Recent Clinical Update of Acute Myeloid Leukemia: Focus on Epigenetic Therapies.
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ABSTRACT:
SUBMITTER: Lee E
PROVIDER: S-EPMC8021975 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Acute myeloid leukemia (AML) is a highly heterogeneous disease arising from acquired genetic and epigenetic aberrations which stifle normal development and differentiation of hematopoietic precursors. Despite the complex and varied biological underpinnings, induction therapy for AML has remained fairly uniform over 4 decades and outcomes remain poor for most patients. Recently, enhanced understanding of the leukemic epigenome has resulted in the translational investigation of a number of epigenetic modifying agents currently in various stages of clinical development. These novel therapies are based on mechanistic rationale and offer the potential to improve AML patient outcomes. In light of many recent advances in this field, we provide an updated, clinically oriented review of the evolving landscape of epigenetic modifying agents for the treatment of AML.
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Project description:Acute myeloid leukemia (AML) is the most common acute leukemia in adults. While survival for younger patients over the last several decades has improved nearly sixfold with the optimization of intensive induction chemotherapy and allogeneic stem cell transplantation (alloHSCT), this effect has been largely mitigated in older and less fit patients as well as those with adverse-risk disease characteristics. However, the last 10 years has been marked by major advances in the molecular profiling of AML characterized by a deeper understanding of disease pathobiology and therapeutic vulnerabilities. In this regard, the classification of AML subtypes has recently evolved from a morphologic to a molecular and genetic basis, reflected by recent updates from the World Health Organization and the new International Consensus Classification system. After years of stagnation in new drug approvals for AML, there has been a rapid expansion of the armamentarium against this disease since 2017. Low-intensity induction therapy with hypomethylating agents and venetoclax has substantially improved outcomes, including in those previously considered to have a poor prognosis. Furthermore, targeted oral therapies against driver mutations in AML have been added to the repertoire. But with an accelerated increase in treatment options, several questions arise such as how to best sequence therapy, how to combine therapies, and if there is a role for maintenance therapy in those who achieve remission and cannot undergo alloHSCT. Moreover, certain subtypes of AML, such as those with TP53 mutations, still have dismal outcomes despite these recent advances, underscoring an ongoing unmet need and opportunity for translational advances. In this review, we will discuss recent updates in the classification and risk stratification of AML, explore the literature regarding low-intensity and novel oral combination therapies, and briefly highlight investigative agents currently in early clinical development for high-risk disease subtypes.
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Project description:Over the past decades, our molecular understanding of acute myeloid leukemia (AML) pathogenesis dramatically increased, thanks also to the advent of next-generation sequencing (NGS) technologies. Many of these findings, however, have not yet translated into new prognostic markers or rationales for treatments. We now know that AML is a highly heterogeneous disease characterized by a very low mutational burden. Interestingly, the few mutations identified mainly reside in epigenetic regulators, which shape and define leukemic cell identity. In the light of these discoveries and given the increasing number of drugs targeting epigenetic regulators in clinical development and testing, great interest is emerging for the use of small molecules targeting leukemia epigenome. Together with their effects on leukemia cell-intrinsic properties, such as proliferation and survival, epigenetic drugs may affect the way leukemic cells communicate with the surrounding components of the tumor and immune microenvironment. Here, we review current knowledge on alterations in the AML epigenetic landscape and discuss the promises of epigenetic therapies for AML treatment. Finally, we summarize emerging molecular studies elucidating how epigenetic rewiring in cancer cells may as well exert immune-modulatory functions, boost the immune system, and potentially contribute to better patient outcomes.
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Project description:Acute myeloid leukemia (AML) is a genetically heterogeneous disease. Certain cytogenetic and molecular genetic mutations are recognized to have an impact on prognosis, leading to their inclusion in some prognostic stratification systems. Recently, the advent of high-throughput whole genome or exome sequencing has led to the identification of several novel recurrent mutations in AML, a number of which have been found to involve genes concerned with epigenetic regulation. These genes include in particular DNMT3A, TET2, and IDH1/2, involved with regulation of DNA methylation, and EZH2 and ASXL-1, which are implicated in regulation of histones. However, the precise mechanisms linking these genes to AML pathogenesis have yet to be fully elucidated as has their respective prognostic relevance. As massively parallel DNA sequencing becomes increasingly accessible for patients, there is a need for clarification of the clinical implications of these mutations. This review examines the literature surrounding the biology of these epigenetic modifying genes with regard to leukemogenesis and their clinical and prognostic relevance in AML when mutated.
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Project description:The prognosis of adult acute myeloid leukemia (AML) remains poor, with the long-term survival rate less than 50%. However, the current paradigms of treatment are changing through a better understanding of the disease genetics and pathophysiology. Since 2017, eight new drugs have been approved by the U.S. Food and Drug Administration for the treatment of AML, including the FLT3 inhibitors midostaurin and gilteritinib, the IDH inhibitors ivosidenib and enasidenib, the anti-CD33 monoclonal antibody gemtuzumab ozogamicin, liposomal daunorubicin and cytarabine, the hedgehog pathway inhibitor glasdegib and the BCL-2 inhibitor venetoclax. Preclinical data demonstrated the anti-leukemic efficacy of venetoclax in AML and its synergy when combined with hypomethylating agents or chemotherapy agents. Clinical trials have demonstrated the clinical benefit of venetoclax-based therapies in newly diagnosed AML, leading to the recent FDA approval of venetoclax in combination with hypomethylating agents or low-dose cytarabine for older adults with newly diagnosed AML. Herein, we focus on the role of single-agent BCL-2 inhibition in AML and review the clinical studies of venetoclax-based combination regimens and the evolving mechanisms of resistance.
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Project description:The introduction of new targeted therapies to the treatment algorithm of acute myeloid leukemia (AML) offers new opportunities, but also presents new challenges. Patients diagnosed with AML receiving targeted therapies as part of lower intensity regimens will relapse inevitably due to primary or secondary resistance mechanisms. In this review, we summarize the current knowledge on the main mechanisms of resistance to targeted therapies in AML. Resistance to FLT3 inhibitors is mainly mediated by on target mutations and dysregulation of downstream pathways. Switching the FLT3 inhibitor has a potential therapeutic benefit. During treatment with IDH inhibitors resistance can develop due to aberrant cell metabolism or secondary site IDH mutations. As a unique resistance mechanism the mutated IDH isotype may switch from IDH1 to IDH2 or vice versa. Resistance to gemtuzumab-ozogamicin is determined by the CD33 isotype and the degradation of the cytotoxin. The main mechanisms of resistance to venetoclax are the dysregulation of alternative pathways especially the upregulation of the BCL-2-analogues MCL-1 and BCL-XL or the induction of an aberrant cell metabolism. The introduction of therapies targeting immune processes will lead to new forms of therapy resistance. Knowing those mechanisms will help to develop strategies that can overcome resistance to treatment.
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