New Targets and Therapies of Acute Myeloid Leukemia

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Methods and Technologies Development".

Deadline for manuscript submissions: closed (10 February 2023) | Viewed by 23744

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Guest Editor
Department of Hematology, CHU Lille, F-59000 Lille, France
Interests: leukemia; tumor dormancy; clonal hematopoiesis; PD-L1; immunoescape
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Special Issue Information

Dear Colleagues,

Treatment of acute myeloid leukemia (AML) has remained the same for nearly three decades. Options remained limited between intensive 3+7 regimen and low-dose and poorly effective chemotherapy, and progress was only related to better risk stratifications, improved allogeneic transplant procedures, and supportive care. These last few years have finally seen the emergence of new targets and drugs. Most of these new therapies remain in development, and very few have received approval from the FDA and EMA. This is in sharp contrast with other hematological malignancies such as multiple myeloma where drug approval rate has remained steady in recent decades in spite of little evidence of improved curability. Thus, developing new treatments for AML appears to be highly challenging. This is not because of a lack of model and scientific knowledge. AML is probably one of the most studied cancers, with numerous relevant mouse models, omics studies, clonal evolution follow-up, and minimal residual disease tools. Major advances in AML therapy will certainly come from thinking outside the box.

This Special Issue of Cancers therefore encompasses new research articles and timely reviews on all aspects of new targets and therapies of acute myeloid leukemia.

Prof. Dr. Bruno Quesnel
Guest Editor

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Published Papers (7 papers)

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Research

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13 pages, 1666 KiB  
Article
Haploidentical versus Double-Cord Blood Stem Cells as a Second Transplantation for Relapsed Acute Myeloid Leukemia
by Jong-Hyuk Lee, Byung-Sik Cho, Daehun Kwag, Gi-June Min, Sung-Soo Park, Silvia Park, Jae-Ho Yoon, Sung-Eun Lee, Ki-Seong Eom, Yoo-Jin Kim, Seok Lee, Chang-Ki Min, Seok-Goo Cho, Jong-Wook Lee and Hee-Je Kim
Cancers 2023, 15(2), 454; https://doi.org/10.3390/cancers15020454 - 10 Jan 2023
Viewed by 1597
Abstract
There are limited data on second stem cell transplantation (SCT2) outcomes with alternative donors for relapsed AML after the first stem cell transplantation (SCT1). We analyzed the outcomes of 52 adult AML patients who received SCT2 from haploidentical donors (HIT, N = 32) [...] Read more.
There are limited data on second stem cell transplantation (SCT2) outcomes with alternative donors for relapsed AML after the first stem cell transplantation (SCT1). We analyzed the outcomes of 52 adult AML patients who received SCT2 from haploidentical donors (HIT, N = 32) and double-cord blood (dCBT, N = 20) between 2008 and 2021. The HIT group received T-cell-replete peripheral blood stem cells after reduced-toxicity conditioning with anti-thymocyte globulin (ATG), while the dCBT group received myeloablative conditioning. For a median follow-up of 64.9 months, the HIT group, compared to the dCBT group, had earlier engraftment, superior 2-year overall survival (OS), disease-free survival (DFS), and non-relapse mortality (NRM) with similar relapse. Multivariate analysis demonstrated that HIT was significantly associated with better OS, DFS, and lower NRM than dCBT. Both longer remission duration after SCT1 and complete remission at SCT2 were significantly associated with a lower relapse rate. In addition, bone marrow WT1 measurable residual disease (MRD) positivity was significantly associated with inferior OS and higher relapse. This study suggests that T-cell-replete HIT with ATG-based GVHD prophylaxis may be preferred over dCBT as SCT2 for relapsed AML and that WT1-MRD negativity may be warranted for better SCT2 outcomes. Full article
(This article belongs to the Special Issue New Targets and Therapies of Acute Myeloid Leukemia)
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19 pages, 8793 KiB  
Article
NEO212, a Perillyl Alcohol-Temozolomide Conjugate, Triggers Macrophage Differentiation of Acute Myeloid Leukemia Cells and Blocks Their Tumorigenicity
by Thomas C. Chen, Radu O. Minea, Steve Swenson, Zhuoyue Yang, Thu Zan Thein and Axel H. Schönthal
Cancers 2022, 14(24), 6065; https://doi.org/10.3390/cancers14246065 - 9 Dec 2022
Cited by 3 | Viewed by 1798
Abstract
Many patients with acute myeloid leukemia (AML) are still dying from this disease. In the past, the alkylating agent temozolomide (TMZ) has been investigated for AML and found to be partially effective; however, the presence of O6-methylguanine DNA methyltransferase (MGMT; a DNA repair [...] Read more.
Many patients with acute myeloid leukemia (AML) are still dying from this disease. In the past, the alkylating agent temozolomide (TMZ) has been investigated for AML and found to be partially effective; however, the presence of O6-methylguanine DNA methyltransferase (MGMT; a DNA repair enzyme) in tumor cells confers profound treatment resistance against TMZ. We are developing a novel anticancer compound, called NEO212, where TMZ was covalently conjugated to perillyl alcohol (a naturally occurring monoterpene). NEO212 has revealed robust therapeutic activity in a variety of preclinical cancer models, including AML. In the current study, we investigated its impact on a panel of human AML cell lines and found that it exerted cytotoxic potency even against MGMT-positive cells that were highly resistant to TMZ. Furthermore, NEO212 strongly stimulated the expression of a large number of macrophage-associated marker genes, including CD11b/ITGAM. This latter effect could not be mimicked when cells were treated with TMZ or an equimolar mix of individual agents, TMZ plus perillyl alcohol. The superior cytotoxic impact of NEO212 appeared to involve down-regulation of MGMT protein levels. In a mouse model implanted with TMZ-resistant, MGMT-positive AML cells, two 5-day cycles of 25 mg/kg NEO212 achieved an apparent cure, as mice survived >300 days without any signs of disease. In parallel toxicity studies with rats, a 5-day cycle of 200 mg/kg NEO212 was well tolerated by these animals, whereas animals that were given 200 mg/kg TMZ all died due to severe leukopenia. Together, our results show that NEO212 exerts pleiotropic effects on AML cells that include differentiation, proliferation arrest, and eventual cell death. In vivo, NEO212 was well tolerated even at dosages that far exceed the therapeutic need, indicating a large therapeutic window. These results present NEO212 as an agent that should be considered for development as a therapeutic agent for AML. Full article
(This article belongs to the Special Issue New Targets and Therapies of Acute Myeloid Leukemia)
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16 pages, 2232 KiB  
Article
EGCG Prevents the Transcriptional Reprogramming of an Inflammatory and Immune-Suppressive Molecular Signature in Macrophage-like Differentiated Human HL60 Promyelocytic Leukemia Cells
by Celia Kassouri, Sahily Rodriguez Torres, Narjara Gonzalez Suarez, Stéphanie Duhamel and Borhane Annabi
Cancers 2022, 14(20), 5065; https://doi.org/10.3390/cancers14205065 - 16 Oct 2022
Cited by 3 | Viewed by 2021
Abstract
Background: The promyelocytic leukemia cell differentiation process enables recapitulation of the polarized M1 or M2 macrophage-like phenotype with inflammatory and immune-suppressive properties. While evidence supports the anti-inflammatory effect of dietary-derived epigallocatechin-3-gallate (EGCG), its impact on the onset of immune phenotype molecular signature remains [...] Read more.
Background: The promyelocytic leukemia cell differentiation process enables recapitulation of the polarized M1 or M2 macrophage-like phenotype with inflammatory and immune-suppressive properties. While evidence supports the anti-inflammatory effect of dietary-derived epigallocatechin-3-gallate (EGCG), its impact on the onset of immune phenotype molecular signature remains unclear. Methods: Human HL60 promyelocytic cells grown in suspension were differentiated into CD11bHigh/CD14Low adherent macrophages with phorbol 12-myristate 13-acetate (PMA). Gelatin zymography was used to assess the levels of matrix metalloproteinase (MMP)-9, and total RNA was isolated for RNAseq and RT-qPCR assessment of differentially expressed gene levels involved in inflammation and immunity. Protein lysates were used to assess the phosphorylation status of signaling intermediates involved in macrophage-like cell differentiation. Results: Cell adhesion and induction of MMP-9 were indicative of HL60 cell differentiation into a macrophage-like phenotype. The extracellular signal-regulated kinase (ERK), glycogen synthase kinase (GSK)-3, p90 ribosomal S6 kinases (RSK), and cAMP-response-element-binding protein (CREB) were all phosphorylated, and EGCG reduced such phosphorylation status. Increases in inflammation and immunity genes included, among others, CCL22, CSF1, CSF2, IL1B, and TNF, which inductions were prevented by EGCG. This was corroborated by unbiased transcriptomic analysis which further highlighted the capacity of EGCG to downregulate the hematopoietic stem cell regulator CBFA2T3. Conclusion: EGCG inhibits inflammatory signaling crosstalk and prevents the onset of an immune phenotype in macrophage-like differentiated cells. Full article
(This article belongs to the Special Issue New Targets and Therapies of Acute Myeloid Leukemia)
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14 pages, 1915 KiB  
Article
Azacitidine Plus Venetoclax for the Treatment of Relapsed and Newly Diagnosed Acute Myeloid Leukemia Patients
by Sylvain Garciaz, Marie-Anne Hospital, Anne-Sophie Alary, Colombe Saillard, Yosr Hicheri, Bilal Mohty, Jérôme Rey, Evelyne D’Incan, Aude Charbonnier, Ferdinand Villetard, Valerio Maisano, Laura Lombardi, Antoine Ittel, Marie-Joelle Mozziconacci, Véronique Gelsi-Boyer and Norbert Vey
Cancers 2022, 14(8), 2025; https://doi.org/10.3390/cancers14082025 - 16 Apr 2022
Cited by 17 | Viewed by 4837
Abstract
Venetoclax (VEN) belongs the BH3-mimetic class that selectively targets BCL-2, activating apoptosis. The combination of VEN and azacitidine (AZA) has changed the paradigm of treatment of newly diagnosed (ND) acute myeloid leukemia (AML) patients ineligible for intensive chemotherapy. There is scarce evidence for [...] Read more.
Venetoclax (VEN) belongs the BH3-mimetic class that selectively targets BCL-2, activating apoptosis. The combination of VEN and azacitidine (AZA) has changed the paradigm of treatment of newly diagnosed (ND) acute myeloid leukemia (AML) patients ineligible for intensive chemotherapy. There is scarce evidence for the use of VEN–AZA for relapsed or refractory (R/R) AML. We compared the outcome of 39 R/R AML and 38 ND AML patients treated between 01/20 and 12/21. The median age was 69 (22–86) and 73 (61–81) in the R/R and ND groups, respectively. Adverse cytogenetics were found in 36% of patients in the R/R group and 59% of patients in the ND group. Overall response rate was 37% in R/R AML, including 13% CR, 8% CRi, 3% PR and 13% MLFS, and 58% in the ND AML, including 32% CR, 13% CRi and 13% MLFS. Adverse cytogenetics was associated with treatment failure in the R/R group (Relative Risk = 0.13, p = 0.005). Median overall survival (OS) was 5.9 months in the R/R group and 9.4 months in the ND group. Median OS was 2.2 months in the adverse cytogenetics group versus 8.7 months in the intermediate cytogenetics group in the R/R group (p = 0.02). Median leukemia-free survival was not different between the two groups (9.4 months and 10.3 months), indicating that VEN–AZA can be an efficient salvage treatment for selected R/R AML patients. In conclusion, VEN–AZA is a promising treatment for ND AML and for selected R/R AML patients. Full article
(This article belongs to the Special Issue New Targets and Therapies of Acute Myeloid Leukemia)
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Review

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26 pages, 1179 KiB  
Review
Targeting Apoptosis in AML: Where Do We Stand?
by Kinga Krawiec, Piotr Strzałka, Magdalena Czemerska, Aneta Wiśnik, Izabela Zawlik, Agnieszka Wierzbowska and Agnieszka Pluta
Cancers 2022, 14(20), 4995; https://doi.org/10.3390/cancers14204995 - 12 Oct 2022
Cited by 7 | Viewed by 3091
Abstract
More than 97% of patients with acute myeloid leukemia (AML) demonstrate genetic mutations leading to excessive proliferation combined with the evasion of regulated cell death (RCD). The most prominent and well-defined form of RCD is apoptosis, which serves as a defense mechanism against [...] Read more.
More than 97% of patients with acute myeloid leukemia (AML) demonstrate genetic mutations leading to excessive proliferation combined with the evasion of regulated cell death (RCD). The most prominent and well-defined form of RCD is apoptosis, which serves as a defense mechanism against the emergence of cancer cells. Apoptosis is regulated in part by the BCL-2 family of pro- and anti-apoptotic proteins, whose balance can significantly determine cell survival. Apoptosis evasion plays a key role in tumorigenesis and drug resistance, and thus in the development and progression of AML. Research on the structural and biochemical aspects of apoptosis proteins and their regulators offers promise for new classes of targeted therapies and strategies for therapeutic intervention. This review provides a comprehensive overview of current AML treatment options related to the mechanism of apoptosis, particularly its mitochondrial pathway, and other promising concepts such as neddylation. It pays particular attention to clinically-relevant aspects of current and future AML treatment approaches, highlighting the molecular basis of individual therapies. Full article
(This article belongs to the Special Issue New Targets and Therapies of Acute Myeloid Leukemia)
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16 pages, 700 KiB  
Review
Updates on the Management of Acute Myeloid Leukemia
by Sofía Huerga-Domínguez, Sara Villar, Felipe Prósper and Ana Alfonso-Piérola
Cancers 2022, 14(19), 4756; https://doi.org/10.3390/cancers14194756 - 29 Sep 2022
Cited by 8 | Viewed by 4960
Abstract
Acute myeloid leukemia is a heterogeneous disease defined by a large spectrum of genetic aberrations that are potential therapeutic targets. New targeted therapies have changed the landscape for a disease with poor outcomes. They are more effective than standard chemotherapy with a good [...] Read more.
Acute myeloid leukemia is a heterogeneous disease defined by a large spectrum of genetic aberrations that are potential therapeutic targets. New targeted therapies have changed the landscape for a disease with poor outcomes. They are more effective than standard chemotherapy with a good safety profile. For “fit patients” in first-line, the combination of gemtuzumab ozogamicin or midostaurin with intensive chemotherapy or Vyxeos is now considered the “standard of care” for selected patients. On the other hand, for “unfit patients”, azacitidine-venetoclax has been consolidated as a frontline treatment, while other combinations with magrolimab or ivosidenib are in development. Nevertheless, global survival results, especially in relapsed or refractory patients, remain unfavorable. New immunotherapies or targeted therapies, such as Menin inhibitors or sabatolimab, represent an opportunity in this situation. Future directions will probably come from combinations of different targeted therapies (“triplets”) and maintenance strategies guided by measurable residual disease. Full article
(This article belongs to the Special Issue New Targets and Therapies of Acute Myeloid Leukemia)
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22 pages, 2363 KiB  
Review
Modulation of the Gal-9/TIM-3 Immune Checkpoint with α-Lactose. Does Anomery of Lactose Matter?
by Christian Bailly, Xavier Thuru and Bruno Quesnel
Cancers 2021, 13(24), 6365; https://doi.org/10.3390/cancers13246365 - 18 Dec 2021
Cited by 8 | Viewed by 4677
Abstract
The disaccharide lactose is an excipient commonly used in pharmaceutical products. The two anomers, α- and β-lactose (α-L/β-L), differ by the orientation of the C-1 hydroxyl group on the glucose unit. In aqueous solution, a mutarotation process leads to an equilibrium of about [...] Read more.
The disaccharide lactose is an excipient commonly used in pharmaceutical products. The two anomers, α- and β-lactose (α-L/β-L), differ by the orientation of the C-1 hydroxyl group on the glucose unit. In aqueous solution, a mutarotation process leads to an equilibrium of about 40% α-L and 60% β-L at room temperature. Beyond a pharmaceutical excipient in solid products, α-L has immuno-modulatory effects and functions as a major regulator of TIM-3/Gal-9 immune checkpoint, through direct binding to the β-galactoside-binding lectin galectin-9. The blockade of the co-inhibitory checkpoint TIM-3 expressed on T cells with anti-TIM-3 antibodies represents a promising approach to combat different onco-hematological diseases, in particular myelodysplastic syndromes and acute myeloid leukemia. In parallel, the discovery and development of anti-TIM-3 small molecule ligands is emerging, including peptides, RNA aptamers and a few specifically designed heterocyclic molecules. An alternative option consists of targeting the different ligands of TIM-3, notably Gal-9 recognized by α-lactose. Modulation of the TIM-3/Gal-9 checkpoint can be achieved with both α- and β-lactose. Moreover, lactose is a quasi-pan-galectin ligand, capable of modulating the functions of most of the 16 galectin molecules. The present review provides a complete analysis of the pharmaceutical and galectin-related biological functions of (α/β)-lactose. A focus is made on the capacity of lactose and Gal-9 to modulate both the TIM-3/Gal-9 and PD-1/PD-L1 immune checkpoints in oncology. Modulation of the TIM-3/Gal-9 checkpoint is a promising approach for the treatment of cancers and the role of lactose in this context is discussed. The review highlights the immuno-regulatory functions of lactose, and the benefit of the molecule well beyond its use as a pharmaceutical excipient. Full article
(This article belongs to the Special Issue New Targets and Therapies of Acute Myeloid Leukemia)
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