Acute Myelogenous Leukemia

P3, N=777, Active, not recruiting, Stichting Hemato-Oncologie voor Volwassenen Nederland | Trial primary completion date: Dec 2024 --> Oct 2025

P1/2, N=218, Active, not recruiting, AbbVie | Trial completion date: Dec 2024 --> Apr 2026 | Trial primary completion date: Dec 2024 --> Apr 2026

The NPM1 mutant undergoes changes at the C-terminus of the protein that leads to its delocalization in the cytoplasm of the leukemic cells. Here, we focus also on its biological functions discussing the murine models of NPM1 mutations and the various mechanisms that occur at cytoplasmic and nuclear levels to promote and maintain NPM1-mutated AML.

P2, N=164, Active, not recruiting, Takeda | Trial completion date: Dec 2024 --> Mar 2025

P1, N=30, Recruiting, The First Affiliated Hospital of Xiamen University

This tool holds significant promise for enhancing the precision of prognostic assessments in AML, thereby paving the way for more tailored and effective therapeutic interventions. Our findings represent a pivotal step toward the realization of personalized medicine in the management of AML, offering new avenues for research and treatment optimization in this challenging disease landscape.

P1, N=18, Suspended, Terrence J Bradley, MD | Recruiting --> Suspended | Trial primary completion date: Nov 2024 --> Nov 2025

We also conducted a conjoint analysis of the transcriptome and the m5C methylome of the full-length transcripts, uncovering several dysregulated mRNA isoforms. Collectively, our findings indicate that mRNA m5C methylation is implicated during AML progression, and AZA exhibits an overall suppressive effect on this process.

Furthermore, MKX upregulated SESN3 and downregulated BCL2L11, which may together underlie decreased etoposide-induced apoptosis...Taken together, our study identified MKX as novel aberrantly expressed homeobox gene in AML and MM, highlighting the function of IRX1 in normal myelopoiesis and B-cell development, and of IRX-related genes in corresponding malignancies. Our data merit further investigation of MKX and its deregulated target genes to serve as novel markers and/or potential therapeutic targets in AML patient subsets.

Patients in the high-risk group for these factors experienced significantly poor outcomes, which were closely associated with aDC, CD8 T cells, and TH17 cells. In summary, SYTL4 overexpression is linked to poor prognosis and immune infiltration in AML, with the constructed risk model intended as a prognostic evaluation tool for AML patients.

Our previous studies have demonstrated that pegcrisantaspase (PegC), a long-acting Erwinia asparaginase, synergizes with the BCL-2 inhibitor Venetoclax (Ven) in vitro and in vivo; however, the anti-leukemic activity of E. coli-derived asparaginases in combination with BCL-2 inhibition, and potential synergy with inhibitors of MCL-1, a key resistance factor of BCL-2 inhibition, has yet to be determined. Using a combination of human AML cells lines, primary samples, and in vivo xenograft mouse models, we established the anti-leukemic activity of the BCL-2 inhibitor S55746 and the MCL-1 inhibitor S63845, alone and in combination with the long-acting E. coli asparaginase calaspargase pegol-mknl (CalPegA)...The S55746-CalPegA combination inhibited protein synthesis and increased eIF4E/4EBP1 interaction, suggesting an inhibition of translational complex formation. These results support the clinical evaluation of CalPegA in combination with BCL-2 inhibition for AML.

The simultaneous analysis of IC receptors on the T cell subsets and their ligands on blasts showed the prognostic value of a specific IC receptor-ligand pair and the feasibility of risk stratification based on their diverse patterns. Our findings clarified the BM T cell landscape in AML, unveiling the prognostic value of γδ T cells in both diagnosis and remission predictions.

These include new JAK inhibitors with greater specificity for JAK2, as well as "add-on" medications designed to enhance the effectiveness of ruxolitinib, in both patients who are new to the drug and in those who have shown suboptimal responses. Additionally, there is ongoing exploration of novel therapeutic targets. In this review, we will explore the immunotherapy approaches that are currently used in clinical practice for MPNs, as well as emerging strategies that are likely to change the treatment of these diseases in the coming years.

Improved survival was observed with transplantation in groups DP2, DP7, and DP9. These findings highlight the role of genomic classifications in guiding personalized treatment strategies, ultimately enhancing the understanding and management of myeloid neoplasms.

By integrating these diverse strategies, we propose a comprehensive therapeutic paradigm that targets multiple points of the leukemic transcriptional and epigenetic network. These combination approaches aim to disrupt key oncogenic pathways, reduce resistance, and enhance treatment efficacy, ultimately providing more durable remissions and improved survival for patients with KMT2A-rearranged leukemias.

Gilter/quizar monotherapy are effective and tolerable options for patients with R/R FLT3mut AML in a real-world setting. Response and toxicity rates are similar to those reported in the phase 3 trials, despite the more heterogeneous nature of the study population.

Additionally, inflammatory cytokines have favored certain populations of hematopoietic stem and progenitor cells with mutated clonal hematopoiesis genes. This article summarizes current knowledge about inflammatory cytokines and signaling pathways in AML, their modes of action and the implications for immune tolerance and clonal hematopoiesis, with the aim of finding potential therapeutic interventions to improve clinical outcomes in AML patients.

In conclusion, under physiological conditions, connexin 43 and N-Cadherin interaction preserves stemness of both CD34+ HSCs and MSCs, a process that is compromised in acute myeloid leukemia, pointing to the possible role of gap junctions in modulating stemness.

TP53 and NRAS mutations were associated with increased risk of death (hazard ratio = 3.98 and 5.50, respectively). In a survey of physicians at the participating centers, 63% reported that the genomic panel was clinically useful, particularly for assessing clinical risk and evaluating indications for hematopoietic stem cell transplantation.

The analysis revealed a network of TFs regulating IKZF1, among which HDAC1 emerged as a promising candidate due to its low mutation rate, association with better survival outcomes, and direct interaction with IKZF1. This suggests HDAC1 could be a valuable biomarker and therapeutic target for AML treatment.

This study investigates the potential of Bentonite (BNT)-based nanoparticles (NPs) as drug carriers for azacitidine (AZA) in treating THP-1 and K562 myeloid leukemia (AML) cell lines, aiming to improve drug stability, bioavailability, and therapeutic efficacy while ensuring controlled release...BNT nanoparticles are promising carriers for AZA, enhancing targeted delivery, reducing side effects, and potentially lowering the required dose for leukemia treatment. These findings support further investigation into the clinical application of BNT-AZA in hematologic cancers.

Moreover, we demonstrated a stabilizing effect through GAPDH binding to target transcripts including its own mRNA. The present findings provide new insights on the RNA functions and characteristics of GAPDH in AML.

We show that PHIP loss phenocopies PHF6 loss, and that PHF6 requires PHIP to occupy chromatin and exert downstream transcriptional effects. Our work unifies PHF6 and PHIP, two disparate leukemia-mutated proteins, into a common functional complex that suppresses AML stemness.

The ICC diagnostic criteria are clinically significant for determining AML prognosis. In line with the changing treatment paradigm for AML, future research is needed to continuously validate diagnostic and risk stratification systems.

Cellular thermal shift assays confirmed SH3 domain-dependent interaction of PDA1 with wild-type Hck in myeloid leukemia cells and with a kinase domain gatekeeper mutant (T338M). These results identify PDA1 as a starting point for Src-family kinase allosteric inhibitor development that may work in concert with ATP-site inhibitors to suppress the evolution of resistance.

In conclusion, our findings suggested that SD can lead to altered drug disposition and effects in vivo, and Bmal1 plays a crucial role in the crosstalk between SD-induced circadian clock disruption and drug metabolism. It initiates a new direction for the understanding of drug efficacy and toxicity changes in SD conditions and provides a scientific basis for improving the rationality of drug use.

After acute thrombocytopenia platelet-mediated hemostasis and immune modulation by newly generated platelets are impaired, underscoring the clinical relevance of understanding platelet function alterations in (post)thrombocytopenic conditions for therapeutic optimization.

P=N/A, N=200, Not yet recruiting, Astellas Pharma Singapore Pte. Ltd.

P1/2, N=179, Active, not recruiting, AbbVie | Trial completion date: Dec 2025 --> Dec 2026

Importantly, DLX3 knock-out abrogated leukemia initiation in this ETO2::GLIS2 iPSC model. Collectively, characterization of a novel human iPSC-derived AMKL model revealed hijacking of the osteogenic homeobox transcription factor DLX3 as an essential early step in chromatin changes and leukemogenesis driven by the ETO2::GLIS2 fusion oncogene.

Notably, we observed confirmational evidence of CD36 relevance in the AML context, which has emerged recently as a potential marker for PMN-MDSCs. Our study highlights significant findings associating increased MDSC-like subsets and poor prognostic factors in AML.

Two lncRNAs out of eleven (lncRNA-XIST and GAS5) impacted OS, and two other lncRNAs (UCA1 and HIFAL) affected CR in adult de novo AML patients. LncRNA-PTCSC3 predict relapse, however, further validation is still required.

These findings confirm the unique utility of the NGS-based RNA fusion panel as a diagnostic tool to identify gene rearrangements that drive haematological malignancies. It can identify novel and rare gene rearrangements to assist with diagnosis, prognostication and treatment decisions.

The Mayo genetic risk models offer pre-treatment and response-based prognostic tools for ND-AML treated with Ven-HMA. The current study underscores the prognostically indispensable role of achieving CR/CRi and ASCT.

P2, N=27, Recruiting, University of Illinois at Chicago | Trial completion date: Nov 2024 --> Dec 2026 | Trial primary completion date: Nov 2024 --> Dec 2026

P3, N=727, Completed, ECOG-ACRIN Cancer Research Group | Active, not recruiting --> Completed

The aim of this study was to investigate the effects of renal function and CYP3A5 polymorphism on the drug interaction between venetoclax and fluconazole in thirty acute myeloid leukemia patients.The area under the plasma concentration-time curve (AUC) and trough concentration (C0) of venetoclax and the fluconazole C0 were obtained from plasma samples on day 7 later after initiation of venetoclax 200 mg/day combined with fluconazole.The fluconazole C0 values in patients with moderate and severe renal impairment were significantly higher than those in patients with normal or mild impairment (median values 7037, 6234, and 4813 ng/mL, respectively, P = 0.026).In patients with CYP3A5*3/*3 genotype, the AUC0-24 and C0 of venetoclax were not associated with fluconazole C0; however, in patients with a CYP3A5*1 allele, a significant positive correlation was observed between venetoclax C0 and fluconazole C0 (r = 0.782, P = 0.004).The metabolism of venetoclax by CYP3A4 is inhibited even at low fluconazole C0. In patients with a CYP3A5*1 allele, CYP3A5 is inhibited when high fluconazole C0 is induced by renal impairment.The dose of fluconazole for prophylaxis may be 100 mg in patients with severe renal impairment receiving venetoclax therapy.

No abstract available

This Viewpoint describes the discovery of inhibitors targeting point mutants and the development of SILA123, a highly potent and selective type II FLT3 inhibitor. In in vivo studies, SILA-123 significantly suppressed tumor growth in allograft models, demonstrating its potential in treating resistant AML.

Oral TUS markedly extended survival in subcutaneously and orthotopically inoculated xenograft models of FLT3 mutant human AML, was well tolerated, and delivered enhanced activity when combined with venetoclax or 5-azacytidine...Cells selected for stable acquired resistance to TUS exhibited increased BAX and hypersensitivity to venetoclax (1900-fold), navitoclax and MCL1 inhibitors. MV-4-11 FLT3-ITD clones expressing NRASG12D revealed that high-level expression of NRASG12D generated modest resistance to TUS and greater resistance to venetoclax (VEN), yet the TUS/VEN combination exhibited synergy in NRASG12D AML model. Favorable preclinical safety and pharmacology properties, the efficacy of the TUS/VEN combination in a murine model, and the synthetic lethal vulnerability to VEN that accompanies TUS resistance provide the basis for exploration of the TUS/VEN combination in patients with relapsed or refractory AML.

We factored patient age, TP53 aberration burden, therapy intensity and use of venetoclax in the AML subgroup, and allogeneic hematopoietic stem cell transplantation (HSCT) to interrogate outcomes. TP53 was annotated as high-risk (TP53HR) if >1 mutation, one mutation + allelic deletion or a single mutation with variant allele frequency (VAF) ≥40%; TP53 low risk (TP53LR) included a single TP53 mutation VAF.

P1, N=19, Terminated, M.D. Anderson Cancer Center | Active, not recruiting --> Terminated; Administratively Complete