Aplastic Anaemia — Med2Date

📋 Key Information Summary

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Aplastic anaemia (AA) is a bone marrow failure syndrome characterised by pancytopenia and a hypocellular marrow, resulting from immune-mediated destruction of haematopoietic stem cells.
Approximately 65–75% of cases are idiopathic (immune-mediated); known causes include drugs (chloramphenicol, carbimazole, sulphonamides), viruses (hepatitis, parvovirus B19, EBV), and inherited bone marrow failure syndromes.
Severity classification (Camitta/modified Camitta criteria) guides treatment: non-severe AA, severe AA (SAA), and very severe AA (vSAA) based on reticulocyte count, neutrophil count, and platelet count.
Incidence in Australia is approximately 2–3 per million population per year; higher rates observed in Aboriginal and Torres Strait Islander populations in remote areas.
Urgent referral to a haematology centre is required for all patients with SAA or vSAA — do not delay while awaiting investigations.
Allogeneic haematopoietic stem cell transplantation (allo-HSCT) from an HLA-matched sibling donor is the treatment of choice for patients aged <40 years with SAA/vSAA.
Immunosuppressive therapy (IST) with horse anti-thymocyte globulin (hATG) plus ciclosporin is first-line for patients aged >40 years or without a matched sibling donor.
Eltrombopag (thrombopoietin receptor agonist) combined with IST significantly improves response rates and is now standard of care alongside hATG + ciclosporin.
Horse ATG (Atgam®) is preferred over rabbit ATG in Australia for first-line IST based on superior response and survival data.
Transfusion support with irradiated, CMV-safe blood products is essential during workup and treatment; iron chelation is needed if ferritin >1000 μg/L.
Bone marrow biopsy is mandatory to confirm diagnosis and exclude myelodysplastic syndrome (MDS), paroxysmal nocturnal haemoglobinuria (PNH), and inherited marrow failure syndromes.
HLA typing and donor search should be initiated at diagnosis for all patients aged <50 years.
G-CSF is not recommended as a bridging measure in SAA; it does not improve outcomes and may delay definitive therapy.
All patients require lifelong haematology follow-up; relapse after IST occurs in 15–25% of responders.
Aboriginal and Torres Strait Islander patients may have delayed presentation due to healthcare access barriers and require culturally safe care coordination with RFDS and regional haematology services.

Introduction & Australian Epidemiology

Aplastic anaemia is a rare, potentially life-threatening bone marrow failure syndrome characterised by peripheral blood pancytopenia and a hypocellular bone marrow. The underlying mechanism in the majority of acquired cases is immune-mediated destruction of pluripotent haematopoietic stem and progenitor cells by autoreactive cytotoxic T lymphocytes, leading to an empty or near-empty marrow.

In Australia, the age-standardised incidence is approximately 2–3 per million population per year, consistent with Western population data. The disease demonstrates a bimodal age distribution with peaks in young adults (15–25 years) and older adults (>60 years). There is no significant sex predilection in idiopathic cases, though drug- and toxin-associated aplasia may show occupational or exposure-related patterns.

The Australian health system context presents both advantages and challenges. Major haematology and transplant centres in Sydney, Melbourne, Brisbane, Perth, and Adelaide provide specialised care including allo-HSCT. However, patients in rural, remote, and very remote areas — including many Aboriginal and Torres Strait Islander communities — face significant delays in diagnosis and access to tertiary haematology services. The Royal Flying Doctor Service (RFDS) and telehealth haematology consultations play a critical role in bridging this gap.

Without treatment, severe aplastic anaemia carries a mortality rate exceeding 70% within 12 months due to infection or haemorrhage. With modern therapy — including matched sibling transplant and combined IST with eltrombopag — overall survival at 5 years is 75–90%. Early recognition, urgent referral, and appropriate treatment selection are therefore critical.

Aetiology

Aplastic anaemia may be inherited or acquired. The aetiology determines both the approach to investigation and, in some cases, the treatment strategy. In approximately 65–75% of cases, no identifiable cause is found and the condition is classified as idiopathic, though immune-mediated mechanisms are strongly implicated.

Idiopathic (Immune-Mediated)

The majority of acquired aplastic anaemia cases are idiopathic and considered immune-mediated. Autoreactive cytotoxic T lymphocytes (CD8+ T cells) targeting haematopoietic stem cells are identified in the bone marrow of most patients. Clonal expansion of these T cells, often oligoclonal, leads to targeted destruction of stem cells via Fas-ligand and perforin/granzyme pathways. Cytokine-mediated suppression (TNF-α, IFN-γ) further inhibits residual haematopoiesis.

This immune basis explains the response to immunosuppressive therapy and the occasional co-existence of aplastic anaemia with other autoimmune conditions including thyroiditis, systemic lupus erythematosus, and thymoma.

Drug-Associated

A number of medications have been associated with aplastic anaemia, either through dose-dependent myelosuppression or idiosyncratic immune-mediated reactions:

Drug Category	Examples	Mechanism	Reversibility
Dose-dependent myelotoxins	Cytotoxic chemotherapy agents (alkylators, antimetabolites), benzene	Direct stem cell toxicity	Usually reversible on cessation
Idiosyncratic (dose-independent)	Chloramphenicol, carbimazole, methimazole, sulphonamides, NSAIDs (phenylbutazone, indomethacin), gold salts, D-penicillamine, allopurinol	Immune-mediated or direct toxicity with genetic susceptibility	May be irreversible despite drug withdrawal
Anticonvulsants	Carbamazepine, phenytoin, sodium valproate	Idiosyncratic immune-mediated	Usually reversible, but may persist
Antibiotics	Co-trimoxazole, flucloxacillin (rare)	Idiosyncratic	Variable

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Clinical pearl: Chloramphenicol (largely historical in Australia) was the classic drug-associated cause. The idiosyncratic reaction is not dose-dependent and can occur with any route of administration. A thorough drug history including over-the-counter and herbal preparations must be taken in all patients presenting with pancytopenia.

Viral-Associated

Several viral infections have been implicated in aplastic anaemia, either through direct marrow suppression or immune-mediated mechanisms:

Hepatitis viruses: Hepatitis-associated aplastic anaemia (HAAA) accounts for approximately 5% of cases. Typically occurs 2–3 months after acute hepatitis, often seronegative hepatitis (non-A to E). Mortality is high without treatment. HAAA is particularly important in younger patients.
Parvovirus B19: Causes selective red cell aplasia rather than true pancytopenic aplastic anaemia, though severe immunodeficiency may lead to broader marrow suppression.
Epstein-Barr virus (EBV): Rare association with aplastic anaemia, usually in the context of severe EBV infection or post-transplant lymphoproliferative disease.
HIV: Direct marrow infection and opportunistic infections (CMV, mycobacteria) can cause marrow failure; distinguish from HIV-associated cytopenias.
Cytomegalovirus (CMV): Particularly relevant in immunocompromised patients and post-transplant settings.

Inherited Bone Marrow Failure Syndromes

Inherited causes must be considered especially in children, young adults, and those with a family history or associated physical anomalies:

Fanconi anaemia: Autosomal recessive or X-linked; chromosomal breakage test (diepoxybutane or mitomycin C) is diagnostic. Associated with short stature, radial ray anomalies, skin pigmentation, and predisposition to MDS/AML.
Dyskeratosis congenita: Telomere biology disorder; mucosal leukoplakia, nail dystrophy, skin pigmentation. TERC and TERT gene mutations.
Shwachman-Diamond syndrome: Exocrine pancreatic insufficiency, skeletal anomalies, neutropenia progressing to aplastic anaemia.
先天性角化不良 (DC) and other telomere biology disorders may present in adulthood and should be considered in apparently acquired AA, as IST may be less effective.

Clinical Features & Severity Classification

Clinical Presentation

The clinical presentation of aplastic anaemia reflects the consequences of pancytopenia. Onset is typically insidious over weeks to months, though hepatitis-associated cases may present more acutely:

Anaemia

Fatigue & Dyspnoea

Progressive fatigue, exertional dyspnoea, pallor, tachycardia. May present as incidental finding of low Hb.

Typically the first cytopenia to cause symptoms

Neutropenia

Infections

Recurrent or severe infections — oral ulceration, pharyngitis, pneumonia, skin/soft tissue infections, invasive fungal disease. Risk increases significantly when ANC <0.5 × 10⁹/L.

May present as fever without focus

Thrombocytopenia

Bleeding

Petechiae, purpura, epistaxis, gingival bleeding, menorrhagia, GI haemorrhage. Life-threatening intracranial haemorrhage when platelets <10 × 10⁹/L.

Urgent platelet transfusion threshold <10 × 10⁹/L or active bleeding

Other clinical features may include mild hepatosplenomegaly (rare in idiopathic AA; if present, consider PNH or MDS), lymphadenopathy (should prompt consideration of lymphoma or viral infection), and congenital anomalies suggesting inherited marrow failure syndrome.

Severity Classification

Severity classification is essential for treatment decisions and is based on peripheral blood counts and bone marrow cellularity. The modified Camitta criteria are used internationally and in Australian practice:

Parameter	Non-Severe AA	Severe AA (SAA)	Very Severe AA (vSAA)
Bone marrow cellularity	<25% (or 25–50% with <30% haematopoietic cells)	<25%	<25%
Reticulocyte count	≥20 × 10⁹/L	<20 × 10⁹/L (<1%)	<20 × 10⁹/L (<1%)
Neutrophil count (ANC)	≥0.5 × 10⁹/L	<0.5 × 10⁹/L	<0.2 × 10⁹/L
Platelet count	≥20 × 10⁹/L	<20 × 10⁹/L	<20 × 10⁹/L

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Emergency: Patients with SAA or vSAA require urgent referral to a haematology centre with transplant capability. Do not delay referral for further investigations. Neutropenic precautions must be initiated immediately. All blood products must be irradiated and CMV-safe.

Clonal Evolution

Approximately 10–15% of patients with aplastic anaemia may evolve to myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) over 10 years. Monosomy 7 and trisomy 8 are the most common cytogenetic abnormalities detected at clonal evolution. PNH clones are detectable in 40–50% of patients at diagnosis and may expand over time; however, progression to clinically significant haemolysis occurs in a minority.

Investigations

A systematic approach to investigation is essential to confirm the diagnosis, assess severity, exclude secondary causes, and guide treatment selection. Bone marrow biopsy is the cornerstone diagnostic investigation.

Baseline Blood Investigations

Essential

Full blood count with differential and reticulocyte count

Confirms pancytopenia. Reticulocyte count must be absolute (not percentage). Calculates severity grade.

Essential

Peripheral blood film

Assess for dysplastic features (suggest MDS), blasts (suggest leukaemia), macrocytosis, teardrop cells (suggest myelofibrosis).

Essential

Liver function tests, renal function, LDH, haptoglobin

Screen for hepatitis-associated aplasia, haemolysis (PNH).

Essential

Iron studies (ferritin, transferrin saturation), vitamin B12, folate

Assess iron stores (transfusion-related overload). Rule out B12/folate deficiency as cause of pancytopenia.

Available

PNH clone detection (flow cytometry)

FLAER-based flow cytometry for GPI-anchored proteins on granulocytes and monocytes. Detectable in 40–50% of AA. MBS item available through specialist pathology.

Available

Hepatitis serology (A, B, C), EBV, CMV, parvovirus B19 IgM/IgG and PCR

Viral screen for hepatitis-associated aplasia and immunodeficiency status. Parvovirus B19 PCR if reticulocytopenic anaemia predominates.

Available

HIV serology

All patients should be screened. HIV-associated marrow failure requires specific management.

Available

ANA, dsDNA, thyroid function

Screen for associated autoimmune conditions (SLE, thyroiditis).

Available

HLA typing (Class I and II)

Initiate at diagnosis for all patients aged <50 years. Required for sibling donor assessment and unrelated donor search.

Bone Marrow Biopsy

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Mandatory investigation: Bone marrow trephine biopsy (not aspirate alone) is required for diagnosis of aplastic anaemia. The aspirate alone may be haemodilute and misleading. A trephine of adequate length (≥1.5 cm) must be obtained for histopathological assessment of cellularity.

Bone marrow biopsy findings in aplastic anaemia include:

Cellularity: Markedly hypocellular marrow (<25% cellularity for age). In patients under 60 years, normal cellularity is 30–70%; thus <25% is clearly abnormal.
Haematopoietic cells: Severely reduced trilineage haematopoiesis. Residual haematopoietic islands may be seen.
Stroma: Predominantly fat and stromal cells. No increase in blasts (<5%). No significant fibrosis (reticulin stain should be ≤MF-1).
Trephine immunohistochemistry: CD34+ cells markedly reduced. Useful to exclude MDS (dysplastic megakaryocytes) and lymphoproliferative infiltrates.
Cytogenetics: Conventional karyotyping on bone marrow aspirate. Clonal cytogenetic abnormalities (monosomy 7, trisomy 8) suggest coexisting MDS.

Additional Specialised Investigations

Specialist

Chromosomal breakage analysis (diepoxybutane/mitomycin C)

Screen for Fanconi anaemia in all patients aged <40 years, and any patient with suggestive clinical features. Perform on peripheral blood lymphocytes.

Specialist

Telomere length assessment (flow-FISH)

Short telomeres suggest telomere biology disorder (dyskeratosis congenita). Important as IST may be less effective in these patients.

Specialist

Next-generation sequencing (myeloid gene panel)

Identifies somatic mutations (e.g., PIGA, BCOR/BCORL1, DNMT3A) that may indicate clonal evolution or coexisting PNH/MDS. Increasingly used in Australian centres.

Referral

Echocardiography

Pre-treatment cardiac assessment. Required prior to HSCT conditioning and to assess iron overload cardiomyopathy.

Differential Diagnosis to Exclude

Diagnosis	Distinguishing Features	Key Investigation
Myelodysplastic syndrome (MDS)	Dysplastic morphology, ring sideroblasts, clonal cytogenetics	BM trephine morphology, karyotype, NGS panel
Paroxysmal nocturnal haemoglobinuria (PNH)	Haemolysis, thrombosis, large PNH clone	FLAER flow cytometry
Acute leukaemia	Blasts ≥20% in marrow	BM aspirate morphology, flow cytometry
Hypersplenism	Splenomegaly, marrow hypercellular	Ultrasound, BM biopsy
Vitamin B12/folate deficiency	Macrocytic anaemia, megaloblastic changes	Serum B12, folate, homocysteine, MMA
Inherited marrow failure	Congenital anomalies, family history, young age	Chromosomal breakage, telomere length, genetic testing

Management

Treatment of aplastic anaemia depends on disease severity, patient age, donor availability, and comorbidities. The three principal treatment modalities are allogeneic haematopoietic stem cell transplantation (allo-HSCT), immunosuppressive therapy (IST), and supportive care. Eltrombopag has transformed IST outcomes and is now integrated into first-line regimens.

Treatment Algorithm

1

Assess severity

Classify as non-severe, severe, or very severe AA using modified Camitta criteria.

2

HLA typing & donor search

Initiate immediately for all patients. Sibling typing; if no match, begin unrelated donor search through ABMDR.

3

Matched sibling donor available?

If yes AND patient aged <40 years → proceed to allo-HSCT. If aged 40–50 years → discuss risks/benefits of transplant vs IST.

4

No matched sibling donor

First-line IST with hATG + ciclosporin + eltrombopag. Consider unrelated donor HSCT if IST fails.

5

Non-severe AA

Observation with supportive care if stable. IST if progressing or transfusion-dependent.

Allogeneic Haematopoietic Stem Cell Transplantation (allo-HSCT)

Allo-HSCT from an HLA-matched sibling donor (MSD) is the treatment of choice for patients aged <40 years with SAA or vSAA, offering cure rates of 75–90%. Transplant should be performed as soon as possible after diagnosis, ideally before the patient becomes heavily transfused (which increases rejection and GVHD risk).

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Conditioning Regimen

Standard for MSD transplant in AA

Standard regimen Cyclophosphamide 50 mg/kg/day IV × 4 days (days −5 to −2) + hATG (equine) 30 mg/kg/day IV × 3 days (days −4 to −2)

Alternative (older patients) Fludarabine 30 mg/m² IV × 4 days + cyclophosphamide 300 mg/m²/day IV × 4 days + low-dose TBI (2 Gy) — reduced intensity

GVHD prophylaxis Ciclosporin 3 mg/kg/day IV then PO, commencing day −1. Methotrexate 15 mg/m² day +1, then 10 mg/m² days +3, +6, +11 (short course)

PBS status ✔ PBS General Benefit

Key transplant considerations in Australia:

All blood products must be irradiated and CMV-safe (leucodepleted, CMV-seronegative or equivalent) from diagnosis onwards.
Red cell and platelet transfusions should be antigen-matched where possible (especially for red cells) to reduce alloimmunisation.
For patients aged 40–50 years with an MSD, reduced-intensity conditioning regimens are increasingly used with acceptable outcomes. Decisions should be made at a multidisciplinary transplant meeting.
Unrelated donor HSCT is considered second-line (after IST failure) or first-line if a well-matched unrelated donor is rapidly available. Outcomes have improved with high-resolution HLA matching through the Australian Bone Marrow Donor Registry (ABMDR).
Cord blood transplant is an alternative when no matched donor is available, though engraftment rates are lower.

Immunosuppressive Therapy (IST)

IST is first-line treatment for patients aged >40 years without a matched sibling donor, and for younger patients awaiting a donor or with comorbidities precluding transplant. The combination of horse ATG (hATG) with ciclosporin and eltrombopag is the current standard of care.

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Horse vs Rabbit ATG: Horse ATG (Atgam®) is preferred over rabbit ATG (Thymoglobulin®) for first-line IST in Australia based on superior complete response rates and overall survival demonstrated in the landmark NIH trials. Rabbit ATG may be used for second-line retreatment or if horse ATG is unavailable.

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Horse Anti-Thymocyte Globulin (hATG)

Atgam® · Equine ATG · Polyclonal antibody

Adult dose 40 mg/kg/day IV for 4 consecutive days (days 1–4). Administer via central line. Premedicate with paracetamol, antihistamine, and corticosteroids.

Paediatric dose 40 mg/kg/day IV for 4 days. Dose-adjusted for weight.

Renal adjustment No specific dose adjustment. Monitor renal function closely.

Key adverse effects Infusion reactions (fever, rigors, rash), serum sickness (day 7–14), cytopenias, increased infection risk. Monitor for serum sickness — treat with corticosteroids.

PBS status ⚠ PBS Authority Required

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Ciclosporin

Neoral® · Generic · Calcineurin inhibitor

Adult dose 5 mg/kg/day PO in 2 divided doses. Commence day 1 of IST. Trough level target 200–400 ng/mL (first 6 months), then taper gradually.

Paediatric dose 5 mg/kg/day PO in 2 divided doses. Adjust for trough levels.

Duration Minimum 6–12 months if responding. Many patients require ≥2 years; taper slowly over 12–24 months once stable response achieved.

Renal adjustment Use with caution if eGFR <30 mL/min. Dose reduce and monitor closely.

Key monitoring Trough levels, renal function, BP, magnesium, lipids. Drug interactions (CYP3A4).

PBS status ✔ PBS General Benefit

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Eltrombopag

Revolade® · Thrombopoietin receptor agonist

Adult dose (with IST) 150 mg PO daily (adults ≥40 kg). Commence day 1 concurrently with ATG + ciclosporin. Continue for at least 6 months; may be continued if responding.

Paediatric dose Dose by body weight: <28 kg: 2.5 mg/kg/day; 28–44 kg: 75 mg/day; ≥44 kg: 150 mg/day. PO daily.

Route Oral. Must be taken on an empty stomach (1 hour before or 2 hours after food). Separate from dairy, antacids, and polyvalent cation-containing products by ≥4 hours.

Key adverse effects Hepatotoxicity (monitor LFTs every 2 weeks initially), skin rash, elevated bilirubin (unconjugated, benign). Theoretical risk of marrow fibrosis — monitor serial BM biopsies.

Renal adjustment No dose adjustment required. Monitor LFTs.

PBS status ⛔ PBS Authority Required (Specialist only)

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Key evidence — IST + Eltrombopag: The NIH 2017 study (Patel et al., NEJM) demonstrated that the addition of eltrombopag to hATG + ciclosporin achieved an overall response rate of 94% at 6 months (compared to 66% with IST alone) and a complete response rate of 58% (vs 10% with IST alone). This combination is now considered standard of care for first-line IST.

Second-Line Therapy

For patients who fail to respond to first-line IST (no response at 4–6 months) or who relapse after initial response, second-line options include:

Repeat IST with rabbit ATG + ciclosporin + eltrombopag: Response rate approximately 30–40% for second course. Preferred if patient is not a transplant candidate.
Allo-HSCT from unrelated donor: Consider for younger patients (<50 years) with an available well-matched donor. Outcomes have improved significantly with high-resolution HLA matching.
Eltrombopag monotherapy: May be used in IST-refractory patients not eligible for transplant. Response rate approximately 40% in this setting.
Haploidentical HSCT: Emerging option using post-transplant cyclophosphamide for GVHD prophylaxis. Outcomes approaching MSD transplant in selected centres.

Supportive Care

Supportive care is essential for all patients, regardless of definitive therapy:

🩸 Transfusion Support

All blood products must be irradiated (prevent transfusion-associated GVHD) and CMV-safe.
Red cell transfusion threshold: maintain Hb >70 g/L (or >80 g/L if symptomatic cardiovascular disease).
Platelet transfusion threshold: <10 × 10⁹/L prophylactic; <20 × 10⁹/L with fever; any count if active bleeding.
Antigen-matched red cells where possible (extended phenotype matching).
Iron chelation (deferasirox 10–20 mg/kg/day PO) when ferritin >1000 μg/L and ongoing transfusion requirement.

🦠 Infection Prevention

Neutropenic precautions when ANC <0.5 × 10⁹/L.
Antibacterial prophylaxis: ciprofloxacin 500 mg PO BD if ANC <0.5 × 10⁹/L (per eTG guidelines).
Antifungal prophylaxis: fluconazole 200 mg PO daily; escalate to posaconazole if prolonged profound neutropenia or HSCT.
Antiviral prophylaxis: aciclovir 400 mg PO BD (HSV/VZV prophylaxis).
PJP prophylaxis: co-trimoxazole 480 mg PO daily or 960 mg PO 3 times/week if on IST (use cautiously — may worsen cytopenias).
Vaccination review — live vaccines contraindicated during IST and for 6 months after.

⚠️

Do NOT use G-CSF: Granulocyte colony-stimulating factor (G-CSF) is not recommended as a bridging measure in aplastic anaemia. It does not reduce infection-related mortality, may delay initiation of definitive therapy, and carries a theoretical risk of promoting clonal evolution.

Monitoring Response to IST

Week 1–4

Expect transient worsening of cytopenias during ATG. Close monitoring for infection and bleeding. Ciclosporin trough levels.

Month 3

First formal response assessment. Partial response = transfusion independence and no longer meeting SAA criteria. May take up to 6 months.

Month 6

Standard response assessment time point. Complete response = Hb ≥100 g/L, ANC ≥1.0 × 10⁹/L, platelets ≥100 × 10⁹/L. Partial response = no longer meeting SAA criteria.

Month 12–24

Begin ciclosporin taper if stable response. Monitor for relapse during taper. Continue eltrombopag if responding.

Long-term

Lifelong monitoring: FBC every 3–6 months, annual bone marrow biopsy, PNH clone monitoring, cytogenetic surveillance for clonal evolution.

Special Populations

🤰 Pregnancy

Management: Aplastic anaemia may present or relapse during pregnancy. IST (ciclosporin alone) can be used in the second and third trimesters. ATG is generally avoided in pregnancy unless life-threatening.

Transfusion: Irradiated, CMV-safe products. Platelet transfusion if <20 × 10⁹/L or prior to delivery (<50 × 10⁹/L for epidural).

Delivery: Plan delivery at tertiary centre. Vaginal delivery preferred if platelets >50 × 10⁹/L. Coordinate with obstetric and haematology teams.

Ciclosporin: Compatible with breastfeeding. ATG: generally compatible (large molecule, not absorbed orally).

Refer to specialist obstetric haematology service for management.

👶 Paediatrics

Inherited causes: Always consider Fanconi anaemia, dyskeratosis congenita, and other inherited BMF syndromes in children. Perform chromosomal breakage testing and telomere length assessment before IST.

Transplant: MSD allo-HSCT is first-line for children with SAA/vSAA. Outcomes are generally better than in adults.

IST: hATG 40 mg/kg/day × 4 days + ciclosporin 5 mg/kg/day + eltrombopag (weight-based dosing) if no MSD.

Eltrombopag: Now PBS-listed for paediatric use in AA. Weight-based dosing. Monitor LFTs closely.

All children should be referred to a paediatric haematology centre. Family genetic counselling is essential.

👴 Elderly (≥60 years)

Treatment: IST with hATG + ciclosporin + eltrombopag is first-line. Transplant generally not offered due to high TRM, though reduced-intensity MSD transplant may be considered in selected fit patients aged 60–65.

Comorbidities: Renal impairment is common — adjust ciclosporin dose. Cardiovascular disease affects transfusion thresholds.

MDS overlap: Higher incidence of clonal evolution and MDS in elderly. Monitor closely with cytogenetics and molecular testing.

Goals of care discussion important. Supportive care alone may be appropriate if IST not tolerated.

🫘 Renal Impairment

Ciclosporin: Dose reduce if eGFR <30 mL/min. Nephrotoxic — monitor creatinine closely. May need to switch to alternative immunosuppressant (e.g., tacrolimus) if nephrotoxicity develops.

Eltrombopag: No dose adjustment required. Monitor for hepatotoxicity.

Iron chelation: Deferasirox contraindicated if eGFR <40 mL/min. Use desferrioxamine (SC/IV) instead.

Coordinate with nephrology. Monitor fluid balance during ATG infusion.

🫁 Hepatic Impairment

Hepatitis-associated AA: Manage underlying hepatitis (antiviral therapy if HBV/HCV positive). HAAA (seronegative) may respond to IST but outcomes may be inferior.

Ciclosporin: Hepatotoxic. Monitor LFTs closely. Metabolised hepatically — consider dose reduction in significant liver disease.

Eltrombopag: Monitor LFTs every 2 weeks for first 3 months, then monthly. Discontinue if ALT >5× ULN.

Hepatology referral for hepatitis-associated aplasia. Hepatic encephalopathy may complicate management.

🛡️ Immunocompromised

HIV-associated: Treat underlying HIV with ART. AA may improve with immune reconstitution. IST may be used cautiously if CD4 count adequate.

Post-transplant: Graft failure after allo-HSCT requires donor lymphocyte infusion, second transplant, or supportive care.

Infection risk: Extremely high during IST and post-transplant. Broad-spectrum antimicrobial prophylaxis essential. Consider CMV pre-emptive therapy (valganciclovir) if CMV D+/R−.

Infectious disease specialist involvement recommended for complex infection management.

🇦🇺 Aboriginal and Torres Strait Islander Health Considerations

Aboriginal and Torres Strait Islander Health

Aplastic anaemia in Aboriginal and Torres Strait Islander peoples requires particular attention to healthcare access, cultural safety, and the unique epidemiological and social context of Indigenous Australian communities. Data from the AIHW and jurisdictional cancer registries suggest that while overall incidence may be similar to the non-Indigenous population, outcomes are often poorer due to delayed diagnosis and barriers to accessing specialist care.

Delayed presentation

Aboriginal and Torres Strait Islander patients in remote and very remote areas may present later with more advanced cytopenias due to limited primary healthcare access, geographic isolation, and cultural barriers to seeking medical care. Primary care clinicians in remote settings must maintain a high index of suspicion for pancytopenia and initiate urgent referral.

Transplant access

Allo-HSCT requires relocation to a major capital city transplant centre for weeks to months. This presents significant cultural, social, and financial barriers for Aboriginal and Torres Strait Islander patients, particularly those with family and community obligations in remote areas. Transplant centres should provide culturally safe accommodation and support services, including Aboriginal Health Worker involvement.

IST delivery

IST with hATG requires admission to a specialist centre. Ciclosporin and eltrombopag require ongoing monitoring (trough levels, LFTs, renal function) which may be difficult to arrange in remote areas. Telehealth haematology consultations and RFDS retrieval services are essential. Community pharmacy access for dispensing ciclosporin and eltrombopag must be confirmed.

Transfusion logistics

All transfusions require irradiated, CMV-safe products. Supply of these specialised products may be limited in remote blood banks. The Australian Red Cross LifeBlood service must be notified early to plan logistics. Emergency transfusion protocols should be established for remote patients.

Inherited marrow failure

Some inherited bone marrow failure syndromes may be more prevalent in specific communities due to founder effects and consanguinity. Genetic counselling and family screening should be offered in a culturally appropriate manner. Referral to clinical genetics services should be facilitated.

Cultural safety

Engage Aboriginal Health Workers and Liaison Officers throughout the care pathway. Provide culturally appropriate health education materials. Ensure informed consent processes are culturally safe and appropriately explained. Allow time for family and community consultation in decision-making. Respect sorry business and cultural obligations. Use interpreters when English is not the first language.

Social determinants

Address housing, nutrition, transportation, and financial barriers that impact treatment adherence and outcomes. Link patients with Indigenous-specific support services (e.g., Closing the Gap PBS co-payment measure, patient-assisted travel schemes).

📚 References

1. Patel BA, Groarke EM, Lotter J, et al. Long-term outcomes in patients with severe aplastic anaemia treated with immunosuppression and eltrombopag: a phase 2 study. Lancet Haematol. 2022;9(11):e804–e814. doi:10.1016/S2352-3026(22)00282-X
2. Townsley DM, Scheinberg P, Winkler T, et al. Eltrombopag added to standard immunosuppression for aplastic anemia. N Engl J Med. 2017;376(16):1540–1550. doi:10.1056/NEJMoa1613878
3. Bacigalupo A. How I treat acquired aplastic anemia. Blood. 2017;129(11):1428–1436. doi:10.1182/blood-2016-08-693689
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5. Peffault de Latour R, Tabbara IA, Bhatt VR, et al. Allogeneic transplantation for aplastic anemia. Biol Blood Marrow Transplant. 2020;26(8):e162–e169. doi:10.1016/j.bbmt.2020.04.022
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7. Scheinberg P, Young NS. How I treat acquired aplastic anemia. Blood. 2012;120(6):1185–1196. doi:10.1182/blood-2011-12-274019
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