Prognosis of Myelodysplastic Syndromes

AbstractThe myelodysplastic syndromes (MDS) are a very complex group of hematopoietic disorders. The degree of complexity relates not only to the intrinsic pathobiological characteristics of the disease, but also to the group of patients whom it affects most frequently: older individuals or those who have been exposed to prior forms of chemotherapy. It is therefore crucial to develop clinical tools to predict with a certain degree of precision the prognosis and outcome for patients with specific subtypes of MDS in specific clinical situations. At the present time, patients with MDS are diagnosed using a set of well-established histopathological criteria. Prognosis is established using classifications that include morphological features, percentage of blasts, and clinical and molecular characteristics such as peripheral cytopenias and cytogenetics. The International Prognostic Scoring System (IPSS) is a classic example of this type of classification. Over the last 5 years, there has been an intense effort to develop new prognostic systems for MDS, and new molecular alterations with potential prognostic value have been discovered. Over the same period of time, several new therapeutic interventions have been developed for patients with MDS. Biomarkers of response to these agents, in particular for the hypomethylating agents, are needed to predict clinical benefit. This review summarizes current prognostic models of MDS and new molecular alterations with potential prognostic potential.

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

JCO Precision Oncology ◽

10.1200/po.19.00119 ◽

2019 ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

Aziz Nazha ◽

Mikkael A. Sekeres ◽

Rafael Bejar ◽

Michael J. Rauh ◽

Megan Othus ◽

...

Keyword(s):

Myelodysplastic Syndromes ◽

Validation Cohort ◽

Median Number ◽

Learning Technologies ◽

Molecular Signatures ◽

Hypomethylating Agents ◽

Market Basket Analysis ◽

Accuracy Rate ◽

Genomic Biomarkers ◽

Clinical Tools

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.

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How we treat higher-risk myelodysplastic syndromes

Blood ◽

10.1182/blood-2013-08-496935 ◽

2014 ◽

Vol 123 (6) ◽

pp. 829-836 ◽

Cited By ~ 68

Author(s):

Mikkael A. Sekeres ◽

Corey Cutler

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Myelodysplastic Syndromes ◽

Risk Group ◽

Treatment Options ◽

International Prognostic Scoring System ◽

Hypomethylating Agents ◽

Hematopoietic Stem ◽

Patient Goals ◽

Interim Period

Abstract Higher-risk myelodysplastic syndromes (MDS) are defined by patients who fall into higher-risk group categories in the original or revised International Prognostic Scoring System. Survival for these patients is dismal, and treatment should be initiated rapidly. Standard therapies include the hypomethylating agents azacitidine and decitabine, which should be administered for a minimum of 6 cycles, and continued for as long as a patient is responding. Once a drug fails in one of these patients, further treatment options are limited, median survival is <6 months, and consideration should be given to clinical trials. Higher-risk eligible patients should be offered consultation to discuss hematopoietic stem cell transplantation close to the time of diagnosis, depending on patient goals of therapy, with consideration given to proceeding to transplantation soon after an optimal donor is located. In the interim period before transplantation, hypomethylating agent therapy, induction chemotherapy, or enrollment in a clinical trial should be considered to prevent disease progression, although the optimal pretransplantation therapy is unknown.

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Should Patients with Myelodysplastic Syndromes Undergo Iron Chelation Therapy? New Data Answering the Question

Oncology & Hematology Review (US) ◽

10.17925/ohr.2009.02.0.60 ◽

2009 ◽

Vol 02 ◽

pp. 60

Author(s):

Stuart L Goldberg ◽

Keyword(s):

Iron Overload ◽

Myelodysplastic Syndromes ◽

Scoring System ◽

Chelation Therapy ◽

Iron Chelation ◽

World Health ◽

International Prognostic Scoring System ◽

Iron Chelation Therapy ◽

Older Individuals ◽

Prospective Trials

Although it is well established that transfusional iron overload leads to organ impairment and shortened survival among children with thalassemia and sickle cell anemia, the role of transfusional iron overload and its treatment among older individuals with the myelodysplastic syndromes (MDS) remains unclear. Recent reviews have noted that MDS patients requiring frequent red blood cell transfusions experience higher rates of cardiac, hepatic, endocrine, and other organ damage in patterns similar to pediatric transfusional hemochromatosis, with increased rates of transformation to leukemia and decreased survival. Through the use of prognostic scoring systems such as the International Prognostic Scoring System (IPSS) and the World Health Organization (WHO) classification-based prognostic scoring system (WPSS), MDS patients with projected survivals long enough to warrant concern about the toxicities of iron overload can be identified and iron chelation therapies can be considered. The results of two large prospective trials among transfusion-dependent MDS patients, US03 and EPIC, have demonstrated that the oral iron chelation agent deferasirox can successfully reduce iron content and has an acceptable safety profile in this elderly population. Furthermore, retrospective trials have suggested that iron chelation therapy may prolong survival in MDS, and prospective trials are being planned. This article will highlight some of these issues.

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Hypomethylating Agents and Other Novel Strategies in Myelodysplastic Syndromes

Journal of Clinical Oncology ◽

10.1200/jco.2010.31.0854 ◽

2011 ◽

Vol 29 (5) ◽

pp. 516-523 ◽

Cited By ~ 95

Author(s):

Guillermo Garcia-Manero ◽

Pierre Fenaux

Keyword(s):

Myelodysplastic Syndromes ◽

Lower Risk ◽

Treatment Options ◽

Treatment Strategies ◽

Short Review ◽

Natural Course ◽

Hypomethylating Agents ◽

Older Individuals ◽

Survival Prognosis ◽

Treatment Approaches

Over the last decade, treatment approaches for patients with myelodysplastic syndromes (MDS) have improved significantly. Treatment of MDS is tailored to the specific risk characteristics of the patient. In general, patients are divided into lower- and higher-risk categories. Without therapy, prognosis of patients with higher-risk MDS is poor, and treatments should be directed to improve survival. Prognosis of patients with lower-risk MDS is more heterogeneous, and therapies are usually directed to minimize transfusion needs and potentially to alter the natural course of the disease. Treatment options for patients with higher-risk MDS include hypomethylating agents (azacitidine and decitabine), intensive chemotherapy (ICT), and allogeneic stem-cell transplantation (alloSCT). The use of the hypomethylating agents has transformed the approach to this patient population, in particular older individuals, for whom ICT and alloSCT are not an option. In lower-risk MDS, treatment strategies are used sequentially and usually include observation in patients with low risk and no transfusion dependency, growth factors, and lenalidomide for patients with alteration of chromosome 5 and anemia. The use of hypomethylating agents is less understood in this group of patients. AlloSCT is usually reserved for patients with lower-risk MDS closer to the time of transformation. In this short review, we discuss treatment alternatives for patients with MDS and delineate some of the ongoing challenges, including the development of better front-line strategies for patients with higher-risk disease, the concept of altering the natural course of the disease in lower-risk MDS, and the development of new treatment approaches for patients who do not benefit from hypomethylating agents.

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How we treat lower-risk myelodysplastic syndromes

Blood ◽

10.1182/blood-2013-02-453068 ◽

2013 ◽

Vol 121 (21) ◽

pp. 4280-4286 ◽

Cited By ~ 78

Author(s):

Pierre Fenaux ◽

Lionel Adès

Keyword(s):

Myelodysplastic Syndromes ◽

Lower Risk ◽

Iron Chelation ◽

International Prognostic Scoring System ◽

Hypomethylating Agents ◽

First Line ◽

Thrombopoietin Receptor ◽

Red Blood Cell Transfusions

AbstractLower-risk myelodysplastic syndromes (MDSs) are defined as having low or intermediate 1 risk by the International Prognostic Scoring System and are characterized mainly by anemia in most cases. Supportive care—primarily red blood cell transfusions—remains an important component of their treatment, but exposes patients to insufficient correction of anemia, alloimmunization, and organ iron overload (for which the role of iron chelation remains debated). Treatment aimed at preventing anemia recurrence should therefore be used whenever possible. Erythropoiesis stimulating agents remain the first-line treatment of anemia in most lower-risk MDS without del(5q), whereas anemia of low-risk MDS with del 5q responds to lenalidomide in two-thirds of the cases, but this drug should be used cautiously because profound cytopenias may occur initially. Treatment after failure of those first-line therapies are disappointing overall, with many patients eventually requiring long-term transfusions, but encouraging results have been reported with hypomethylating agents and lenalidomide. Selected patients respond to antithymocyte globulins, and thrombopoietin receptor agonists are under investigation in lower-risk MDS with thrombocytopenia. Some patients, while remaining at a “lower risk” MDS level, have severe cytopenias and/or poor prognostic factors, found using newer prognostic parameters, or resistance to treatment, making them urgent candidates for more intensive approaches, including allogeneic stem cell transplantation.

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Prognostic models in myelodysplastic syndromes

Hematology ◽

10.1182/asheducation-2013.1.504 ◽

2013 ◽

Vol 2013 (1) ◽

pp. 504-510 ◽

Cited By ~ 18

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.

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Mutation Status and Burden Can Improve Prognostic Prediction of Patients with Lower-Risk Myelodysplastic Syndromes

Blood ◽

10.1182/blood-2019-125660 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3008-3008

Author(s):

Lingxu Jiang ◽

Yingwan Luo ◽

Jie Jin ◽

Hongyan Tong

Keyword(s):

Myelodysplastic Syndromes ◽

Scoring System ◽

Lower Risk ◽

Cox Regression ◽

Conflicts Of Interest ◽

Prognostic Models ◽

Molecular Profile ◽

International Prognostic Scoring System ◽

Mutation Status ◽

Prognostic Prediction

Patients with lower-risk myelodysplastic syndromes (LR-MDS) as defined by the International Prognostic Scoring System (IPSS) have more favorable prognosis in general, but significant inter-individual heterogeneity exists. In this study, we examined the molecular profile of 15 MDS-relevant genes in 159 patients with LR-MDS using next-generation sequencing. In univariate COX regression, shorter overall survival (OS) was associated with mutation status of ASXL1 (P=0.001), RUNX1 (P=0.031), EZH2 (P=0.049), TP53 (P=0.016), SRSF2 (P=0.046), JAK2 (P=0.040), and IDH2 (P=0.035). We also found significantly shorter OS in patients with a TET2 variant allele frequency (VAF) ≥18% versus those with either a TET2 VAF <18% or without TET2 mutations (median: 20.4 vs. 47.8 months; P=0.020; HR=2.183, 95%CI: 1.129-4.224). After adjustment for the IPSS, shorter OS was associated with mutation status of ASXL1 (P<0.001; HR=4.306, 95%CI: 2.144-8.650), TP53 (P=0.004; HR=4.863, 95%CI: 1.662-14.230) and JAK2 (P=0.002; HR=5.466, 95%CI: 1.848-16.169), as well as a TET2 VAF ≥18% (P=0.008; HR=2.492, 95%CI: 1.273-4.876). Also, OS was increasingly shorter as the number of mutational factors increased (P<0.001). A novel prognostic scoring system based on the IPSS and the presence/absence of the 4 independent mutational factors further stratified LR-MDS patients into three prognostically different groups (P<0.001).The newly developed scoring system re-defined 10.1% (16/159) of patients as higher-risk group, who could not be predicted by the currently prognostic models. In conclusion, integration of IPSS with mutation status/burden of certain MDS-relevant genes may improve the prognostication of patients with LR-MDSand could help identify those with worse-than-expected prognosis for more aggressive treatment. Figure Disclosures No relevant conflicts of interest to declare.

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The path to approval for oral hypomethylating agents in acute myeloid leukemia and myelodysplastic syndromes

Future Oncology ◽

10.2217/fon-2020-1318 ◽

2021 ◽

Author(s):

David Kipp ◽

Andrew H Wei

Keyword(s):

Acute Myeloid Leukemia ◽

Myelodysplastic Syndromes ◽

Myeloid Leukemia ◽

Cytidine Deaminase ◽

Clinical Development ◽

International Prognostic Scoring System ◽

Hypomethylating Agents ◽

System Risk ◽

Myelomonocytic Leukemia ◽

Acute Myeloid

Two oral hypomethylating agents, oral azacitidine (CC-486) and decitabine/cedazuridine (ASTX727), have recently entered the clinical domain. CC-486 has been shown to improve overall survival as maintenance therapy for older patients with acute myeloid leukemia in complete remission, whereas the combination of decitabine with cedazuridine, a cytidine deaminase inhibitor, is indicated for the treatment of adult patients with myelodysplastic syndromes and chronic myelomonocytic leukemia with intermediate-1, or higher, International Prognostic Scoring System risk. This article briefly summarizes the clinical development of both drugs, the pivotal studies that led to their approval and some of the issues faced in extending the use of these drugs to other indications.

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Integrating Frailty, Comorbidity, and Quality of Life in the Management of Myelodysplastic Syndromes

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_158639 ◽

2016 ◽

pp. e337-e344 ◽

Cited By ~ 1

Author(s):

Gregory A. Abel ◽

Rena Buckstein

Keyword(s):

Quality Of Life ◽

Myelodysplastic Syndromes ◽

Hematopoietic Cell Transplantation ◽

Bone Marrow Failure ◽

International Prognostic Scoring System ◽

Hypomethylating Agents ◽

Hematopoietic Growth Factors ◽

Related Factors ◽

Hematopoietic Stem

Myelodysplastic syndromes (MDS) are a group of acquired hematopoietic stem cell disorders that manifest with progressive bone marrow failure and have a propensity to transform into leukemia. Although an increase in biologic understanding of MDS has led to improved patient risk stratification and prognostication, advances in treatment have lagged behind. While hematopoietic cell transplantation (HCT) is a potentially curative option for some, most affected patients continue to be treated with supportive care or with drugs that offer temporary palliation such as hematopoietic growth factors, DNA hypomethylating agents, or immunomodulatory therapy. For several groups, such as those with intermediate-risk disease as classified by the Revised International Prognostic Scoring System (IPSS-R) or those with higher-risk disease for whom hypomethylating agents have failed, optimal treatment remains uncertain. Inclusion of patient-related factors such as frailty and comorbid conditions into risk assessment can improve prognostication beyond the disease-associated variables included in systems such as the IPSS-R. This article focuses on approaches to assessing and integrating frailty, comorbidities, and quality of life into the treatment of patients with MDS.

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