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Cancers
Special Issues
Targeted Therapy for Acute Myeloid Leukemia
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Targeted Therapy 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 (28 February 2023) | Viewed by 8935

Special Issue Editor

Dr. Fernando Ramos

E-Mail Website
Guest Editor
Clinical Hematology, Hospital Universitario de León, 24071 León, Spain
Interests: acute myeloid leukemia; myelodysplastic syndrome; older adults; clinical epidemiology; clinical trials; targeted therapy; quality of life
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Acute myeloid leukemia (AML) is the most frequent acute leukemia and is genetically heterogenous, as underlined by World Health Organization, National Comprehensive Network and European LeukemiaNet, among others. In AML, mutations, gene fusions, and chromosome deletions are frequent, but the number of co-mutations ranks lowest (average 13 mutations, only 5 of them recurrent) among adult cancers and constitute an actionable target in clinical medicine.

In recent years, a number of agents have been developed, and some of them have already been adopted in clinical practice because of their proved impact on overall survival, or promising results on other surrogate end-points, such as event-free survival or treatment response. These include different inhibitors targeting FLT3  (midostaurin, gilteritinib, quizartinib, crenolanib, etc.), IDH1/2 (ivosidenib, enasidenib), BCL2  (venetocla), Hedgehog pathway (glasdegib), exportin  (selinexor), TP53-directed therapy (eprenetapopt), PML-RARA-directed therapy (ATRA, ATO), and immuno-conjugated agents (gemtuzumab-ozogamicin). Many other new agents are under evaluation (OPB-111077, idasanutlin, alvocidib, AZD1152, GMI-1271, FT-2102, MEN1112, TJ011133, S65487, MBG453, JNJ-74856665, etc.).

These drugs are being used or tested in the frontline, rescue, and maintenance setting (after chemotherapy or hematopoietic cell transplantation). In addition, targeted cell therapy is also being explored in AML, although it remains in a less mature stage of research development.

This Special Issue aims to assemble a number of papers (original as well as reviews) that deal with targeted therapy for AML, both in the research and daily practice settings, with the aim to communicate and disseminate new avenues in this field.

Dr. Fernando Ramos
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
  • FLT3
  • IDH
  • BCL2
  • TP53
  • PML-RARA
  • immunoconjugates
  • cell therapy

Published Papers (4 papers)

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Research

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13 pages, 2480 KiB  
Article
Evolving Risk Classifications in AML in a Real-Life Scenario: After Changes upon Changes, Is It More and More Adverse?
by Clara Aparicio-Pérez, Esther Prados de la Torre, Joaquin Sanchez-Garcia, Carmen Martín-Calvo, Carmen Martínez-Losada, Javier Casaño-Sanchez, Juana Serrano-López and Josefina Serrano
Cancers 2023, 15(5), 1425; https://doi.org/10.3390/cancers15051425 - 23 Feb 2023
Cited by 2 | Viewed by 1651
Abstract
Acute myeloid leukemia (AML) is a heterogeneous disease classified into three risk categories (favorable, intermediate and adverse) with significant differences in outcomes. Definitions of risk categories evolve overtime, incorporating advances in molecular knowledge of AML. In this study, we analyzed the impacts of [...] Read more.
Acute myeloid leukemia (AML) is a heterogeneous disease classified into three risk categories (favorable, intermediate and adverse) with significant differences in outcomes. Definitions of risk categories evolve overtime, incorporating advances in molecular knowledge of AML. In this study, we analyzed the impacts of evolving risk classifications in 130 consecutive AML patients in a single-center real-life experience. Complete cytogenetic and molecular data were collected using conventional qPCR and targeted Next Generation Sequencing (NGS). Five-year OS probabilities were consistent among all classification models (roughly 50–72%, 26–32% and 16–20% for favorable, intermediate and adverse risk groups, respectively). In the same way, the medians of survival months and prediction power were similar in all models. In each update, around 20% of patients were re-classified. The adverse category consistently increased over time (31% in MRC, 34% in ELN2010, 50% in ELN2017), reaching up to 56% in the recent ELN2022. Noteworthily, in multivariate models, only age and the presence of TP53 mutations remained statistically significant. With updates in risk-classification models, the percentage of patients assigned to the adverse group is increasing, and so will the indications for allogeneic stem cell transplantation. Full article
(This article belongs to the Special Issue Targeted Therapy for Acute Myeloid Leukemia)
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14 pages, 1230 KiB  
Article
Clinical Implications of the FLT3-ITD Allelic Ratio in Acute Myeloid Leukemia in the Context of an Allogeneic Stem Cell Transplantation
by Madlen Jentzsch, Lara Bischof, Dominic Brauer, Donata Backhaus, Jule Ussmann, Georg-Nikolaus Franke, Vladan Vucinic, Uwe Platzbecker and Sebastian Schwind
Cancers 2023, 15(4), 1312; https://doi.org/10.3390/cancers15041312 - 18 Feb 2023
Cited by 2 | Viewed by 1847
Abstract
Although the presence of FLT3-ITD, as well as levels of the FLT3-ITD allelic ratio, have been described as prognostic factors in acute myeloid leukemia (AML), little is known about how the FLT3-ITD allelic ratio impacts patients’ outcomes when receiving an [...] Read more.
Although the presence of FLT3-ITD, as well as levels of the FLT3-ITD allelic ratio, have been described as prognostic factors in acute myeloid leukemia (AML), little is known about how the FLT3-ITD allelic ratio impacts patients’ outcomes when receiving an allogeneic hematopoietic stem cell transplantation (HSCT). We analyzed 118 patients (median age at diagnosis 58.3, range 14.3–82.3 years) harboring FLT3-ITD, of whom 94 patients were consolidated with an allogeneic HSCT and included in outcome analyses. A high FLT3-ITD allelic ratio was associated with a higher white blood cell count, higher blood and bone marrow blasts, and worse ELN2017 risk at diagnosis. Patients with a high FLT3-ITD allelic ratio more often had NPM1 mutations, while patients with a low allelic ratio more often had FLT3-TKD mutations. Patients with a high FLT3-ITD allelic ratio were less likely to achieve a measurable residual disease (MRD)-negative remission prior to allogeneic HSCT and had a trend for a shorter time to relapse. However, there was no distinct cumulative incidence of relapse, non-relapse mortality, or overall survival according to the FLT3-ITD allelic ratio in transplanted patients. While co-mutated FLT3-TKD was associated with better outcomes, the MRD status at HSCT was the most significant factor for outcomes. While our data indicates that an allogeneic HSCT may mitigate the adverse effect of a high FLT3-ITD allelic ratio, comparative studies are needed to evaluate which FLT3-ITD mutated patients benefit from which consolidation strategy. Full article
(This article belongs to the Special Issue Targeted Therapy for Acute Myeloid Leukemia)
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16 pages, 20951 KiB  
Article
Identifying Lethal Dependencies with HUGE Predictive Power
by Marian Gimeno, Edurne San José-Enériz, Angel Rubio, Leire Garate, Estíbaliz Miranda, Carlos Castilla, Xabier Agirre, Felipe Prosper and Fernando Carazo
Cancers 2022, 14(13), 3251; https://doi.org/10.3390/cancers14133251 - 1 Jul 2022
Cited by 4 | Viewed by 1851
Abstract
Recent functional genomic screens—such as CRISPR-Cas9 or RNAi screening—have fostered a new wave of targeted treatments based on the concept of synthetic lethality. These approaches identified LEthal Dependencies (LEDs) by estimating the effect of genetic events on cell viability. The multiple-hypothesis problem [...] Read more.
Recent functional genomic screens—such as CRISPR-Cas9 or RNAi screening—have fostered a new wave of targeted treatments based on the concept of synthetic lethality. These approaches identified LEthal Dependencies (LEDs) by estimating the effect of genetic events on cell viability. The multiple-hypothesis problem is related to a large number of gene knockouts limiting the statistical power of these studies. Here, we show that predictions of LEDs from functional screens can be dramatically improved by incorporating the “HUb effect in Genetic Essentiality” (HUGE) of gene alterations. We analyze three recent genome-wide loss-of-function screens—Project Score, CERES score and DEMETER score—identifying LEDs with 75 times larger statistical power than using state-of-the-art methods. Using acute myeloid leukemia, breast cancer, lung adenocarcinoma and colon adenocarcinoma as disease models, we validate that our predictions are enriched in a recent harmonized knowledge base of clinical interpretations of somatic genomic variants in cancer (AUROC > 0.87). Our approach is effective even in tumors with large genetic heterogeneity such as acute myeloid leukemia, where we identified LEDs not recalled by previous pipelines, including FLT3-mutant genotypes sensitive to FLT3 inhibitors. Interestingly, in-vitro validations confirm lethal dependencies of either NRAS or PTPN11 depending on the NRAS mutational status. HUGE will hopefully help discover novel genetic dependencies amenable for precision-targeted therapies in cancer. All the graphs showing lethal dependencies for the 19 tumor types analyzed can be visualized in an interactive tool. Full article
(This article belongs to the Special Issue Targeted Therapy for Acute Myeloid Leukemia)
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Review

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16 pages, 1199 KiB  
Review
What’s Next after Hypomethylating Agents Failure in Myeloid Neoplasms? A Rational Approach
by Hussein Awada, Carmelo Gurnari, Zhuoer Xie, Jan Philipp Bewersdorf and Amer M. Zeidan
Cancers 2023, 15(8), 2248; https://doi.org/10.3390/cancers15082248 - 12 Apr 2023
Cited by 2 | Viewed by 2860
Abstract
Hypomethylating agents (HMA) such as azacitidine and decitabine are a mainstay in the current management of patients with myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML) as either single agents or in multidrug combinations. Resistance to HMA is not uncommon, and it can [...] Read more.
Hypomethylating agents (HMA) such as azacitidine and decitabine are a mainstay in the current management of patients with myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML) as either single agents or in multidrug combinations. Resistance to HMA is not uncommon, and it can result due to several tumor cellular adaptations. Several clinical and genomic factors have been identified as predictors of HMA resistance. However, the management of MDS/AML patients after the failure of HMA remains challenging in the absence of standardized guidelines. Indeed, this is an area of active research with several potential therapeutic agents currently under development, some of which have demonstrated therapeutic potential in early clinical trials, especially in cases with particular mutational characteristics. Here, we review the latest findings and give a rational approach for such a challenging scenario. Full article
(This article belongs to the Special Issue Targeted Therapy for Acute Myeloid Leukemia)
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