Resistance to Targeted Therapies in Hematological Malignancies

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

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 9394

Special Issue Editors


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Guest Editor
Hematology Laboratory and Transfusion Center, Legnano General Hospital, 20025 Legnano, Italy
Interests: laboratory hematology; flow cytometry; cell immunophenotyping of hematological malignancies for immunology studies; development and validation of laboratory assays; external quality control

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Guest Editor
Haematology and Stem Cell Transplant Unit, Department of Biomedicine and Prevention, University of Rome ‘Tor Vergata’, 00133 Rome, Italy
Interests: clinical hematology; acute leukemias; acute myeloid leukemia; immunophenotyping of hematological malignancies; allogeneic transplantation; measurable residual disease by flow cytometry and molecular techniques
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Special Issue Information

Dear Colleagues,

Hematological malignancies are successfully treated with chemo-immunotherapy in a large proportion of cases, with a limited rate of primary resistance. However, secondary resistance acquired during treatment appears to be an almost unavoidable occurrence, leading to relapse in approximately one third of patients. Targeted therapies, including monoclonal antibodies, conjugated or modified antibodies and small molecules, have replaced conventional chemotherapy in many clinical settings, since the latter approach has reached its limit of tolerability, which cannot be further improved.

Similar to microorganisms, malignant blood cells have an immense potential to avoid treatment, especially when targeted therapies are used as single agents. The resistance phenomena also affect CAR-modified effectors. The biological processes responsible for the resistance to targeted therapies are manifold, acting on the cell membrane with antigen loss or down-regulation, on the tumor microenvironment and effector–ligand relationship, or at genetic and epigenetic levels due to clonal evolution, mutations acquired during treatment or emerging subclones. Strategies aimed at counteracting the resistance to treatment are under intensive study.

The remission or relapse in hematological malignancies can be efficiently monitored by state-of-the art detection techniques using high-resolution multicolor flow cytometry and molecular assays, which can be tailored according to the disease involved and the specific targeted therapy.

Dr. Bruno Brando
Dr. Francesco Buccisano
Guest Editors

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Published Papers (3 papers)

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Research

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15 pages, 2301 KiB  
Article
MRD as Biomarker for Response to Donor Lymphocyte Infusion after Allogeneic Hematopoietic Cell Transplantation in Patients with AML
by Katrin Teich, Michael Stadler, Razif Gabdoulline, Jyoti Kandarp, Clara Wienecke, Bennet Heida, Piroska Klement, Konstantin Büttner, Letizia Venturini, Martin Wichmann, Wolfram Puppe, Christian Schultze-Florey, Christian Koenecke, Gernot Beutel, Matthias Eder, Arnold Ganser, Michael Heuser and Felicitas Thol
Cancers 2023, 15(15), 3911; https://doi.org/10.3390/cancers15153911 - 1 Aug 2023
Cited by 2 | Viewed by 1202
Abstract
Donor lymphocyte infusions (DLIs) can directly target leukemic cells through a graft-versus-leukemia effect and play a key role in the prevention and management of relapse after allogeneic hematopoietic cell transplantation (alloHCT). Predictors of response to DLIs are not well established. We evaluated measurable [...] Read more.
Donor lymphocyte infusions (DLIs) can directly target leukemic cells through a graft-versus-leukemia effect and play a key role in the prevention and management of relapse after allogeneic hematopoietic cell transplantation (alloHCT). Predictors of response to DLIs are not well established. We evaluated measurable residual disease (MRD) before, 30 and 90 days after DLI treatment as biomarkers of response. MRD was assessed by next-generation sequencing in 76 DLI-treated acute myeloid leukemia patients. MRD status before DLI treatment was independently prognostic for event-free survival (EFS, p < 0.001) and overall survival (OS, p < 0.001). Within 90 days of DLI treatment, 73% of MRD+ patients converted to MRD and 32% of patients without remission achieved remission. MRD status 90 days after DLI treatment was independently prognostic for the cumulative incidence of relapse (CIR, p = 0.011) and relapse-free survival (RFS, p = 0.001), but not for OS. To evaluate the role of DLI treatment in MRD patients, 23 MRD patients who received DLIs were compared with a control cohort of 68 MRD patients not receiving DLIs. RFS (p = 0.23) and OS (p = 0.48) were similar between the two cohorts. In conclusion, MRD is prognostic before (EFS, OS) and after (CIR, RFS) DLI treatment and may help in the selection of patients who benefit most from DLIs. Full article
(This article belongs to the Special Issue Resistance to Targeted Therapies in Hematological Malignancies)
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Review

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19 pages, 1233 KiB  
Review
Venetoclax Resistance in Acute Myeloid Leukemia
by Sylvain Garciaz, Marie-Anne Hospital, Yves Collette and Norbert Vey
Cancers 2024, 16(6), 1091; https://doi.org/10.3390/cancers16061091 - 8 Mar 2024
Cited by 5 | Viewed by 5548
Abstract
Venetoclax is a BH3-mimetics agent interacting with the anti-apoptotic protein BCL2, facilitating cytochrome c release from mitochondria, subsequent caspases activation, and cell death. Venetoclax combined with azacitidine (VEN-AZA) has become a new standard treatment for AML patients unfit for intensive chemotherapy. In the [...] Read more.
Venetoclax is a BH3-mimetics agent interacting with the anti-apoptotic protein BCL2, facilitating cytochrome c release from mitochondria, subsequent caspases activation, and cell death. Venetoclax combined with azacitidine (VEN-AZA) has become a new standard treatment for AML patients unfit for intensive chemotherapy. In the phase III VIALE-A study, VEN-AZA showed a 65% overall response rate and 14.7 months overall survival in comparison with 22% and 8 months in the azacitidine monotherapy control arm. Despite these promising results, relapses and primary resistance to venetoclax are frequent and remain an unmet clinical need. Clinical and preclinical studies have been conducted to identify factors driving resistance. Among them, the most documented are molecular alterations including IDH, FLT3, TP53, and the newly described BAX mutations. Several non-genetic factors are also described such as metabolic plasticity, changes in anti-apoptotic protein expression, and dependencies, as well as monocytic differentiation status. Strategies to overcome venetoclax resistance are being developed in clinical trials, including triplet therapies with targeted agents targeting IDH, FLT3, as well as the recently developed menin inhibitors or immunotherapies such as antibody–drug conjugated or monoclonal antibodies. A better understanding of the molecular factors driving venetoclax resistance by single-cell analyses will help the discovery of new therapeutic strategies in the future. Full article
(This article belongs to the Special Issue Resistance to Targeted Therapies in Hematological Malignancies)
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19 pages, 2270 KiB  
Review
Mechanisms of Resistance to Small Molecules in Acute Myeloid Leukemia
by Tonio Johannes Lukas Lang, Frederik Damm, Lars Bullinger and Mareike Frick
Cancers 2023, 15(18), 4573; https://doi.org/10.3390/cancers15184573 - 15 Sep 2023
Cited by 7 | Viewed by 2167
Abstract
In recent years, great progress has been made in the therapy of AML by targeting cellular processes associated with specific molecular features of the disease. Various small molecules inhibiting FLT3, IDH1/IDH2, and BCL2 have already gained approval from the respective authorities and are [...] Read more.
In recent years, great progress has been made in the therapy of AML by targeting cellular processes associated with specific molecular features of the disease. Various small molecules inhibiting FLT3, IDH1/IDH2, and BCL2 have already gained approval from the respective authorities and are essential parts of personalized therapeutic regimens in modern therapy of AML. Unfortunately, primary and secondary resistance to these inhibitors is a frequent problem. Here, we comprehensively review the current state of knowledge regarding molecular processes involved in primary and secondary resistance to these agents, covering both genetic and nongenetic mechanisms. In addition, we introduce concepts and strategies for how these resistance mechanisms might be overcome. Full article
(This article belongs to the Special Issue Resistance to Targeted Therapies in Hematological Malignancies)
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