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Document Code: EMCN-DC-0183-13 Date of Issue: Feb 13 Review Date: Feb 15

Written By: Prof Russell, Dr Hunter & Dr Mittal C Loughran Authorised by: Page Number: 1/9
Issue No: 1 Website: Check for latest version

East Midlands Cancer Network Guidelines for the
Management of Aplastic Anaemia in Adults

Written by: Prof Nigel Russell, Dr Ann Hunter,
Dr Sajjan Mittal & Dr Jenny Byrne

Consultation Group: EMCN Haematology NSSG

Diagnostic Criteria
All patients presenting with aplastic anaemia should be carefully
assessed to confirm the diagnosis and exclude other possible causes
of pancytopenia with a hypocellular bone marrow.
The disease severity must be classified using standard blood and bone
marrow criteria.
The presence of a PNH or cytogenetic clone must be documented.
A possible late onset inherited bone marrow failure disorder must be
Although most cases of aplastic anaemia are idiopathic, a careful drug
and occupational exposure history should be taken. Any putative drug
should be discontinued and should not be given again to the patient.
Any possible association of aplastic anaemia with drug exposure
should be reported to the MHRA using the yellow card scheme.
Essential Investigations
Full blood count and reticulocyte count
Blood film examination
HbF% in children
Bone marrow aspirate and trephine biopsy, including cytogenetics
Peripheral blood chromosomal breakage analysis to exclude Fanconis
anaemia if <50 years old
Flow cytometry for GPI-anchored protein
Vitamin B12 and folate and ferritin
Liver function tests
Virology; Hepatitis A, B and C, EBV, HIV and CMV
Anti-nuclear antibody and anti-dsDNA
Chest xray
Abdominal ultrasound and echocardiogram
Peripheral blood gene mutation analysis for dyskeratosis congenital if
clinical features or lack of response to immunosuppressive therapy.
HLA typing

Document Code: EMCN-DC-0183-13 Date of Issue: Feb 13 Review Date: Feb 15
Written By: Prof Russell, Dr Hunter & Dr Mittal C Loughran Authorised by: Page Number: 2/9
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Disease Severity

To define aplastic anaemia there must be at least 2 of the following:
(i) haemoglobin <100g/l
(ii) platelet count <50 x 10
(iii) neutrophil count <1.5 x 10

(International Agranulocytosis and Aplastic Anaemia Study Group, 1987)

Severe AA BM cellularity<25% or 25-50% with <30% residual
Haemopoietic cells

2/3 of following neutrophil count <0.5 x 10
Platelet count <20 x 10
Reticulocyte count <20 x 10

Very severe AA As for severe, except neutrophils<0.2 x 10

Non-severe AA Patients not fulfilling the criteria for severe or very severe
aplastic anaemia

Primary Treatment

BCSH guidelines should be followed for all patients with aplastic anaemia.

Hospitals providing level 2b care should be able to safely treat patients with
severe aplastic anaemia, providing they have experience of using ATG. ATG
treatment should only take place by those familiar with administering ATG and
that the medical and nursing teams are aware of the side effects and how to
treat these promptly and appropriately. Allogeneic transplants should be
performed in an EMCN approved/ J ACIE accredited transplant centre.

Supportive Care
It is recommended to give prophylactic platelet transfusions when
platelets are less than 10 x 10/l (or less than 20 x 10/l in presence of
If the patient is a potential BMT candidate, CMV negative products
should be used until CMV status is known.
Irradiated blood products should be used in patients receiving
immunosuppressive therapy.
Prophylactic antibiotics and antifungal drugs should be given to
patients with an absolute neutrophil count <0.2 x 10/l according to
institutional guidelines.
Patients who are severely neutropenic (ANC <0.2 x 10/l) should
ideally be nursed in protective isolation.

Document Code: EMCN-DC-0183-13 Date of Issue: Feb 13 Review Date: Feb 15
Written By: Prof Russell, Dr Hunter & Dr Mittal C Loughran Authorised by: Page Number: 3/9
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A short course of GCSF may be considered for severe systemic
infection that is not responding to intravenous antibiotics and
antifungals, but it should be discontinued after seven days if there is no
improvement in the neutrophil count.
There should be early consideration for the use of antifungals if
neutropenic fevers persist according to institutional guidelines.
Irradiated granulocyte transfusions may be used in life-threatening
Iron chelation should be considered in transfusion dependent patients
when the serum ferritin is 1000g/l.
Psychological support is extremely important, and the chronic nature
and slow response to treatment should be discussed early. They
should be offered information about relevant support groups.
Definitive Treatment
Infection or uncontrolled bleeding should be treated first before giving
immunosuppressive therapy. This also applies to patients scheduled for BMT,
although it may sometimes be necessary to proceed straight to BMT in the
presence of severe infection as a BMT may offer the best chance of early
neutrophil recovery.

Definitive treatment should be given once the patient has been clinically
stabilised, the disease confirmed, its severity assessed, potential sibling
donor(s) HLA tissue typed and a management plan discussed in collaboration
with a BMT unit if appropriate.

HLA-identical Sibling BMT
Allogeneic BMT from an identical sibling is the treatment of choice for a newly
diagnosed patient if they are under 40 and has SAA or VSAA. This would also
be the case in children with non-severe AA in whom treatment is indicated.
Ideally bone marrow as the source of stem cells should be used. There is no
indication for irradiation based conditioning regimes. Sibling BMT may be
considered in patients aged over 40 if they have no co-morbidities.

Immunosuppressive Therapy (ATG and ciclosporin)

ATG Immunosuppressive therapy is indicated in patients who are not eligible
for a sibling BMT. This includes:
i) patients with non-severe aplastic anaemia who are dependent on
blood or platelet transfusions or have a significant neutropenia, and
ii) patients with SAA or VSAA over 40 or without a matched sibling

Recent guidance from the European Blood and Marrow transplant (EBMT)
Severe Aplastic Anaemia Working Party and the British Committee for
Standards in Haematology (BCSH) advises that horse ATG (ATGAM) with
ciclosporin is currently the preferred first choice of immunosuppressive
therapy for patients with AA.

Document Code: EMCN-DC-0183-13 Date of Issue: Feb 13 Review Date: Feb 15
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ATG (antithymoglobulin, Lymphoglobuline Genzyme) is no longer available.
Rabbit ATG (Thymoglobulin, Genzyme) has been compared with horse ATG
as first line of treatment for AA in 2 studies. Surprisingly a significantly worse
response was seen with rabbit ATG (35-37% at 6 months, compared to
around 75% with horse ATG). Furthermore, survival outcomes were
significantly inferior after rabbit ATG (67%) compared to horse ATG (78%),
and inferior transplant free survival of 37% for rabbit ATG compared to 70%
for horse ATG). In the EBMT study there were a higher number of deaths
from infection after rabbit ATG. Therefore ATGAM is the recommended first
line immunosuppressive therapy in combination with Ciclosporin

ATG is highly immunosuppressive. It should only be used in centres with
at least level 2 facilities. Patients should be nursed in a single isolation
room. ATG must never be given as an out-patient.
Always give ATG through a central line, or a PICC line in the antecubital
Methylprednisolone 1mg/kg i.v. as a 30 minute infusion, 30minutes before
each dose of ATG. From day 5 onwards oral prednisolone 0.5mg/kg/day
should be prescribed and the dose tapered by half every 5 days.

Patients over the age of 60 years, in particular, should be carefully
assessed medically beforehand to determine whether they are fit enough
to tolerate ATG treatment
The dose of ATGAM

is 40mg/kg/day for 4 days. For obese patients, the

dose must be calculated according to ideal body weight.(see Appendix 1 for
details of ATGAM administration)
It is important to ensure an adequate platelet increment occurs after platelet
transfusions, because ATG results in a drop in the platelet count and can
precipitate bleeding. If refractory to random donor platelets, postpone ATG
treatment until further investigations. If HLA antibodies are detected, arrange
adequate supply of HLA matched platelets to cover course of ATG. Irradiated
platelets are to be used.

Ciclosporin Start oral ciclosporin on Day 1 of ATG to maintain a trough blood
level of 100-200mcg/l

CSA is given for a minimum of 12 months and usually much longer. If a
response occurs, CSA is continued at full dose until the blood count has
stopped rising and has plateaued. It is then continued for a further 12 months,
followed by a slow taper of around 25mg every 2-3 months. Too rapid dose
reduction is associated with a high incidence of relapse of aplastic anaemia.
Some patients, however, are CSA dependent and will need a low dose for a
long period of time. In these patients it may be impossible to stop the CSA

Document Code: EMCN-DC-0183-13 Date of Issue: Feb 13 Review Date: Feb 15
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Other points
Oral antibiotic prophylaxis: as per institutional practice. Anti-viral prophylaxis with
oral aciclovir

Anti-fungal prophylaxis: Recommendations are itraconazole suspension 2.5mg/kg 12
hourly or oral posaconazole 200mg TDS or liposomal amphotericin 2mg/kg on
Monday, Wednesday and Fridays according to institutional practice

NB, if using itraconazole or posaconazole, the dose of ciclosporin must be reduced to
half the normal dose (i.e. 2.5mg/kg daily) because itraconazole and posaconazole
increase ciclosporin blood levels. Anti-viral prophylaxis: oral aciclovir 200mg 8 hourly

Duration of prophylaxis: for all patients, prophylaxis should continue for a minimum of
4 weeks, and longer if very severe AA with neutrophil count <0.2 x 10

Norethisterone 5mg 8 hourly for pre-menopausal females

Platelet transfusions should be used to keep the platelet count >30 during ATG
therapy and not given whilst ATG is being infused. Poor platelet increments should
be investigated prior to starting ATG. HLA matched platelets may be required

Indications for a MUD BMT

The results of unrelated donor transplantation have improved dramatically in
the last decade using fludarabine, cyclophosphamide and ATG or
alemtuzumab conditioning. MUD transplantation may be considered when
patients have a fully matched donor (8/8 matched at HLA-A B C DR), they
have a good performance status and have a failed at least one course of ATG
and ciclosporin and have SAA. MUD transplantation may be considered
earlier in young patients (<25 years with VSAA) who lack a sibling donor.

Algorithm for the Treatment of Acquired Severe Aplastic Anaemia

Document Code: EMCN-DC-0183-13 Date of Issue: Feb 13 Review Date: Feb 15
Written By: Prof Russell, Dr Hunter & Dr Mittal C Loughran Authorised by: Page Number: 6/9
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Treatment of Non-severe Acquired Aplastic Anaemia

In patients with non-severe aplastic anaemia, ie. who dont fulfil the criteria for
SAA or VSAA, best supportive care and observation is advised.

If they become red cell and/or platelet transfusion dependent a course of
immunosuppressive therapy (ATG and ciclosporin) is recommended in the
first instance. If there is no response to this at 4 months, a bone marrow
transplant may be considered in those patients whom are deemed
appropriate, and if not a second course of immunosuppressive treatment may
be used.

Document Code: EMCN-DC-0183-13 Date of Issue: Feb 13 Review Date: Feb 15
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Appendix 1: ATGAM

(Horse ATG) Administration

1. Presentation

5ml vial contains 250mg of Horse anti-thymocyte globulin

(ATG) ie 50mg/ml.

2. Instructions for dilution (if made in a clinical area)
Dilute required dose in 1000ml Sodium chloride 0.9%
(Max concentration 4mg/ml)
Expiry 24 hours

3. Method of administration
Methylprednisolone sodium succinate (Solu Medrone

) 1mg/kg IV infusion in
100ml Sodium chloride 0.9% over 30mins, starting 30 minutes before ATG
(ie before test dose on day 1 and Full dose on day 2 to 4).
From day 5 onwards oral prednisolone 0.5mg/kg/day should be prescribed
and the dose tapered by half every 5 days.
Chlorphenamine 10mg IV bolus
Platelets should be administered before each daily dose of ATGAM to
maintain platelets at >30 (see page 5). Do not administer platelets at the
same time as ATG.

Test dose
A test dose must be given on day 1. This is done by infusing part of the daily
dose (see 2. above) due on day 1. Infuse intravenously at 5ml/hr for 1 hour.

A doctor should supervise the test dose with epinephrine (as per local
anaphylaxis protocol), chlorphenamine (10mg IV) and hydrocortisone (100mg
IV) drawn up beforehand.

If no severe reaction occurs, infuse the remainder of the infusion over 17

A severe systemic reaction or anaphylaxis to the test dose is an absolute
contraindication to proceeding with ATG treatment.

Infusion rate for days 2 to 4
If tolerated subsequent doses can be given over 12 hours.

Use an infusion pump and 0.2 micron in line filter via a central line

Flush with sodium chloride 0.9%

Document Code: EMCN-DC-0183-13 Date of Issue: Feb 13 Review Date: Feb 15
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4. Monitoring the patient
Carefully monitor patient clinically for evidence of bleeding, infection, fluid
retention and hypo- or hypertension:
weigh patient twice daily
keep strict fluid balance chart daily
4 hourly temperature, pulse, BP, oxygen saturations and respiratory
daily urine test for glucose
daily FBC, U&Es and LFTs

5. Immediate side effects (during administration of ATG) and treatment:
Anaphylaxis (rare) make sure resuscitation equipment is available.
Discontinue ATG immediately and treat anaphylaxis appropriately.
Allergic: Fevers and rigors (tend to be worse on the first day and
diminish with subsequent doses of ATG). Rash, pruritus, urticaria.
Usually responds to a dose of hydrocortisone and chlorphenamine. If
persistent, give pethidine 25mg i.v. Pyrexia during ATG may also be due
to infection, so broad spectrum i.v. antibiotics (as per local protocol for
neutropenic patients) must be commenced after obtaining blood cultures.
Fluid retention occurs commonly. Acute pulmonary oedema and
cardiac failure can develop rapidly if left untreated. Fluid retention
needs very close monitoring and early treatment with furosemide. It is
usually multi-factorial in origin, for example, N Saline diluent, blood and
platelet transfusions, corticosteroids, chronic anaemia. Treat fluid
retention promptly with furosemide and review fluid balance later the same
day. If the patient gains more than one kg in weight, or if the amount in is
one litre more than the amount out in 24 hours, then give a dose of
furosemide. However, assess clinically first, because if febrile, and
increased insensible loss, furosemide may not be appropriate.
Hypotension or hypertension. If patient is hypertensive, treat any fluid
retention if present, and use appropriate anti-hypertensive.
Elevation of serum transaminases occur commonly
Cardiac arrhythmias: bradycardia or tachycardias
Chest pain, loin pain, back pain occasionally
Nausea, vomiting, diarrhoea may sometimes occur
Positive direct antiglobulin test and difficulty with cross matching blood
due to the presence of anti-red cell antibodies in ATG
Phlebitis can occur when administered through a peripheral vein
Other rare reported side effects are acute haemolysis, massive
pulmonary haemorrhage and adult respiratory distress syndrome,
acute renal failure and renal impairment. If bleeding occurs during ATG,
stop the ATG infusion and give additional platelets. Resume ATG when
bleeding has resolved. Also, check the coagulation screen if bleeding
persists despite adequate platelet increment.
Lymphopenia, neutropenia and thrombocytopenia.

Document Code: EMCN-DC-0183-13 Date of Issue: Feb 13 Review Date: Feb 15
Written By: Prof Russell, Dr Hunter & Dr Mittal C Loughran Authorised by: Page Number: 9/9
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6. Late side effects after administration of ATG due to serum sickness
The onset of serum sickness is typically 7-14 days after starting ATG. If a
second course of ATG is given, serum sickness may occur earlier.
The manifestations of serum sickness are:
Fever, rash (maculopapular or urticarial starting on trunk or
extremities). Serpiginous palmar-plantar distribution is classical. Rash
may become purpuric due to platelet consumption during the time of
serum sickness.
Arthralgia, myalgia, nausea, vomiting, proteinuria (usually mild), rarely
splenomegaly and lymphadenopathy.
Increased platelet transfusion requirements due to platelet
Glycosuria and/or hyperglycaemia due to corticosteroids.

Rarely, worsening of autoimmune thyroid disorders and fibrosing
alveolitis, and precipitation of Guillan Barre syndrome.
AA patients treated with ATG are at increased risk of later clonal
disorders such as MDS, AML and PNH, and to a lesser degree, solid


Guidelines for the diagnosis and management of aplastic anaemia.
BCSH guideline 2009

Facilities for the Treatment of Adults with Haematological Malignancies
Levels of Care
BCSH guidelines 2010

Protocol for the treatment of aplastic anaemia with horse ATG (ATGAM)
KCH/KHP (Professor J Marsh/ Dr A Kulasekararaj; J une 2012)