Aplastic anaemia or bone marrow failure
Description
- Pancytopenia + hypocellular marrow, no infiltrate, no dysplasia, no fibrosis
- A hypocellular marrow in a pancytopenic patient = aplastic anaemia (acquired or inherited) OR hypoplastic MDS. Separating these is the whole diagnostic task
Categories
- Acquired AA - ~80% idiopathic, immune-mediated
- Inherited bone marrow failure - Fanconi, dyskeratosis congenita, Shwachman-Diamond, Diamond-Blackfan
- Single-lineage failure - pure red cell aplasia, congenital amegakaryocytic thrombocytopenia
- Congenital dyserythropoietic anaemias - anaemia + ineffective erythropoiesis + secondary iron overload from inc gut absorption
Severity - Camitta criteria
- Severe: marrow cellularity <25%, PLUS 2 of 3:
- Neutrophils <0.5
- Platelets <20
- Reticulocytes <20 x10^9/L
- Very severe: as above with neutrophils <0.2
- Non-severe: everything else
- Severity drives urgency and eligibility for definitive therapy, nothing else
Epidemiology
- 2-3 per million/yr in the West; 2-3x higher in East and South Asia
- Bimodal: 15-25 y and >60 y
- M = F
- Commonest non-malignant indication for allogeneic HSCT
- Immune-mediated mechanism is the commonest attributable cause of sporadic disease
Aetiopathogenesis
Mechanism (acquired)
- Oligoclonal cytotoxic T-cell attack on HSC (autoantigen usually unidentified)
- inc IFN-gamma, TNF-alpha -> HSC apoptosis + dec CD34+ pool
- Telomere attrition even in acquired disease -> clonal escape
- Immune escape clones survive selectively
- PNH clone (GPI-anchor loss) and HLA class I loss clones - benign, evidence of immune pressure
- Contrast maladaptive escape: PIGA-independent clones with BCOR/BCORL1 (good prognosis) vs del(7)/ASXL1/RUNX1 (drives MDS/AML)
Acquired causes
- Idiopathic ~80%
- Drugs - chloramphenicol, carbamazepine, phenytoin, gold, penicillamine, sulfonamides, NSAIDs, thionamides, linezolid
- Chemicals/radiation - benzene, glue/solvent vapour, insecticides, irradiation
- Viral - seronegative hepatitis (classically 2-3 mo after a hepatitis illness, young male, severe), EBV, HIV, parvovirus B19
- Immune - SLE, eosinophilic fasciitis, GVHD, thymoma/thymic carcinoma
- PNH - ~1/3 of PNH patients develop AA (and vice versa - the same immune process)
- Pregnancy - usually resolves after delivery
Inherited
| Inheritance | Extra-haematological | |
|---|---|---|
| Fanconi | AR (rare X-linked, FANCB) | Thumb/radial anomaly, short stature, microcephaly, cafe-au-lait + hyperpigmentation, renal + cardiac defects |
| Dyskeratosis congenita | X-linked (DKC1), AD, AR - telomere genes | Nail dystrophy + oral leukoplakia + reticulate pigmentation; pulmonary fibrosis, cirrhosis |
| Shwachman-Diamond | AR (SBDS) | Exocrine pancreatic insufficiency, metaphyseal dysostosis, short stature, neutropenia-dominant |
| Diamond-Blackfan | AD (ribosomal protein genes) | Craniofacial ~50%, upper limb/thumb ~30%, urogenital, cardiac |
| Down syndrome | - | Transient abnormal myelopoiesis, later leukaemia |
Diagnosis
Bloods
- Pancytopenia with low/absent reticulocytes (the key - this is failure, not destruction)
- No blasts, no dysplasia, no leucoerythroblastic film
- Macrocytosis common; inc HbF in inherited disease
Bone marrow - aspirate AND trephine (essential)
- Fatty replacement, cellularity <25%, near-absent CD34+ cells
- Loss of all three precursor lines; residual lymphocytes and plasma cells
| Aplastic anaemia | Hypoplastic MDS | |
|---|---|---|
| CD34+ cells | Near absent | Normal or increased |
| Megakaryocytes | Absent | Dysplastic (present but abnormal) |
| Cytogenetics | Usually normal | Clonal abnormality (esp. -7) |
Mandatory workup
- Flow cytometry for PNH clone (CD55/CD59 loss; FLAER) - present in ~50%
- Chromosome breakage / clastogen challenge (DEB, mitomycin C) - Fanconi. Do this in every young patient before conditioning
- Telomere length (lymphocyte flow-FISH) + germline BMF panel
- Viral: hepatitis serology, EBV, CMV, HIV, parvovirus B19
- B12/folate, ANA, CT chest for thymoma
- HLA typing of patient and siblings at diagnosis
Pure red cell aplasia
- Anaemia alone, reticulocytopenia, absent erythroid precursors in an otherwise normal cellular marrow
- Causes: parvovirus B19, thymoma, CLL / large granular lymphocytic leukaemia, SLE, EPO antibodies, pregnancy, drugs
Diamond-Blackfan
- Profound macrocytic anaemia at 2-6 months, low reticulocytes, isolated erythroid failure
- inc erythrocyte adenosine deaminase
- vs transient erythroblastopenia of childhood: DBA has macrocytosis, congenital anomalies, inc eADA
- Exclude parvovirus B19 - commonest cause of transient red cell aplasia and mimics DBA
Management
All patients
- Withdraw the candidate drug/toxin - and never rechallenge
- Transfusion support: irradiated, leucodepleted; avoid family donors if transplant candidate
- Minimise transfusions - alloimmunisation worsens graft outcome
- Antibacterial + antifungal prophylaxis while severely neutropenic
- Neutropenic fever = medical emergency; G-CSF not routine
Definitive therapy - severe or very severe (ASH 2026)
Axis is donor availability and age
| Situation | First-line |
|---|---|
| Matched sibling donor, any age (fit) | Allogeneic HSCT |
| Matched unrelated donor, age <=40 | HSCT or IST - either acceptable |
| Age >40 | IST preferred over MUD HSCT |
| No donor | IST |
- IST = horse ATG + ciclosporin + eltrombopag
- **Horse ATG, not rabbit** - rabbit ATG inferior response and survival in front-line SAA
- Prednisolone ~2 weeks for serum sickness only (not for the response)
- Eltrombopag added upfront (RACE 2022) - CR at 3 mo 22% vs 10%, faster and deeper response
- Superseded the old practice of reserving eltrombopag for refractory disease
- Ciclosporin continued and tapered slowly - abrupt withdrawal precipitates relapse
- Response slow: 70% over 2-4 months; do not declare failure before 3-6 months
- Non-responder at 6 months -> HSCT (unrelated or haploidentical), or second IST course
Non-severe disease
- Observe if transfusion-independent and not neutropenic
- Treat (IST) if transfusion-dependent or neutrophils <0.5
- Androgens (oxymetholone, danazol) - option in mild/moderate disease or the elderly; also lengthen telomeres in telomere-biology disorders
Inherited
- Fanconi - allo-HSCT with reduced-intensity, fludarabine-based, low/no irradiation conditioning
- Standard conditioning is lethal - the DNA repair defect. Screen family donors for the same mutation
- Androgens if no donor - response ~50%, best in the erythroid line
- Lifelong solid tumour surveillance (head and neck, gynaecological SCC)
- Diamond-Blackfan - corticosteroids, often deferred past 1 year of age (growth and neurocognitive harm), chronic transfusion in the interim; HSCT if steroid-refractory
- Dyskeratosis congenita - HSCT for cytopenias; reduced-intensity conditioning - lung and liver are the limiting organs
Pure red cell aplasia
- Treat the cause: IVIG for parvovirus B19, thymectomy for thymoma, ciclosporin/steroid for idiopathic or LGL-associated
Associations
- PNH - bidirectional; clone in ~50% at diagnosis
- Hypoplastic MDS - overlapping, and a late clonal outcome
- Thymoma - PRCA more often than full aplasia
- Seronegative hepatitis
- SLE, eosinophilic fasciitis, GVHD
- LGL leukaemia and CLL - PRCA, neutropenia
- Down syndrome, Fanconi, Shwachman-Diamond - inherited pancytopenia
- Pregnancy - AA and PRCA, both usually remitting post-partum
Natural history & complications
- Untreated very severe AA: death within months from infection or haemorrhage
- Treated: 5-year survival now >75-80%
After IST
- Response ~70% at 2-4 months
- Relapse ~35% (often ciclosporin-dependent - responds to reintroduction)
- Clonal evolution to MDS/AML ~15% at 10 years
- Monitor with annual marrow + cytogenetics
- Monosomy 7 is the ominous one
- Clinical PNH ~10%
After HSCT
- Matched sibling in the young: >90% long-term survival
- Graft failure/rejection higher than in malignancy (immune disease, prior transfusion)
- Chronic GVHD is the main determinant of late quality of life
Inherited
- Fanconi: median survival ~30 y; MDS/AML and head-and-neck SCC risk persists after transplant (higher after conditioning)
- Dyskeratosis congenita: pulmonary fibrosis, cirrhosis, malignancy - marrow failure is only one organ
- Congenital dyserythropoietic anaemia: iron overload even without transfusion -> chelate
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