression in AML cells. Lico A exerted the anti-proliferative and pro-ferroptosis effects by downregulating IGF2BP3. Moreover, IGF2BP3 enhanced the stability and expression of MDM2 mRNA through an m6A-dependent manner. Downregulation of IGF2BP3 impeded AML cell proliferation and enhanced ferroptosis via repressing MDM2. Furthermore, Lico A could affect the MDM2/p53 pathway by downregulating IGF2BP3 expression. Lico A exerts the anti-proliferative and pro-ferroptosis activity in AML cells by affecting the IGF2BP3/MDM2/p53 pathway, providing new evidence for Lico A as a promising agent for the treatment of AML.

CXCR4 as a therapeutic target in acute myeloid leukemia.

Extensive research on the CXCL12-CXCR4 axis in acute myeloid leukemia (AML) has resulted in the incorporation of novel anti-leukemia drugs targeting this axis into therapeutic strategies. However, despite this progress, a comprehensive and up-to-date review addressing the role of the CXCL12-CXCR4 axis in AML's oncogenic processes is lacking. In this review, we examine its molecular aspects influencing cancer progression, such as its impact on autonomous proliferation, apoptotic regulation, chemoresistance mechanisms, and interactions with non-leukemic cells such as MSCs and Treg cells. 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.

Discovery of SILA-123 as a Highly Potent FLT3 Inhibitor for the Treatment of Acute Myeloid Leukemia with Various FLT3 Mutations.

The FLT3-ITD (internal tandem duplication) mutant has been a promising target for acute myeloid leukemia (AML) drug discovery but is now facing the challenge of resistance due to point mutations. Herein, we have discovered a type II FLT3 inhibitor, SILA-123. This inhibitor has shown highly potent inhibitory effects against FLT3-WT (IC50 = 2.1 nM) and FLT3-ITD (IC50 = 1.0 nM), tumor cells with the FLT3-ITD mutant such as MOLM-13 (IC50 = 0.98 nM) and MV4-11 (IC50 = 0.19 nM), as well as BaF3 cells associated with the FLT3-ITD mutant and point mutations like BaF3-FLT3-ITD-G697R (IC50 = 3.0 nM). Moreover, SILA-123 exhibited promising kinome selectivity against 310 kinases (S score (10) = 0.06). 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.

Monitoring Apoptosis and Myeloid Differentiation of Acridine Orange-Mediated Sonodynamic Therapy-Induced Human Promyelocytic Leukemia HL60 Cells.

In the treatment of acute myeloid leukemia (AML), conventional therapies can lead to severe side effects and drug resistance. There is a need for alternative treatments that do not cause treatment resistance and have minimal or no side effects. Sonodynamic therapy (SDT), due to its noninvasive, multiple repeatability, localized treatment feature and do not cause treatment resistance, emerges as an alternative treatment option. However, it has not received sufficient attention in the treatment of AML especially acute promyelocytic leukemia (APL). The aim of the study was to investigate the potential differentiation and antileukemic effects of acridine orange (AO)-mediated SDT on HL60 cells. Cell viability was determined by the 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT)method in the control, ultrasound, AO concentrations, and ultrasound-exposed AO concentrations groups. Transmission electron microscopy (TEM) was used to determine morphology, and flow cytometry was used to determine apoptosis, DNA cycle, cell volume, mitochondria membrane potential (Δψm), reactive oxygen species (ROS) production, and differentiation markers (CD11b and CD15) expressions. Additionally, toluidine blue staining for semithin sections was used to determine differentiation. The cytotoxicity of AO-mediated SDT on HL60 cells was significantly higher than other groups, and TEM images showed that it caused various morphological changes typical for apoptosis. Flow cytometry results showed the presence of early apoptosis, subG1 arrest, loss of Δψm, increase of intracellular ROS production, decreased cell volume, and increased expression of CD11b (1.3-fold) antigen and CD15 (1.2-fold) antigen. Data showed that AO-mediated SDT significantly induced apoptosis in HL60 cells. Increased expression of CD11b and CD15 antigens and morphological findings demonstrated that AO-mediated SDT contributes to granulocytic differentiation in HL60 cells. AO-mediated SDT has potential as an alternative treatment of APL.

C-FLIP and microRNA 708-5p gene expression in newly diagnosed and chemotherapy in acute myeloid leukemia of Iraqi patient

Abstract: BACKGROUND: C-FLICE-like inhibitory protein (c-FLIP) is a protein that does not merely block apoptosis signaling but also adjusts further pathways of cell death. Acute myeloid leukemia (AML), a nonhomogeneous hematologic malignancy, is the highly common form of AML among adults and is described through the clonal enlargement of myeloid blasts in the bone marrow (BM), peripheral blood, and/or else tissues. OBJECTIVES: The aims of this study were to investigate the role of c-FLIP and microRNA (miRNA) 708-5p as a prospective prognostic biomarker as well as the therapeutic goal in AML. PATIENTS MATERIALS AND METHODS: This study includes two groups of patients (40) individuals newly diagnosed AML patients, (20) AML taking chemotherapy, and (50) apparently healthy volunteers. The study was conducted at the National Center of Hematology/Mustansiriyah University. The methods employed in the analysis include total RNA extraction, complementary cDNA synthesis, and quantitative real-time polymerase chain reaction (PCR) were used to evaluate the gene expression of cFLIP and miRNA-708-5p. Complete blood count to estimate some hematological parameters. RESULTS: The expression of c-FLIP was notably higher in both newly diagnosed and patients under chemotherapy compared to controls with fold expression (3.291 and 2.92), respectively, with a highly significant (P = 0.0001). The increase in miRNA 708-5p expression in newly diagnosed patients with fold expression (5.345), whereas downregulation in patients under chemotherapy with fold expression (0.789) indicates that treatment may restore its levels, contributing to the suppression of c-FLIP and promoting apoptosis. CONCLUSION: The c-FLIP and miRNA708-5p gene might be used as a biological marker for the AML initial diagnosis. The researches emphasize the role of miRNA 708-5p as a tumor suppressor, which negatively regulates the antiapoptotic protein c-FLIP, indicating its potential as a therapeutic target in AML treatment. By modulating the levels of miRNA708-5p, it may be possible to regulate the expression of c-FLIP, thus enhancing the effectiveness of apoptosis-inducing therapies. This suggests the promising development of miRNA-based therapies as part of AML treatment strategies. Furthermore, miRNA 708-5p can act as a prognostic indicator in AML, with its expression levels offering valuable insights into disease progression and patient response to treatment. Further research into miRNA 708-5p can lead to a better understanding of its role in AML pathogenesis and its potential applications in clinical practice.

Implementation of a Novel Pathway to Integrate Palliative and Oncology Care for Patients With Acute Myeloid Leukemia in a Community Hospital

PURPOSE Historically, patients with hematologic malignancies are referred to palliative care less often and later in the disease trajectory than those with solid tumors. Recent evidence demonstrates the benefit of early, integrated inpatient palliative care (PC) for patients with acute myeloid leukemia (AML) receiving chemotherapy at academic centers. The current study evaluated the feasibility of implementing standardized early palliative care services (PCS) during hospitalization for AML treatment in a community setting. METHODS Starting June 2018, automated consultations for PCS were incorporated into clinical pathways to encourage early, integrated services for patients receiving chemotherapy for AML with an expected hospital stay of 4-6 weeks. Expectations were established that consultations would be performed within 72 hours of request; patients would have two visits per week by a palliative care clinician and at least one visit by a member of the interdisciplinary team. To measure the feasibility of this intervention, data on number of patients who received palliative care consultation and time to palliative care consultation were compared with institutional historical controls. RESULTS On the basis of retrospective chart review, the postintervention group (n = 21) had greater PCS compared with historical controls (n = 28; 95% v 36%). The average number of PC team member visits per patient was significantly greater after the intervention: PC clinicians (1.04-8.05, P < .001), chaplains (1.3-3.3, P = .0085), and social workers (1.0-4.3, P < .001). Of those patients who received PCS, 74% had their initial palliative medicine consultation within 3 days of a clinician's order and 100% within 4 days. CONCLUSION We have demonstrated the feasibility of implementing standardized integration of PCS for patients with AML hospitalized for treatment in a community setting.

Simultaneous inhibition of FLT3 and HDAC by novel 6-ethylpyrazine-2-Carboxamide derivatives provides therapeutic advantages in acute myelocytic leukemia

Synergetic inhibition of FMS-like tyrosine kinase 3 (FLT3) and histone deacetylase (HDAC) by small molecule chimera presents a promising therapeutic approach for acute myeloid leukemia (AML) with FLT3 mutations. In this study, we first observed that the combined use of FLT3 inhibitor gilteritinib and HDAC inhibitor vorinostat increased the survival rate of leukemia xenograft mouse model. Then, we employed a pharmacophore fusion strategy to develop a novel series of FLT3/HDAC dual inhibitors. Among them, compound 25h demonstrated superior inhibitory activity against both FLT3 and HDAC. In particular, compound 25h exhibited enhanced anti-proliferation activity against MOLM-13 cells in comparison to gilteritinib, vorinostat, and their combination, while maintaining reduced cytotoxicity towards normal cells. Mechanistically, the heightened anti-tumor effect of compound 25h was attributed to its more potent regulation of intracellular pathways, notably phosphorylation of ERK, compared to single drug and combination treatments. Furthermore, compound 25h demonstrated superior anti-tumor efficacy in the MOLM-13 xenograft model compared to combination therapy, along with reduced in vivo toxicity. To conclude, we have identified a novel FLT3/HDAC dual inhibitor that could serve as a potential candidate for the treatment of AML.

Advances in pathogenesis research and challenges in treatment development for acute myeloid leukemia.

Acute myeloid leukemia (AML) develops when hematopoietic stem cells acquire chromosomal and genetic abnormalities, transforming into leukemia stem cells (LSCs) and further gaining driver mutations. Advances in genomic analysis have identified numerous new gene mutations involved in AML development. Recent research has shown that individuals with germline mutations in genes like DDX41 and CEBPA develop AML upon acquiring additional somatic mutations, and the latest WHO classification separates AML with such mutations into distinct disease groups. LSCs are regulated by different metabolic processes than normal stem cells, contributing to drug resistance and relapse. LSCs rely on oxidative phosphorylation (OXPHOS) metabolism for energy production, and venetoclax inhibits this process, affecting LSCs. Resistant LSCs show enhanced glycolysis, which suggests that targeting both OXPHOS and glycolysis is crucial. While targeted therapies like FLT3, BCL-2, and IDH inhibitors have shown efficacy, resistance remains an issue, highlighting the need for new treatment strategies. CAR-T cell therapy is an emerging immunotherapy that shows particular promise for targeting CD123 and CLL-1, with acceptable toxicity. Future developments in CAR-T cell therapy and other immunotherapies are anticipated to improve AML treatment outcomes.

Combining Clinical and Molecular Data for Personalized Treatment in Acute Myeloid Leukemia: A Machine Learning Approach

Background and ObjectiveThe standard of care in Acute Myeloid Leukemia patients has remained essentially unchanged for nearly 40 years. Due to the complicated mutational patterns within and between individual patients and a lack of targeted agents for most mutational events, implementing individualized treatment for AML has proven difficult. We reanalysed the BeatAML dataset employing Machine Learning algorithms. The BeatAML project entails patients extensively characterized at the molecular and clinical levels and linked to drug sensitivity outputs. Our approach capitalizes on the molecular and clinical data provided by the BeatAML dataset to predict the ex vivo drug sensitivity for the 122 drugs evaluated by the project. MethodsWe utilized ElasticNet, which produces fully interpretable models, in combination with a two-step training protocol that allowed us to narrow down computations. We automated the genes’ filtering step by employing two metrics, and we evaluated all possible data combinations to identify the best training configuration settings per drug. ResultsWe report a Pearson correlation across all drugs of 0.36 when clinical and RNA sequencing data were combined, with the best-performing models reaching a Pearson correlation of 0.67. When we trained using the datasets in isolation, we noted that RNA Sequencing data (Pearson: 0.36) attained three times the predictive power of whole exome sequencing data (Pearson: 0.11), with clinical data falling somewhere in between (Pearson 0.26). Lastly, we present a paradigm of clinical significance. We used our models’ prediction as a drug sensitivity score to rank an individual's expected response to treatment. We identified 78 patients out of 89 (88%) that the proposed drug was more potent than the administered one based on their ex vivo drug sensitivity data. ConclusionsIn conclusion, our reanalysis of the BeatAML dataset using Machine Learning algorithms demonstrates the potential for individualized treatment prediction in Acute Myeloid Leukemia patients, addressing the longstanding challenge of treatment personalization in this disease. By leveraging molecular and clinical data, our approach yields promising correlations between predicted drug sensitivity and actual responses, highlighting a significant step forward in improving therapeutic outcomes for AML patients.

Facile Synthesis and Antitumor Activity of o-Iodoaromatic Ether

Abstract: In this study, an efficient method for the synthesis of one type of aromatic ether was introduced, and its antitumor activity was investigated. Specifically, (diacetoxyiodo)arene was prepared from 2-methyliodobenzene and used to oxidize the 4-nitrophenol to give the aromatic ether. Our study further found that aromatic ether has a strong apoptotic effect on U937 monocytes, suggesting that it might be developed as a new drug for the treatment of acute myeloid leukemia.

AML-521 Treatment of Acute Myeloid Leukemia With Orca-T

AML-521 Treatment of Acute Myeloid Leukemia With Orca-T

Point of care CD19 chimeric antigen receptor (CAR) T-cells for relapsed/refractory acute myeloid leukemia (AML) with aberrant CD19 antigen expression

Relapsed/refractory (r/r) acute myeloid leukemia (AML) is associated with poor prognosis. CD19 is a B-cell marker, is aberrantly expressed in AML, mostly with t(8; 21)(q22; q22.1). Here we report the results of a phase 2 study giving point of care produced CD19 CAR T- cells for r/r AML with aberrant expression of CD19 (NCT04257175). Lymphodepletion included fludarabine and cyclophosphamide The response was evaluated by bone marrow (BM) aspiration on day 28. Six patients (5 adults and 1 child) were included. Median number of previous chemotherapy lines was 4 (range, 3-8) and four patients received CAR T-cells 8-18 months post allogeneic hematopoietic stem cell transplantation (allo-HSCT). Cytokine release syndrome (CRS) of any grade occurred in all patients, and 1 patient had grade 3 CRS. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 2 patients at low grades. Tocilizumab was administered to 2 patients and corticosteroids to 3 patients. Four patients achieved a complete remission (CR), while 2/6 progressed (PD). Three patients (2 with CR and 1 with PD) underwent allo-HSCT (it was the second transplant in 2) 2-5 months post CAR T-cells infusion. The median duration of response in patients achieving CR was 8.5 (range; 3-14) months. However, all patients eventually died within 5 (1-18) months.In conclusion, CD19 CAR T- cell treatment for AML is feasible and safe. However, the response is short and should be followed by allo-HSCT. Hopefully, future long term results will be improved by combining the CAR T- cell therapy with the emerging novel effective anti-leukemic compounds.

The Expression and Clinical Significance of USF1 in Newly Diagnosed Acute Myeloid Leukemia.

This study aimed to assess the expression level of upstream stimulator 1 (USF1) in the bone marrow of newly diagnosed acute myeloid leukemia (AML) patients and investigate its clinical and prognostic significance. Bone marrow samples from 60 newly diagnosed AML patients constituted the observation group, while 20 samples from healthy individuals formed the control group. Real-time quantitative PCR (qRT-PCR) was used to measure the USF1 expression in both groups and to analyze its correlation with clinicopathological features and prognosis in AML patients. Kaplan-Meier curves were utilized to assess the impact of USF1 on the overall survival (OS) in AML patients. The prognostic factors of AML were examined by using Cox regression analysis. A univariate analysis revealed a significantly higher USF1 expression in the AML patients compared to the control group (p < 0.001), with no difference in the clinicopathological features between the low-expression group and the control group. However, there was a significant difference between the high-expression group and the control group (p < 0.01). Moreover, the OS of the high USF1 expression group was notably shorter than of the low USF1 expression group (p < 0.0001). A multivariate analysis identified high USF1 expression and age ≥ 60 years as independent risk factors for a poor AML prognosis. High expression of USF1 is linked to a worse prognosis and shorter survival time in AML patients. USF1 may serve as an indicator of prognosis and survival in AML patients and could be a potential target for AML treatment.

Enhancing Therapeutic Efficacy of FLT3 Inhibitors with Combination Therapy for Treatment of Acute Myeloid Leukemia.

FMS-like tyrosine kinase 3 (FLT3) mutations are genetic changes found in approximately thirty percent of patients with acute myeloid leukemia (AML). FLT3 mutations in AML represent a challenging clinical scenario characterized by a high rate of relapse, even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The advent of FLT3 tyrosine kinase inhibitors (TKIs), such as midostaurin and gilteritinib, has shown promise in achieving complete remission. However, a substantial proportion of patients still experience relapse following TKI treatment, necessitating innovative therapeutic strategies. This review critically addresses the current landscape of TKI treatments for FLT3+ AML, with a particular focus on gilteritinib. Gilteritinib, a highly selective FLT3 inhibitor, has demonstrated efficacy in targeting the mutant FLT3 receptor, thereby inhibiting aberrant signaling pathways that drive leukemic proliferation. However, monotherapy with TKIs may not be sufficient to eradicate AML blasts. Specifically, we provide evidence for integrating gilteritinib with mammalian targets of rapamycin (mTOR) inhibitors and interleukin-15 (IL-15) complexes. The combination of gilteritinib, mTOR inhibitors, and IL-15 complexes presents a compelling strategy to enhance the eradication of AML blasts and enhance NK cell killing, offering a potential for improved patient outcomes.

Role of WT1 in Measurable Residual Disease Follow-Up in the Post Allogeneic Stem Cell Transplant Setting.

Objectives: The Wilms' tumor gene 1 (WT1) plays a critical role in cell development and the regulation of essential genes involved in cell growth and metabolism. In the context of hematopoietic tumors, including acute myeloid leukemia (AML), WT1 has been identified as a potential marker for measurable residual disease (MRD) assessment. Relapse after allogeneic hematopoietic stem cell transplantation (allo-SCT) remains a significant challenge in AML treatment, highlighting the importance of MRD monitoring for risk stratification and treatment decisions. This study aimed to investigate the clinical significance of WT1 as a molecular marker for MRD and its correlation with chimerism in AML patients post-allo-SCT setting. Methods: We have included 58 patients with WT1-expression-positive acute myeloid leukemia (AML) who received allo-SCT in our center between 2016-2022. The exclusion criteria are as follows: not having WT1 polymerase chain reaction (PCR) measurement at diagnosis, not receiving allo-SCT, and not having a serial measurement of WT1 post-transplant. Pre- and post-transplant assessments were made with flow cytometry, WT1 PCR, and bone marrow morphological evaluations. Statistical analyses were carried out to explore correlations between WT1 levels, MRD markers, and chimerism post-transplantation. Results: We found that WT1 had a significant correlation with flow cytometry and bone marrow morphological evaluation, but not with chimerism. Interestingly, high WT1 expressors exhibited a more robust correlation with chimerism compared to the general cohort. The negative predictive value for post-allo-SCT relapse was 91.8% for the whole WT1 cohort; for high WT1 expressors, it was similar, at 87.5%. The negative predictive value for post-allo-SCT relapse was high for the whole WT1 cohort; for high WT1 expressors, it was similar. The WT1 MRD assay showed a high negative predictive value for post-allo-SCT relapse, consistent across both the entire cohort (91.8%) and high WT1 expressors (87.5%). Conclusions: WT1 expression levels may serve as a valuable ancillary marker in MRD assessment and relapse prediction post-allo-SCT in AML patients, particularly for those lacking specific fusion genes or mutations. However, further large-scale, controlled studies are needed to standardize WT1 MRD assays and establish clear guidelines for their clinical application.

Recent advancements in biomarkers, therapeutics, and associated challenges in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a common type of leukemia that has a high mortality rate. The reasons for high mortality in patients with AML are therapeutic resistance, limited ability to predict duration of response, and likelihood of cancer relapse. Biomarkers, such as leukemic stem cell biomarkers, circulatory biomarkers, measurable residual disease biomarkers, and molecular biomarkers, are used for prognosis, diagnosis, and targeted killing to selectively eliminate AML cells. They also play an indispensable role in providing therapeutic resistance to patients with AML. Therefore, targeting these biomarkers will improve the outcome of AML patients. However, identifying biomarkers that can differentiate between treatment-responsive and non-responsive AML patients remains a challenge. This review discusses recent advancements in AML biomarkers, promising therapeutics, and associated challenges in the treatment of AML.