Myelodysplastic Syndromes in the Postgenomic Era and Future Perspectives for Precision Medicine

Abstract

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal disorders caused by sequential accumulation of somatic driver mutations in hematopoietic stem and progenitor cells (HSPCs). MDS is characterized by ineffective hematopoiesis with cytopenia, dysplasia, inflammation, and a variable risk of transformation into secondary acute myeloid leukemia. The advent of next-generation sequencing has revolutionized our understanding of the genetic basis of the disease. Nevertheless, the biology of clonal evolution remains poorly understood, and the stochastic genetic drift with sequential accumulation of genetic hits in HSPCs is individual, highly dynamic and hardly predictable. These continuously moving genetic targets pose substantial challenges for the implementation of precision medicine, which aims to maximize efficacy with minimal toxicity of treatments. In the current postgenomic era, allogeneic hematopoietic stem cell transplantation remains the only curative option for younger and fit MDS patients. For all unfit patients, regeneration of HSPCs stays out of reach and all available therapies remain palliative, which will eventually lead to refractoriness and progression. In this review, we summarize the recent advances in our understanding of MDS pathophysiology and its impact on diagnosis, risk-assessment and disease monitoring. Moreover, we present ongoing clinical trials with targeting compounds and highlight future perspectives for precision medicine.

Bone Marrow Changes in Septic Shock: A Comprehensive Review

“…Monitoring these indicators can aid in risk stratification and help predict patient outcomes. Patients with more severe bone marrow dysfunction may require more intensive interventions and closer monitoring [ 43 ].…”

Management of patients with lower-risk myelodysplastic syndromes

“…Following an appropriate MDS diagnosis and risk stratification, treatment is tailored toward the individual patient [ 10 ]. Most patients with LR-MDS will live with malignant hematopoiesis for many years, therefore, treatment goals focus on the improvement of disease-related symptoms and QoL.…”

“…a ESMO 2014 [ 45 ]: RBC < 2 per month or sEPO <500 U/L. b ESMO 2014 [ 45 ]: if age <60–65 years and favorable features (including hypoplastic bone marrow, blasts <5%, normal karyotype, HLA-DR15-positivity, younger age [<60 years], lower risk according to IPSS [ 10 , 95 ]) for response to ATG; ESMO 2021 [ 16 ]: if age <65–70 years and favorable features for response to ATG. Abbreviations: ATG anti-thymocyte globulin, BM bone marrow, EPO erythropoietin, ESMO European Society for Medical Oncology, G-CSF granulocyte colony-stimulating factor, IPSS International Prognostic Scoring System, MDS myelodysplastic syndromes, MDS-RS myelodysplastic syndrome with ring sideroblasts, sEPO serum erythropoietin, TPO-RA thrombopoietin-receptor agonist.…”

“…However, the presence of anemia and complications related to cytopenias, transfusions, and inflammation can negatively affect comorbid conditions, potentially reducing the quality of life (QoL) and increasing the mortality of these patients relative to the general population [ 7 , 8 ]. Molecular sub-characterization of MDS has emerged following the discovery of recurrent somatic driver mutations [ 9 ], though understanding of the mechanisms involved in clonal evolution and its impact on disease phenotype remains incomplete [ 10 ]. Together with the emergence of effective therapies for LR-MDS targeting disease-associated pathways and processes, e.g., involving transforming growth factor beta (TGF-β) signaling, DNA methylation, and other epigenetic targets, our understanding of the LR-MDS pathogenesis also advances [ 11 ].…”

CPX-351 Pharmacokinetics and Safety in Adults with Hematologic Malignancies and Renal Function Impairment: Phase 1 Trial

“…Many patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and high-risk myelodysplastic syndrome (MDS) have a poor long-term prognosis [ 1 , 2 , 3 , 4 ] and require therapies that maximize anti-tumor efficacy [ 3 , 5 ]. While conventional cytotoxic chemotherapeutics are generally thought to have maximal efficacy at the highest tolerable doses [ 3 , 6 ], many patients present with significant comorbidities, including renal impairment, which may require administering therapies at attenuated doses or even a transition to palliation-oriented therapy [ 7 , 8 , 9 , 10 , 11 ].…”