Acute Myeloid Leukemia Therapy Research Articles

Emerging CART Therapies for Pediatric Acute Myeloid Leukemia.

The prognosis of children with acute myeloid leukemia (AML) has improved incrementally over the last decades. However, at relapse, overall survival (OS) ∼40% to 50% and is even lower for patients with chemorefractory disease. Effective and less-toxic therapies are urgently needed for these children. In the last years, immune-directed therapies such as chimeric antigen receptor (CAR)-T cells were introduced, which showed outstanding clinical activity against B-cell malignancies. CART therapies are being developed for AML on the basis of the results obtained for other hematologic malignancies. The biggest challenge of CART therapy for AML is to identify a specific target antigen, since antigens expressed in AML cells are usually shared with healthy hematopoietic stem cells. An overview of prospects of CART in pediatric AML, focused on the common antigens targeted by CART in AML that have been tested or are currently under investigation, is provided in this manuscript.

Incidence of infection in patients with acute myeloid leukemia receiving high-dose cytarabine consolidation.

Infection risk during high-dose cytarabine (HiDAC) consolidation following induction therapy for acute myeloid leukemia (AML) is not well understood complicating decisions regarding antimicrobial prophylaxis during this period. We performed a retrospective chart review of adult patients with AML undergoing HiDAC consolidation between June 2016 and November 2021 at our institution. The primary endpoint was microbiologically confirmed infection within 30 days of HiDAC administration. This study included 111 patients who received a total of 264 cycles of HiDAC therapy. 36% of patients undergoing HiDAC consolidation had at least 1 infection over the course of their consolidation therapy. Infection complicated 18% of HiDAC cycles. The majority of infections were bacterial (81%), primarily caused by gram-negative organisms. Fluoroquinolone prophylaxis was associated with a lower hazard of bacterial infection (HR 0.46, 95% CI 0.24, 0.88). However, 26% of bacterial infections broke through antibiotic therapy with multiple cases concerning for fluoroquinolone resistance. Viral and fungal infections were rare (14% and 3% of infections respectively).

SRSF12 is a prognostic biomarker involved in immune infiltration in acute myeloid leukemia

ABSTRACT Background Acute myeloid leukemia (AML) is a disease characterized by the proliferation of abnormal cells originating from blood stem cells. Understanding the pathogenesis and progression of AML, as well as identifying molecular markers for early diagnosis and prognosis assessment, is of paramount importance. Methods The AML dataset was obtained from the Cancer Genome Atlas (TCGA), while the normal sample dataset was derived from the Genotype-Tissue Expression(GTEx) dataset. Furthermore, the association between SRSF12 expression and drug response was assessed using the Cancer Therapeutic Response Portal (CTRP) database to evaluate its potential therapeutic value. Finally, SRSF12 expression in AML cells was measured using quantitative real-time PCR (qRT-PCR). Result The difference in SRSF12 expression between 13 types of tumors and normal tissue samples was found to be statistically significant (P < 0.05). SRSF12 exhibited predominantly high expression in AML, indicating its potential as a diagnostic and prognostic marker for AML patients. High expression of SRSF12, along with age and cytogenetic risk, emerged as independent predictors of favorable prognosis in AML patients (P < 0.05). PCR demonstrated a significant increase in SRSF12 expression in AML patients. Conclusion Overall, our findings suggest that the high expression of SRSF12 in AML patients is a poor prognostic factor, which may provide a new option for the diagnosis, and targeted therapy of AML.

A novel approach for the treatment of AML, through GHRH antagonism: MIA-602.

Acute myeloid leukemia (AML) is the most aggressive and prevalent form of leukemia in adults. The gold-standard intervention revolves around the use of chemotherapy, and in some cases hematopoietic stem cell transplantation. Drug resistance is a frequent complication resulting from treatment, as it stands there are limited clinical measures available for refractory AML besides palliative care. The goal of this review is to renew interest in a novel targeted hormone therapy in the treatment of AML utilizing growth hormone-releasing hormone (GHRH) antagonism, given it may provide a potential solution for current barriers to achieving complete remission post-therapy. Recapitulating pre-clinical evidence, GHRH antagonists (GHRH-Ant) have significant anti-cancer activity across experimental human AML cell lines in vitro and in vivo and demonstrate significant inhibition of cancer in drug resistant analogs of leukemic cell lines as well. GHRH-Ant act in manners that are orthogonal to anthracyclines and when administered in combination synergize to produce a more potent anti-neoplastic effect. Considering the adversities associated with standard AML therapies and the developing issue of drug resistance, MIA-602 represents a novel approach worth further investigation.

Anagrelide and idarubicin combination induces GSDME-mediated pyroptosis as a potential therapy for high-PDE3A acute myeloid leukemia.

Acute myeloid leukemia (AML) is an invasive hematopoietic malignancy requiring novel treatment strategies. In this study, we identified phosphodiesterase 3 A (PDE3A) as a potential new target for drug repositioning in AML. PDE3A was preferentially overexpressed in AML cells than in normal cells, and high expression of PDE3A was correlated with lower event-free survival (EFS) in de novo AML patients. The PDE3A inhibitor anagrelide (ANA) profoundly suppresses the proliferation of high PDE3A-expressing AML cells while exhibiting minimal impact on those with low PDE3A expression. Moreover, synergistic effect of ANA with other chemotherapeutic drugs in high PDE3A expression AML cells was observed. The ANA-idarubicin (IDA) combination showed the most remarkable synergistic effect among all ANA-chemotherapeutic drugs commonly used in AML cell line models. Mechanistically, the synergy between ANA and IDA inhibited the survival of PDE3Ahigh AML cell lines through pyroptosis. This mechanism was initiated by GSDME cleavage triggered by caspase-3 activation. In vivo combination treatment of leukemic animals with high PDE3A expression significantly reduced leukemia burden and prolonged survival time compared with single-drug and vehicle control treatments. Our findings suggest that combined ANA and IDA treatment is an innovative and promising therapeutic strategy for AML patients with high PDE3A expression.

Emerging Role of CAR-T Therapy in Acute Myeloid Leukemia

Acute myeloid leukemia (AML), a malignant clonal disease originating from hematopoietic stem cells. In the past few decades, AML treatment has been dominated by a "3+7" regimen (anthracyclines + cytarabine), and the survival curve has stagnated. However, these procedures are associated with serious adverse effects. The development of chimeric antigen receptor (CAR)-T cell treatment provides a viable alternative, with decreased non-relapse death rates. Despite its potential, CAR-T cell therapy for AML confronts significant obstacles due to the disease's heterogeneity and accompanying toxicity. Genetic alteration strategies are being investigated to improve its safety and efficacy. Engineering CAR-T cells to express inhibitory receptors or suicide genes can help regulate T cell activity and prevent excessive immune activation. In summary, while CAR-T cell treatment has promise for AML, overcoming its hurdles through genetic modification and target refining is crucial. This review focuses on the existing landscape and future directions of CAR-T cell treatment for AML.

Acquired BCL2 variants associated with venetoclax resistance in acute myeloid leukemia

We report and characterize three venetoclax-resistant BCL2 variants arising during venetoclax/azacitidine therapy in acute myeloid leukemia (AML). Our results indicate the potential for on-target venetoclax resistance in patients with AML at relapse.

517LBA (PB-517) LBA Posters: Computational prediction of survival post induction therapy for acute myeloid leukaemia

517LBA (PB-517) LBA Posters: Computational prediction of survival post induction therapy for acute myeloid leukaemia

CAR T-cell therapy in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aggressive leukemic malignancy that affects myeloid lineage progenitors. Relapsed or refractory AML patients continue to have poor prognoses, necessitating the development of novel therapy alternatives. Adoptive T-cell therapy with chimeric antigen receptors (CARs) is an intriguing possibility in the field of leukemia treatment. Chimeric antigen receptor T-cell therapy is now being tested in clinical trials (mostly in phase I and phase II) using AML targets including CD33, CD123, and CLL-1. Preliminary data showed promising results. However, due to the cellular and molecular heterogeneity of AML and the co-expression of some AML targets on hematopoietic stem cells, these clinical investigations have shown substantial "on-target off-tumor" toxicities, indicating that more research is required. In this review, the latest significant breakthroughs in AML CAR T cell therapy are presented. Furthermore, the limitations of CAR T-cell technology and future directions to overcome these challenges are discussed.

Single low-dose decitabine as frontline therapy of acute myeloid leukaemia, with venetoclax salvage.

Single low-dose decitabine as frontline therapy of acute myeloid leukaemia, with venetoclax salvage.

Advances in Drug Delivery Systems for the Treatment of Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a common and catastrophic hematological neoplasm with high mortality rates. Conventional therapies, including chemotherapy, hematopoietic stem cell transplantation (HSCT), immune therapy, and targeted agents, have unsatisfactory outcomes for AML patients due to drug toxicity, off-target effects, drug resistance, drug side effects, and AML relapse and refractoriness. These intrinsic limitations of current treatments have promoted the development and application of nanomedicine for more effective and safer leukemia therapy. In this review, the classification of nanoparticles applied in AML therapy, including liposomes, polymersomes, micelles, dendrimers, and inorganic nanoparticles, is reviewed. In addition, various strategies for enhancing therapeutic targetability in nanomedicine, including the use of conjugating ligands, biomimetic-nanotechnology, and bone marrow targeting, which indicates the potential to reverse drug resistance, are discussed. The application of nanomedicine for assisting immunotherapy is also involved. Finally, the advantages and possible challenges of nanomedicine for the transition from the preclinical phase to the clinical phase are discussed.

Targeting Molecular Signaling Pathways and Cytokine Responses to Modulate c-MYC in Acute Myeloid Leukemia.

Overexpression of the MYC oncogene, encoding c-MYC protein, contributes to the pathogenesis and drug resistance of acute myeloid leukemia (AML) and many other hematopoietic malignancies. Although standard chemotherapy has predominated in AML therapy over the past five decades, the clinical outcomes and patient response to treatment remain suboptimal. Deeper insight into the molecular basis of this disease should facilitate the development of novel therapeutics targeting specific molecules and pathways that are dysregulated in AML, including fms-like tyrosine kinase 3 (FLT3) gene mutation and cluster of differentiation 33 (CD33) protein expression. Elevated expression of c-MYC is one of the molecular features of AML that determines the clinical prognosis in patients. Increased expression of c-MYC is also one of the cytogenetic characteristics of drug resistance in AML. However, direct targeting of c-MYC has been challenging due to its lack of binding sites for small molecules. In this review, we focused on the mechanisms involving the bromodomain and extra-terminal (BET) and cyclin-dependent kinase 9 (CDK9) proteins, phosphoinositide-Akt-mammalian target of rapamycin (PI3K/AKT/mTOR) and Janus kinase-signal transduction and activation of transcription (JAK/STAT) pathways, as well as various inflammatory cytokines, as an indirect means of regulating MYC overexpression in AML. Furthermore, we highlight Food and Drug Administration (FDA)-approved drugs for AML, and the results of preclinical and clinical studies on novel agents that have been or are currently being tested for efficacy and tolerability in AML therapy. Overall, this review summarizes our current knowledge of the molecular processes that promote leukemogenesis, as well as the various agents that intervene in specific pathways and directly or indirectly modulate c-MYC to disrupt AML pathogenesis and drug resistance.

Efficacy and safety of venetoclax combined with decitabine, modified HA regimen and DLI in the treatment of relapsed pediatric AML/MDS after allogeneic hematopoietic stem cell transplantation

Objective: To investigate the efficacy and safety of venetoclax combined with the decitabine, cytarabine, and homoharringtonine (HHT) regimen and donor lymphocyte infusion (DLI) for the preventive and salvage therapy of pediatric acute myeloid leukemia (AML) /myelodysplastic syndrome (MDS) after allogeneic hematopoietic stem cell transplantation (HSCT) . Methods: A total of 29 relapsed pediatric/minimal residual disease-positive AML after HSCT were recruited at the Peking University Institute of Hematology from January 1, 2021, to June 1, 2023. They were treated with the above combination regimen and administered with DLI after 24-48 hours at the end of chemotherapy, and the treatment response and adverse reactions were regularly assessed. Results: The overall response rate (ORR) was 75.8%, CR rate was 88.9% (8/9) in the hematologic relapse group, and MRD negativity rate was 61.1% (11/18) in the MRD-positive group. The incidence of agranulocytosis, anemia, and thrombocytopenia with a classification above grade 3 were 100%, 82.7%, and 100%, respectively. The median time of the granulocyte deficiency period was 15 days. Acute graft-versus-host diseases (aGVHD) with a classification of grades Ⅲ-Ⅳ occurred in 11.1% of the patients after DLI, while moderate or severe cGVHD occurred in 7.4% of the patients. The single risk factor for ORR was MNC counts of less than 10×10(8)/kg, and the relapse occurred within 100 days. At a median follow-up of 406 days, the 1-year OS was 65%, and the 1-year OS was 57% in the group with no reaction (P=0.164) compared with 71% in the group who had an overall reaction. Conclusion: The combined regimen based on the DAC, VEN, and modified HA regimen showed a high response rate in the salvage therapy for pediatric AML after the relapse of HSCT. However, bridging to transplantation should be performed immediately after remission to result in a long survival rate.

CD13-targeting and TRAIL-displaying Protein Nanoparticles Effectively Induce Apoptotic Cell Death of Acute Myeloid Leukemia, Prolonging Survival in Mouse Models

Acute myeloid leukemia (AML) is a rapidly proliferating blood cancer, necessitating treatments that specifically target and swiftly eradicate it. In this study, we develop an AML-specific, apoptotic cell death-inducing protein nanoparticle, AaLS/TRAIL/aCD13Nb, by simultaneously displaying multiple CD13-binding nanobodies (aCD13Nb) and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) molecules on a single AaLS protein nanoparticle using the SpyCatcher/SpyTag protein ligation system. AaLS/TRAIL/aCD13Nb selectively binds to various CD13-overexpressing AML cell lines and effectively accumulates near U937 AML tumor sites through systemic administration, demonstrating its AML targeting capabilities. The tight binding of AaLS/TRAIL/aCD13Nb to CD13-overexpressing AML cells, mediated by aCD13Nb, results in close and continuous contact between TRAIL molecules and death receptors, triggering robust apoptotic cell death. Systemic administrations of AaLS/TRAIL/aCD13Nb into U937 AML-engrafted NSG mice significantly reduce the AML burden and nearly double the mice’s survival period, especially under advanced and severe AML conditions. Collectively, our study paves the way for targeted therapies in AML, utilizing protein nanoparticles as nanoplatforms. Substantial therapeutic efficacy across various cancers can be achieved by strategically combining cancer-specific targeting ligands with apoptotic cancer cell death-inducing molecules, tailored to specific cancer types.

AML-437 Outcome of Post-Induction Therapy for Acute Myeloid Leukemia in Nanakaly Hospital-Erbil

AML-437 Outcome of Post-Induction Therapy for Acute Myeloid Leukemia in Nanakaly Hospital-Erbil

Risk Factor for Rash in Patients Receiving Cytarabine and Idarubicin Induction Therapy for Acute Myeloid Leukemia.

Rash is a common adverse event (AE) observed during cytarabine and idarubicin induction therapy in patients with acute myeloid leukemia (AML). Previous studies have highlighted the challenge in predicting the onset and duration of rash. This study aimed to determine the factors that affect the onset of rash in patients receiving induction therapy for AML. This retrospective study involved 97 patients with AML who received induction chemotherapy with cytarabine and idarubicin at the Department of Hematology, Kyushu University Hospital between January 2008 and June 2022. The factors associated with rash were identified through a multivariate stepwise logistic regression analysis. Subsequently, the patient's characteristics were compared between those with risk factors and those without risk factors using a matched pair analysis. Pre-existing leukopenia [odds ratio (OR)=3.294; 95% confidence interval (CI)=1.272-8.531] and good performance status (PS=0) (OR=2.717; 95%CI=1.087-6.792) were significant risk factors for rash development. Conversely, the matched pair analysis indicated that patients with pre-existing leukopenia, excluding those with a PS score of 0, exhibited a significantly (p=0.015) higher incidence of rash than those without it. Both multivariate logistic regression analysis and matched pair analysis identified pre-existing leukopenia as a primary risk factor for rash development associated with cytarabine and idarubicin chemotherapy.

Cutting-edge developments in acute myeloid leukaemia: innovations in diagnosis and treatment

Acute Myeloid Leukaemia (AML) is a fast-growing hematologic malignancy that is distinguished by the clonal proliferation of myeloid progenitors in bone marrow. Recent advances in molecular biology and genomic technology have altered the landscape of AML diagnosis and therapy, resulting in more tailored and successful therapeutic approaches. This study reviews recent innovations in the diagnosis and treatment of AML, focusing on genomic profiling, next-generation sequencing (NGS), and novel targeted therapies. Data was collected from recent clinical trials, peer-reviewed journals, and case studies. Comparative analysis was conducted to evaluate the efficacy of emerging diagnostic tools and treatments. NGS and MRD monitoring have greatly improved diagnosis accuracy and therapy customization. Targeted medicines have enhanced remission rates and decreased recurrence rates in individuals with certain genetic alterations. Immunotherapies have showed long-term efficacy and controllable safety profiles. Combining modern diagnostic technologies with customized medicines ushers in a new era of AML care, enhancing prognosis and quality of life. Ongoing research and clinical trials are critical for improving these therapies and expanding their advantages to a larger patient group.

TOPORS E3 ligase mediates resistance to hypomethylating agent cytotoxicity in acute myeloid leukemia cells

Hypomethylating agents (HMAs) are frontline therapies for Myelodysplastic Neoplasms (MDS) and Acute Myeloid Leukemia (AML). However, acquired resistance and treatment failure are commonplace. To address this, we perform a genome-wide CRISPR-Cas9 screen in a human MDS-derived cell line, MDS-L, and identify TOPORS as a loss-of-function target that synergizes with HMAs, reducing leukemic burden and improving survival in xenograft models. We demonstrate that depletion of TOPORS mediates sensitivity to HMAs by predisposing leukemic blasts to an impaired DNA damage response (DDR) accompanied by an accumulation of SUMOylated DNMT1 in HMA-treated TOPORS-depleted cells. The combination of HMAs with targeting of TOPORS does not impair healthy hematopoiesis. While inhibitors of TOPORS are unavailable, we show that inhibition of protein SUMOylation with TAK-981 partially phenocopies HMA-sensitivity and DDR impairment. Overall, our data suggest that the combination of HMAs with inhibition of SUMOylation or TOPORS is a rational treatment option for High-Risk MDS (HR-MDS) or AML.

The pro-differentiating capability of a flavonoid-rich extract of Citrus bergamia juice prompts autophagic death in THP-1 cells

Acute myeloid leukemia (AML) is a hematologic neoplasm, characterized by a blockage of differentiation and an unconstrained proliferation of immature myeloid cells. Recently, the survival of leukemia patients has increased thanks to the use of differentiating agents, though these may cause serious side effects. Hence, the search for safer differentiating compounds is necessary. Our aim was to assess the pro-differentiating effects of a flavonoid-rich extract of bergamot juice (BJe) in human monocytic leukemia THP-1 cells, an in vitro AML model. For the first time, we showed that treatment with BJe induced differentiation of THP-1 cells, changes in cell morphology and increased expression of differentiation-associated surface antigens CD68, CD11b and CD14. Moreover, BJe enhanced protein levels of autophagy-associated markers, such as Beclin-1 and LC3, as well as induced the phosphorylation of the MAPKs JNK, ERK and p38, hence suggesting a potential mechanism underlying its antiproliferative effects. Indeed, parallel experiments highlighted that BJe was able to hamper THP-1 cell growth. In conclusion, our study suggests that BJe induces the differentiation of THP-1 cells and reduces their proliferation, highlighting its potential in differentiation therapy of AML.

Venetoclax for pediatric patients with newly diagnosed acute myeloid leukemia.

This retrospective study at the University of Texas MD Anderson Cancer Center evaluated frontline venetoclax combination therapy in 11 pediatric/adolescent patients with acute myeloid leukemia (AML). Despite the small sample size and retrospective nature, the treatment demonstrated safety and potential efficacy, with most patients achieving early complete remission. Adverse events were consistent with other AML therapies, and no discontinuations due to toxicity occurred. While acknowledging study limitations, including selection bias and diverse concurrent therapies, this research underscores the promising role of venetoclax in pediatric AML. Further investigation is crucial to validate its long-term efficacy in this population.