New Insight Into the Biology, Risk Stratification, and Targeted Treatment of Myelodysplastic Syndromes

2017 ◽  
pp. 480-494
Author(s):  
Mintallah Haider ◽  
Eric J. Duncavage ◽  
Khalid F. Afaneh ◽  
Rafael Bejar ◽  
Alan F. List
Keyword(s):  
Risk Stratification ◽  
Myelodysplastic Syndromes ◽  
Rna Splicing ◽  
Somatic Mutations ◽  
Prognostic Significance ◽  
Gene Mutations ◽  
International Prognostic Scoring System ◽  
Prognostic Assessment ◽  
Sequencing Part ◽  
Gene Panels

In myelodysplastic syndromes (MDS), somatic mutations occur in five major categories: RNA splicing, DNA methylation, activated cell signaling, myeloid transcription factors, and chromatin modifiers. Although many MDS cases harbor more than one somatic mutation, in general, there is mutual exclusivity of mutated genes within a class. In addition to the prognostic significance of individual somatic mutations, more somatic mutations in MDS have been associated with poor prognosis. Prognostic assessment remains a critical component of the personalization of care for patient with MDS because treatment is highly risk adapted. Multiple methods for risk stratification are available with the revised International Prognostic Scoring System (IPSS-R), currently considered the gold standard. Increasing access to myeloid gene panels and greater evidence for the diagnostic and predictive value of somatic mutations will soon make sequencing part of the standard evaluation of patients with MDS. In the absence of formal guidelines for their prognostic use, well-validated mutations can still refine estimates of risk made with the IPSS-R. Not only are somatic gene mutations advantageous in understanding the biology of MDS and prognosis, they also offer potential as biomarkers and targets for the treatment of patients with MDS. Examples include deletion 5q, spliceosome complex gene mutations, and TP53 mutations.

Comparison of Risk Models for Patients with Lower Risk Myelodysplastic Syndromes

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1919-1919
Author(s):  
Hye Ryoun Kim ◽  
Guillermo Garcia-Manero ◽  
Carlos E. Bueso-Ramos ◽  
Hagop M. Kantarjian ◽  
Sourindra Maiti ◽  
...  
Keyword(s):  
Molecular Markers ◽  
Risk Stratification ◽  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Prognostic Significance ◽  
Gene Mutations ◽  
International Prognostic Scoring System ◽  
Cancer Center ◽  
Study Cohort ◽  
University Of Texas

Abstract Accurate prognostication is essential for patients with myelodysplastic syndromes (MDS) to facilitate optimal patient management. Several systems for predicting the outcome of patients with MDS are commonly used in clinics, including the International Prognostic Scoring System (IPSS), revised IPSS, and a low risk MDS model developed by The University of Texas MD Anderson Cancer Center (MDA). We designed this study to evaluate and compare these three models in lower risk MDS patients in order to accurately identify patients with a poor prognosis who may need early therapeutic intervention. A total of 733 adult patients, median age 69 years (range, 24-91), who were diagnosed as lower risk MDS (IPSS low or intermediate-1) with complete cytogenetic evaluations at MDA were included in this study. Both IPSS and revised IPSS systems stratified the study cohort into groups with significantly different overall survival (OS) (P<0.001 in both). The MDA model further stratified patients into significantly different OS groups (P<0.001), and further stratified the revised IPSS low group (N=248, P<0.001) by OS, but not the very low or intermediate (INT) groups. Because both IPSS models are heavily weighted toward cytogenetic features, but over half of MDS patients present with normal (diploid) cytogenetics, we compared the effectiveness of these models in risk stratification among diploid MDS patients. Without the effects of cytogenetics, all 3 models still stratified OS significantly (P<0.001 for all). Revised IPSS further stratified IPSS low (N=171, P<0.001) and INT-1 (N=184, P=0.005) into significant different OS groups. The MDA model further stratified IPSS low (P=0.041) and INT-1 (p<0.001) into significant different OS groups. Multivariate analyses showed that age, bone marrow blast count, and hemoglobin and platelet levels were independent factors for survival in all MDS patients and in diploid MDS patients, whereas absolute neutrophil count was not significant for either group. Molecular markers hold promise for further risk stratification in diploid MDS patients. We assessed the prognostic significance of common gene mutations, such as NPM1, FLT3, DNMT3A, NRAS and KIT. We also identified a signature of plasma microRNAs of which expression levels can predict survival of diploid MDS patients more accurately than all three models. In summary, the revised IPSS system has improved the stratification of patients in the IPSS low and INT-1 categories. The MDA model improves the OS stratification in IPSS low and INT-1 groups, as well as the revised IPSS low group. All three systems effectively predict survivals in diploid MDS patients. Development of novel molecular markers will enable further risk stratification of MDS patients, especially in the diploid MDS group. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Kantarjian: ARIAD, Pfizer, Amgen: Research Funding. Cooper:InCellerate: Equity Ownership; Sangamo: Patents & Royalties; Targazyme: Consultancy; GE Healthcare: Consultancy; Ferring Pharmaceuticals: Consultancy; Fate Therapeutics: Consultancy; Janssen Pharma: Consultancy; BMS: Consultancy; Miltenyi: Honoraria.

Prognostic models in myelodysplastic syndromes

Hematology ◽  
2013 ◽  
Vol 2013 (1) ◽  
pp. 504-510 ◽  
Author(s):  
Rafael Bejar
Keyword(s):  
Risk Stratification ◽  
Myelodysplastic Syndromes ◽  
Somatic Mutations ◽  
Scoring Systems ◽  
Accurate Estimate ◽  
Prognostic Models ◽  
International Prognostic Scoring System ◽  
Clinical Predictors ◽  
Molecular Abnormalities ◽  
Prognostic Scoring Systems

Abstract Establishing the prognosis for patients with myelodysplastic syndromes (MDS) is a key element of their care. It helps patients understand the severity of their disease and set expectations for their future. For physicians, an accurate estimate of prognosis drives decisions about the timing and choice of therapeutic options to consider. The International Prognostic Scoring System (IPSS) has been the standard tool for MDS risk stratification since it was released in 1997. It has been used to describe patients in pivotal clinical trials and is a key element of practice guidelines. Subsequent changes to the classification scheme for MDS and an underestimation of risk in some patients from the low and intermediate-1 categories have led to the development of several newer prognostic models. The most recent is the revised IPSS (IPSS-R), which addresses several of the perceived deficiencies of its predecessor. Despite their utility, none of the available prognostic systems incorporates disease-related molecular abnormalities such as somatic mutations. These lesions are present in the nearly all cases and many have been shown to improve upon existing prognostic models. However, the interpretation of somatic mutations can be challenging and it is not yet clear how best to combine them with clinical predictors of outcome. Here I review several prognostic scoring systems developed after the IPSS and describe the emerging use of molecular markers to refine risk stratification in the MDS patient population.

scholarly journals Clonal haematopoiesis in chronic ischaemic heart failure: prognostic role of clone size for DNMT3A- and TET2-driver gene mutations

2020 ◽  
Author(s):  
Birgit Assmus ◽  
Sebastian Cremer ◽  
Klara Kirschbaum ◽  
David Culmann ◽  
Katharina Kiefer ◽  
...  
Keyword(s):  
Heart Failure ◽  
Somatic Mutations ◽  
Prognostic Significance ◽  
Gene Mutations ◽  
Amplicon Sequencing ◽  
Driver Mutations ◽  
Driver Gene ◽  
Roc Curve Analysis ◽  
Driver Genes ◽  
Clone Size

Abstract Aims Somatic mutations of the epigenetic regulators DNMT3A and TET2 causing clonal expansion of haematopoietic cells (clonal haematopoiesis; CH) were shown to be associated with poor prognosis in chronic ischaemic heart failure (CHF). The aim of our analysis was to define a threshold of variant allele frequency (VAF) for the prognostic significance of CH in CHF. Methods and results We analysed bone marrow and peripheral blood-derived cells from 419 patients with CHF by error-corrected amplicon sequencing. Cut-off VAFs were optimized by maximizing sensitivity plus specificity from a time-dependent receiver operating characteristic (ROC) curve analysis from censored data. 56.2% of patients were carriers of a DNMT3A- (N = 173) or a TET2- (N = 113) mutation with a VAF &gt;0.5%, with 59 patients harbouring mutations in both genes. Survival ROC analyses revealed an optimized cut-off value of 0.73% for TET2- and 1.15% for DNMT3A-CH-driver mutations. Five-year-mortality was 18% in patients without any detected DNMT3A- or TET2 mutation (VAF &lt; 0.5%), 29% with only one DNMT3A- or TET2-CH-driver mutations above the respective cut-off level and 42% in patients harbouring both DNMT3A- and TET2-CH-driver mutations above the respective cut-off levels. In carriers of a DNMT3A mutation with VAF ≥ 1.15%, 5-year mortality was 31%, compared with 18% mortality in those with VAF &lt; 1.15% (P = 0.048). Likewise, in patients with TET2 mutations, 5-year mortality was 32% with VAF ≥ 0.73%, compared with 19% mortality with VAF &lt; 0.73% (P = 0.029). Conclusion The present study defines novel threshold levels for clone size caused by acquired somatic mutations in the CH-driver genes DNMT3A and TET2 that are associated with worse outcome in patients with CHF.

Epigenetic Biomarkers Are Applicable for Risk Stratification in Myelodysplastic Syndromes

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3194-3194 ◽  
Author(s):  
Anna Mies ◽  
Tanja Božić ◽  
Michael Kramer ◽  
Julia Franzen ◽  
Gerhard Ehninger ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Myelodysplastic Syndromes ◽  
Somatic Mutations ◽  
Chronological Age ◽  
Prognostic Impact ◽  
Cpg Site ◽  
Epigenetic Biomarkers ◽  
Epigenetic Aging ◽  
Epigenetic Age ◽  
Dnam Level

Abstract Introduction: Myelodysplastic syndromes (MDS) are frequently associated with somatic mutations in epigenetic modifiers such as de novo methyltransferase 3A (DNMT3A). However, so far the significance of specific epigenetic modifications for disease stratification remains largely unknown. In this study, we investigated if epigenetic biomarkers, which were previously described to be relevant in acute myeloid leukemia (AML), are also of prognostic impact in MDS. Methods: Peripheral blood samples of MDS patients (n=126; f/m=59/67; median age 66; range 26-93) equally distributed across all risk groups based on the revised International Prognostic Scoring System (IPSS-R; very low/low=43; int=37; high/very high=43; n.a.=3) were analyzed at initial diagnosis. Genomic DNA was isolated, bisulfite converted, and DNA methylation (DNAm) level at selected genomic regions were determined by pyrosequencing as described before: (1) hypermethylation at a CpG site in complement component 1 subcomponent R (C1R), (2) an epigenetic age prediction with an Epigenetic-Aging-Signature based on three CpG sites located in the genes ITGA2B, ASPA and PDE4C, and (3) an epimutation in the DNMT3A locus, mimicking somatic mutations of this gene, were all reported to correlate with overall survival (OS) in AML patients. Results were subsequently compared to clinical parameters such as IPSS-R, leukemic progression, and OS. Results: A clear tendency for longer OS of MDS patients was observed if DNAm level at C1R was above median (22%; two-year survival 67% [95% CI 53-84%] in hypo- vs. 84% [95% CI 74-95%] in hypermethylated samples; P=0.071), which is in line with previous findings in AML samples. The predicted epigenetic age determined by the Epigenetic-Aging-Signature correlated moderately with the chronological age of the investigated MDS patients (R=0.42) and their OS (P=0.029). This effect was also seen in a multivariable analysis of this cohort including predicted and chronological age (P=0.040). Finally, we stratified MDS patients by the DNAm level of 10% in DNMT3A. Similar to AML, also MDS patients with higher methylation at the CpG site represented on a microarray (cg23009818) showed in tendency shorter OS (two-year survival 79% [95% CI 69-89%] in hypo- vs. 65% [95% CI 45-93%] in hypermethylated samples; P=0.110). In fact, this association was even more pronounced at a neighboring CpG site (two-year survival 83% [95% CI 74-92%] in hypo- vs. 49% [95% CI 29-84%] in hypermethylated samples; P=0.009; Figure A). Moreover, increased DNAm level at this neighboring CpG site in DNMT3A was indicative for progression into AML (after two years: 15% [95% CI 6-24%] in hypo- vs. 44% [95% CI 12-76%] in hypermethylated samples; P=0.011; Figure B). Of note, none of these markers correlated with IPSS-R categories indicating that they might provide independent prognostic parameters. Conclusion: The analyzed epigenetic biomarkers revealed prognostic relevance in MDS patients and we suggest considering them in future risk stratification models. Particularly the aberrant hypermethylation of DNMT3A, which may also result in alternative splicing of DNMT3A transcripts, was associated with accelerated leukemic progression and shorter OS. Figure Figure. Disclosures Božić: Cygenia GmbH: Consultancy. Wagner:Cygenia GmbH: Equity Ownership.

scholarly journals Lower risk but high risk

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 428-434
Author(s):  
Amy E. DeZern
Keyword(s):  
High Risk ◽  
Risk Stratification ◽  
Myelodysplastic Syndromes ◽  
Genetic Information ◽  
Lower Risk ◽  
Molecular Genetic ◽  
Scoring Systems ◽  
International Prognostic Scoring System ◽  
Disease Characteristics ◽  
Prognostic Scoring Systems

Abstract Risk stratification is crucial to the appropriate management of most cancers, but in patients with myelodysplastic syndromes (MDS), for whom expected survival can vary from a few months to more than a decade, accurate disease prognostication is especially important. Currently, patients with MDS are often grouped into higher-risk (HR) vs lower-risk (LR) disease using clinical prognostic scoring systems, but these systems have limitations. Factors such as molecular genetic information or disease characteristics not captured in the International Prognostic Scoring System–Revised (IPSS-R) can alter risk stratification and identify a subset of patients with LR-MDS who actually behave more like those with HR-MDS. This review describes the current identification and management of patients with LR-MDS whose condition is likely to behave in a less favorable manner than predicted by the IPSS-R.

Increased Bone Marrow Erythroid Precursors Is Associated with Shorter Survival in Low-Grade Myelodysplastic Syndromes.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2371-2371
Author(s):  
Hesham M. Amin ◽  
Sherry A. Pierce ◽  
Hagop M. Kantarjian ◽  
Michael J. Keating ◽  
Emil J. Freireich ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndromes ◽  
Prognostic Significance ◽  
Refractory Anemia ◽  
International Prognostic Scoring System ◽  
Low Grade ◽  
Nucleated Red Blood Cells ◽  
Erythroid Precursors ◽  
History Of

Abstract According to the FAB and WHO classifications, the diagnosis of acute erythroid leukemia is based on the numbers of nucleated red blood cells and myeloid blasts in the bone marrow. The WHO classification recognizes two types of acute erythroid leukemia; M6A with 51–80% erythroid precursors and with 20% or more of the non-erythroid precursors being myeloid blasts; and M6B with more than 80% of the nucleated cells in the bone marrow consisting of erythroid precursors, regardless of the percentage of the myeloid blasts. Previous studies have shown that many cases of acute erythroid leukemia arise in patients with a history of myelodysplastic syndrome and in other cases acute erythroid leukemia is associated with significant dysplastic features. The significance of the number of erythroid precursors is not well known in the myelodysplastic syndromes. In the present study, we included 617 consecutive patients with low-grade myelodysplasia (482 patients with refractory anemia [RA] and 135 patients with refractory anemia with ringed sideroblasts [RARS]). Among this group, 82 patients with 50% or more of erythroid precursors had shorter survival compared with 535 patients with less than 50% erythroid precursors (P &lt; .01; Figure 1). The shorter survival in those with 50% or more of erythroid precursors may reflect the tendency of these patients to have worse International Prognostic Scoring System (IPSS) scores. Thus, among the patients with less than 50% erythroid precursors and primary MDS, 35% were IPSS low, 52% IPSS intermediate 1, and 13% IPSS intermediate 2. For the patients with 50% or more of erythroid precursors, the corresponding proportions were 14%, 57%, and 29%, respectively (P &lt; .001). As a result of the association between IPSS and the percentage of erythroid precursors, the percentage of erythroid precursors had no effect on survival within individual IPSS groups. Similarly, the percentage of erythroid precursors had no prognostic significance in patients with refractory anemia with excess blasts (RAEB) or chronic myelomonocytic leukemia (CMML). Our findings demonstrate that in low-grade dysplasia (RA and RARS) the number of erythroid precursors may represent an important prognostic marker. These findings implicate that the percentage of erythroid precursors should be considered in the classification of the low-grade myelodysplastic syndromes. A multivariate analysis will be performed to ascertain the relative effects of IPSS score and the percentage of erythroid precursors on prognosis in patients with low-grade myelodysplasia. Figure Figure

Myelodysplastic Syndromes: Recent Advancements in Risk Stratification and Unmet Therapeutic Challenges

2013 ◽  
pp. e256-e270
Author(s):  
Rafael Bejar ◽  
Ramon V. Tiu ◽  
Mikkael A. Sekeres ◽  
Rami S. Komrokji
Keyword(s):  
Risk Stratification ◽  
Myelodysplastic Syndromes ◽  
Myeloproliferative Neoplasms ◽  
Treatment Options ◽  
Gene Mutations ◽  
The Past ◽  
Clinically Significant ◽  
Novel Therapeutic Strategies ◽  
First Time ◽  
Key Questions

Significant advances have been achieved in understanding and treating myelodysplastic syndromes (MDS) in the past decade. For the first time, three drugs were approved specifically for this disease. Novel sequencing techniques have expanded our understanding of the molecular basis of MDS. Several clinically significant recurrent gene mutations have been identified. The classification and risk stratification of MDS continues to evolve in light of such advances. However, treatment options remain limited and novel therapeutic strategies are needed. In this review we address key questions for management of MDS. How do we better classify and risk stratify MDS, tailoring treatment accordingly? How do we diagnose and manage the challenging group of patients with MDS/myeloproliferative neoplasms (MPN) overlap? And finally, what is on the horizon for novel therapies?

High-resolution whole genome tiling path array CGH analysis of CD34+ cells from patients with low-risk myelodysplastic syndromes reveals cryptic copy number alterations and predicts overall and leukemia-free survival

Blood ◽  
2008 ◽  
Vol 112 (8) ◽  
pp. 3412-3424 ◽  
Author(s):  
Daniel T. Starczynowski ◽  
Suzanne Vercauteren ◽  
Adele Telenius ◽  
Sandy Sung ◽  
Kaoru Tohyama ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Copy Number ◽  
Prognostic Significance ◽  
Normal Karyotype ◽  
Low Risk ◽  
International Prognostic Scoring System ◽  
Comparative Genomic ◽  
Whole Genome ◽  
Copy Number Alterations ◽  
Cd34 Cells

Abstract Myelodysplastic syndromes (MDSs) pose an important diagnostic and treatment challenge because of the genetic heterogeneity and poorly understood biology of the disease. To investigate initiating genomic alterations and the potential prognostic significance of cryptic genomic changes in low-risk MDS, we performed whole genome tiling path array comparative genomic hybridization (aCGH) on CD34+ cells from 44 patients with an International Prognostic Scoring System score less than or equal to 1.0. Clonal copy number differences were detected in cells from 36 of 44 patients. In contrast, cells from only 16 of the 44 patients displayed karyotypic abnormalities. Although most patients had normal karyotype, aCGH identified 21 recurring copy number alterations. Examples of frequent cryptic alterations included gains at 11q24.2-qter, 17q11.2, and 17q12 and losses at 2q33.1-q33.2, 5q13.1-q13.2, and 10q21.3. Maintenance of genomic integrity defined as less than 3 Mb total disruption of the genome correlated with better overall survival (P = .002) and was less frequently associated with transformation to acute myeloid leukemia (P = .033). This study suggests a potential role for the use of aCGH in the clinical workup of MDS patients.

Improving diagnostic and prognostic accuracy of myeloid neoplasms (MNs) by next generation sequencing.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e18567-e18567
Author(s):  
Candice Schwartz ◽  
Jason Nathaniel Macklis ◽  
Lela Buckingham ◽  
Jamile M. Shammo
Keyword(s):  
Rna Splicing ◽  
Somatic Mutations ◽  
Prognostic Significance ◽  
Primary Myelofibrosis ◽  
Definitive Diagnosis ◽  
Driver Mutations ◽  
Or Management ◽  
Panel Testing ◽  
Gene Panel Testing ◽  
The Impact

e18567 Background: Molecular aberrations in MNs have been well described. Driver mutations such as JAK2, MPL, and CALR, are pathognomonic for MNs, whereas other somatic mutations are less specific but have prognostic significance. Multi-gene panel testing for known somatic mutations has been utilized for diagnostic and prognostic purposes, and testing for somatic mutations to identify clonal hematopoiesis has been adopted by the WHO 2016 classification of myeloid malignancies. We sought to assess the impact of testing for somatic mutations by NGS on diagnosis and management of pts with MNs. Methods: We employed a myeloid panel (MP) of 40 commonly mutated genes involving RNA splicing, chromatin remodeling, and signaling pathways. Testing was performed on ptswho presented to the clinic between 2/2015 and 12/2016. Initial diagnosis and rationale for testing (diagnostic or prognostic) were recorded. We then determined whether the MP resulted in a change in diagnosis, prognosis, or management. Results: 55 pts with a known or suspected MN had a MP performed.Diagnoses at presentation were: MDS (27), MF (8), MPN-U (8), MDS/MPN (4), multiple diagnoses (2), and no definitive diagnosis of MN (6). 87% (48/55) of pts had at least one somatic mutation.In 13 pts (23.6%) the MP led to a definitive diagnosis or a change in diagnosis. For example, 2 pts initially diagnosed with MPN-U were diagnosed with CNL after detection of CSF3R mutation. All 4 pts initially diagnosed with MDS with fibrosis were subsequently diagnosed with primary myelofibrosis; 3 had a MPL mutation and 1 had a CALR mutation. Management was altered in 12 pts (21.8%) and prognosis was changed in 11 pts (20.0%). For example, 2 pts were treated with a JAK-2 inhibitor and 2 pts with low risk MDS were referred for transplant evaluation due to the presence of a TP53mutation. Conclusions: Our study confirms that panel testing meaningfully improves diagnostic accuracy and provides prognostic value. In total, the MP resulted in a change in diagnosis, prognosis, or management in 43.6% (24/55) of cases. Confirmation of these observations merits prospective evaluation for a larger number of pts.

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