Browse
Submit Data
Databases
API
Help

Dataset Information

27 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Baseline and serial molecular profiling predicts outcomes with hypomethylating agents in myelodysplastic syndromes.

ABSTRACT: Hypomethylating agents (HMAs) are widely used in the treatment of myelodysplastic syndromes (MDSs), yet identifying those patients unlikely to benefit remains challenging. We assessed response and overall survival (OS) in 247 patients molecularly profiled by next-generation sequencing (NGS) before first-line HMA therapy, and a subset of 108 patients were sequenced serially during treatment. The most common mutations included TP53 (33.1%), ASXL1 (19%), TET2 (16.5%), DNMT3A (14.1%), and SRSF2 (12.1%). The overall response rate was 42.1%, with the composite TET2-mutant/ASXL1 wild-type genotype representing the strongest predictor of response (overall response rate, 62.1%; complete remission rate, 34.5%). The median OS for the cohort was 15 months, and the number of mutations detected by NGS (hazard ratio [HR], 1.22; P = .02), as well as mutations in TP53 (HR, 2.33; P = .001) and EZH2 (HR, 2.41; P = .04) were identified as independent covariates associated with inferior OS in multivariable analysis. Serial molecular profiling revealed that clearance of TP53 mutations during HMA therapy was associated with superior OS (HR, 0.28; P = .001) and improved outcome in patients proceeding to allogeneic hematopoietic cell transplantation. These data support baseline molecular profiling by NGS in MDS patients treated with HMAs and provide novel observations of sequential profiling during therapy that provide particular value in TP53-mutated disease.

SUBMITTER: Hunter AM

PROVIDER: S-EPMC7903224 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Beyond hypomethylating agents failure in patients with myelodysplastic syndromes.

Project description:Although hypomethylating agents (HMAs) significantly improve outcomes in myelodysplastic syndromes (MDS), only half the patients achieve objective responses, and most responders lose response within 1-2 years. Azacitidine prolongs survival by a median of only 9.5 months. Failure of HMA therapy is associated with a very dismal prognosis. Therefore, novel therapeutic approaches are clearly needed.The sequential use of the alternative HMA after failure of first line HMA is associated with modest efficacy. The improved understanding of the biologic underpinnings of the disease have opened the door to study investigational agents that target disrupted molecular pathways critical to the pathogenesis of MDS. Combination treatment strategies using an azacitidine backbone are demonstrating promising early results. Expanding the applicability of allogeneic stem cell transplantation (alloSCT), the only curative modality, by reducing toxicity and relapse rates is another area of active research.Sequential switching to the alternative HMA, clinical trials of novel targeted therapies, azacitidine-based combination therapeutic strategies, and improvements in the alloSCT platform are the main directions in improving outcomes of MDS post HMA failure.

| S-EPMC4124617 | biostudies-literature

Association of provider experience and clinical outcomes in patients with myelodysplastic syndromes receiving hypomethylating agents.

Project description:Population level survival of patients with myelodysplastic syndromes (MDS) treated with hypomethylating agents (HMA) is inferior to clinical trials. Using SEER-Medicare data, we identified 2086 MDS patients diagnosed in 2004-13, aged ≥66 years at diagnosis, and receiving ≥1 HMA cycle after 2005. We used multivariate logistic regression and Cox proportional hazards models to assess the impact of provider experience on persistent HMA therapy and overall survival (OS), respectively. Median number of HMA cycles was 4 and median OS was 10 months. Thirty-two percent of patients were treated by providers with ≥1 prior HMA initiation in the last 2 years and were more likely to receive ≥4 cycles of HMA therapy (OR = 1.29, 95% CI = 1.06-1.57; p = .01). No significant association was found between MDS or HMA initiation volume and survival. In conclusion, while HMA initiation volume was associated with persistent HMA treatment, neither MDS nor HMA initiation volumes were associated with OS in older MDS patients.

| S-EPMC7732188 | biostudies-literature

Management of myelodysplastic syndromes after failure of response to hypomethylating agents.

Project description:Hypomethylating agents (HMAs) are the standard of care for patients with myelodysplastic syndrome (MDS). However, only around 50% of patients respond to these agents, and responses tend to be transient, with loss of response frequently happening within 2 years and being associated with very poor prognosis and limited therapeutic options. Identification of patients who will respond to HMAs is challenging. Mechanisms underlying resistance to HMAs are not clear yet. Recently, absence of response has been associated with increased cell-cycle quiescence among the hematopoietic progenitor cells. There are no standard-of-care options for patients after HMA failure. However, the increasing knowledge of MDS pathogenesis has led to the development of new potential therapies, including HMAs with longer half-life and exposure, inhibition of the antiapoptotic BCL2 protein with venetoclax or inhibition of immune-checkpoint regulatory proteins such as PD-1 or CTLA-4, innate immunity and targeting of CD33/CD3 with multiple monoclonal antibodies. In addition, multiple targeted agents are opening opportunities to treat subgroups of patients whose disease harbors mutations in TP53, IDH, FLT3, and genes involved in splicing machinery. Newer formulations of intensive chemotherapy and its different combinations may be considered a valid option in selected patients after HMA failure. Finally, decision making at the time of failure of response to HMAs should be personalized, taking into account that allogenic stem-cell transplantation remains the only therapeutic approach with curative potential in these patients. In the current review, we will focus on all the above aspects.

| S-EPMC6515843 | biostudies-literature

Clinical implications of TP53 mutations in myelodysplastic syndromes treated with hypomethylating agents.

Project description:We screened TP53 mutations in 168 MDS patients who were treated with HMA and evaluated predictive and prognostic value of TP53 mutations. Overall response to HMA was not different based on TP53 mutation status (45% vs. 32% in TP53-mutated and wild type [WT], respectively, P = 0.13). However, response duration was significantly shorter in TP53-mutated patients compared to WT patients (5.7 months vs. 28.5 months, P = 0.003). Longitudinal analysis of TP53 mutations after HMA showed that TP53 mutations almost always persisted at times of disease progression. TP53-mutated patients showed significantly worse overall survival (OS) compared to WT patients (9.4 months vs. 20.7 months, P <0.001). Further, TP53 mutations distinguished prognosis in the subgroup of patients with complex karyotype and Revised International Prognostic Scoring System (IPSS-R) defined very high-risk disease. Multivariate analysis showed that TP53 mutation status is significantly prognostic for OS after adjusting prognostic effect from other factors. The current study provides evidence that TP53 mutations are independently prognostic in MDS patients treated with HMA. While TP53-mutated MDS patients initially respond well to HMA, their duration of response is significantly shorter than WT patients. Novel strategies to improve duration of response in TP53-mutated MDS are urgently needed.

| S-EPMC4924706 | biostudies-literature

Hypomethylating Agents and Immunotherapy: Therapeutic Synergism in Acute Myeloid Leukemia and Myelodysplastic Syndromes.

Project description:Decitabine and guadecitabine are hypomethylating agents (HMAs) that exert inhibitory effects against cancer cells. This includes stimulation of anti-tumor immunity in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients. Treatment of AML and MDS patients with the HMAs confers upregulation of cancer/testis antigens (CTAs) expression including the highly immunogenic CTA NY-ESO-1. This leads to activation of CD4+ and CD8+ T cells for elimination of cancer cells, and it establishes the feasibility to combine cancer vaccine with HMAs to enhance vaccine immunogenicity. Moreover, decitabine and guadecitabine induce the expression of immune checkpoint molecules in AML cells. In this review, the accumulating knowledge on the immunopotentiating properties of decitabine and guadecitabine in AML and MDS patients are presented and discussed. In summary, combination of decitabine or guadecitabine with NY-ESO-1 vaccine enhances vaccine immunogenicity in AML patients. T cells from AML patients stimulated with dendritic cell (DC)/AML fusion vaccine and guadecitabine display increased capacity to lyse AML cells. Moreover, decitabine enhances NK cell-mediated cytotoxicity or CD123-specific chimeric antigen receptor-engineered T cells antileukemic activities against AML. Furthermore, combination of either HMAs with immune checkpoint blockade (ICB) therapy may circumvent their resistance. Finally, clinical trials of either HMAs combined with cancer vaccines, NK cell infusion or ICB therapy in relapsed/refractory AML and high-risk MDS patients are currently underway, highlighting the promising efficacy of HMAs and immunotherapy synergy against these malignancies.

| S-EPMC7947882 | biostudies-literature

Impact of the number of mutations in survival and response outcomes to hypomethylating agents in patients with myelodysplastic syndromes or myelodysplastic/myeloproliferative neoplasms.

Project description:The prognostic and predictive value of sequencing analysis in myelodysplastic syndromes (MDS) has not been fully integrated into clinical practice. We performed whole exome sequencing (WES) of bone marrow samples from 83 patients with MDS and 31 with MDS/MPN identifying 218 driver mutations in 31 genes in 98 (86%) patients. A total of 65 (57%) patients received therapy with hypomethylating agents. By univariate analysis, mutations in BCOR, STAG2, TP53 and SF3B1 significantly influenced survival. Increased number of mutations (? 3), but not clonal heterogeneity, predicted for shorter survival and LFS. Presence of 3 or more mutations also predicted for lower likelihood of response (26 vs 50%, p = 0.055), and shorter response duration (3.6 vs 26.5 months, p = 0.022). By multivariate analysis, TP53 mutations (HR 3.1, CI 1.3-7.5, p = 0.011) and number of mutations (? 3) (HR 2.5, CI 1.3-4.8, p = 0.005) predicted for shorter survival. A novel prognostic model integrating this mutation data with IPSS-R separated patients into three categories with median survival of not reached, 29 months and 12 months respectively (p < 0.001) and increased stratification potential, compared to IPSS-R, in patients with high/very-high IPSS-R. This model was validated in a separate cohort of 413 patients with untreated MDS. Although the use of WES did not provide significant more information than that obtained with targeted sequencing, our findings indicate that increased number of mutations is an independent prognostic factor in MDS and that mutation data can add value to clinical prognostic models.

| S-EPMC5839396 | biostudies-literature

Hypomethylating agents (HMA) treatment for myelodysplastic syndromes: alternatives in the frontline and relapse settings.

Project description:Hypomethylating agents (HMA) have played a pivotal role for treating myelodysplastic syndromes (MDS) over the past decade, inducing sustained hematological responses and delaying progression to leukemia. However, a vast majority of patients will experience treatment failure within 2 years, with poor prognoses and limited options, and management of this growing patient population remains unclear. Areas covered: With the introduction of new agents in the MDS field, a better understanding of the biology of MDS, and updated information on standard of care options (including allogeneic transplantation), we re-evaluate the global treatment strategy in MDS via novel agents, focusing in particular on investigational approaches for patients who fail to respond to HMA when applicable. This review aims to address two questions: what are reasonable alternatives to HMA in MDS, and what strategies can be used for patients experiencing HMA failure. Expert opinion/commentary: HMA therapy remains a mainstay of treatment, even if additional research is still warranted to maximize its benefits for the different groups of patients. The outcome of patients experiencing HMA failure remains grim, without standard of care, but several new approaches seem promising, as there is an increasing focus on studying treatments for patients refractory to HMA treatment.

| S-EPMC6121132 | biostudies-literature

Hypomethylating Chemotherapeutic Agents as Therapy for Myelodysplastic Syndromes and Prevention of Acute Myeloid Leukemia.

Project description:Myelodysplastic Syndromes (MDSs) affect the elderly and can progress to Acute Myeloid Leukemia (AML). Epigenetic alterations including DNA methylation and chromatin modification may contribute to the initiation and progression of these malignancies. DNA hypomethylating agents such as decitabine and azacitidine are used as therapeutic treatments and have shown to promote expression of genes involved in tumor suppression, apoptosis, and immune response. Another anti-cancer drug, the proteasome inhibitor bortezomib, is used as a chemotherapeutic treatment for multiple myeloma (MM). Phase III clinical trials of decitabine and azacitidine used alone and in combination with other chemotherapeutics demonstrated their capacity to treat hematological malignancies and prolong the survival of MDS and AML patients. Although phase III clinical trials examining bortezomib's role in MDS and AML patients are limited, its underlying mechanisms in MM highlight its potential as a chemotherapeutic for such malignancies. Further research is needed to better understand how the epigenetic mechanisms mediated by these chemotherapeutic agents and their targeted gene networks are associated with the development and progression of MDS into AML. This review discusses the mechanisms by which decitabine, azacitidine, and bortezomib alter epigenetic programs and their results from phase III clinical trials.

| S-EPMC8308509 | biostudies-literature

Genomic Biomarkers to Predict Resistance to Hypomethylating Agents in Patients With Myelodysplastic Syndromes Using Artificial Intelligence.

Project description:PURPOSE:We developed an unbiased framework to study the association of several mutations in predicting resistance to hypomethylating agents (HMAs) in patients with myelodysplastic syndromes (MDS), analogous to consumer and commercial recommender systems in which customers who bought products A and B are likely to buy C: patients who have a mutation in gene A and gene B are likely to respond or not respond to HMAs. METHODS:We screened a cohort of 433 patients with MDS who received HMAs for the presence of common myeloid mutations in 29 genes that were obtained before the patients started therapy. The association between mutations and response was evaluated by the Apriori market basket analysis algorithm. Rules with the highest confidence (confidence that the association exists) and the highest lift (strength of the association) were chosen. We validated our biomarkers in samples from patients enrolled in the S1117 trial. RESULTS:Among 433 patients, 193 (45%) received azacitidine, 176 (40%) received decitabine, and 64 (15%) received HMA alone or in combination. The median age was 70 years (range, 31 to 100 years), and 28% were female. The median number of mutations per sample was three (range, zero to nine), and 176 patients (41%) had three or more mutations per sample. Association rules identified several genomic combinations as being highly associated with no response. These molecular signatures were present in 30% of patients with three or more mutations/sample with an accuracy rate of 87% in the training cohort and 93% in the validation cohort. CONCLUSION:Genomic biomarkers can identify, with high accuracy, approximately one third of patients with MDS who will not respond to HMAs. This study highlights the importance of machine learning technologies such as the recommender system algorithm in translating genomic data into useful clinical tools.

| S-EPMC6818517 | biostudies-literature

Impact of achievement of complete cytogenetic response on outcome in patients with myelodysplastic syndromes treated with hypomethylating agents.

Project description:Two hundred and sixteen consecutive patients with MDS and abnormal karyotype treated with hypomethylating agents between 4/04 and 10/12 were reviewed. Median follow-up was 17 months. Using IWG criteria, best responses were complete response (CR) in 79 patients (37%), partial response (PR) in 4 (2%), and hematologic improvement (HI) in 10 (5%). Cytogenetic response (CyR) was achieved in 78 patients (36%): complete (CCyR) in 62 (29%) and partial in 16 (7%). CyR was achieved in 48 of 79 patients (61%) with CR, 1 of 14 (7%) with PR/HI, and in 29 of the 123 (24%) with no morphologic response. Median overall survival (OS) and leukemia-free survival (LFS) for patients with and without CCyR were 21 and 13 months (P = .007), and 16 and 9 months (P = .001), respectively. By multivariate analysis, the achievement of CCyR was predictive for better OS (HR?=?2.1; P < .001). In conclusion, CyR occurs at a rate of 36% (complete in 29%) in patients with MDS treated with HMA and is not always associated with morphological response. The achievement of CCyR is associated with survival improvement and constitutes a major predictive factor for outcome particularly in patients without morphologic response. Therefore, the achievement of CCyR should be considered a milestone in the management of patients with MDS.

| S-EPMC5439522 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data