Acquired Aplastic Anaemia

Acquired Aplastic Anaemia



§        Peripheral blood cytopenia and reduced marrow cellularity (<30%), absence of infiltrate and no increased reticulin

§        At least 2 of:

§        Hb <10

§        Plt <50

§        Neu < 1.5


Exclusion of other causes of pancytopenia:

§        Congenital marrow failure, eg. Fanconi’s anaemia (AR)

§        FA cells show excessive chromosomal breakage when exposed to di-epoxybutane or mitomycin-C

§        Family history

§        Short stature, café au lait spots, skeletal abnormalities

§        Dyskeratosis congenita = leucoplakia, nail dystrophy, skin pigmentation

§        Hypoplastic MDS

§        Can be difficult to distinguish as the immune mechanisms involved in AA probably contribute to the cytopenia in MDS

§        Dyserythropoiesis and macrocytosis is common in AA, Pelger-Huet neutrophils more in keeping with MDS

§        ALIP

§        Cytogenetic abnormalities

§        PNH (flow cytometry +/- Ham)

§        Myelofibrosis

§        Hairy cell leukaemia

§        LGL leukaemia

§        Infections (TB, Histoplasmosis, HIV)

§        Liver disease (post hepatitic AA)

§        Haematinic deficiency

§        AI disease (SLE)


Incidence (4 per million)

§        Highest in E Asia x 4

§        Biphasic

§        10-25, >60yrs

§        M=F


Possible Causes

§        Majority idiopathic

§        Drugs

§        Chloramphenicol, sulphonamides, gold, penicillamine, diclofenac, carbimazole, dothiepin, chloroquine, clopidogrel

§        Occupation

§        Benzene, pesticides, cutting oils, ecstasy

§        Infection (EBV, CMV, Hepatitis (non A/B/C), HIV

§        Pregnancy

§        Thymoma / thymic carcinoma

§        GvHD

§        ALL

§        Particularly in children

§        Aplasia not distinguishable on haematological grounds from pure AA

§        Infections / splenomegaly / relative preservation of platelets may be clues

§        Aplasia lasts 3-6 weeks followed by a period of apparent recovery

§        ALL follows after 1-3 months

§        Treatment – early bone marrow transplant especially if a HLA identical sibling is available (can use transfusion to support whilst waiting for a donor)

§        Attempts to induce remission without transplant are often unsuccessful as the aplastic marrow often remains aplastic.



§        Non-severe = PMN >0.5

§        Severe (<20% 1 year survival without treatment)

§        BM cellularity <25% or 2 out of 3 of:

§        PMN 0.2-0.5

§        Plts <20

§        Retics <20

§        Very severe = PMN <0.2



§        80% of idiopathic probably due to T cell mediated destruction of stem cells via IFN gamma and TNF

§        Microenvironment may also be a factor


§        Glycosyl-phosphatidyl-inositol (GPI) = anchors surfaces proteins to normal HSCs.

§        GPI-negative cells also exist as a result of somatic mutations in an X-linked gene, PIG-A.

§        CD52 is a GPI linked protein  = alemtuzamab target

§        T-cell recovery after alemtuzumab is CD52-, ie. also GPI- = evidence that an antibody can select for GPI- cells.

§        In AA the emergence of a GPI- clone is predictive of response to IST.

§        GPI- cells could be spared from an auto-immune attack, suggesting that one of the putative antigens may be GPI linked.

§        Testing for GPI-linked antigens is now part of routine diagnostic and follow-up procedures.

§        Up to 25% may have a small PNH clone, but without evidence of haemolysis – significance of which is unclear




1. Spontaneous recovery

§   Reasonable to wait up to 2 weeks if likely to be secondary to medication


2. Supportive care

§        Transfusion independent

§        Prophylactic antibiotics

§        Norethisterone

§        Dental hygiene / chlorhexidine mouthwash

§        Tranexamic acid


§        Transfusion dependent

§        CMV negative and leucodepleted products

§        (Irradiated products)

§        Consider apheresis / HLA matched plts (triggers <10 / 20 if septic)

§        Iron chelation


3Immunosupressive therapy

§        Takes around 3 months to respond to treatment



§   Multiple antibodies CD3. CD5, CD11a, CD18, CD45, B2M – vary with preparation

§        Horse v. rabbit

§        Standard 1st line is horse ATG +CsA

§        2nd line – horse again or rabbit, but if same prep used twice, higher rate of allergy and serum sickness

Allergic reactions

§        Steroids/ antihistamines/ slow infusion (24hrs)

§        Usual course is 5 days

§        Cytopenia will be worse in the first few weeks

Serum sickness

§        75% develop 7-10 days following administration

§        Fever, arthralgia, rash, proteinuria but not renal failure

§        Prednisolone 1mg/kg should be started on d5 to help prevent this

§        Should be kept as inpatient for observation until risk of serum sickness over (14 days)

§        Anti-platelet effect

§        Plateletshould be give before and after the infusion but not during it


§        ATG + androgens (eg. Oxymetholone) or CsA yield better response rates but not survival than  ATG alone


§        Median time to response with ATG is 120days, therefore no second course before 4 months

§        40-80% become transfusion independent

§        Delaying treatment >23 days increases risk of non-response.

§        ATG is not recommended in the presence of a significant PNH clone with evidence of haemolysis because of the risk of acute intravascular haemolysis during serum sickness

§        Second course can be given after 4-6 months if there is no response


§        Requiring transfusion after having been transfusion independant for at least 3 months

§        Risk of relapse is about 30%

§        Can be successfully rescued by an additional course of ATG

§        Vaccinations

§        May trigger relapse

§        Live polio vaccine to be avoided after ATG/ transplant



§        Can be used in combination with ATG – improves speed of recovery of counts and failure free survival but not overall survival

§        Can be used as a single agent when there are contraindications to ATG but significantly lower response rates

§        Recent data suggests starting to taper CsA at 12 rather than 6 months

§        Taper should be very slow (<10% dose/ month)

§        Taper for at least 1 year

§        Need to measure BP / renal function / levels


Prognostic factors after IST

§        Negative

§        Age >16yrs

§        < 20yrs 10yr survival = 73%

§        >40yrs 10yr survival = 47%

§        IST protocol other than ATG +CsA

§        Interval between diagnosis and treatment >23days

§        Neutrophil count had NO impact


Pregnancy after IST

§        Successful pregnancy is possible but associated with risk of relapse

§        Relapse more frequent in partial responders

§        Supportive care is the main stay of treatment with regular FBC

§        Experience from renal transplants suggest CsA may be safe


4. Growth Factors


§        Should not be used alone in early disease in the mistaken belief they may cure

§        Advantage = faster neutrophil recovery, and allows early identification of non-responders and therefore early referral for transplant

§        Disadvantage = expensive, no improved survival at 3 years

§        May be considered during severe systemic infections

§        High dose GSCF  = no advantage

§        Epo – not recommended, most pts already have high epo levels, and concern re antibody formation and red cell aplasia


§        Used historically

§        Oxymthenalone shown in one trial to increase response rates to ATG

§        Virilising side effects / peliosis hepatis  – therefore cyclosporin used more often 



5. Bone marrow transplantation

§        Patients <20yrs with very severe AA are candidates for 1st line transplantation

§        Avoid transfusion pre transplant if possible as sensitisation to minor HLA antigens increases graft rejection rates

§        Good prognostic factors

§        Matched sibling donor

§        < 16yrs

§        Interval between diagnosis and transplant of <83days

§        No radiation

§        Survival in these groups = 91%


HLA-identical siblings

§        Conditioning with cyclophosphamide 200mg/kg and ATG

§        No infertility or secondary tumours

§        PB not recommended because of increased cGVHD

§        GVHD prophylaxis with CsA and MTX


§        EBMT is exploring low dose cyclophosphamide +low dose fludarabine + ATG in patients over 30yrs with encouraging results

§        Reduced TRM cf. with Cy alone


§   70% 3 year survival

§   Retain fertility if cyclophosphamide conditioning used

§   25% have chronic GVHD



Unrelated transplant donors

§        Candidates

§        Fully matched donor

§        <40yrs

§        Adults – failed at least 2 courses of ATG

§        Children – failed at least one

§        Severe AA

§        No evidence of active infection/ bleeding at time of transplant

§        Conditioning

§        Best results with lower dose radiation (2Gy)

§        EBMT currently testing FLU/CY/ATG and low dose radiation


§   Historically poor prognosis with only 30% disease free survival

§   More recent studies report improved prognosis probably due to better matching using high resolution HLA typing


Clonal evolution/ second malignancies

§        GPI- clone/ PNH

§        MDS

§        AML

§        Overall risk at 10yrs is 5-20%

§        Risk of MDS/ AML is significantly higher after IST cf. BMT, suggesting that MDS/ AML is assoc. with the IST as the conditioning for BMT is unlikely to eradicate a neoplastic clone

§        2nd tumours more likely after radiation

§        Radiation currently not recommended for HLA-identical sibling transplants