Myelodysplastic Syndrome (MDS)

IPSS-M molecular risk scoring, classification, luspatercept and lenalidomide for lower-risk MDS, hypomethylating agents and imetelstat for higher-risk disease, and allogeneic SCT

Key Points

• MDS is a clonal disorder of hematopoietic stem cells characterized by ineffective hematopoiesis (cytopenias despite a cellular marrow), dysplasia in ≥1 lineage, and risk of transformation to acute myeloid leukemia — it is the most common myeloid malignancy in adults over 65.
• The 2022 WHO/ICC classification reorganizes MDS by genetic driver (TP53-biallelic, SF3B1-mutated, del(5q)) and morphologic features — MDS with SF3B1 mutation (MDS-SF3B1) defines a distinct entity with ringed sideroblasts and favorable prognosis.
• IPSS-M (Molecular International Prognostic Scoring System), incorporating genomic mutations alongside clinical variables, is now the preferred prognostic tool — it reclassifies ~30% of patients compared to IPSS-R and more accurately predicts AML transformation risk.
• Lower-risk MDS (IPSS-R very low/low/intermediate, transfusion-dependent): luspatercept for MDS-SF3B1, lenalidomide for del(5q) MDS, ESAs for EPO <500 mU/mL, and red cell transfusions with iron chelation.
• Higher-risk MDS (IPSS-R intermediate-high/very high): azacitidine or decitabine (hypomethylating agents, HMAs) are the standard backbone — imetelstat (Rytelo) received FDA approval in June 2024 for HMA-refractory lower-risk MDS with transfusion dependence.
• Allogeneic HSCT is the only curative therapy and should be offered to eligible patients with higher-risk MDS — reduced-intensity conditioning has expanded eligibility to older adults (aged 65–75) with adequate organ function.

Classification, Genetics, and Pathogenesis

**The clonal landscape of MDS:** MDS arises from somatic mutations in hematopoietic stem cells that confer a proliferative advantage, leading to clonal expansion of morphologically abnormal progenitors that fail to differentiate normally. Unlike AML (where proliferation of arrested blasts dominates), MDS is defined by dysplasia and ineffective differentiation — the marrow is often hypercellular, yet blood counts are low because abnormal cells undergo accelerated apoptosis before reaching the periphery. **Most commonly mutated genes (detected in ≥5% of MDS):** - *Splicing factors:* SF3B1…

Lower-Risk MDS — Treatment Strategies

Lower-risk MDS (IPSS-R very low, low, and intermediate ≤3.5; or IPSS-M low/moderate-low) is managed primarily to control cytopenias and improve quality of life, with the goal of avoiding or reducing transfusion dependence. Allogeneic SCT is generally deferred unless molecular features suggest higher risk. **Erythropoiesis-stimulating agents (ESAs):** First-line for anemia in lower-risk MDS without del(5q). Recommended when serum EPO 500. Reassess response at 8–12 weeks — if Hgb does not rise ≥1.5 g/dL, discontinue. Adding G-CSF to ESA improves response in SRSF2-mutated disease.…

Higher-Risk MDS — HMAs, Imetelstat, and Transplant

Higher-risk MDS (IPSS-R intermediate ≥3.5, high, very high; or IPSS-M moderate-high/high/very high) carries a median survival of 1–2 years and a high risk of AML transformation. Treatment goals shift toward disease modification and, when possible, cure with allogeneic SCT. **Hypomethylating agents (HMAs) — first-line:** Azacitidine and decitabine are the standard of care for higher-risk MDS patients ineligible for or awaiting SCT. *Azacitidine (Vidaza):* 75 mg/m² SC or IV × 7 days every 28 days. AZA-001 trial (Lancet Oncol 2009): azacitidine prolonged median OS vs. conventional care (24.5…

Monitoring and AML Transformation

**Routine monitoring:** - CBC with differential: every 4–6 weeks for lower-risk stable patients; every 2–4 weeks during HMA therapy - Bone marrow biopsy: at diagnosis; at 3–6 month intervals if blasts are elevated or response assessment needed (especially during HMA therapy); at suspected transformation - Peripheral blood NGS: repeat at 12-month intervals or at progression — new mutations (FLT3, NRAS/KRAS, IDH2) emerging in serial samples are a harbinger of transformation - LFTs: during HMA therapy (azacitidine hepatotoxicity) - Ferritin, LIC MRI: for transfusion-dependent patients **AML…