Entospletinib with decitabine in acute myeloid leukemia with mutant <i>TP53</i> or complex karyotype: A phase 2 substudy of the Beat AML Master Trial

Duong, Vu H.; Ruppert, Amy S.; Mims, Alice S.; Borate, Uma; Stein, Eytan M.; Stock, Wendy; Kovacsovics, Tibor; Blum, William; Arellano, Martha; Schiller, Gary J.; Olin, Rebecca L.; Foran, James M.; Litzow, Mark R.; Lin, Tara L.; Patel, Prapti A.; Foster, Matthew C.; Redner, Robert L.; Al‐Mansour, Zeina; Cogle, Christopher R.; Swords, Ronan; Collins, Robert H.; Vergilio, Jo‐Anne; Heerema, Nyla A.; Rosenberg, Leonard; Yocum, Ashley O.; Marcus, Sonja; Chen, Timothy; Druggan, Franchesca; Stefanos, Mona; Gana, Theophilus J.; Shoben, Abigail B.; Druker, Brian J.; Burd, Amy; Byrd, John C.; Levine, Ross L.; Boyiadzis, Michael

doi:10.1002/cncr.34780

Cited by 2 publications

(2 citation statements)

References 52 publications

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“…In a randomized phase II study to investigate the addition of bortezomib, a proteasome inhibitor on 10-day decitabine showed a poor response in patients with TP53-mutated AML [69]. A substudy of the Beat AML Master Trial tested the combination of a Syk inhibitor, entospletinib, and 10-day decitabine as a phase II study, which also demonstrated a disappointingly low CR rate of 13.3% and short median OS of 6.5 months [70] (Table 1). However, the addition of venetoclax, a promising novel drug in the field of AML treatment, did not increase the response rate of TP53-mutated AML.…”

Section: Despair and Hope In Tp53-mutated Aml: Is The Future Bright?mentioning

confidence: 99%

TP53 Mutation in Acute Myeloid Leukemia: An Old Foe Revisited

Shin

2023

Cancers

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Introduction: TP53 is the most commonly mutated gene in human cancers and was the first tumor suppressor gene to be discovered in the history of medical science. Mutations in the TP53 gene occur at various genetic locations and exhibit significant heterogeneity among patients. Mutations occurring primarily within the DNA-binding domain of TP53 result in the loss of the p53 protein’s DNA-binding capability. However, a complex phenotypic landscape often combines gain-of-function, dominant negative, or altered specificity features. This complexity poses a significant challenge in developing an effective treatment strategy, which eradicates TP53-mutated cancer clones. This review summarizes the current understanding of TP53 mutations in AML and their implications. TP53 mutation in AML: In patients with acute myeloid leukemia (AML), six hotspot mutations (R175H, G245S, R248Q/W, R249S, R273H/S, and R282W) within the DNA-binding domain are common. TP53 mutations are frequently associated with a complex karyotype and subgroups of therapy-related or secondary AML. The presence of TP53 mutation is considered as a poor prognostic factor. TP53-mutated AML is even classified as a distinct subgroup of AML by itself, as TP53-mutated AML exhibits a significantly distinct landscape in terms of co-mutation and gene expression profiles compared with wildtype (WT)-TP53 AML. Clinical Implications: To better predict the prognosis in cancer patients with different TP53 mutations, several predictive scoring systems have been proposed based on screening experiments, to assess the aggressiveness of TP53-mutated cancer cells. Among those scoring systems, a relative fitness score (RFS) could be applied to AML patients with TP53 mutations in terms of overall survival (OS) and event-free survival (EFS). The current standard treatment, which includes cytotoxic chemotherapy and allogeneic hematopoietic stem cell transplantation, is largely ineffective for patients with TP53-mutated AML. Consequently, most patients with TP53-mutated AML succumb to leukemia within several months, despite active anticancer treatment. Decitabine, a hypomethylating agent, is known to be relatively effective in patients with AML. Numerous trials are ongoing to investigate the effects of novel drugs combined with hypomethylating agents, TP53-targeting agents or immunologic agents. Conclusions: Developing an effective treatment strategy for TP53-mutated AML through innovative and multidisciplinary research is an urgent task. Directly targeting mutated TP53 holds promise as an approach to combating TP53-mutated AML, and recent developments in immunologic agents for AML offer hope in this field.

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Section: Despair and Hope In Tp53-mutated Aml: Is The Future Bright?mentioning

confidence: 99%

TP53 Mutation in Acute Myeloid Leukemia: An Old Foe Revisited

Shin

2023

Cancers

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“…Acute myeloid leukemia (AML) is a highly prevalent malignancy of the blood system. , Its mortality rate has steadily increased in recent years . The treatment of AML has seen limited advancements in recent decades, apart from conventional chemotherapy and hematopoietic stem cell transplantation. − Furthermore, the residual leukemia cells are difficult to be completely eliminated, and the side effects of conventional therapies are significant .…”

Section: Introductionmentioning

confidence: 99%

Self-Stimulated Photodynamic Nanoreactor in Combination with CXCR4 Antagonists for Antileukemia Therapy

Zhang,

Chen,

et al. 2024

ACS Appl. Mater. Interfaces

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The treatment of acute myeloid leukemia (AML) remains unsatisfactory, owing to the absence of efficacious therapy regimens over decades. However, advances in molecular biology, including inhibiting the CXCR4/CXCL12 biological axis, have introduced novel therapeutic options for AML. Additionally, self-stimulated phototherapy can solve the poor light penetration from external sources, and it will overcome the limitation that traditional phototherapy cannot be applied to the treatment of AML. Herein, we designed and manufactured a self-stimulated photodynamic nanoreactor to enhance antileukemia efficacy and suppress leukemia recurrence and metastasis in AML mouse models. To fulfill our design, we utilized the CXCR4/CXCL12 biological axis and biomimetic cell membranes in conjunction with selfstimulated phototherapy. This nanoreactor possesses the capability to migrate into the bone marrow cavity, inhibit AML cells from infiltrating into the visceral organ, significantly enhance the antileukemia effect, and prolong the survival time of leukemic mice. Therefore, this nanoreactor has significant potential for achieving high success rates and low recurrence rates in leukemia treatment.

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Entospletinib with decitabine in acute myeloid leukemia with mutant TP53 or complex karyotype: A phase 2 substudy of the Beat AML Master Trial

Cited by 2 publications

References 52 publications

TP53 Mutation in Acute Myeloid Leukemia: An Old Foe Revisited

TP53 Mutation in Acute Myeloid Leukemia: An Old Foe Revisited

Self-Stimulated Photodynamic Nanoreactor in Combination with CXCR4 Antagonists for Antileukemia Therapy

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