Hypomethylating agents for the treatment of myelodysplastic syndromes and acute myeloid leukemia: Past discoveries and future directions

Short, Nicholas J.; Kantarjian, Hagop M.

doi:10.1002/ajh.26667

Cited by 22 publications

(13 citation statements)

References 69 publications

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“…Several studies and international classifications (National Comprehensive Cancer Network, European LeukemiaNet, and others) have highlighted the importance of incorporating mutational studies into the risk modeling of AML. [83][84][85][86][87] Some have proposed to define AML risk groups based only on cytogenetic and mutational abnormalities, thus discounting the effect of simpler and easily collected variables such as age, performance status, organ dysfunctions, and comorbidities. 88 An important question is, after accounting for such variables and newer therapies (addition of FLT3 or IDH inhibitors), what are the mutations that remain predictive and relevant for survival.…”

Section: Lower-intensity Therapy In Amlmentioning

confidence: 99%

Prediction of survival with lower intensity therapy among older patients with acute myeloid leukemia

Sasaki

Ravandi

Kadia

et al. 2023

Cancer

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Background The aim of this study was to develop a prognostic model for survival in older/unfit patients with newly diagnosed acute myeloid leukemia (AML) who were treated with lower‐intensity chemotherapy regimens. Methods The authors reviewed all older/unfit patients with newly diagnosed AML who received lower‐intensity chemotherapy from 2000 until 2020 at their institution. A total of 1462 patients were included. They were divided (3:1 basis) into a training (n = 1088) and a validation group (n = 374). Results In the training cohort of 1088 patients (median age, 72 years), the multivariate analysis identified 11 consistent independent adverse factors associated with survival: older age, therapy‐related myeloid neoplasm, existence of previous myelodysplastic syndrome or myeloproliferative neoplasms, poor performance status, pulmonary comorbidity, anemia, thrombocytopenia, elevated lactate dehydrogenase, cytogenetic abnormalities, and the presence of infection at diagnosis, and therapy not containing venetoclax. The 3‐year survival rates were 52%, 24%, 10%, and 1% in favorable, intermediate, poor, and very poor risk, respectively. This survival model was validated in an independent cohort. In a subset of patients in whom molecular mutation profiles were performed in more recent times, adding the mutation profiles after accounting for the effects of previous factors identified IDH2 (favorable), NPM1 (favorable), and TP53 (unfavorable) mutations as molecular prognostic factors. Conclusion The proposed survival model with lower‐intensity chemotherapy in older/unfit patients with newly diagnosed AML may help to advise patients on their expected outcome, to propose different strategies in first complete remission, and to compare the results of different existing or future investigational therapies. Plain Language Summary Lower intensity therapy can be considered for older patients to avoid severe toxicities and adverse events. However, survival prediction in AML was commonly developed in patients who received intensive chemotherapy. In this study, we have proposed a survival model to guide therapeutic approach in older patients who received lower‐intensity therapy.

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Section: Lower-intensity Therapy In Amlmentioning

confidence: 99%

Prediction of survival with lower intensity therapy among older patients with acute myeloid leukemia

Sasaki

Ravandi

Kadia

et al. 2023

Cancer

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“…Decitabine is another hypomethylating agent which has been approved by the Food and Drug Administration (FDA) for the treatment of patients with MDS ( 82 ). Incubation of culture expanded BM-MSCs from MDS patients in the presence of Decitabine resulted in a significant decrease in the proportion of cells in the G0/G1 phases as compared to MDS-derived BM-MSCs incubated in the absence of the drug (control group).…”

Section: Properties Of Ex Vivo Expanded Mds-derive...mentioning

confidence: 99%

The mesenchymal compartment in myelodysplastic syndrome: Its role in the pathogenesis of the disorder and its therapeutic targeting

2023

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Myelodysplastic syndromes include a broad spectrum of malignant myeloid disorders that are characterized by dysplastic ineffective hematopoiesis, reduced peripheral blood cells counts and a high risk of progression to acute myeloid leukemia. The disease arises primarily because of accumulating chromosomal, genetic and epigenetic changes as well as immune-mediated alterations of the hematopoietic stem cells (HSCs). However, mounting evidence suggests that aberrations within the bone marrow microenvironment critically contribute to myelodysplastic syndrome (MDS) initiation and evolution by providing permissive cues that enable the abnormal HSCs to grow and eventually establish and propagate the disease. Mesenchymal stromal cells (MSCs) are crucial elements of the bone marrow microenvironment that play a key role in the regulation of HSCs by providing appropriate signals via soluble factors and cell contact interactions. Given their hematopoiesis supporting capacity, it has been reasonable to investigate MSCs’ potential involvement in MDS. This review discusses this issue by summarizing existing findings obtained by in vitro studies and murine disease models of MDS. Furthermore, the theoretical background of targeting the BM-MSCs in MDS is outlined and available therapeutic modalities are described.

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“…The hypomethylating agents (HMA) azacitidine (AZA) and decitabine (DEC) have been a mainstay of the treatment of myeloid neoplasms for almost two decades now. These two closely-related agents primarily act by epigenetic mechanisms, the disruption of which is central to the pathogenesis of these disorders, thereby reinducing the expression of silenced critical genes [ 1 ]. In particular, HMA inhibits DNA methyltransferase-1 (DNMT-1) by forming covalent bonds between this enzyme and the DNA containing the molecules, which are incorporated during DNA synthesis [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

“…These two closely-related agents primarily act by epigenetic mechanisms, the disruption of which is central to the pathogenesis of these disorders, thereby reinducing the expression of silenced critical genes [ 1 ]. In particular, HMA inhibits DNA methyltransferase-1 (DNMT-1) by forming covalent bonds between this enzyme and the DNA containing the molecules, which are incorporated during DNA synthesis [ 1 ]. HMA also possesses direct cytotoxic effects, especially at higher doses [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

“…In particular, HMA inhibits DNA methyltransferase-1 (DNMT-1) by forming covalent bonds between this enzyme and the DNA containing the molecules, which are incorporated during DNA synthesis [ 1 ]. HMA also possesses direct cytotoxic effects, especially at higher doses [ 1 ]. Both HMAs have been approved in oral and injectable forms by the Food and Drug Administration (FDA) for specific indications that are not interchangeable in the treatment of myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML) [ 1 , 2 , 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

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What’s Next after Hypomethylating Agents Failure in Myeloid Neoplasms? A Rational Approach

Awada

Gurnari

Xie

et al. 2023

Cancers

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Hypomethylating agents (HMA) such as azacitidine and decitabine are a mainstay in the current management of patients with myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML) as either single agents or in multidrug combinations. Resistance to HMA is not uncommon, and it can result due to several tumor cellular adaptations. Several clinical and genomic factors have been identified as predictors of HMA resistance. However, the management of MDS/AML patients after the failure of HMA remains challenging in the absence of standardized guidelines. Indeed, this is an area of active research with several potential therapeutic agents currently under development, some of which have demonstrated therapeutic potential in early clinical trials, especially in cases with particular mutational characteristics. Here, we review the latest findings and give a rational approach for such a challenging scenario.

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Hypomethylating agents for the treatment of myelodysplastic syndromes and acute myeloid leukemia: Past discoveries and future directions

Cited by 22 publications

References 69 publications

Prediction of survival with lower intensity therapy among older patients with acute myeloid leukemia

Prediction of survival with lower intensity therapy among older patients with acute myeloid leukemia

The mesenchymal compartment in myelodysplastic syndrome: Its role in the pathogenesis of the disorder and its therapeutic targeting

What’s Next after Hypomethylating Agents Failure in Myeloid Neoplasms? A Rational Approach

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