In this episode of Hospital Medicine Unplugged, we break down myelodysplastic syndromes—recognize the unexplained cytopenias, understand the modern molecular classification, and risk-stratify patients before progression to AML.

The WHO 2022 classification shifted MDS from a purely morphologic disease to a genetically informed diagnosis. New entities include MDS with SF3B1 mutation, isolated del(5q), and biallelic TP53-mutated MDS, one of the highest-risk subtypes. Blast categories are now simplified into low blasts, increased blasts-1 (5–9%), and increased blasts-2 (10–19%).

Diagnosis requires: • Persistent cytopenias • Dysplasia in >10% of a marrow lineage or defining cytogenetic abnormalities • Exclusion of alternative causes

Bone marrow biopsy remains essential, and unexplained cytopenias with clonal mutations that don’t meet MDS criteria are now classified as CCUS.

Risk stratification centers on the IPSS-R, incorporating: • Cytogenetics • Blast percentage • Hemoglobin • Platelets • Neutrophil count

Lower-risk disease focuses on symptom control and transfusion reduction. Higher-risk disease focuses on delaying AML transformation and improving survival.

For anemia in lower-risk MDS: • ESAs remain common first-line therapy • Luspatercept is especially effective in SF3B1-mutated or ring sideroblast disease and outperformed epoetin alfa in recent trials.

For higher-risk disease: • Azacitidine is standard frontline therapy and improves overall survival • Decitabine is an alternative • Oral decitabine-cedazuridine allows outpatient treatment

Key pearl: responses to hypomethylating agents are delayed—patients often need at least 4–6 cycles before declaring failure.

The only curative therapy is allogeneic stem cell transplantation: • Consider for higher-risk disease and select lower-risk patients with severe cytopenias or poor-risk mutations • Reduced-intensity conditioning expanded transplant eligibility into older adults • TP53-mutated disease remains particularly challenging, even after transplant

We close with the system moves: investigate unexplained macrocytic anemia and cytopenias early, integrate molecular testing into diagnosis and prognosis, avoid prematurely stopping hypomethylating therapy, and refer transplant-eligible patients before progression to AML.

Not every pancytopenia is “just aging marrow”—sometimes it’s a clonal stem-cell disorder announcing itself before leukemia arrives.