Myelodysplastic Syndrome

Definition, Epidemiology and Pathophysiology

Diagnostic Criteria

Category Defining criteria Key exam point

A. MDS WITH DEFINING GENETIC ABNORMALITIES

MDS with low blasts and Blood blasts <2%, marrow blasts <5%; isolated The "5q− syndrome" — elderly woman, isolated del(5q) — MDS-5q del(5q), or with one other abnormality except macrocytic anaemia, normal or high platelets, −7/del(7q) hypolobated micromegakaryocytes. Best prognosis; responds to lenalidomide MDS with low blasts and SF3B1 Blood blasts <2%, marrow blasts <5%; SF3B1 Replaces the old "MDS with ring mutation — MDS-SF3B1 mutation. ≥15% ring sideroblasts may sideroblasts". Favourable prognosis. Practically substitute where mutation testing is unavailable important in India, where the morphological surrogate is still permitted MDS with biallelic TP53 Marrow blasts <20%; two or more TP53 New category and the worst prognosis of all inactivation — MDS-biTP53 mutations, or one mutation with loss of the — median survival about 10 months, usually other allele (17p deletion or copy-neutral LOH) with complex karyotype. Overrides every other subtype B. MDS DEFINED MORPHOLOGICALLY MDS with low blasts — MDS-LB Blood blasts <2%, marrow blasts <5% Replaces the old single- and multi-lineage dysplasia categories MDS, hypoplastic — MDS-h Marrow cellularity ≤25% (age-adjusted) New entity. Must be separated from aplastic anaemia; often responds to immunosuppressive therapy MDS with increased blasts 1 — Blood blasts 2–4% or marrow blasts 5–9% Higher-risk disease; consider hypomethylating MDS-IB1 agents MDS with increased blasts 2 — Blood blasts 5–19% or marrow blasts 10–19% or Auer rods alone make it IB2 regardless of MDS-IB2 Auer rods present blast count MDS with fibrosis — MDS-f Blood blasts 2–19% or marrow blasts 5–19% with New entity. Poor prognosis — median survival grade 2–3 reticulin fibrosis about 15 months. Aspirate is often a "dry tap", so trephine is essential The parallel ICC 2022 classification — know the three differences The International Consensus Classification was published in the same year and is used alongside WHO. It requires SF3B1 with a variant allele frequency ≥10%, and excludes del(5q), monosomy 7, complex karyotype and RUNX1 mutation, whereas WHO permits ring sideroblasts as a surrogate.

ICC created a new transitional category, "MDS/AML" for 10–19% marrow blasts, replacing "excess blasts-2" and signalling proximity to acute leukaemia. WHO keeps these cases as MDS-IB2.

ICC groups TP53 cases as "myeloid neoplasms with mutated TP53" spanning MDS and MDS/AML, while WHO confines MDS-biTP53 to under 20% blasts.

Prognostic Assessment

Group Conditions How to distinguish

Nutritional deficiency Vitamin B12 deficiency, folate deficiency, Megaloblastic change with hypersegmented copper deficiency (including after zinc excess or neutrophils; low B12/folate/copper; corrects fully bariatric surgery) with replacement. Copper deficiency is the classic mimic — it produces ring sideroblasts and vacuolated precursors Toxins and drugs Alcohol, isoniazid, chloramphenicol, linezolid, Careful drug and alcohol history; changes reverse on methotrexate, azathioprine, mycophenolate, withdrawal. Alcohol and lead both cause ring valproate, lead, arsenic sideroblasts Infection HIV, hepatitis B and C, parvovirus B19, Serology and marrow examination. In India, kala-tuberculosis, visceral leishmaniasis (kala-azar) azar and disseminated tuberculosis are important causes of pancytopenia with marrow dysplasia Other marrow failure Aplastic anaemia, paroxysmal nocturnal Hypoplastic MDS versus aplastic anaemia is the haemoglobinuria, pure red cell aplasia hardest distinction — look for dysplasia, blasts and a clonal cytogenetic lesion. Send flow cytometry for PNH clone in every case Other clonal myeloid disease Acute myeloid leukaemia (≥20% blasts), chronic CMML requires persistent monocytosis >1,000/ myelomonocytic leukaemia, MDS/MPN overlap, µL and ≥10% monocytes. Myelofibrosis shows primary myelofibrosis, atypical CML leucoerythroblastic blood with teardrop cells and marked splenomegaly Pre-clonal states ICUS (idiopathic cytopenia of undetermined CHIP = mutation without cytopenia; ICUS = significance), CHIP (clonal haematopoiesis of cytopenia without mutation or dysplasia; CCUS indeterminate potential), CCUS (clonal cytopenia of = both mutation and cytopenia, but no undetermined significance) diagnostic dysplasia. These require surveillance, not treatment Systemic and autoimmune Chronic kidney disease, hypothyroidism, chronic Renal and thyroid profile, autoantibodies, T-cell disease liver disease, SLE, rheumatoid arthritis, Felty clonality studies syndrome, large granular lymphocytic leukaemia Marrow infiltration Metastatic carcinoma, lymphoma, multiple Trephine biopsy is far more sensitive than myeloma aspirate. Send serum protein electrophoresis and free light chains in every older patient Outline of Management

Latest Updates (2023–present)

Classification has shifted from morphology to genetics The WHO 5th edition (2022) and the ICC (2022) both now place genetically defined categories first. Validation in the Düsseldorf MDS Registry (5,010 patients, median age 71) confirmed that TP53 mutational status and multilineage dysplasia are independently associated with poor outcome, and that MDS-biTP53 and MDS-f carry the highest risk of leukaemic transformation and the poorest survival. Reclassification studies show the 2022 WHO criteria stratify patients more effectively than the 2017 criteria (C-index 0.705 versus 0.681). Median survival for MDS-biTP53 was 10 months and for MDS-f 15 months, against 45 months for MDS overall.

A practical caveat now recognised: TP53 mutational burden matters. Cases with a variant allele frequency below 10% behave better — lower IPSS-R scores, more favourable cytogenetics, more SF3B1 mutations and longer survival — supporting the ICC's 10% cut-off.

IPSS-M has become the reference prognostic tool

Comparative work confirms that IPSS-M risk is highest in biallelic/multi-hit TP53 disease and lowest in MDS-SF3B1, with median leukaemia-free survival of only 0.7 years in multi-hit TP53 and not reached in MDS with low blasts. Roughly 70% of patients are still classified morphologically and 30% genetically under both systems.

Importantly for practice, response to hypomethylating agents was not associated with IPSS-M risk category — so a high IPSS-M score predicts poor survival but does not predict failure of azacitidine.

Two new drugs for anaemia in lower-risk disease

COMMANDS established luspatercept as superior to epoetin alfa in ESA-naïve, transfusion-dependent lower-risk MDS, moving it into the first line rather than after ESA failure.

IMerge, the first phase 3 trial of a telomerase inhibitor, tested imetelstat 7.5 mg/kg intravenously every 4 weeks in transfusion-dependent non-del(5q) lower-risk MDS relapsed after or refractory to ESAs (median age 72–73 years). 40% achieved 8-week red cell transfusion independence, with longer duration of independence and a greater rise in haemoglobin than luspatercept achieved in MEDALIST — and notably this included ring-sideroblast-negative patients. FDA approval followed in June 2024.

NCCN now recommends imetelstat as category 1 second-line therapy after ESAs or luspatercept where serum erythropoietin is ≤500 mU/mL, and as category 2A first-line therapy where erythropoietin exceeds 500 mU/mL. Sequencing after front-line luspatercept remains poorly defined — in IMerge, of the few patients previously given luspatercept, 86% had a reduction in transfusion burden but none achieved transfusion independence.

Transplantation has extended into the eighth decade Reduced-intensity conditioning with modern graft-versus-host disease prophylaxis has made allogeneic transplantation feasible for fit patients with higher-risk MDS into their early seventies — see Topic 2.

Current Practice Update

Area Textbook position Current practice (2023–2026)

Nomenclature Myelodysplastic syndromes Myelodysplastic neoplasms (WHO 2022), abbreviation MDS retained Classification basis Morphology — lineage dysplasia, ring sideroblasts, Genetics first — del(5q), SF3B1, biallelic TP53; then blast count morphology Ring sideroblasts "MDS with ring sideroblasts" is a defined entity Replaced by MDS-SF3B1; ≥15% ring sideroblasts is now only a surrogate for the mutation New entities Not described MDS-biTP53, MDS-h (hypoplastic), MDS-f (with fibrosis)

Blasts 10–19% MDS with excess blasts-2 WHO: MDS-IB2. ICC: a new "MDS/AML" category Prognostic score IPSS-R IPSS-M — adds 31 mutations, six strata, restratifies about 46% of patients Lower-risk anaemia ESAs; lenalidomide for del(5q); transfusion Add luspatercept first-line (COMMANDS) and imetelstat (IMerge, approved 2024)

Transplantation Allogeneic transplant mentioned for higher-risk Reduced-intensity transplant now offered to fit disease patients into their early seventies Pre-clonal states CHIP and CCUS noted Formally defined and separated from MDS; surveillance, not treatment Exam one-liners MDS = hypercellular marrow with peripheral cytopenia — ineffective haematopoiesis, not underproduction. Three things must be present: persistent cytopenia + dysplasia (or excess blasts, or a defining mutation) + exclusion of everything else.

Blast thresholds: <5% low, 5–19% increased, ≥20% acute myeloid leukaemia. Auer rods = IB2 regardless of count. Three genetic categories: del(5q) — best; SF3B1 — favourable; biallelic TP53 — worst (about 10 months). Three new morphological entities: hypoplastic (MDS-h), with fibrosis (MDS-f), and the renamed low-blast group. Before diagnosing MDS, always exclude B12, folate, copper, alcohol, drugs, HIV, kala-azar and PNH. Copper deficiency is the great mimic — it reproduces ring sideroblasts and vacuolated precursors, and it is completely reversible.

IPSS-R for counts and karyotype; IPSS-M when a mutation panel is available.

Lower-risk = treat the anaemia. Higher-risk = treat the disease.

Azacitidine needs 4–6 cycles before response — never stop early.