Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
7.4
5.2
Journals
Cancers
Special Issues
New Therapeutic Strategies for Acute Myeloid Leukemia
share announcement

New Therapeutic Strategies for Acute Myeloid Leukemia

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 50518

Special Issue Editor

Prof. Dr. Christian Récher

E-Mail Website
Guest Editor
Haematology Department, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer Toulouse Oncopole, Centre de Recherche en Cancérologie de Toulouse, Université de Toulouse 3 Paul Sabatier, Toulouse Cedex 9, France
Interests: acute myeloid leukemia; leukemic stem cells; targeted therapies; oncometabolism; inflammation; clinical trials
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

In acute myeloid leukemia research, the last twenty years have been shaped by the advent of novel biology technologies including high-throughput sequencing or multiparameter flow cytometry that improved prognostic classification and response evaluation through the quantification of residual disease and the launch of research on targeted therapies. Our knowledge of leukemogenesis, AML genetic diversity, gene-gene interactions, clonal evolution and treatment response assessment has also greatly improved. New classifications based on chromosomal abnormalities and gene mutations are now integrated on a routine basis. These considerable efforts contributed to the discovery and development of promising drugs, which specifically target gene mutations, apoptotic pathways, and cell surface antigens. In just a few years, nine novels drugs have been approved for the treatment of newly diagnosed or relapse/refractory AML patients and many others are being intensively investigated, in particular immune therapies. There are now numerous clinical research opportunities offered to clinicians thanks to these new treatment options. We are only at the start of a new era, which should see major disruptions in the way we understand, treat, and monitor patients with AML.

In this Special Issue, the experts will discuss recent developments and outline the most promising areas of clinical development in the field of AML.

Prof. Christian Récher
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • acute myeloid leukemia
  • targeted therapy
  • immune therapy
  • chemotherapy
  • chemoresistance
  • minimal/measurable residual disease
  • maintenance treatment
  • allogeneic stem cell transplantation

Published Papers (16 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Research

Jump to: Review, Other

15 pages, 287 KiB  
Article
Effect of Antibacterial Prophylaxis on Febrile Neutropenic Episodes and Bacterial Bloodstream Infections in Dutch Pediatric Patients with Acute Myeloid Leukemia: A Two-Center Retrospective Study
by Romy E. Van Weelderen, Kim Klein, Bianca F. Goemans, Wim J. E. Tissing, Tom F. W. Wolfs and Gertjan J. L. Kaspers
Cancers 2022, 14(13), 3172; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14133172 - 28 Jun 2022
Viewed by 1503
Abstract
Bloodstream infections (BSIs), especially those caused by Gram-negative rods (GNR) and viridans group streptococci (VGS), are common and potentially life-threatening complications of pediatric acute myeloid leukemia (AML) treatment. Limited literature is available on prophylactic regimens. We retrospectively evaluated the effect of different antibacterial [...] Read more.
Bloodstream infections (BSIs), especially those caused by Gram-negative rods (GNR) and viridans group streptococci (VGS), are common and potentially life-threatening complications of pediatric acute myeloid leukemia (AML) treatment. Limited literature is available on prophylactic regimens. We retrospectively evaluated the effect of different antibacterial prophylaxis regimens on the incidence of febrile neutropenic (FN) episodes and bacterial BSIs. Medical records of children (0–18 years) diagnosed with de novo AML and treated at two Dutch centers from May 1998 to March 2021 were studied. Data were analyzed per chemotherapy course and consecutive neutropenic period. A total of 82 patients had 316 evaluable courses: 92 were given with single-agent ciprofloxacin, 138 with penicillin plus ciprofloxacin, and 51 with teicoplanin plus ciprofloxacin. The remaining 35 courses with various other prophylaxis regimens were not statistically compared. During courses with teicoplanin plus ciprofloxacin, significantly fewer FN episodes (43 vs. 90% and 75%; p < 0.0001) and bacterial BSIs (4 vs. 63% and 33%; p < 0.0001) occurred than with single-agent ciprofloxacin and penicillin plus ciprofloxacin, respectively. GNR and VGS BSIs did not occur with teicoplanin plus ciprofloxacin and no bacterial BSI-related pediatric intensive care unit (PICU) admissions were required, whereas, with single-agent ciprofloxacin and penicillin plus ciprofloxacin, GNR BSIs occurred in 8 and 1% (p = 0.004), VGS BSIs in 24 and 14% (p = 0.0005), and BSI-related PICU admissions were required in 8 and 2% of the courses (p = 0.029), respectively. Teicoplanin plus ciprofloxacin as antibacterial prophylaxis is associated with a lower incidence of FN episodes and bacterial BSIs. This may be a good prophylactic regimen for pediatric AML patients during treatment. Full article
(This article belongs to the Special Issue New Therapeutic Strategies for Acute Myeloid Leukemia)
14 pages, 1761 KiB  
Article
The Multi-Kinase Inhibitor EC-70124 Is a Promising Candidate for the Treatment of FLT3-ITD-Positive Acute Myeloid Leukemia
by Belen Lopez-Millan, Paula Costales, Francisco Gutiérrez-Agüera, Rafael Díaz de la Guardia, Heleia Roca-Ho, Meritxell Vinyoles, Alba Rubio-Gayarre, Rémi Safi, Julio Castaño, Paola Alejandra Romecín, Manuel Ramírez-Orellana, Eduardo Anguita, Irmela Jeremias, Lurdes Zamora, Juan Carlos Rodríguez-Manzaneque, Clara Bueno, Francisco Morís and Pablo Menendez
Cancers 2022, 14(6), 1593; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061593 - 21 Mar 2022
Cited by 2 | Viewed by 2500
Abstract
Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Patients with AML harboring a constitutively active internal tandem duplication mutation (ITDMUT) in the FMS-like kinase tyrosine kinase (FLT3) receptor generally have a poor prognosis. Several tyrosine kinase/FLT3 inhibitors [...] Read more.
Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Patients with AML harboring a constitutively active internal tandem duplication mutation (ITDMUT) in the FMS-like kinase tyrosine kinase (FLT3) receptor generally have a poor prognosis. Several tyrosine kinase/FLT3 inhibitors have been developed and tested clinically, but very few (midostaurin and gilteritinib) have thus far been FDA/EMA-approved for patients with newly diagnosed or relapse/refractory FLT3-ITDMUT AML. Disappointingly, clinical responses are commonly partial or not durable, highlighting the need for new molecules targeting FLT3-ITDMUT AML. Here, we tested EC-70124, a hybrid indolocarbazole analog from the same chemical space as midostaurin with a potent and selective inhibitory effect on FLT3. In vitro, EC-70124 exerted a robust and specific antileukemia activity against FLT3-ITDMUT AML primary cells and cell lines with respect to cytotoxicity, CFU capacity, apoptosis and cell cycle while sparing healthy hematopoietic (stem/progenitor) cells. We also analyzed its efficacy in vivo as monotherapy using two different xenograft models: an aggressive and systemic model based on MOLM-13 cells and a patient-derived xenograft model. Orally disposable EC-70124 exerted a potent inhibitory effect on the growth of FLT3-ITDMUT AML cells, delaying disease progression and debulking the leukemia. Collectively, our findings show that EC-70124 is a promising and safe agent for the treatment of AML with FLT3-ITDMUT. Full article
(This article belongs to the Special Issue New Therapeutic Strategies for Acute Myeloid Leukemia)
►▼ Show Figures

Figure 1

13 pages, 771 KiB  
Article
Comparison of Melphalan Combined with Treosulfan or Busulfan as High-Dose Chemotherapy before Autologous Stem Cell Transplantation in AML
by Ekaterina Gurevich, Michael Hayoz, Yolanda Aebi, Carlo R. Largiadèr, Behrouz Mansouri Taleghani, Ulrike Bacher and Thomas Pabst
Cancers 2022, 14(4), 1024; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14041024 - 17 Feb 2022
Cited by 4 | Viewed by 1838
Abstract
(1) Background: High-dose chemotherapy (HDCT) before autologous stem cell transplantation (ASCT) in acute myeloid leukemia (AML) patients predominantly combines busulfan with cyclophosphamide or melphalan. Treosulfan compares favorably regarding lower inter-individual bioavailability and neurotoxicity, but so far, had not been studied before ASCT in [...] Read more.
(1) Background: High-dose chemotherapy (HDCT) before autologous stem cell transplantation (ASCT) in acute myeloid leukemia (AML) patients predominantly combines busulfan with cyclophosphamide or melphalan. Treosulfan compares favorably regarding lower inter-individual bioavailability and neurotoxicity, but so far, had not been studied before ASCT in AML. (2) Methods: This single-center study investigated AML patients undergoing ASCT in CR1 between November 2017 and September 2020. The first 16 patients received busulfan 16 mg/kg b.w. (days −5 to −2) and melphalan 140 mg/m2 (day −1) (BuMel). In a subsequent (TreoMel) cohort, 20 patients received treosulfan 14 g/m2 (days −4 to −2) and melphalan. Plasma concentrations of busulfan and treosulfan were determined by mass spectrometry. (3) Results: Neutrophil engraftment and platelet recovery were similar, and PFS and OS were comparable. In only the BuMel cohort, patients reported central nervous toxicities, including seizures (6%) and encephalopathy (12%). The mean AUC for busulfan was 1471.32 μM*min, and for treosulfan it was 836.79 mg/L*h, with ranges of 804.1–2082 μM*min and 454.2–1402 mg/L*h. The peak values for busulfan ranged between 880.19–1734 μg/L and for treosulfan between 194.3–489.25 mg/L. (4) Conclusions: TreoMel appears to be safe and effective for pre-ASCT treatment in AML patients. Due to considerable interindividual biovariability, pharmacologic monitoring may also be warranted for the use of treosulfan. Full article
(This article belongs to the Special Issue New Therapeutic Strategies for Acute Myeloid Leukemia)
►▼ Show Figures

Figure 1

12 pages, 1738 KiB  
Communication
High Metabolic Dependence on Oxidative Phosphorylation Drives Sensitivity to Metformin Treatment in MLL/AF9 Acute Myeloid Leukemia
by Longlong Liu, Pradeep Kumar Patnana, Xiaoqing Xie, Daria Frank, Subbaiah Chary Nimmagadda, Annegret Rosemann, Marie Liebmann, Luisa Klotz, Bertram Opalka and Cyrus Khandanpour
Cancers 2022, 14(3), 486; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14030486 - 19 Jan 2022
Cited by 12 | Viewed by 2452
Abstract
Acute myeloid leukemia (AML) is a group of hematological cancers with metabolic heterogeneity. Oxidative phosphorylation (OXPHOS) has been reported to play an important role in the function of leukemic stem cells and chemotherapy-resistant cells and are associated with inferior prognosis in AML patients. [...] Read more.
Acute myeloid leukemia (AML) is a group of hematological cancers with metabolic heterogeneity. Oxidative phosphorylation (OXPHOS) has been reported to play an important role in the function of leukemic stem cells and chemotherapy-resistant cells and are associated with inferior prognosis in AML patients. However, the relationship between metabolic phenotype and genetic mutations are yet to be explored. In the present study, we demonstrate that AML cell lines have high metabolic heterogeneity, and AML cells with MLL/AF9 have upregulated mitochondrial activity and mainly depend on OXPHOS for energy production. Furthermore, we show that metformin repressed the proliferation of MLL/AF9 AML cells by inhibiting mitochondrial respiration. Together, this study demonstrates that AML cells with an MLL/AF9 genotype have a high dependency on OXPHOS and could be therapeutically targeted by metformin. Full article
(This article belongs to the Special Issue New Therapeutic Strategies for Acute Myeloid Leukemia)
►▼ Show Figures

Figure 1

17 pages, 12829 KiB  
Article
An HLA-A*11:01-Binding Neoantigen from Mutated NPM1 as Target for TCR Gene Therapy in AML
by Dyantha I. van der Lee, Georgia Koutsoumpli, Rogier M. Reijmers, M. Willy Honders, Rob C. M. de Jong, Dennis F. G. Remst, Tassilo L. A. Wachsmann, Renate S. Hagedoorn, Kees L. M. C. Franken, Michel G. D. Kester, Karl J. Harber, Lisanne M. Roelofsen, Annemiek M. Schouten, Arend Mulder, Jan W. Drijfhout, Hendrik Veelken, Peter A. van Veelen, Mirjam H. M. Heemskerk, J.H. Frederik Falkenburg and Marieke Griffioen
Cancers 2021, 13(21), 5390; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13215390 - 27 Oct 2021
Cited by 2 | Viewed by 2798
Abstract
Acute myeloid leukemia (AML) is a hematological malignancy caused by clonal expansion of myeloid progenitor cells. Most patients with AML respond to chemotherapy, but relapses often occur and infer a very poor prognosis. Thirty to thirty-five percent of AMLs carry a four base [...] Read more.
Acute myeloid leukemia (AML) is a hematological malignancy caused by clonal expansion of myeloid progenitor cells. Most patients with AML respond to chemotherapy, but relapses often occur and infer a very poor prognosis. Thirty to thirty-five percent of AMLs carry a four base pair insertion in the nucleophosmin 1 gene (NPM1) with a C-terminal alternative reading frame of 11 amino acids. We previously identified various neopeptides from the alternative reading frame of mutant NPM1 (dNPM1) on primary AML and isolated an HLA-A*02:01-restricted T-cell receptor (TCR) that enables human T-cells to kill AML cells upon retroviral gene transfer. Here, we isolated T-cells recognizing the dNPM1 peptide AVEEVSLRK presented in HLA-A*11:01. The TCR cloned from a T-cell clone recognizing HLA-A*11:01+ primary AML cells conferred in vitro recognition and lysis of AML upon transfer to CD8 cells, but failed to induce an anti-tumor effect in immunodeficient NSG mice engrafted with dNPM1 OCI-AML3 cells. In conclusion, our data show that AVEEVSLRK is a dNPM1 neoantigen on HLA-A*11:01+ primary AMLs. CD8 cells transduced with an HLA-A*11:01-restricted TCR for dNPM1 were reactive against AML in vitro. The absence of reactivity in a preclinical mouse model requires further preclinical testing to predict the potential efficacy of this TCR in clinical development. Full article
(This article belongs to the Special Issue New Therapeutic Strategies for Acute Myeloid Leukemia)
►▼ Show Figures

Figure 1

18 pages, 6774 KiB  
Article
Disrupting Mitochondrial Electron Transfer Chain Complex I Decreases Immune Checkpoints in Murine and Human Acute Myeloid Leukemic Cells
by Raquel Luna-Yolba, Justine Marmoiton, Véronique Gigo, Xavier Marechal, Emeline Boet, Ambrine Sahal, Nathalie Alet, Ifat Abramovich, Eyal Gottlieb, Virgile Visentin, Michael R. Paillasse and Jean-Emmanuel Sarry
Cancers 2021, 13(14), 3499; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13143499 - 13 Jul 2021
Cited by 9 | Viewed by 3045
Abstract
Oxidative metabolism is crucial for leukemic stem cell (LSC) function and drug resistance in acute myeloid leukemia (AML). Mitochondrial metabolism also affects the immune system and therefore the anti-tumor response. The modulation of oxidative phosphorylation (OxPHOS) has emerged as a promising approach to [...] Read more.
Oxidative metabolism is crucial for leukemic stem cell (LSC) function and drug resistance in acute myeloid leukemia (AML). Mitochondrial metabolism also affects the immune system and therefore the anti-tumor response. The modulation of oxidative phosphorylation (OxPHOS) has emerged as a promising approach to improve the therapy outcome for AML patients. However, the effect of mitochondrial inhibitors on the immune compartment in the context of AML is yet to be explored. Immune checkpoints such as ectonucleotidase CD39 and programmed dead ligand 1 (PD-L1) have been reported to be expressed in AML and linked to chemo-resistance and a poor prognosis. In the present study, we first demonstrated that a novel selective electron transfer chain complex (ETC) I inhibitor, EVT-701, decreased the OxPHOS metabolism of murine and human cytarabine (AraC)-resistant leukemic cell lines. Furthermore, we showed that while AraC induced an immune response regulation by increasing CD39 expression and by reinforcing the interferon-γ/PD-L1 axis, EVT-701 reduced CD39 and PD-L1 expression in vitro in a panel of both murine and human AML cell lines, especially upon AraC treatment. Altogether, this work uncovers a non-canonical function of ETCI in controlling CD39 and PD-L1 immune checkpoints, thereby improving the anti-tumor response in AML. Full article
(This article belongs to the Special Issue New Therapeutic Strategies for Acute Myeloid Leukemia)
►▼ Show Figures

Figure 1

Review

Jump to: Research, Other

15 pages, 930 KiB  
Review
Targeting Menin and CD47 to Address Unmet Needs in Acute Myeloid Leukemia
by Andrew H. Matthews, Keith W. Pratz and Martin P. Carroll
Cancers 2022, 14(23), 5906; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14235906 - 29 Nov 2022
Cited by 3 | Viewed by 2682
Abstract
After forty years of essentially unchanged treatment in acute myeloid leukemia (AML), innovation over the past five years has been rapid, with nine drug approvals from 2016 to 2021. Increased understanding of the molecular changes and genetic ontology of disease have led to [...] Read more.
After forty years of essentially unchanged treatment in acute myeloid leukemia (AML), innovation over the past five years has been rapid, with nine drug approvals from 2016 to 2021. Increased understanding of the molecular changes and genetic ontology of disease have led to targeting mutations in isocitrate dehydrogenase, FMS-like tyrosine kinase 3 (FLT3), B-cell lymphoma 2 and hedgehog pathways. Yet outcomes remain variable; especially in defined molecular and genetic subgroups such as NPM1 (Nucleophosmin 1) mutations, 11q23/KMT2A rearranged and TP53 mutations. Emerging therapies seek to address these unmet needs, and all three of these subgroups have promising new therapeutic approaches. Here, we will discuss the normal biological roles of menin in acute leukemia, notably in KMT2A translocations and NPM1 mutation, as well as current drug development. We will also explore how CD47 inhibition may move immunotherapy into front-line settings and unlock new treatment strategies in TP53 mutated disease. We will then consider how these new therapeutic advances may change the management of AML overall. Full article
(This article belongs to the Special Issue New Therapeutic Strategies for Acute Myeloid Leukemia)
►▼ Show Figures

Figure 1

24 pages, 967 KiB  
Review
New Therapeutic Strategies for Adult Acute Myeloid Leukemia
by Hiroto Ishii and Shingo Yano
Cancers 2022, 14(11), 2806; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14112806 - 05 Jun 2022
Cited by 15 | Viewed by 5288
Abstract
Acute myeloid leukemia (AML) is a genetically heterogeneous hematological malignancy. Chromosomal and genetic analyses are important for the diagnosis and prognosis of AML. Some patients experience relapse or have refractory disease, despite conventional cytotoxic chemotherapies and allogeneic transplantation, and a variety of new [...] Read more.
Acute myeloid leukemia (AML) is a genetically heterogeneous hematological malignancy. Chromosomal and genetic analyses are important for the diagnosis and prognosis of AML. Some patients experience relapse or have refractory disease, despite conventional cytotoxic chemotherapies and allogeneic transplantation, and a variety of new agents and treatment strategies have emerged. After over 20 years during which no new drugs became available for the treatment of AML, the CD33-targeting antibody–drug conjugate gemtuzumab ozogamicin was developed. This is currently used in combination with standard chemotherapy or as a single agent. CPX-351, a liposomal formulation containing daunorubicin and cytarabine, has become one of the standard treatments for secondary AML in the elderly. FMS-like tyrosine kinase 3 (FLT3) inhibitors and isocitrate dehydrogenase 1/2 (IDH 1/2) inhibitors are mainly used for AML patients with actionable mutations. In addition to hypomethylating agents and venetoclax, a B-cell lymphoma-2 inhibitor is used in frail patients with newly diagnosed AML. Recently, tumor protein p53 inhibitors, cyclin-dependent kinase inhibitors, and NEDD8 E1-activating enzyme inhibitors have been gaining attention, and a suitable strategy for the use of these drugs is required. Antibody drugs targeting cell-surface markers and immunotherapies, such as antibody–drug conjugates and chimeric antigen receptor T-cell therapy, have also been developed for AML. Full article
(This article belongs to the Special Issue New Therapeutic Strategies for Acute Myeloid Leukemia)
►▼ Show Figures

Figure 1

19 pages, 876 KiB  
Review
Are We Moving the Needle for Patients with TP53-Mutated Acute Myeloid Leukemia?
by Rory M. Shallis, Jan P. Bewersdorf, Maximilian F. Stahl, Stephanie Halene and Amer M. Zeidan
Cancers 2022, 14(10), 2434; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14102434 - 14 May 2022
Cited by 7 | Viewed by 4117
Abstract
The currently available therapeutic options for patients with TP53-mutated acute myeloid leukemia (AML) are insufficient, as they translate to a median overall of only 6–9 months, and less than 10% of patients undergoing the most aggressive treatments, such as intensive induction therapy [...] Read more.
The currently available therapeutic options for patients with TP53-mutated acute myeloid leukemia (AML) are insufficient, as they translate to a median overall of only 6–9 months, and less than 10% of patients undergoing the most aggressive treatments, such as intensive induction therapy and allogeneic hematopoietic stem cell transplantation, will be cured. The lack of clear differences in outcomes with different treatments precludes the designation of a standard of care. Recently, there has been growing attention on this critical area of need by way of better understanding the biology of TP53 alterations and the disparities in outcomes among patients in this molecular subgroup, reflected in the development and testing of agents with novel mechanisms of action. Promising preclinical and efficacy data exist for therapies that are directed at the p53 protein rendered dysfunctional via mutation or that inhibit the CD47/SIRPα axis or other immune checkpoints such as TIM-3. In this review, we discuss recently attractive and emerging therapeutic agents, their preclinical rationale and the available clinical data as a monotherapy or in combination with the currently accepted backbones in frontline and relapsed/refractory settings for patients with TP53-mutated AML. Full article
(This article belongs to the Special Issue New Therapeutic Strategies for Acute Myeloid Leukemia)
►▼ Show Figures

Figure 1

16 pages, 685 KiB  
Review
Immune-Based Therapeutic Strategies for Acute Myeloid Leukemia
by Matthias Böhme and Sabine Kayser
Cancers 2022, 14(1), 105; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14010105 - 27 Dec 2021
Cited by 6 | Viewed by 4108
Abstract
The development and design of immune-based strategies have become an increasingly important topic during the last few years in acute myeloid leukemia (AML), based on successful immunotherapies in solid cancer. The spectrum ranges from antibody drug conjugates, immune checkpoint inhibitors blocking programmed cell [...] Read more.
The development and design of immune-based strategies have become an increasingly important topic during the last few years in acute myeloid leukemia (AML), based on successful immunotherapies in solid cancer. The spectrum ranges from antibody drug conjugates, immune checkpoint inhibitors blocking programmed cell death protein 1 (PD1), cytotoxic T lymphocyte antigen 4 (CTLA4) or T cell immunoglobulin and mucin domain containing-3 (TIM3), to T-cell based monoclonal and bispecific T-cell engager antibodies, chimeric antigen receptor-T-cell (CAR-T) approaches and leukemia vaccines. Currently, there are many substances in development and multiple phase I/II studies are ongoing. These trials will help us to deepen our understanding of the pathogenesis of AML and facilitate the best immunotherapeutic strategy in AML. We discuss here the mode of action of immune-based therapies and provide an overview of the available data. Full article
(This article belongs to the Special Issue New Therapeutic Strategies for Acute Myeloid Leukemia)
►▼ Show Figures

Figure 1

13 pages, 1448 KiB  
Review
Harnessing Macrophages through the Blockage of CD47: Implications for Acute Myeloid Leukemia
by Luciana Melo Garcia and Frédéric Barabé
Cancers 2021, 13(24), 6258; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13246258 - 13 Dec 2021
Cited by 12 | Viewed by 3259
Abstract
CD47 is a surface membrane protein expressed by all normal tissues. It is the so-called “don’t eat me signal” because it protects the cells against phagocytosis. The CD47 interacts with the signal regulatory protein alpha (SIRPα) on the surface of macrophages, leading to [...] Read more.
CD47 is a surface membrane protein expressed by all normal tissues. It is the so-called “don’t eat me signal” because it protects the cells against phagocytosis. The CD47 interacts with the signal regulatory protein alpha (SIRPα) on the surface of macrophages, leading to downstream inhibitory signaling that dampens phagocytic capacity. Since macrophages exert immune surveillance against cancers, cancer cells overexpress CD47 to defend themselves against phagocytosis. Acute myeloid leukemia (AML) is a cancer of hematopoietic stem/progenitor cells (HSPC), and similar to other types of cancers, leukemic blasts show enhanced levels of CD47. In patients with AML, CD47 has been associated with a higher disease burden and poor overall survival. Blockage of CD47-SIRPα signaling leads to improved phagocytosis of AML cells and better overall survival in xenograft models. However, the introduction of a pro-phagocytic signal is needed to induce greater phagocytic capacity. These pro-phagocytic signals can be either Fc receptor stimulants (such as monoclonal antibodies) or natural pro-phagocytic molecules (such as calreticulin). Based on these pre-clinical findings, various clinical trials investigating the blockade of CD47-SIRPα interaction have been designed as monotherapy and in combination with other anti-leukemic agents. In this review, we will discuss CD47 biology, highlight its implications for AML pathophysiology, and explore the potential clinical translation of disrupting CD47-SIRPα to treat patients with AML. Full article
(This article belongs to the Special Issue New Therapeutic Strategies for Acute Myeloid Leukemia)
►▼ Show Figures

Figure 1

19 pages, 569 KiB  
Review
Current Limitations and Perspectives of Chimeric Antigen Receptor-T-Cells in Acute Myeloid Leukemia
by Marius Maucher, Micha Srour, Sophia Danhof, Hermann Einsele, Michael Hudecek and Ibrahim Yakoub-Agha
Cancers 2021, 13(24), 6157; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13246157 - 07 Dec 2021
Cited by 9 | Viewed by 3431
Abstract
Adoptive transfer of gene-engineered chimeric antigen receptor (CAR)-T-cells has emerged as a powerful immunotherapy for combating hematologic cancers. Several target antigens that are prevalently expressed on AML cells have undergone evaluation in preclinical CAR-T-cell testing. Attributes of an ‘ideal’ target antigen for CAR-T-cell [...] Read more.
Adoptive transfer of gene-engineered chimeric antigen receptor (CAR)-T-cells has emerged as a powerful immunotherapy for combating hematologic cancers. Several target antigens that are prevalently expressed on AML cells have undergone evaluation in preclinical CAR-T-cell testing. Attributes of an ‘ideal’ target antigen for CAR-T-cell therapy in AML include high-level expression on leukemic blasts and leukemic stem cells (LSCs), and absence on healthy tissues, normal hematopoietic stem and progenitor cells (HSPCs). In contrast to other blood cancer types, where CAR-T therapies are being similarly studied, only a rather small number of AML patients has received CAR-T-cell treatment in clinical trials, resulting in limited clinical experience for this therapeutic approach in AML. For curative AML treatment, abrogation of bulk blasts and LSCs is mandatory with the need for hematopoietic recovery after CAR-T administration. Herein, we provide a critical review of the current pipeline of candidate target antigens and corresponding CAR-T-cell products in AML, assess challenges for clinical translation and implementation in routine clinical practice, as well as perspectives for overcoming them. Full article
(This article belongs to the Special Issue New Therapeutic Strategies for Acute Myeloid Leukemia)
►▼ Show Figures

Figure 1

21 pages, 546 KiB  
Review
Venetoclax in Acute Myeloid Leukemia: Molecular Basis, Evidences for Preclinical and Clinical Efficacy and Strategies to Target Resistance
by Sylvain Garciaz, Colombe Saillard, Yosr Hicheri, Marie-Anne Hospital and Norbert Vey
Cancers 2021, 13(22), 5608; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13225608 - 09 Nov 2021
Cited by 11 | Viewed by 4036
Abstract
Venetoclax is a BH3-mimetics agent specifically interacting with the antiapoptotic protein BCL-2, facilitating cytochrome c release from mitochondria, subsequent caspases activation, and cell death. Utilization of venetoclax has profoundly changed the landscape of treatment for the poor-prognosis category of AML patients unfit for [...] Read more.
Venetoclax is a BH3-mimetics agent specifically interacting with the antiapoptotic protein BCL-2, facilitating cytochrome c release from mitochondria, subsequent caspases activation, and cell death. Utilization of venetoclax has profoundly changed the landscape of treatment for the poor-prognosis category of AML patients unfit for intensive chemotherapy. In the phase III VIALE-A study, Venetoclax, in combination with the hypomethylating agent azacitidine, showed a 65% overall response rate and 14.7-month overall survival, in comparison with 22% and 8 months in the control arm. These results led to the widespread use of venetoclax in this indication. Other combination regimens, consisting of low-intensity, intensive, or targeted therapies are currently under evaluation. Despite promising results, preventing relapses or resistance to venetoclax is still an unmet clinical need. Numerous studies have been conducted to identify and overcome venetoclax resistance in preclinical models or in clinical trials, including the inhibition of other antiapoptotic proteins, the induction of proapoptotic BH3-only proteins, and/or the targeting of the mitochondrial metabolism and machinery. Full article
(This article belongs to the Special Issue New Therapeutic Strategies for Acute Myeloid Leukemia)
►▼ Show Figures

Figure 1

21 pages, 1088 KiB  
Review
Genomic Abnormalities as Biomarkers and Therapeutic Targets in Acute Myeloid Leukemia
by Sara Ribeiro, Anna M. Eiring and Jamshid S. Khorashad
Cancers 2021, 13(20), 5055; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13205055 - 09 Oct 2021
Cited by 4 | Viewed by 2563
Abstract
Acute myeloid leukemia (AML) is a highly heterogeneous malignancy characterized by the clonal expansion of myeloid stem and progenitor cells in the bone marrow, peripheral blood, and other tissues. AML results from the acquisition of gene mutations or chromosomal abnormalities that induce proliferation [...] Read more.
Acute myeloid leukemia (AML) is a highly heterogeneous malignancy characterized by the clonal expansion of myeloid stem and progenitor cells in the bone marrow, peripheral blood, and other tissues. AML results from the acquisition of gene mutations or chromosomal abnormalities that induce proliferation or block differentiation of hematopoietic progenitors. A combination of cytogenetic profiling and gene mutation analyses are essential for the proper diagnosis, classification, prognosis, and treatment of AML. In the present review, we provide a summary of genomic abnormalities in AML that have emerged as both markers of disease and therapeutic targets. We discuss the abnormalities of RARA, FLT3, BCL2, IDH1, and IDH2, their significance as therapeutic targets in AML, and how various mechanisms cause resistance to the currently FDA-approved inhibitors. We also discuss the limitations of current genomic approaches for producing a comprehensive picture of the activated signaling pathways at diagnosis or at relapse in AML patients, and how innovative technologies combining genomic and functional methods will improve the discovery of novel therapeutic targets in AML. The ultimate goal is to optimize a personalized medicine approach for AML patients and possibly those with other types of cancers. Full article
(This article belongs to the Special Issue New Therapeutic Strategies for Acute Myeloid Leukemia)
►▼ Show Figures

Figure 1

16 pages, 1148 KiB  
Review
Targeted Therapies for the Evolving Molecular Landscape of Acute Myeloid Leukemia
by Khashayar Ahmadmehrabi, Ali R. Haque, Ahmed Aleem, Elizabeth A. Griffiths and Gregory W. Roloff
Cancers 2021, 13(18), 4646; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13184646 - 16 Sep 2021
Cited by 7 | Viewed by 3647
Abstract
Despite considerable growth in our understanding of the heterogeneous biology and pathogenesis of acute myeloid leukemia (AML) in recent decades, for nearly forty years, little progress was gained in the realm of novel therapeutics. Since 2017, however, nine agents have been FDA-approved for [...] Read more.
Despite considerable growth in our understanding of the heterogeneous biology and pathogenesis of acute myeloid leukemia (AML) in recent decades, for nearly forty years, little progress was gained in the realm of novel therapeutics. Since 2017, however, nine agents have been FDA-approved for patients with AML in both the upfront and relapsed/refractory (R/R) settings. Most of these compounds function as inhibitors of key cell cycle enzymatic pathways or mediators of leukemic proliferation and survival. They have been approved both as single agents and in combination with conventional or reduced-intensity conventional chemotherapeutics. In this article, we review the molecular landscape of de novo vs. R/R AML and highlight the potential translational impact of defined molecular disease subsets. We also highlight several recent agents that have entered the therapeutic armamentarium and where they fit in the AML treatment landscape, with a focus on FLT3 inhibitors, IDH1 and IDH2 inhibitors, and venetoclax. Finally, we close with a survey of two promising novel agents under investigation that are poised to enter the mainstream clinical arena in the near future. Full article
(This article belongs to the Special Issue New Therapeutic Strategies for Acute Myeloid Leukemia)
►▼ Show Figures

Figure 1

Other

Jump to: Research, Review

14 pages, 940 KiB  
Commentary
Clinical Impact of Measurable Residual Disease in Acute Myeloid Leukemia
by Tali Azenkot and Brian A. Jonas
Cancers 2022, 14(15), 3634; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14153634 - 26 Jul 2022
Cited by 3 | Viewed by 1866
Abstract
Measurable residual disease (MRD) has emerged as a primary marker of risk severity and prognosis in acute myeloid leukemia (AML). There is, however, ongoing debate about MRD-based surveillance and treatment. A literature review was performed using the PubMed database with the keywords MRD [...] Read more.
Measurable residual disease (MRD) has emerged as a primary marker of risk severity and prognosis in acute myeloid leukemia (AML). There is, however, ongoing debate about MRD-based surveillance and treatment. A literature review was performed using the PubMed database with the keywords MRD or residual disease in recently published journals. Identified articles describe the prognostic value of pre-transplant MRD and suggest optimal timing and techniques to quantify MRD. Several studies address the implications of MRD on treatment selection and hematopoietic stem cell transplant, including patient candidacy, conditioning regimen, and transplant type. More prospective, randomized studies are needed to guide the application of MRD in the treatment of AML, particularly in transplant. Full article
(This article belongs to the Special Issue New Therapeutic Strategies for Acute Myeloid Leukemia)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-16
Back to TopTop