Highlights
- Advances in genetics and classification improve MDS diagnosis and treatment options significantly.
- Personalized medicine and emerging therapies promise enhanced survival and quality of life for patients.
Summary and Overview
Myelodysplastic syndromes (MDS) are diverse hematologic disorders marked by ineffective blood cell production, leading to cytopenias and risk of acute myeloid leukemia (AML). Advances in molecular genetics and next-generation sequencing have refined MDS classification and prognosis, exemplified by the 2022 WHO classification and the Molecular International Prognostic Scoring System (IPSS-M), which integrate genetic mutations for improved diagnosis and risk stratification. About 15% of cases involve germline mutations, highlighting the role of genetic testing, especially for allogeneic hematopoietic stem cell transplantation (HSCT).
MDS symptoms range from asymptomatic cytopenias to fatigue and systemic signs. Diagnosis combines bone marrow morphology and genetic profiling to identify subtypes like SF3B1- or TP53-mutant MDS. Treatments are risk-adapted, balancing disease severity, molecular profile, and patient factors. Hypomethylating agents (HMAs) remain foundational for higher-risk patients, while newer agents like luspatercept and venetoclax expand options. Allogeneic HSCT offers the only cure, with evolving strategies extending eligibility despite associated risks.
Clinical Presentation and Diagnosis
MDS often presents with fatigue, pallor, and nonspecific symptoms from blood cytopenias; about half of cases are incidentally diagnosed. Signs like fever and splenomegaly may indicate overlapping myelodysplastic/myeloproliferative neoplasms. Diagnosis relies on bone marrow biopsy, cytogenetics, and molecular profiling via next-generation sequencing, which identifies mutations critical for prognosis and informs treatment decisions using tools like IPSS-M.
Treatment Strategies
Treatment is guided by risk stratification, primarily using IPSS-M, which combines clinical and genetic data for precise prognosis. Lower-risk patients receive supportive care to improve quality of life and reduce transfusion needs, while higher-risk patients require aggressive therapy to prevent leukemic progression.
Hypomethylating agents such as azacitidine and decitabine are standard for higher-risk MDS. AML-like chemotherapy and CPX-351 are used in select cases, often as a bridge to HSCT. Immunotherapies like checkpoint inhibitors have shown limited success alone but remain under investigation, including combination regimens. Venetoclax combined with chemotherapy shows promise for higher-risk patients.
Supportive care addresses anemia, infections, and bleeding. Luspatercept is approved for anemia in certain MDS subtypes, reducing transfusion dependence. Allogeneic HSCT remains the only curative therapy, with donor selection and conditioning regimens tailored to patient fitness and disease characteristics. Multidisciplinary care is essential, particularly for older patients, to balance efficacy and toxicity.
Treatment Decision-Making
Decisions integrate disease risk, patient age, comorbidities, and preferences. Risk tools like IPSS-R and molecular profiling guide therapy intensity. HSCT is reserved for fit patients with higher-risk disease or refractory cases. Novel combinations such as azacitidine with venetoclax improve responses, while agents like luspatercept target specific MDS subtypes. Personalized treatment aims to maximize benefits and minimize side effects.
Side Effects and Quality of Life
Treatment side effects vary by therapy and patient factors. HMAs can cause early cytopenias but are generally better tolerated than intensive chemotherapy. New agents like imetelstat improve both hematologic outcomes and quality of life, particularly by reducing fatigue. Some drugs, such as ivosidenib, carry serious risks like differentiation syndrome requiring prompt management.
Patient Advocacy and Support
Patient advocacy provides critical resources, education, and emotional support throughout MDS care. Organizations offer 24/7 specialist access, promote community engagement, and facilitate patient feedback to improve care models. Educational programs enhance understanding of MDS and support informed decision-making, emphasizing comprehensive supportive care.
Emerging Research and Future Directions
Two main classification systems, WHO5 and ICC 2022, currently guide MDS diagnosis, with efforts to unify them underway. Immunotherapy trials have yielded mixed results, but ongoing studies aim to optimize checkpoint inhibitors and combinations with other agents. Functional biomarkers like BH3 profiling help predict response and resistance. Novel agents such as luspatercept and imetelstat show promise in modifying disease and improving transfusion independence. Additional clinical trials investigate combination therapies to improve outcomes in high-risk and refractory MDS.
Prognosis and Outcomes
MDS prognosis depends on blast percentage, cytogenetics, and molecular abnormalities, integrated into scores like IPSS-R and IPSS-M. Median survival is about 2.5 years but varies widely. Low-risk patients fare better, while high-risk cases have elevated AML progression risk. HMAs improve quality of life and survival in high-risk MDS. Allogeneic HSCT offers potential cure, with 30–70% long-term survival, though relapse and graft-versus-host disease remain challenges.
The content is provided by Sierra Knightley, Scopewires
