HaematologyTier 1Disease (DEADMAN)

Haematological malignancies - myelodysplasia

Description

Clonal haematopoietic stem cell neoplasm: dysplasia + ineffective haematopoiesis + peripheral cytopenias
- The paradox: hypercellular marrow, empty blood - cells are made and then die in the marrow
~1/3 progress to AML; the rest die of the cytopenias

WHO 5th edition - two arms

MDS with defining genetic abnormality (morphology does not decide these)

MDS with low blasts and isolated del(5q)
MDS with low blasts and SF3B1 mutation (replaces "ring sideroblasts" as the defining lesion)
MDS with biallelic TP53 inactivation - very poor prognosis, behaves like AML

Morphologically defined

MDS with low blasts (<5%)
MDS, hypoplastic (overlaps aplastic anaemia)
MDS with increased blasts: IB1 (5-9%), IB2 (10-19%)
MDS with fibrosis

Related: CHIP (mutation, normal counts) -> CCUS (mutation + cytopenia, no dysplasia) -> MDS
MDS/MPN overlap - CMML, atypical CML, MDS/MPN-RS-T

Epidemiology

~4-5 per 100,000/yr overall, 30-50 per 100,000 over age 70
Median age at diagnosis 70-75; M>F
Commoner than AML and the commonest cause of acquired marrow failure in older adults
Therapy-related MDS: ~10-15% of cases, rising with cancer survivorship

Aetiopathogenesis

Mutational landscape

Splicing: SF3B1 (favourable, ring sideroblasts), SRSF2, U2AF1, ZRSR2
Epigenetic: TET2, DNMT3A, ASXL1, EZH2, IDH1/2
Transcription/other: RUNX1, TP53, STAG2, BCOR, NRAS
*Biallelic TP53 is the single worst molecular lesion* - complex karyotype, therapy-related, rapid AML

Cytogenetics

	Prognosis
Isolated del(5q), normal karyotype, del(20q), -Y	Good
+8, del(12p), single other	Intermediate
-7/del(7q), inv(3), double including -7	Poor
Complex (>=3 abnormalities)	Very poor

Causes

Primary/age-related - accumulated somatic mutation in the HSC pool
Therapy-related - alkylating agents and radiation (5-7 yr latency, complex karyotype, TP53); topoisomerase II inhibitors (shorter latency)
Benzene, smoking, prior aplastic anaemia or PNH
Germline predisposition - DDX41 (often presents in the 60s-70s and is easily missed), GATA2, RUNX1, CEBPA, telomere biology disorders, Fanconi
- *Screen before using a related stem cell donor*

Mechanism of the cytopenias

Excess intramedullary apoptosis + inflammasome activation (pyroptosis) and inc TGF-beta signalling
-> cells produced, destroyed before release, plus functional defects in those that escape
- Neutrophils are dysfunctional as well as few - infection risk exceeds the count

Diagnosis

Suspect it

Unexplained, persistent cytopenia in an older adult
Macrocytic anaemia is the commonest abnormality, more often than neutropenia or thrombocytopenia
Reticulocytes inappropriately low; monocytosis suggests CMML

Exclusions before calling it MDS

B12, folate, copper deficiency, alcohol, HIV, recent chemotherapy or G-CSF, lead, zinc excess
Autoimmune cytopenia, PNH clone, LGL leukaemia, hypothyroidism
Copper deficiency is the great mimic: cytopenias, ring sideroblasts and vacuolated precursors, and it is fully reversible

Blood film

Pseudo-Pelger-Huet neutrophils (bilobed), hypogranular neutrophils
Dimorphic red cells, macro-ovalocytes, basophilic stippling
Giant/hypogranular platelets, circulating blasts

Bone marrow - essential

Dysplasia >=10% of cells in a lineage in one to three lineages
Blast percentage - determines category and transformation risk
Perls stain: ring sideroblasts (>=5 iron granules encircling >=1/3 of the nucleus)
Cytogenetics + FISH + NGS myeloid panel - mandatory; ~50% have a clonal cytogenetic abnormality
Trephine for cellularity, fibrosis, abnormal localisation of immature precursors (ALIP)

Prognosis

IPSS-R: cytogenetics, marrow blast %, Hb, platelets, ANC -> very low to very high risk
*IPSS-M (2022) adds 31 gene mutations and is now the reference model*
- Reclassifies ~half of patients versus IPSS-R, mostly upstaging
- Changes transplant decisions - this is the practical consequence
The old IPSS (blasts, cytogenetics, number of cytopenias) is superseded

Management

*Split at lower vs higher risk. The goal in lower risk is the blood count and quality of life; in higher risk it is survival and transformation.*

A. Lower-risk MDS (IPSS-R <=3.5 / IPSS-M low)

Anaemia - the dominant problem

Serum EPO <=500 mU/L: luspatercept is now preferred first-line (COMMANDS - superior transfusion independence vs epoetin alfa), or an ESA (epoetin/darbepoetin) +/- G-CSF
- Luspatercept = TGF-beta superfamily ligand trap promoting late-stage erythroid maturation; greatest benefit with SF3B1/ring sideroblasts
Serum EPO >500 or ESA failure: imetelstat (telomerase inhibitor; transfusion independence in ESA-relapsed/refractory disease)
Isolated del(5q): lenalidomide - transfusion independence in ~two-thirds
Hypoplastic MDS, younger patient, HLA-DR15, PNH clone: immunosuppression (ATG + ciclosporin)
Transfusion + iron chelation after ~20-40 units or ferritin >1000 microg/L, if life expectancy or transplant plan justifies it
Thrombocytopenia: TPO receptor agonists (caution with excess blasts); tranexamic acid
Neutropenia: treat infection early and aggressively; G-CSF not routine

B. Higher-risk MDS (IPSS-R >3.5 / IPSS-M high)

Azacitidine is first-line
- Response 30-50%; prolongs survival and delays AML transformation vs conventional care
- *Response takes 2-3 months - give at least 6 cycles before declaring failure*
- Continue until progression or unacceptable toxicity; stopping in a responder loses the response
- Oral decitabine/cedazuridine is an alternative where available
Allogeneic HSCT is the only curative treatment
- Refer early - assess fitness and donor at diagnosis in anyone potentially eligible
- Reduced-intensity conditioning extends eligibility into the 70s
AML-type intensive chemotherapy (anthracycline + cytarabine): CR 40-60% but usually short-lived; largely used as a bridge to transplant
Low-dose cytarabine: response 15-20%, no survival benefit

C. All patients

Vaccination, prompt treatment of infection, transfusion support with irradiated products if transplant candidate
Discuss trajectory and advance care planning early - many patients are older with limited reserve

Associations

Autoimmune and inflammatory disease in ~10-20% - relapsing polychondritis, vasculitis, neutrophilic dermatoses (Sweet syndrome), inflammatory arthritis
VEXAS syndrome (somatic UBA1 mutation in older men): fever, chondritis, cutaneous vasculitis, macrocytic anaemia, vacuoles in myeloid and erythroid precursors - often labelled MDS
PNH clone, aplastic anaemia overlap
CMML and other MDS/MPN overlap syndromes
Prior chemotherapy/radiotherapy; germline predisposition syndromes
Iron overload from chronic transfusion

Natural history & complications

Median survival by IPSS-R: very low risk ~9 years -> very high risk <1 year
~1/3 transform to AML - risk tracks blast percentage, cytogenetics and mutation profile
Secondary AML is chemoresistant - outcomes far worse than de novo AML

Favourable

Isolated del(5q) syndrome - older women, macrocytic anaemia, normal or raised platelets, hypolobated megakaryocytes; lenalidomide-responsive, low transformation risk
SF3B1-mutated with ring sideroblasts - indolent

Adverse

Biallelic TP53, complex karyotype, -7
Excess blasts, multilineage dysplasia, marrow fibrosis
Transfusion dependence (independently predicts survival, beyond the anaemia itself)
Therapy-related disease

Causes of death

Infection and bleeding from the cytopenias more often than AML transformation
Iron overload-related cardiac and hepatic disease in long-term transfused patients
Comorbidity - most patients are elderly

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