Cargando…

Are We Moving the Needle for Patients with TP53-Mutated Acute Myeloid Leukemia?

SIMPLE SUMMARY: TP53-mutated acute myeloid leukemia (AML) represents one of the most informative examples of adverse risk AML. As the currently available therapies have not translated to meaningful advances in the survival of these patients, a clinical trial should be the recommendation for all newl...

Descripción completa

Detalles Bibliográficos
Autores principales: Shallis, Rory M., Bewersdorf, Jan P., Stahl, Maximilian F., Halene, Stephanie, Zeidan, Amer M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9140008/
https://www.ncbi.nlm.nih.gov/pubmed/35626039
http://dx.doi.org/10.3390/cancers14102434
_version_ 1784714994047254528
author Shallis, Rory M.
Bewersdorf, Jan P.
Stahl, Maximilian F.
Halene, Stephanie
Zeidan, Amer M.
author_facet Shallis, Rory M.
Bewersdorf, Jan P.
Stahl, Maximilian F.
Halene, Stephanie
Zeidan, Amer M.
author_sort Shallis, Rory M.
collection PubMed
description SIMPLE SUMMARY: TP53-mutated acute myeloid leukemia (AML) represents one of the most informative examples of adverse risk AML. As the currently available therapies have not translated to meaningful advances in the survival of these patients, a clinical trial should be the recommendation for all newly diagnosed patients. CD47/SIRPα axis and TIM-3 inhibition appear to be some of the more promising strategies, but other agents with novel mechanisms of action are in development. We review the pathobiology of TP53-mutated AML, the possible heterogeneity among patients with this disease and how some of the novel and emerging therapies may fit into the treatment landscape in the hopefully not-so-distant future. 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 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.
format Online
Article
Text
id pubmed-9140008
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-91400082022-05-28 Are We Moving the Needle for Patients with TP53-Mutated Acute Myeloid Leukemia? Shallis, Rory M. Bewersdorf, Jan P. Stahl, Maximilian F. Halene, Stephanie Zeidan, Amer M. Cancers (Basel) Review SIMPLE SUMMARY: TP53-mutated acute myeloid leukemia (AML) represents one of the most informative examples of adverse risk AML. As the currently available therapies have not translated to meaningful advances in the survival of these patients, a clinical trial should be the recommendation for all newly diagnosed patients. CD47/SIRPα axis and TIM-3 inhibition appear to be some of the more promising strategies, but other agents with novel mechanisms of action are in development. We review the pathobiology of TP53-mutated AML, the possible heterogeneity among patients with this disease and how some of the novel and emerging therapies may fit into the treatment landscape in the hopefully not-so-distant future. 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 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. MDPI 2022-05-14 /pmc/articles/PMC9140008/ /pubmed/35626039 http://dx.doi.org/10.3390/cancers14102434 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Shallis, Rory M.
Bewersdorf, Jan P.
Stahl, Maximilian F.
Halene, Stephanie
Zeidan, Amer M.
Are We Moving the Needle for Patients with TP53-Mutated Acute Myeloid Leukemia?
title Are We Moving the Needle for Patients with TP53-Mutated Acute Myeloid Leukemia?
title_full Are We Moving the Needle for Patients with TP53-Mutated Acute Myeloid Leukemia?
title_fullStr Are We Moving the Needle for Patients with TP53-Mutated Acute Myeloid Leukemia?
title_full_unstemmed Are We Moving the Needle for Patients with TP53-Mutated Acute Myeloid Leukemia?
title_short Are We Moving the Needle for Patients with TP53-Mutated Acute Myeloid Leukemia?
title_sort are we moving the needle for patients with tp53-mutated acute myeloid leukemia?
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9140008/
https://www.ncbi.nlm.nih.gov/pubmed/35626039
http://dx.doi.org/10.3390/cancers14102434
work_keys_str_mv AT shallisrorym arewemovingtheneedleforpatientswithtp53mutatedacutemyeloidleukemia
AT bewersdorfjanp arewemovingtheneedleforpatientswithtp53mutatedacutemyeloidleukemia
AT stahlmaximilianf arewemovingtheneedleforpatientswithtp53mutatedacutemyeloidleukemia
AT halenestephanie arewemovingtheneedleforpatientswithtp53mutatedacutemyeloidleukemia
AT zeidanamerm arewemovingtheneedleforpatientswithtp53mutatedacutemyeloidleukemia