The 2023 Symposium will focus on recent advances in the diagnosis, classification and management of patients with myelodysplastic syndromes (MDS). The program combines recent data, application of new tools and evidence on current practice with information that might be applied in the future.
RBC transfusions and erythropoietin (EPO) remain the 1st line treatment for anemia. EPO is safe and might delay the need for RBC transfusions. A recent EUMDS study suggests a prolonged survival with EPO. Lenalidomide remains effective for MDS with del(5q) (50% response), but also somewhat effective (27%) in non-del(5q) patients. Luspatercept appears as an effective second-line (maybe 1st ?) agent. We will discuss it here. Several experimental agents are investigated, including oral azacytidine, imetelstat, a pyruvate-kinase activator and roxadustat. For thrombocytopenia two agents, romiplostim and eltrombopag, were shown to be effective. However, due to safety concerns their development has been stopped.
Patients with HR-MDS are offered HMA as the standard 1st line treatment. Younger patients may respond to antileukemic treatment with or without transplant. Ways to improve the HMA effect include treating the HMA-related complications; modified HMA formulation; combinations of HMA with other agents (venetoclax appears to be the frontrunner), novel agents and targeted molecules.
Mario Cazzola, MD Fondazione IRCCS Policlinico San Matteo and University of Pavia, 27100 Pavia, Italy
Myelodysplastic syndromes (MDS) are myeloid neoplasms characterized by ineffective erythropoiesis, peripheral cytopenia, and a variable risk of progression to acute myeloid leukemia (AML). In the last 15 years, our understanding of these disorders has advanced substantially with the use of massively parallel DNA sequencing methods in translational studies. This has enabled the development of novel diagnostic and prognostic approaches and has also promoted innovative clinical trials aimed at defining precision treatments. An abundance of clinical and biological data is currently being collected on individual patients. Interpreting these data and navigating the genomic complexity of MDS represents an increasing challenge for clinicians. Current classifications of MDS and related disorders account for only a minor portion of genomic data. Exploiting artificial intelligence and machine learning to take advantage of genomic characterization becomes mandatory: the final objective of a mechanistic classification is to best inform clinical decision-making. This requires international collaboration, the creation of knowledge banks, the preparation of web portal tools, and the conduction of clinician-driven clinical trials.
Michael R. Savona, MD
Clonal hematopoiesis (CH) is an over-representation of mature blood cells derived from a single, genetically identical clone.1 CH is genetically heterogeneous, with most cases resulting from somatically-derived mutations in leukemogenic driver genes within hematopoietic stem cells.2 Variants have been reported from >70 CH driver genes, though more than two-thirds of CH mutations are found in one of three genes: DNMT3A, TET2, and ASXL1 (‘DTA’ mutations).1-5 While CH-associated genes span a diverse set of cellular functions and processes, including epigenetic regulation, transcription, and RNA splicing,6 the resulting effect of a CH driver mutation is enhanced cellular fitness leading to a selective advantage for the clone and subsequent clonal expansion.6
Most commonly, CH presents as clonal hematopoiesis of indeterminate potential (CHIP), an asymptomatic state with normal blood counts. CHIP is highly correlated with increasing age, with 15% of patients over the age of 65 estimated to have CH with a variant allele fraction (VAF) of at least 2%.1-3 Clonal cytopenia of uncertain significance (CCUS) occurs in the presence of a clone and one or more associated cytopenias without a clear identifiable cause and a bone marrow biopsy without myelodysplasia, and clonal monocytosis of undetermined significance (CMUS) represents a phenotype of monocytosis without marrow changes classifiable as CMML.7 Numerous studies have demonstrated that CH increases potential to progress to hematologic malignancy, thus, CH is considered a premalignant state, and it is estimated that 0.5-1% of CHIP cases transform into an overt hematologic malignancy per year after acquiring additional somatic mutations. By definition, CCUS and CMUS are accompanied with hematologic phenotypes and thus can be more pervasive, particularly in patients with multiple mutations, high VAFs, and/or those with non-DTA, myeloid-neoplasm type clones.8 A more recent analysis of over 400,000 UK biobank participants added red blood cell indices to these features to yield a CH risk score (CHRS) now available online: www.CHRSapp.com.9
Existing research points toward aberrant inflammatory signaling as a putative mechanism for CH pathology.10-13 Given the diversity of genes involved in CH, it is unlikely that a single mechanism exists for all downstream pathologies. As such, the prevailing immune dysregulation hypothesis as it currently exists does not completely reflect the complexity of CH across disease manifestations, and future work should focus on articulating mutation-specific effects on inflammation and secondary inflammatory consequences. In addition to malignancy risk, CH is associated with a high burden of organ dysfunction, and confers a 40% increase in all-cause mortality.1-2 Recent reports of CH-associated organ dysfunction include increased risk of stroke and atherosclerotic vascular disease (ASCVD),11-14 inflammation and autoimmune disease,15-17 chronic obstructive pulmonary disease,18 and chronic kidney disease,19-20 among others.21
The CHIVE (Clonal Hematopoiesis and Inflammation in the VasculaturE) Registry and Repository was established with the goal of relating genotype-phenotype relations and understanding the natural history of CH. Patients who are at risk for CH, or with known CH, provide serial access to blood and tissue collected at normally scheduled visits. CHIVE aims to maximize vascular risk reduction, and understanding the genotype-phenotype relationships of CH to develop new clinical trials in CH. Using guidance from the patterns established from retrospective data, CHIVE investigators monitor patients as ‘low risk’ or ‘high risk’ every 6, or 12 months, respectively. CHIP clinics managing these patients will use the CHRS, and validation and refinement of this tool will enhance risk stratification for myeloid neoplasia; but should not miss the opportunity for patient education around vascular risk reduction. Serial sampling in the CHIVE repository, aggressive attempts to modify vascular disease, and iterative application of lessons learned for new guidance will shape care for higher risk patients with CH, and ultimately lead to guidance for clinical trials in this arena.References
Matteo G Della Porta Center for Accelerating Leukemia/Lymphoma Research (CALR) Cancer Center & AI Center Humanitas Research Hospital – Humanitas University, Milan, Italy
Fatigue due to anaemia is one of the most common symptoms that brings patients diagnosed with lower-risk myelodysplastic syndromes (MDS) to medical attention. As a result, the goals in treating patients with lower-risk myelodysplastic syndromes are often focused on improving cytopenias and quality of life. Erythropoiesis-stimulating agents (ESAs), such as recombinant erythropoietin, are used for transfusion-dependent anaemia, particularly in patients with low serum erythropoietin (<500 U/L) and a red blood cell transfusion requirement of less than 2 red blood cell units per month. Response to ESA-based therapy can be as high as 70%,1 but if serum erythropoietin is higher than 500 U/L, the expected response rate is lower than 10%. In April, 2020, luspatercept—an erythroid maturation agent with a mechanism of action distinct from ESA therapy—was approved by the US Food and Drug Administration for patients with lower-risk myelodysplastic syndromes (with the presence of ring sideroblasts and or SF3B1 mutation) who were transfusion dependent with disease refractory to or unlikely to respond to ESA-based therapy. Luspatercept binds to select transforming growth factor-β superfamily ligands and decreases Smad-2/3 signalling. It is this inhibitory effect on Smad-2/3 signalling that enables late stage erythroblast differentiation.
Due to the favourable responses seen with luspatercept, a possible role for its use as initial therapy for transfusion-dependent patients with lower-risk MDS has emerged. The COMMANDS study is an open-label investigation of luspatercept versus epoetin alfa in ESA-naive patients with lower-risk MDS. The trial enrolled 356 patients and is ongoing for follow-up. In the interim analysis 301 patients were randomly assigned to receive either luspatercept (n=147) or epoetin alfa (n=154). 73% of the study population had MDS that was positive for ring sideroblasts. The primary endpoint was defined as red blood cell transfusion independence for at least 12 weeks with a concurrent increase in mean haemoglobin of at least 1·5 g/dL (weeks 1–24) and was reached in 86 (59%) of 147 patients assigned to luspatercept versus 48 (31%) of 154 patients assigned to erythropoietin alfa therapy (p<0·0001). Furthermore, the median duration of red blood cell transfusion independence lasting at least 12 weeks was longer with luspatercept than with epoetin alfa (127 vs 77 weeks). Overall, luspatercept showed an acceptable safety profile consistent with previous observations. A better response rate with luspatercept was observed in all patient’s subgroups stratified according endogenous EPO levels, and the severity of transfusion dependency. In patients without ring sideroblasts the response rate of the two treatment arms was comparable, the exposure to luspatercept being associated with longer response duration.
These findings show that ESA-naive patients with lower-risk myelodysplastic syndromes benefit from upfront luspatercept-based therapy, particularly those with ring sideroblast-positive status or SF3B1 mutated profiles.
Myelodysplastic syndromes (MDS) encompass a heterogeneous group of clonal hematopoietic disorders, characterized by ineffective hematopoiesis, peripheral blood cytopenias, and a substantial risk of progression to acute myeloid leukemia (AML). Timely diagnosis, accurate prognosis, and optimized treatment are crucial for the management of patients with MDS. With the rapid advancements in technology, Artificial Intelligence (AI) offers a transformative approach in reshaping our understanding and management of MDS.
In this presentation, Dr. Nazha will delve into the transformative role of AI in the management of MDS. He’ll explore how AI-powered models enhance the diagnostic precision by analyzing intricate genetic and clinical data and advanced imaging, refine prognostic capabilities by predicting disease progression and transformation to AML, and optimize treatment selection, pinpointing specific therapies tailored to individual patient needs. Moreover, He will venture into the promising frontier of generative AI, which opens an opportunity to use multimodel approach to improve MDS diagnosis and treatment, heralding a new era in MDS and cancer research.
1Medical Clinic and Policlinic 1, Hematology and Cellular Therapy, Leipzig University Hospital, Leipzig, Germany, 2German MDS Study Group (G-MDS) and 3European Myelodysplastic Syndromes Cooperative Group (EMSCO group, www.emsco.eu)
The heterogeneous nature of myelodysplastic neoplasms (MDS) implies a complex and personalized variety of therapeutic approaches. Among them, the only potentially curative option, still, remains an allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is anyway accessible to only a small number of fit patients. Considering the potential treatment-related complications associated with allo-HSCT in MDS patients, a serious selection process of patients is inevitable. Therefore, identification of patient and disease-related factors, predicting outcome after allo-HSCT, is mandatory. While the IPSS/R/M have been developed mainly to determine the prognostic risk in newly diagnosed MDS patients, their predictive value concerning the post transplantation outcome was confirmed in several studies. Should patients be treated with an HMA or chemotherapy before allo-HSCT? Retrospective analyses have demonstrated that i.e. with HMA the outcome was improved for patients in complete remission compared to those with active disease at the time of allo-HSCT. Importantly, these studies underlie a certain selection bias for patients with chemo-sensitive disease and excluded patients who did not undergo allo-HSCT because of therapy-related toxicity. Therefore, the value of prior therapy is still not clear because of the absence of randomized trials. This is also because HMA and induction chemotherapy can be associated with a considerably short-term toxicity and many patients with MDS tend to have a delayed recovery of their counts. This leaves the question of when and how to “bridge” to transplant often an individual decision e.g. based on the time of identification of a compatible donor. Novel combination therapies may however pave the way for novel, effective and safe approaches prior to allo-HSCT.
Christopher J. Gibson, MD Dana-Farber Cancer Institute/Harvard Medical School
MDS patients who are candidates for allogeneic transplantation are frequently offered cytoreductive therapies prior to transplant. In this talk, I will argue that routine cytoreduction prior to transplant is not supported by available evidence and can in some cases be counterproductive.
Definitions: “Cytoreduction” in the context of MDS can either refer to the administration of a hypomethylating agent, with or without venetoclax, or to conventional induction chemotherapy. The term is most commonly used to refer to patients with excess blasts, in whom the goal of cytoreduction is to reduce the blast count to less than 5% of bone marrow cellularity. In some cases, however, the term is used less precisely to refer to any administration of cytotoxic drugs, irrespective of blast count.
The use of pre-transplant cytoreduction can be considered in two distinct scenarios:
1. Cytoreduction should not generally be employed in MDS patients without excess blasts. The primary benefit of cytoreduction in MDS is the prevention of progression to acute myeloid leukemia.
2. In patients with excess blasts, the use of cytoreduction depends on the trajectory of disease
This activity is designed for an audience of pharmacists, physicians, physician assistants and nurses.
Upon completion of the educational activity, participants should be able to:
Professor of Medicine
Department of Medicine
Tel-Aviv Sourasky Medical Center
Tel-Aviv University Medical School
Associate Professor, Department of Medicine
Odette Cancer Center
Toronto, Ontario, Canada
Director, Sylvester Comprehensive Cancer Center
Professor of Medicine, Biochemistry & Molecular Biology
University of Miami Miller School of Medicine
Miami, Florida, USA
Professor of Hematology
Fondazione IRCCS Policlinico San Matteo
University of Pavia
University of Wisconsin School of Medicine and Public Health
Carbone Cancer Center
Madison, Wisconsin, USA
Humanitas Research Hospital, & Humanitas University
Rozzano Milan, Italy
McCredie Professor of Medicine
Vice Chair, Department of Leukemia
Chief, Section of MDS
The University of Texas MD Anderson Cancer Center
Houston, TX, USA
The University of Texas MD Anderson Cancer Center
Houston, TX, USA
Dana Farber Cancer Institute
Boston, MA, USA
Thomas Jefferson University
Philadelphia, PA, USA
Medical Clinic and Policlinic 1
Hematology and Cellular Therapy
University Hospital Leipzig
Professor of Medicine and Cancer Biology
Vanderbilt University School of Medicine
Nashville, Tennessee, USA
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) & Rena Buckstein, MD (Toronto, Canada)
|07.00 – 07.05 am||Welcome
|07.05 – 07.10 am||MDS challenges in 2023
|07.10 – 07.15 am||Program overview
|07.15 – 07.30 am||Lecture: A classification of myelodysplastic syndromes that aids clinical
|07.30 – 07.35 am||Q & A|
|07.35 – 07.50 am||Lecture: Pre-MDS states: CH, CCUS, ICUS – How to manage in the clinic?
|07.50 – 07.55 am||Q & A|
|07.55 – 08.20 am||Debate I: ESA- Still the 1st line for LR-MDS?
M. Della Porta & A. Giagounidis
|08.20 – 08.35 am||Lecture: Artificial intelligence in MDS practice
|08.35 – 08.40 am||Q & A|
|08.40 – 09.00 am||Patient discussion I
Expert panel: J. Churpek, A. Giagounidis, L. Silverman
|09.00 – 09.15 am||Patient discussion II
Expert panel: J. Churpek, A. Giagounidis, L. Silverman
|09.15 – 09.30 am||Lecture: Can we do better than HMA in HR-MDS?
|09.30 – 09.35 am||Q & A|
|09.35 – 09.55 am||Debate II: Should cytoreduction precede transplant?
U. Platzbecker & C. Gibson
|09.55 – 10.00 am||Closing Remarks
M. Mittelman or R. Buckstein
CE 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.
Credit being awarded: 3.00 ANCC contact hours
AKH Inc., Advancing Knowledge in Healthcare designates this continuing education activity for 3.00 contact hours.
|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|
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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.
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