The 2022 Symposium will focus on recent advances in the diagnosis, classification and management of patients with myelodysplastic syndromes (MDS). The program combines evidence on current practice with information that might be applied in the future.
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Moshe Mittelman, MD The myelodysplastic syndromes (MDS) are clonal bone marrow (BM), stem cell disease(s), characterized by abnormal hematopoiesis, genetic and immune basis. The clinical manifestations are anemia and BM failure. The media age is 74yr, and the leukemic transformation rate is 20%-60%. This a relatively new disorder, and the first report goes back to 1938, a report on refractory anemia. During the next 5 decades several terms were proposed, till the FAB group (Bennett J et al. BJH 1982), characterized this hematological entity and proposed the currently used term, MDS. In the following 2-3 decades, the attention of the clinical and research community increased, and in addition to morphology, methods such as cytogenetics, flowcytometry, and genetics were introduced. This allowed better characterization, recognition of subtypes, prognostic stratification and more effective as well as supportive treatment. In the 21st century new methods such as modern genetics and digital (artificial intelligence) tools are applied, further advancing the field.
In my personal view the next decades will be characterized by further application of these two powerful tools, the genetic and digital, into practice. This will lead to better understanding of the disease biology, and the use of more objective and less invasive techniques. We will see more collaborative investigational projects both in basic research and clinical trials. The tools will allow better data collections with a more useful analysis and conclusions. We will have to deal with the financial toxicity. Patients will benefit from a more personal approach, with more accurate treatment, and patients’ needs will be better addressed. We will hopefully be able to better identify pre-MDS states, to diagnose MDS early and perhaps to prevent or delay disease progression.
On a more specific level, we will hopefully introduce novel anti-anemic agents, and likely to use effective combinations. We need and hopefully will develop solution to the low platelet count, including lifting the embargo on the current agents and introducing new products. The patients with higher-risk disease should be offered better management than hypomethylating monotherapy. Some of the currently evaluated combinations will become the standard, with possible novel approaches like treatments targeting specific mutations and/or immunotherapy. (references available on the MDSF website)
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Sophie Park, MD, PhD Erythropoiesis stimulating agents (ESAs) play an important role in treating anemia. The vast majority of responses to ESAs are observed within the first 12 weeks, although some responses are observed later. A variable proportion of patients treated with ESAs are resistant to ESAs from the outset (primary refractory patients), while others will eventually become resistant secondarily (relapsed patients) after an initial response time close to the median response time of 2 years.
It is important to determine the predictors of response and duration of response to ESA as in an international series involving 1700 patients, the incidence of AML was 16% versus 8% at 5 years in ESA-refractory patients versus persistent responders > 6months.
Therefore, the main predictive factors of response are the extent of transfusion requirements (greater or less than 2 units of packed RBCs/month) and the level of endogenous EPO (greater or less than 200 IU/L). Other favorable prognostic factors for response are an R-IPSS score very low or low, and ferritin level less than 350ng/ml. Molecular biology studies have revealed that only the cumulative number of mutated genes has an unfavorable effect on erythroid response. More recently, the contributions of flow cytometry and an improved understanding of iron metabolism have highlighted two factors that can predict erythroid response and duration of response: the RED Score and the hepcidin:ferritin ratio. After ESA failure, lenalidomide, luspatercept, HMA, iron metabolism modulation, imetelstat, roxadustat and allogeneic transplantation will be discussed. We will see in detail which patients could benefit from these alternative treatments.
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Theo de Witte, MD, PhD Myelodysplastic Syndromes (MDS), and especially lower-risk MDS (LR-MDS), lack prospective randomized interventional data obtained in clinical trials, mainly because of the advanced age and the frequent co-morbidities leading to a poor physical and restricted health-relate quality of (HR-QoL). Prospective collection of longitudinal observational data linked with translational studies in non-selected real-world populations may be the solution to the lack of prospective randomized clinical trials. For this reason the MDS working research group within the European LeukemiaNet started in April 2008 a prospective observational study in patients with recently diagnosed LR-MDS (< 100 days) from 11 European countries. The EUMDS Registry extended gradually to 19 European countries and to all subtypes of MDS, including higher-risk MDS and chronic myelomonocytic leukemia (CMML). Currently, >3100 patients from >400 sites have been registered and >40 studies, including studies on patient-reported outcomes, time-dependent variables, including red blood cell transfusion (RBCT) dependency and iron toxicity parameters, such as hepcidin levels and labile plasma variables. Most studies have been restricted to patients with LR-MDS (87%), because data on the other groups are heterogeneous and more recently obtained. We showed in a large study (1276 patients) that a very low RBCT density, defined as 0.1 to < 0.5units/M was associated with a significantly inferior progression-free survival (PFS), especially after adjustment for interventions with lenalidomide, ESA or iron chelation therapy. In addition, we showed in a recent study on almost 2,400 patients with LR-MDS, that elderly patients older 80 years and very low risk patients die more frequently from competing causes indicated by a 20% higher relative survival in these 2 risk groups. Very low risk and/or elderly patients are usually excluded from regular randomized interventional studies.
We also studied in time-dependent interactive, observational studies the impact of RBCT dependency on the outcome of ESA treatment. We clearly showed that the impact of ESA treatment on RBCT dependency, HRQoL and PFS was more pronounced when ESA treatment was initiated before introduction of regular RBCT. The regular prospective interventional ESA studies define RBCT dependency at much higher levels as defined in the EUMDS studies which will result in an underestimated prognostic outcome in the control groups and an overestimated impact in the interventional control arm. This data show that the classical interventional clinical trials should be confirmed by observational studies in less selected, real-world populations. Unfortunately, funding of the observational studies, is less incorporated in the research programs of pharmaceutical companies.
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Peter C. Grayson, MD The discovery of the VEXAS syndrome in 2020 forms a mechanistic bridge between myelodysplastic syndromes and systemic inflammatory diseases, thereby connecting hematologists and rheumatologists. This talk will focus upon the genotype-first approach employed to identify somatic mutations in UBA1, the master enzyme of cellular ubiquitylation, in association with a novel disease defined by treatment-refractory inflammation and progressive bone marrow failure. The clinical and mechanistic features of VEXAS syndrome will be detailed with focus on whether or not UBA1 mutations should be considered MDS-defining. Prognostic factors and treatment approaches for VEXAS syndrome will be reviewed. Somatic mutations in blood as a causal mechanism of rheumatologic diseases will be discussed. VEXAS syndrome represents a prototype for a new class illnesses termed hematoinflammatory diseases.
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Elizabeth Griffiths, MD The myelodysplastic syndromes (MDS) are bone marrow failure disorders associated with aged hematopoiesis. Patient with MDS can have widely variant prognosis, some progressing rapidly with disease biology that more closely mirrors acute myeloid leukemia (AML) while others have relatively indolent course and can be followed without progression for years. Accurate and reliable prognostication forms the bedrock for clinicians to recommend initial and subsequent treatment allocation. For many years, molecular testing has been recommended for our patients, but until recently incorporation of these data into clinical practice was non-standard. Last year, Dr. Bernard and colleagues presented the long awaited IPSS-molecular scoring system and shortly thereafter the online web-calculator was made available (https://www.mds-risk-model.com/) via the MDS Foundation website (Bernard E. et al. NEJM Evidence 2022). Over the last year the utility of this this novel scoring system has become apparent. IPSS-M risk stratification can afford the opportunity for early intensification of therapy and referral for allogeneic transplantation in select younger patients with intermediate risk disease, before overt clinical disease progression. It can also provide equipoise in delaying therapy for those with intermediate features who do not have biologically high-risk driver mutations. For elderly patients with transfusion independent “poor risk” disease (in whom blast percentage might have upstaged prognosis) a more indolent mutational profile might also afford solace in delaying aggressive initiation of therapy. With more widespread adoption of molecular testing, it is incumbent upon us to understand the results we obtain and to effectively distinguish the difference between pathogenic mutational events expected to drive poor prognosis and variants of unknown significance which may not be clinically meaningful. Finally, despite the increasing value of molecular information for therapeutic decision making, the importance of clinical judgement cannot be forgotten.
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Rafael Bejar, MD, PhD The genetic landscape driving the development and progression of MDS is increasingly well characterized today. As massively parallel next-generation sequencing technologies have become more clinically accessible and less costly, it invites the question, “Are we ready to perform NGS in all MDS patients?” Recent updates to the classification of MDS and AML as well as recognition of related entities like clonal cytopenias (CCUS) and clonal hematopoiesis (CHIP) require DNA analysis up front to establish an accurate diagnosis. For MDS, this includes detection of mutations in SF3B1 and TP53 to classify patients appropriately, as well as several other genes that might exclude patients from being assigned a particular MDS subtype. Then, the newly released IPSS-M formally considers mutation in over 30 genes to predict the prognosis of MDS patients more accurately and aid in treatment decisions. Importantly, the NCCN guidelines for MDS recommend broad DNA sequencing at first presentation to aid with diagnosis, classification, and risk stratification. Finally, certain somatic mutations can identify patients who might benefit from targeted agents approved in AML and under study in MDS. Despite these benefits, questions remain about whether all MDS patients truly require NGS and how much it adds clinically to most cases. Nor is it clear if testing after diagnosis is worthwhile. Cost and insurance coverage remain concerns as does NGS availability outside of referral centers and internationally. This talk will explore if we are ready to employ NGS in all MDS patients.
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Valeria Santini, MD Somatic mutations are present in around 90% of cases of MDS and it has been largely demonstrated that their prognostic significance is stronger than that due to cytogenetic and clinical features. Recently, the International prognostic system Molecular (IPSS-M) was produced with the implementation of NGS data of a predetermined set of genes frequently mutated in MDS in the prognostic scoring variables. The IPSS-M without any doubt allows an improved risk stratification of MDS patients. While IPSS-M definition of risk categories most certainly will drive the choice of therapy, are we ready at present to consider it feasible for all MDS cases? The access to NGS, national health system and health insurance reimbursement vary among Countries and at the same time the awareness of NGS importance for treatment decision is still not shared by all hematologists. Open issues derive from the sustainability of this diagnostic tool. Is there a possibility to define MDS cases for which NGS testing is not mandatory? Equity in the access to the best diagnostic and prognostic tools must be promoted. Preliminary data obtained from a survey investigating the actual number of cases with access to NGS evaluation in different Countries will be shown, and practical issues discussed.
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Rena Buckstein, MD Anemia is the most common cytopenia in MDS. At the time of diagnosis, 80 % are anemic, 22-30% of patients are transfusion-dependent and 52-74% ultimately become dependent on red blood cell (RBC) transfusions. While increasing in number, there remain a paucity of durably effective therapeutic agents that ameliorate anemia or reverse transfusion dependence. Anemia and transfusion dependence (TD) are independently associated with inferior overall and progression-free survival (OS, PFS) and quality of life (QOL) in large prospective registries. Anemia and transfusion dependence have been associated with inferior cardiac disease-free survival likely due to multifactorial reasons. The mitigation of anemia has been associated with improved global QOL, symptom and function scores in many but not all interventional studies, suggesting that there may be a complex interplay of factors contributing to impairments in quality of life. This lecture will review the epidemiology of anemia and transfusion dependence, the impact of these factors on clinically important endpoints, and the prospective randomized studies evaluating higher hemoglobin thresholds for transfusion.
This activity is designed for an audience of pharmacists, physicians, and nurses.
Participants will learn about novel information obtained over the last decade and will hear about potential applications in the field of MDS.
Professor of Medicine
Department of Medicine
Tel-Aviv Sourasky Medical Center
Tel-Aviv University Medical School
AOU Careggi-University of Florence
Director, Sylvester Comprehensive Cancer Center
Professor of Medicine, Biochemistry & Molecular Biology
University of Miami Miller School of Medicine
Miami, Florida, USA
University of California San Diego
La Jolla, California, USA
Associate Professor, Department of Medicine
Odette Cancer Center
Toronto, Ontario, Canada
University of Wisconsin School of Medicine and Public Health
Carbone Cancer Center
Madison, Wisconsin, USA
Professor of Hematology
Radboud University Medical Center
Nijmegen, The Netherlands
Tenure Track Investigator
National Institutes of Health
Bethesda, MD, USA
Roswell Park Comprehensive Cancer Center
State University of New York at Buffalo
Department of Medicine
Buffalo, NY USA
Chief, Department of Hematology
Nagasaki University Graduate School of Biomedical Sciences
Centre hospitalo-universitaire (CHU) Grenoble Alpes
Icahn School of Medicine at Mount Sinai
Director Translational Research Center for the Myelodysplastic Syndrome
Tisch Cancer Institute
New York City, New York, USA
Co-Chairs: Moshe Mittelman, MD (Tel-Aviv, Israel); Valeria Santini, MD (Florence, Italy)
|7:00 – 7:05 am||Welcome
Stephen Nimer, MD (MDSF Chairman)
|7:05 – 7:15 am||The History and Future of MDS
Moshe Mittelman, MD
Program Overview and Objectives
Valeria Santini, MD
|7:15 – 7:35 am||When are erythroid stimulating agents (ESA) effective and what can we offer after their failure?
Sophie Park, MD, PhD
|7:35– 7:55 am||Real-world data and clinical trials – does it matter?
Theo de Witte, MD, PhD
|7:55 – 8:15 am||Inflammaging, comorbidities and VEXAS syndrome in MDS pathogenesis
Peter C. Grayson, MD
|8:15 – 8:30 am||Molecular prognostic scoring (IPSS-M) – How does it improve patient management?
Elizabeth Griffiths, MD
|8:30 – 8:55 am||Debate: Should genetic analysis be standard in every patient evaluated for MDS?
Rafael Bejar, MD, PhD & Valeria Santini, MD
|8:55 – 9:15 am||Anemia: Effects on quality of life and organ function
Rena Buckstein, MD
|9:15 – 9:55 am||Patient Discussion Session – Including two MDS patient case studies
Expert Panel: Jane Churpek, MD, Yasushi Miyazaki, MD & Lewis Silverman, MD
|9:55 – 10:00 am||Closing Remarks
Moshe Mittelman, MD and Valeria Santini, MD
Credit provided by AKH Inc., Advancing Knowledge in Healthcare
In support of improving patient care, this activity has been planned and implemented by AKH Inc., Advancing Knowledge in Healthcare and MDS Foundation. AKH Inc., Advancing Knowledge in Healthcare is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
This activity was planned by and for the healthcare team, and learners will receive 3.00 Interprofessional Continuing Education (IPCE) credit for learning and change.
AKH Inc., Advancing Knowledge in Healthcare designates this live activity for a maximum of 3.00 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
AKH Inc., Advancing Knowledge in Healthcare designates this continuing education activity for 3.00 contact hours.
Credit being awarded: 3.00 ANCC contact hours
AAPA Credit Designation Statement
AKH Inc., Advancing Knowledge in Healthcare has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 3 AAPA Category 1 CME credits. PAs should only claim credit commensurate with the extent of their participation.
|Rena Buckstein, MD||Advisor, Consultant, Researcher||BMS/Celgene, TAIHO Canada
|Jane Churpek, MD||Honoraria||UpToDate, Inc|
|Peter Grayson, MD||N/A||Nothing to disclose|
|Elizabeth Griffiths, MD||Consultant||Picnic Health, Abbvie, CTI biopharma, Appelis, Novartis, BMS,/Celgene, Takeda, Talho, Alexion|
|Honoraria||Abbvie, Medicum Worldwide, Inc, CTI Biopharma, AAMDSIF, Genentech, Physician Educational Resource|
|Research support||Appelis, BMS/Celgene, Astex pharmaceuticals, Alexion, Blueprint Medicines
Abbvie, Medicum Worldwide, Inc, CTI Biopharma, AAMDSIF, Genentech, Physician Educational Resource
Genentech, Appelis, BMS/Celgene, Astex pharmaceuticals, Alexion, Blueprint Medicines
|Yasushi Miyazaki, MD||Honoraria||Nippon Shinyaku, Novartis, Abbvie, Astelias, Sumitomo pharma, SynBio, Chugai, Bristol-Myers|
|Moshe Mittelman, MD||Unrestricted research grant||Novartis, Takeda, Janssen, Roche, Celgene, Gilead|
|Sophie Park, MD||Consultant, Researcher||BMS Celgene, Takeda|
|Independent Contractor||BMS Celgene, Novartis, Takeda|
|Valeria Santini, MD||Advisory board||BMS, Geron, Gilead, Novartis, Takeda|
|Lewis Silverman, MD||Research funding||Gilead, Takeda, Celgene|
|Theo de Witte, MD, PhD||Consultant||Gilead, Novartis|
|Dorothy Caputo, MA, BSN, RN, Senior Director of Continuing Education & Compliance||N/A||Nothing to disclose|
|Michele Bielarski, RN (planner/reviewer)||N/A||Nothing to disclose|
|AKH Inc Staff and Planners||N/A||Nothing to disclose|
|MDS Staff and Planners||N/A||Nothing to disclose|
All of the relevant financial relationships listed for these individuals have been mitigated.
This activity is supported by an educational grant from AbbVie, Astex, Geron Corporation, Gilead Sciences, Inc., Karyopharm, and Taiho Oncology, Inc. Any additional support received will be disclosed prior to start of activity.
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This educational activity may include discussion of uses of agents that are investigational and/or unapproved by the FDA. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.
This course is designed solely to provide the healthcare professional with information to assist in his/her practice and professional development and is not to be considered a diagnostic tool to replace professional advice or treatment. The course serves as a general guide to the healthcare professional, and therefore, cannot be considered as giving legal, nursing, medical, or other professional advice in specific cases. AKH Inc. specifically disclaim responsibility for any adverse consequences resulting directly or indirectly from information in the course, for undetected error, or through participant’s misunderstanding of the content.
*Activity and faculty subject to change
**Please note that CME Credits will only be available to those who attend live to continuing education credits. CME is typically for physicians only; the event offers credit for pharmacy and nurses.