Phase 1 dose-escalation study of oral abexinostat for the treatment of patients with relapsed/refractory higher-risk myelodysplastic syndromes, acute myeloid leukemia, or acute lymphoblastic leukemia

Vey, Norbert; Prébet, Thomas; Thalamas, Claire; Charbonnier, Aude; Rey, Jérôme; Kloos, Ioana; Liu, Emily; Luan, Ying; Vezan, Remus; Graef, Thorsten; Récher, Christian

doi:10.1080/10428194.2016.1263843

Cited by 17 publications

(11 citation statements)

References 43 publications

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“…Other hydroxamate-based HDACi have been recently tested in clinical studies, such as Givinostat (ITF2357) [176,177,178,179], Resminostat (4SC201) [180], Abexinostat (PCI-24781) [181,182,183,184], Quisinostat (JNJ-26481585) [185], and Pracinostat (SB939) [109,110], with all of them being HDAC pan-inhibitors except for Givinostat, which more specifically targets HDAC1, 2, 3, and 6. However, little information is available regarding AML.…”

Section: Histone Deacetylase Inhibitors (Hdaci): Mechanism Of Actimentioning

confidence: 99%

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HDAC Inhibitors in Acute Myeloid Leukemia

José‐Eneriz

Gimenez-Camino

Agirre

et al. 2019

Cancers

134

114

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Acute myeloid leukemia (AML) is a hematological malignancy characterized by uncontrolled proliferation, differentiation arrest, and accumulation of immature myeloid progenitors. Although clinical advances in AML have been made, especially in young patients, long-term disease-free survival remains poor, making this disease an unmet therapeutic challenge. Epigenetic alterations and mutations in epigenetic regulators contribute to the pathogenesis of AML, supporting the rationale for the use of epigenetic drugs in patients with AML. While hypomethylating agents have already been approved in AML, the use of other epigenetic inhibitors, such as histone deacetylases (HDAC) inhibitors (HDACi), is under clinical development. HDACi such as Panobinostat, Vorinostat, and Tricostatin A have been shown to promote cell death, autophagy, apoptosis, or growth arrest in preclinical AML models, yet these inhibitors do not seem to be effective as monotherapies, but rather in combination with other drugs. In this review, we discuss the rationale for the use of different HDACi in patients with AML, the results of preclinical studies, and the results obtained in clinical trials. Although so far the results with HDACi in clinical trials in AML have been modest, there are some encouraging data from treatment with the HDACi Pracinostat in combination with DNA demethylating agents.

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Section: Histone Deacetylase Inhibitors (Hdaci): Mechanism Of Actimentioning

confidence: 99%

“…Interestingly, those cell lines positive for AML1/ETO were more sensitive to this inhibitor [186]. In the case of Abexinostat, this HDACi was tested in a phase I trial in AML patients with limited clinical benefit [182]. Pracinostat showed potent efficacy on AML in preclinical studies.…”

Section: Histone Deacetylase Inhibitors (Hdaci): Mechanism Of Actimentioning

confidence: 99%

HDAC Inhibitors in Acute Myeloid Leukemia

José‐Eneriz

Gimenez-Camino

Agirre

et al. 2019

Cancers

134

114

View full text Add to dashboard Cite

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“…). (B) karyotype showing 46, XX, t(9;11)(p22;q23) [20] . (C) The blasts percentage changes during different regimens of chemotherapy However, in most patients with PRAME-expressing AML, PRAMEspecific CD8 + cytotoxic T lymphocyte (CTL) response is either undetectable or too weak to exert immune surveillance.…”

Section: F I G U R E 1 (A) Bone Marrow Aspirate Showing Monoblasts (Wmentioning

confidence: 99%

Complete molecular remission in relapsed and refractory acute myeloid leukaemia with MLL-AF9 treated with chidamide-based chemotherapy

Yan

Yang

2017

J Clin Pharm Ther

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“…In certain types of T-ALL cell lines, such as Notch-driven T-ALL, panobinostat has been shown to induce apoptosis as well as downregulating Myc [ 129 ]. However, a phase 1 trial of the oral HDAC inhibitor abexinostat, including patients with ALL, showed limited efficacy as a single agent [ 130 ]. Combination therapies where an HDAC inhibitor is combined with cytotoxic agents, such as cytarabine, may be more effective as shown in KMT2A -rearranged ALL murine models [ 131 ].…”

Section: Epigenetic Regulators In Allmentioning

confidence: 99%

Targeted Therapy in Acute Lymphoblastic Leukaemia

Salvaris

Fedele

2021

JPM

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The last decade has seen a significant leap in our understanding of the wide range of genetic lesions underpinning acute lymphoblastic leukaemia (ALL). Next generation sequencing has led to the identification of driver mutations with significant implications on prognosis and has defined entities such as BCR-ABL-like ALL, where targeted therapies such as tyrosine kinase inhibitors (TKIs) and JAK inhibitors may play a role in its treatment. In Philadelphia positive ALL, the introduction of TKIs into frontline treatment regimens has already transformed patient outcomes. In B-ALL, agents targeting surface receptors CD19, CD20 and CD22, including monoclonal antibodies, bispecific T cell engagers, antibody drug conjugates and chimeric antigen receptor (CAR) T cells, have shown significant activity but come with unique toxicities and have implications for how treatment is sequenced. Advances in T-ALL have lagged behind those seen in B-ALL. However, agents such as nelarabine, bortezomib and CAR T cell therapy targeting T cell antigens have been examined with promising results seen. As our understanding of disease biology in ALL grows, as does our ability to target pathways such as apoptosis, through BH3 mimetics, chemokines and epigenetic regulators. This review aims to highlight a range of available and emerging targeted therapeutics in ALL, to explore their mechanisms of action and to discuss the current evidence for their use.

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Phase 1 dose-escalation study of oral abexinostat for the treatment of patients with relapsed/refractory higher-risk myelodysplastic syndromes, acute myeloid leukemia, or acute lymphoblastic leukemia

Cited by 17 publications

References 43 publications

HDAC Inhibitors in Acute Myeloid Leukemia

HDAC Inhibitors in Acute Myeloid Leukemia

Complete molecular remission in relapsed and refractory acute myeloid leukaemia with MLL-AF9 treated with chidamide-based chemotherapy

Targeted Therapy in Acute Lymphoblastic Leukaemia

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