scholarly journals Targeting Apoptotic Pathways in Acute Myeloid Leukaemia

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1660 ◽  
Author(s):  
Jonathan R. Sillar ◽  
Anoop K. Enjeti
Keyword(s):  
Clinical Trials ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
B Cell Lymphoma ◽  
Clinical Work ◽  
Biological Research ◽  
Apoptotic Pathways ◽  
Molecular Landscape ◽  
Early Phase Clinical Trials ◽  
Acute Myeloid

Acute Myeloid Leukaemia is a devastating disease that continues to have a poor outcome for the majority of patients. In recent years, however, a number of drugs have received FDA approval, following on from successful clinical trial results. This parallels the characterization of the molecular landscape of Acute Myeloid Leukaemia (AML) over the last decade, which has led to the development of drugs targeting newly identified recurring mutations. In addition, basic biological research into the pathobiology of AML has identified aberrant programmed cell death pathways in AML. Following on from successful outcomes in lymphoid malignancies, drugs targeting the B Cell Lymphoma 2 (BCL-2) family of anti-apoptotic proteins have been explored in AML. In this review, we will outline the preclinical and clinical work to date supporting the role of drugs targeting BCL-2, with Venetoclax being the most advanced to date. We will also highlight rationale combinations using Venetoclax, ongoing clinical trials and biomarkers of response identified from the early phase clinical trials performed.

scholarly journals Targeting Bcl-2 Proteins in Acute Myeloid Leukemia

2020 ◽  
Vol 10 ◽  
Author(s):  
Yunxiong Wei ◽  
Yaqing Cao ◽  
Rui Sun ◽  
Lin Cheng ◽  
Xia Xiong ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
New Combination ◽  
Intrinsic Apoptosis ◽  
Early Phase Clinical Trials ◽  
The Impact ◽  
Acute Myeloid

B cell lymphoma 2 (BCL-2) family proteins play an important role in intrinsic apoptosis. Overexpression of BCL-2 proteins in acute myeloid leukemia can circumvent resistance to apoptosis and chemotherapy. Considering this effect, the exploration of anti-apoptotic BCL-2 inhibitors is considered to have tremendous potential for the discovery of novel pharmacological modulators in cancer. This review outlines the impact of BCL-2 family proteins on intrinsic apoptosis and the development of acute myeloid leukemia (AML). Furthermore, we will also review the new combination therapy with venetoclax that overcomes resistance to venetoclax and discuss biomarkers of treatment response identified in early-phase clinical trials.

scholarly journals Oncogenic Roles and Inhibitors of DNMT1, DNMT3A, and DNMT3B in Acute Myeloid Leukaemia

2019 ◽  
Vol 14 ◽  
pp. 117727191984645 ◽  
Author(s):  
Kah Keng Wong ◽  
Charles H Lawrie ◽  
Tina M Green
Keyword(s):  
Dna Methylation ◽  
Clinical Trials ◽  
Acute Myeloid Leukaemia ◽  
Clinical Response ◽  
Myeloid Leukaemia ◽  
Dna Methyltransferases ◽  
Clinical Settings ◽  
Hypomethylating Agents ◽  
Dnmt Inhibitors ◽  
Acute Myeloid

Epigenetic alteration has been proposed to give rise to numerous classic hallmarks of cancer. Impaired DNA methylation plays a central role in the onset and progression of several types of malignancies, and DNA methylation is mediated by DNA methyltransferases (DNMTs) consisting of DNMT1, DNMT3A, and DNMT3B. DNMTs are frequently implicated in the pathogenesis and aggressiveness of acute myeloid leukaemia (AML) patients. In this review, we describe and discuss the oncogenic roles of DNMT1, DNMT3A, and DNMT3B in AML. The clinical response predictive roles of DNMTs in clinical trials utilising hypomethylating agents (azacitidine and decitabine) in AML patients are presented. Novel hypomethylating agent (guadecitabine) and experimental DNMT inhibitors in AML are also discussed. In summary, hypermethylation of tumour suppressors mediated by DNMT1 or DNMT3B contributes to the progression and severity of AML (except MLL-AF9 and inv(16)(p13;q22) AML for DNMT3B), while mutation affecting DNMT3A represents an early genetic lesion in the pathogenesis of AML. In clinical trials of AML patients, expression of DNMTs is downregulated by hypomethylating agents while the clinical response predictive roles of DNMT biomarkers remain unresolved. Finally, nucleoside hypomethylating agents have continued to show enhanced responses in clinical trials of AML patients, and novel non-nucleoside DNMT inhibitors have demonstrated cytotoxicity against AML cells in pre-clinical settings.

scholarly journals Venetoclax combination therapy with hypomethylating agents in young adults with relapsed/refractory acute myeloid leukaemia

2021 ◽  
Vol 12 ◽  
pp. 204062072110403
Author(s):  
Nerea Báez-Gutiérrez ◽  
Héctor Rodríguez-Ramallo ◽  
María Antonia-Pérez Moreno ◽  
Eduardo-Rodriguez Arboli ◽  
Laila Abdel-kader Martín
Keyword(s):  
Combination Therapy ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Case Reports ◽  
Young Patients ◽  
B Cell Lymphoma ◽  
The Elderly ◽  
Hypomethylating Agents ◽  
Acute Myeloid ◽  
Refractory Aml

In recent years, one of the most successful advances in treating acute myeloid leukaemia (AML) has been the combination of the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax with hypomethylating agents (decitabine or azacytidine). This combination treatment has an accelerated approval by the Food and Drug Administration for newly diagnosed AML adults who are 75 years of age or older or who have comorbidities and are not eligible to receive intensive induction chemotherapy. AML is the most common form of acute leukaemia in adults, with a median age at diagnosis of 68 years. Consequently, most of the patients included in the studies are elderly. Traditionally, young patients achieve higher remission rates compared with the elderly AML population. Although venetoclax combination therapy could become a treatment option for treating young patients with relapsed/refractory AML, this regimen has not been systematically tested in this setting. In this study, we summarize the currently available evidence on the treatment of venetoclax in combination with hypomethylating agents for the treatment of young relapsed/refractory AML patients, in addition to our experience in clinical practice with two case reports. Venetoclax, combined with hypomethylating agents, seems to be an effective option for young relapsed/refractory AML patients. However, due to the poor quality of the evidence, additional well-designed studies with greater numbers of patients are needed to confirm the effectiveness and safety of venetoclax combination regimens for this population.

scholarly journals PB1719 TRENDS IN EFFICACY PARAMETERS STUDIED IN CLINICAL TRIALS FOR ACUTE MYELOID LEUKAEMIA

HemaSphere ◽  
2019 ◽  
Vol 3 (S1) ◽  
pp. 791
Author(s):  
D. Said ◽  
J.J. Borg ◽  
M. Attard Pizzuto ◽  
A. Serracino-Inglott
Keyword(s):  
Clinical Trials ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Efficacy Parameters ◽  
Acute Myeloid
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