Molecular Targeted Therapy and Immunotherapy for Myelodysplastic Syndrome

Lee, Paul; Yim, Rita; Yung, Yammy; Chu, Hiutung; Yip, Pui-Kwan; Gill, Harinder

doi:10.3390/ijms221910232

Cited by 23 publications

(23 citation statements)

References 276 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Together they deliver a potent phagocytic signal to macrophages ( 253 ). Magrolimab is a monoclonal antibody that blocks CD47 to escape immune surveillance and macrophage-mediated clearance ( 254 ). Clinical trials have shown that magrolimab, is safe when administered as monotherapy ( 255 ).…”

Section: Somatic Mutationsmentioning

confidence: 99%

The genetics of myelodysplastic syndromes and the opportunities for tailored treatments

Kontandreopoulou

Kalopisis²,

Viniou³

et al. 2022

Front. Oncol.

View full text Add to dashboard Cite

Genomic instability, microenvironmental aberrations, and somatic mutations contribute to the phenotype of myelodysplastic syndrome and the risk for transformation to AML. Genes involved in RNA splicing, DNA methylation, histone modification, the cohesin complex, transcription, DNA damage response pathway, signal transduction and other pathways constitute recurrent mutational targets in MDS. RNA-splicing and DNA methylation mutations seem to occur early and are reported as driver mutations in over 50% of MDS patients. The improved understanding of the molecular landscape of MDS has led to better disease and risk classification, leading to novel therapeutic opportunities. Based on these findings, novel agents are currently under preclinical and clinical development and expected to improve the clinical outcome of patients with MDS in the upcoming years. This review provides a comprehensive update of the normal gene function as well as the impact of mutations in the pathogenesis, deregulation, diagnosis, and prognosis of MDS, focuses on the most recent advances of the genetic basis of myelodysplastic syndromes and their clinical relevance, and the latest targeted therapeutic approaches including investigational and approved agents for MDS.

show abstract

Section: Somatic Mutationsmentioning

confidence: 99%

The genetics of myelodysplastic syndromes and the opportunities for tailored treatments

Kontandreopoulou

Kalopisis²,

Viniou³

et al. 2022

Front. Oncol.

View full text Add to dashboard Cite

show abstract

“…Since MCC is considered an aggressive and deadly tumor, there is an urgent need to identify novel effective therapies for its management. As the malignant behaviour of MCC cells can be reverted with iHDACs ( 17 , 69 , 71 , 72 , 77 ), combination multidrug therapies with hypomethylating agents should be considered ( 45 , 107 , 108 ), as has successfully been demonstrated in treating other tumors ( 109 – 111 ). We therefore recommend further rigorous preclinical/clinical studies in this direction ( 112 ).…”

Section: Discussion and Future Perspectivesmentioning

confidence: 99%

The Role of Histone Post-Translational Modifications in Merkel Cell Carcinoma

et al. 2022

View full text Add to dashboard Cite

Merkel Cell Carcinoma (MCC) is a rare but highly aggressive form of non–melanoma skin cancer whose 5-year survival rate is 63%. Merkel cell polyomavirus (MCPyV), a small DNA tumor virus, is the etiological agent of MCC. Although representing a small proportion of MCC cases, MCPyV-negative MCCs have also been identified. The role of epigenetic mechanisms, including histone post-translational modifications (PTMs) in MCC, have been only partially determined. This review aims to describe the most recent progress on PTMs and their regulative factors in the context of MCC onset/development, providing an overview of current findings on both MCC subtypes. An outline of current knowledge on the potential employment of PTMs and related factors as diagnostic and prognostic markers, as well as novel treatment strategies targeting the reversibility of PTMs for MCC therapy is provided. Recent research shows that PTMs are emerging as important epigenetic players involved in MCC onset/development, and therefore may show a potential clinical significance. Deeper and integrated knowledge of currently known PTM dysregulations is of paramount importance in order to understand the molecular basis of MCC and improve the diagnosis, prognosis, and therapeutic options for this deadly tumor.

show abstract

“…Finally, we also sought to investigate candidate biomarkers of responsiveness to azacytidine plus venetoclax therapy, and well-established biomarkers (e.g., WT1 mRNA levels or NBC) or other novel molecules were studied, such as Tim-3 expression levels. For example, Tim-3, a checkpoint receptor, is a promising targeted therapy in cancer immunotherapy, and its inhibitor, cobolimab, has displayed efficacy and safety as monotherapy or in combination with other checkpoint inhibitors in patients with advanced solid tumors in phase I AMBER study ( Falchook GS et al, 2022 ), and has been also proposed in high-risk MDS ( Lee P et al, 2021 ). Indeed, Tim-3 expression is increased on blasts and in high-risk hematological diseases ( Asayama T et al, 2017 ), together with its pathway companion, galectin-9, and proliferation of Tim-3 + MDS blasts can be inhibited by anti-Tim-3 antibody ( Gonçalves Silva I et al, 2017 ; Wolf Y et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Clinical efficacy of azacytidine and venetoclax and prognostic impact of Tim-3 and galectin-9 in acute myeloid leukemia and high-risk myelodysplastic syndromes: A single-center real-life experience

et al. 2022

View full text Add to dashboard Cite

Treatment of acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS) is difficult in older patients with comorbidities and high-risk disease factors. Venetoclax, the first-in-class Bcl-2 inhibitor, has proven efficacy and safety in combination with azacytidine for treatment of high-risk myeloid diseases. In this single-center real-life retrospective study, a total of 27 consecutive patients treated with azacytidine plus venetoclax were included, and clinical outcomes, hematological improvements, and biomarkers of responsiveness to therapy were compared to those observed in an historical cohort of 95 consecutive patients treated with azacytidine as single agent. Azacytidine plus venetoclax was effective and safe in older and frail AML and high-risk MDS patients, with median overall survival of 22.3 months, higher than that reported in phase III trial (14.7 months), and higher than that of historical cohort (5.94 months). Progression-free survival was higher in patients treated with the drug combination compared to those treated with azacytidine as single agent (p = 0.0065). Clinical benefits might increase when azacytidine and venetoclax are administered as upfront therapy (p = 0.0500). We showed that Tim-3 expression could be a promising therapeutic target in refractory/relapsed patients, and galectin-9 a biomarker of responsiveness to therapy. Moreover, patients treated with azacytidine and venetoclax displayed a higher overall survival regardless the presence of negative prognostic markers at diagnosis (e.g., increased WT1 copies and/or normalized blast count). These encouraging results in a real-world setting supported efficacy and safety of azacytidine plus venetoclax as upfront therapy in AML and high-risk MDS, with clinical outcomes comparable to those of clinical trials when an appropriate venetoclax management with bone marrow assessment at every first, second, fourth, and eighth cycle, and dose adjustments for toxicities are performed.

show abstract

Molecular Targeted Therapy and Immunotherapy for Myelodysplastic Syndrome

Cited by 23 publications

References 276 publications

The genetics of myelodysplastic syndromes and the opportunities for tailored treatments

The genetics of myelodysplastic syndromes and the opportunities for tailored treatments

The Role of Histone Post-Translational Modifications in Merkel Cell Carcinoma

Clinical efficacy of azacytidine and venetoclax and prognostic impact of Tim-3 and galectin-9 in acute myeloid leukemia and high-risk myelodysplastic syndromes: A single-center real-life experience

Contact Info

Product

Resources

About