doi:10.1111/jpc.

14996

REVIEW ARTICLE

Aplastic anaemia: Current concepts in diagnosis and management

1
Eliska Furlong and Tina Carter1,2,3
1
Department of Paediatric and Adolescent Haematology, Oncology, Blood and Marrow Transplantation, Perth Children’s Hospital, 2Division of Paediatrics,
School of Medicine, University of Western Australia and 3Paediatric and Adolescent Haematology Service, PathWest Laboratory Medicine WA, Perth,
Western Australia, Australia

Aplastic anaemia is a rare, previously fatal condition with a significantly improved survival rate owing to advances in understanding of the
pathophysiology and improved treatment strategies including haematopoietic stem cell transplantation. Although a rare condition, aplastic anaemia
continues to present a high burden for affected patients, their families and the health system due to the prolonged course of disease
often associated with high morbidity and the uncertainty regarding clinical outcome. Modern molecular and genetic techniques including
next-generation sequencing have contributed to a better understanding of this heterogeneous group of conditions, albeit at a cost of increased com-
plexity of clinical decision-making regarding prognosis and choice of treatment for individual patients. Here we present a concise and comprehensive
review of aplastic anaemia and closely related conditions based on extensive literature review and long-standing clinical experience. The review takes
the reader across the complex pathophysiology consisting of three main causative mechanisms of bone marrow destruction resulting in aplastic
anaemia: direct injury, immune mediated and bone marrow failure related including inherited and clonal disorders. A comprehensive diagnostic algo-
rithm is presented and an up-to-date therapeutic approach to acquired immune aplastic anaemia, the most represented type of aplastic anaemia, is
described. Overall, the aim of the review is to provide paediatricians with an update of this rare, heterogeneous and continuously evolving condition.

Key words: aplastic anaemia; haematopoietic stem cell transplantation; inherited bone marrow failure syndrome; myelodysplasia.

Aplastic anaemia results from a destruction of haematopoietic cells aplastique’ was first used in 1904 by Louis Henri Vaquez, a French
by a variety of mechanisms ranging between direct environmental physicist and remained somewhat misleading terminology for a
insults, dysregulated immune system or an underlying inherited or condition mostly presenting with pancytopenia.
acquired bone marrow failure predisposition. The term ‘anaemia

Key Points
1 Recent advances in understanding and management of aplastic
anaemia have resulted in significantly increased survival rate of
once fatal disease. Nonetheless, the medical and psycho-social
burden remains high due to the prolonged course of the disease
associated with high morbidity and outcome uncertainty.
2 Modern molecular and genetic methods including next-
generation sequencing have become a powerful tool in under-
standing and diagnosing the condition, albeit at a cost of
increase complexity of clinical decision-making.
3 Aplastic anaemia is a rare heterogeneous group of conditions
necessitating multidisciplinary evidence-based clinical
approach supported by ongoing research, clinical trials and
centralisation of data in national and international registries.
Correspondence: Dr Eliska Furlong, Department of Paediatric and Ado-
lescent Haematology, Oncology, Blood and Marrow Transplantation, Perth
Children’s Hospital, 15 Hospital Avenue, Nedlands, WA 6009, Australia.
Fax: +08 6456 2360; email: eliska.furlong@health.wa.gov.au
Conflict of interest: None declared.
Accepted for publication 21 May 2020.
Definition
Aplastic anaemia (AA) is a descriptive term used for a combination
of hypoplastic or aplastic bone marrow and a variable degree of
paucity in at least two of the three main cell lines: red cells, white
cells and/or platelets. The severity of AA is based on the Camitta
criteria, postulated more than 40 years ago1 (Table 1).
Epidemiology
AA is a rare condition, with an estimated incidence rate of 2–2.3
cases/million per year. The incidence in Asia is two to threefolds
higher reaching up to 7.4 cases/million per year.2 In almost all
population-based studies the sex ratio is close to 1:1. There seem
to be two main peaks of age incidence, one among young adults
(20–25 years) and a second in the elderly. The median age at
diagnosis among children and adolescents is 8–9 years.3
Pathophysiology
There are three main mechanisms that can lead to the develop-
ment of AA: (i) direct injury; (ii) immune mediated; and
(iii) bone marrow failure related that can be inherited or acquired
(Table 2).

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Aplastic anaemia E Furlong and T Carter

Table 1 Definition and severity of aplastic anaemia based on the Table 2 Overview of pathophysiological mechanisms leading to
Camitta criteria. aplastic anaemia

Classification Criteria 1. Direct injury

Drugs
Severe Bone marrow (BM) cellularity <25% (or <50% if <30% Chemotherapy agents
of BM are haematopoietic cells) Anticonvulsants
And two or more of the following: Carbamazepine, phenytoin
Peripheral blood neutrophil count <0.5 × 109/L Antibiotics
Peripheral blood platelet count <20 × 109/L Sulphonamides, chloramphenicol
Peripheral blood reticulocyte count <20 × 109/L Anti-thyroid
Very severe As above, but peripheral blood neutrophil count Methimazole
must be <0.2 × 109/L Non-steroidal anti-inflammatory drugs
Non-severe Hypocellular BM with peripheral blood values not Indomethacin, phenylbutazone
meeting criteria for severe aplastic anaemia Other anti-inflammatory
Gold
Chemicals
Benzene, solvents, glue vapours, pesticides
Radiation
Direct injury Infection
Sepsis
Damage to the bone marrow can be iatrogenic and dose depen-
Viral
dent, as with chemotherapy and radiotherapy, resulting in a
Hepatitis A, B and C, parvovirus B19, HIV, Epstein-Barr virus,
predictable temporary state of reduced haematopoiesis. Some cytomegalovirus
drugs can have an idiosyncratic and possibly permanent effect, Infiltration
sometime occurring many weeks after the cessation of the Malignant disease
treatment.4–6 Haematological
Hepatitis-associated AA (haAA) usually develops 2–3 months Metastatic
post an episode of acute hepatitis, is often seronegative and Non-malignant
accounts for up to 10% of all cases of AA.7 An expansion of nar- Hemophagocytic lymphohistiocytosis
row spectrum T-cell receptor lymphocytes during the acute phase Depletion
Haematinic and other vitamin deficiency
of hepatitis-associated AA and its diminishing with immunosup-
Vitamin B12, folic acid, ferritin, vitamin D
pressive treatment suggests an immune-mediated mechanism in
Anorexia nervosa
this type of AA.8 2. Immune mediated
Acquired immune aplastic anaemia
Systemic auto-immune disease
Immune mediated Systemic lupus erythematosus
Eosinophilic fasciitis
Most cases of AA do not have a clear cause and have been Thymoma
labelled idiopathic. The immune mechanism of impaired Constitutional immune dysregulation
haematopoiesis in the so-called acquired idiopathic or immune CTLA-4 deficiency
DADA2
AA (iAA) has long been suspected based on observational clinical
GATA2 deficiency
and laboratory findings as well as animal studies.9 It seems that
3. Bone marrow failure related
cytotoxic T cells are at the centre of the dysregulated immune
Inherited bone marrow failure syndromes
system, either directly (activation of apoptosis via Fas/FasL path- Fanconi anaemia
way) or indirectly (increased INF-γ, TNF-α production) destroying Dyskeratosis congenita
haematopoietic stem cells.10 Regulatory T-cells are reduced in Shwachman–Diamond syndrome
patients with iAA and increase with effective treatment.11 Diamond–Blackfan anaemia
iAA is associated with specific histocompatibility antigens Congenital amegakaryocytic thrombocytopenia
(HLA).12 A clonal expansion of cells within the bone marrow car- Pearson syndrome
rying an acquired loss of heterozygosity at the HLA site of chro- Severe congenital neutropenia
Thrombocytopenia absent radii
mosome 6 can be found in up to 15% of patients with iAA, likely
Ataxia-pancytopenia syndrome
driven by selective advantage of sustained haematopoiesis.13 An
MECOM-associated syndrome
immune drive has also been hypothesised in the evolution of
Clonal disorders
glycosylphosphoinositol (GPI)-anchored protein deficient clones Paroxysmal nocturnal haemoglobinuria
characteristic for paroxysmal nocturnal haemoglobinuria (PNH), Myelodysplasia
a rare form of clonal haematopoietic stem cell disorder clinically Refractory cytopenia of childhood
manifesting as haemolytic anaemia and thrombosis. GPI-deficient
clones can be found in up to 50% of patients with iAA. Unlike in CTLA-4, cytotoxic T-lymphocyte associated antigen; DADA2, deficiency
patients with PNH, these tend to be small and rarely cause clinical of adenosine deaminase 2.
manifestations in patients with iAA.14

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E Furlong and T Carter Aplastic anaemia

Peripheral blood
amenable to prompt diagnosis. Nonetheless, these can be very sub-
(pan)cytopenia tle or even absent resulting in delayed diagnosis if not considered.
+/- low reticulocyte count

Bone marrow trephine Clonal evolution and myelodysplasia

Morphology AA often co-exists with an appearance of distinctive cell clones
hypoplasia/aplasia
dysplasia
arising from the bone marrow. These presumably emerge under
a selective immune pressure as suggested in the case of GPI-
deficient PNH clones and clones with loss of heterozygosity in 6p.
Other haematopoietic clones bear somatic mutations in genes
commonly associated with myelodysplastic syndrome (MDS) and
acute myeloid leukaemia (AML). These typically increase with
age and can be found in up to one third of adult patients with
Bone marrow aspirate
Cytogenetics/FISH AA.20 Favourable prognosis has been associated with more stable
chromosomal abnormalities clones with somatic mutations in PIGA (PNH clones), BCOR
Molecular studies
IBMFS associated mutations
and BCORL1. Other mutations such as DNMT3A and ASXL1 are
MDS/AML associated mutations associated with faster progression to AML and unfavourable
prognosis.21
Peripheral blood
UE+C, LFT Evidence of clonal expansion is reflected in cytogenetic abnor-
CRP, ESR
ANA, anti-ds DNA, RF, C3, C4
malities, present in up to 11% of patients with AA at the time of
CT chest IgG, IgA, IgM diagnosis. Some of these are typically associated with MDS/AML
CT/US abdomen TFT
lymphoproliferative Hepatitis, HIV, EBV, CMV, Parvovirus B19 and bear poor prognosis, such as −7/del(7q) and −5/del(5q);
disease LDH, Uric acid
Ferritin others are more benign and might be amenable to immunosup-
ECG
ECHO
Vitamin B12, folic acid, Vitamin D pressive therapy (IST) (see below), such as +Y and +8.22
Flow cytometry
constitutional disease
detection of PNH clones MDS among children and adolescents is very rare, with an
lymphocyte subsets annual incidence of 1–4 cases/million. The most common type of
Chromosomal fragility test
Fanconi anaemia paediatric MDS, refractory cytopenia of childhood (RCC), pre-
Telomere length studies sents with thrombocytopenia and/or neutropenia, and hypoplas-
Dyskeratosis congenita
tic bone marrow and as such needs to be considered in the
Immune aplastic anaemia differential diagnosis of patients with AA.23 Contrary to iAA,
Diagnosis of exclusion
HLA typing
RCC is typically associated with elevated mean corpuscular vol-
ume, moderately increased haemoglobin F and evidence of line-
Fig 1 Investigations included in the diagnostic algorithm of a patients age dysplasia, such as presence of micromegakaryocytes in the
with suspected aplastic anaemia. marrow.24 Most paediatric patients with RCC do not have associ-
ated chromosomal abnormalities with the exception of mono-
somy 7 found in about 11% of those who frequently present
with normocellular or hypercellular marrow.25
Some primary immunodeficiencies, such as cytotoxic T-lymphocyte
associated antigen (CTLA-4) and deficiency of adenosine deaminase
2 (DADA2) deficiencies, have been associated with the development of Diagnosis and Clinical Presentation
iAA as part of complex immune dysregulation comprising of autoim-
Patients typically present with non-specific symptoms resulting
munity and persistent infections with unusual organisms.15,16 GATA2
from associated cytopenia such as low energy levels, pallor and
deficiency, characterised by defective haematopoietic cell differentia-
headaches with anaemia; mucosal bleeding, bruising/petechiae,
tion and self-renewal, is associated with AA as well as clonal evolution
menorrhagia with thrombocytopenia and fever with or without
to myeloid malignancies alongside an increased susceptibility to
evidence of an infection with neutropenia (Fig. 1).
mycobacteria and papilloma viruses.17 Up to 70% of patients with
Detailed history and clinical examination are particularly perti-
GATA2 deficiency are found to have monosomy 7, a poor prognostic
nent in establishing a possible environmental or genetic cause.
marker associated with aggressive myeloid malignancies.18
Family history of unexplained foetal deaths, poor growth, develop-
mental delay and phenotypic abnormalities (i.e. absent thumbs,
Bone marrow failure related abnormal nails) should alert the clinician to the possibility of an
IBMFS.
Inherited bone marrow failure syndromes Bone marrow examination, including both the aspirate and
Inherited bone marrow failure syndromes (IBMFS) are a group of trephine, is mandatory for establishing the diagnosis. A finding of
inherited conditions that, similarly to the earlier described GATA2 hypoplastic or aplastic marrow supports the diagnosis of AA but
deficiency, are associated with an increased risk of progressing to might be difficult to distinguish from IBMFS or hypoplastic MDS.
AA and clonal myeloid dysplasia. Examples of such conditions are Cytogenetic studies including fluorescence in situ hybridisation
Fanconi anaemia and dyskeratosis congenita, resulting from loss- (FISH) can assist in elucidating the diagnosis. Next-generation
of-function germline mutations affecting the ability to repair DNA sequencing (NGS) panels have become increasingly important in
and telomeres, respectively.19 These congenital syndromes are establishing the diagnosis and are available in most tertiary
typically associated with abnormal physical features making them centres.

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Aplastic anaemia
Peripheral blood investigations aimed at excluding alternative
causes of cytopenia such as viral infection, auto-immune disease,
vitamin deficiencies and malignant disease should be performed.
Lymphocyte subsets and immunoglobulin levels can be abnormal
in the setting of a primary immunodeficiency. PNH clones can be
easily detected by flow cytometry. Increased chromosomal break-
age in patients with Fanconi anaemia can be detected by per-
forming the diepoxybutane test. Telomere length studies are
available in a limited number of centres for the detection of short
telomeres, a hallmark of dyskeratosis congenita.
Treatment
Treatment strategies for iAA, the most represented type of AA,
are described. It is beyond the scope of this review to describe
treatment of IBMFS-associated AA and myelodysplasia. Gener-
ally, allogeneic haematopoietic stem cell transplantation (HSCT)
is the only curative option for patients with an IBMFS-associated
AA and patients with MDS.
Severe iAA (sAA) requires prompt treatment aiming at re-
establishing bone marrow function. Patients with non-sAA
require regular and long-term follow-up as up to two thirds of
them will progress to sAA.26 There are two main ways of
treating iAA.
Haematopoietic stem cell transplantation
HSCT is the preferred and curative treatment option for patients
with iAA considering late clonal disorders such as MDS and AML
occurring in up to 15% of patients initially treated with IST.27
Excellent survival rates of more than 90% in young children and
more than 80% in adolescents have been achieved with HLA-
matched sibling donor (MSD) HSCTs, involving a low rate of
short- and long-term complications such as graft-versus-host dis-
ease (GVHD).28,29
Early identification of a fully HLA-matched unrelated donor
(MUD) using international registries might prompt an up-front
MUD HSCT, especially in paediatric patients where comparable
result to MSD HSCT have been achieved, including a low inci-
dence of GVHD.30,31
Bone marrow is the preferred source of progenitor cells for
both the MSD and MUD HSCT over peripheral blood stem cells
due to considerably lower occurrence of acute and chronic
GVHD.32 Umbilical cord transplantation has been successfully
used in the treatment of iAA, particularly in children due to the
lower absolute progenitor cell count required relative to weight,
with survival rates averaging 90%.33 The major disadvantage has
been delayed engraftment and prolonged neutropenia, increasing
the risk of severe and potentially fatal infections.
Recent advances in transplant conditioning and donor cell
manipulations using T-cell depletion strategies have made half-
matched (haploidentical) donors a potential source for bone mar-
row transplantation (HAPLO HSCT). Although the survival rates
are encouraging, the rate of GVHD and possible late effects
remain high.34,35 HAPLO HSCT should only be considered for
patients who failed at least one course of IST and lack suitable
matched unrelated or cord blood donors.
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E Furlong and T Carter
Immunosuppressive therapy
In the absence of an MSD or alternatively a promptly identified
and available MUD, IST with horse anti-thymocyte globuline and
cyclosporine A remains the first-line choice of treatment for iAA.
The long-term survival rate in children who respond to IST is
comparable to those who have received an up-front MSD
HSCT.36 The overall response rate at 6 months post IST is 74%.
Relapse occurs in approximately 30% of patients but usually
responds to further immunosuppression, although not sustain-
able long term.37 Patients who have failed a first course of IST
should proceed to a MUD or umbilical cord transplantation when
available.
Interestingly, in the absence of a suitable HSCT donor, IST has
been used in the treatment of hypocellular RCC with a similar
rate of response at 6 months but a higher relapse rate of nearly
50%.38 This is in keeping with previous findings suggestive of an
overlap between iAA and RCC.39,40
Many efforts have been made to improve the efficacy of the
anti-thymocyte globuline based immunosuppressive regimen.
The addition of granulocyte-colony stimulating factor failed to
improve overall response rates or long-term outcomes and so
have agents such as mycophenolate mofetil or sirolimus.41
Contrary to that, a synthetic analogue of thrombopoietin,
eltrombopag, has been shown to significantly improve recov-
ery and response rates, and has now become an IST additional
therapeutic agent.42
Supportive Care
Transfusions
Most patients with sAA require regular red blood cell and platelet
transfusions. Transfusion thresholds are usually set by institu-
tional guidelines and guided by international policies. Special
attention should be paid to patients awaiting HSCT where
repeated transfusions can lead to allo-immunisation and an
increased risk of graft failure.43 The use of leukocyte-depleted
blood products has significantly decreased, although not
completely eliminated this risk.44 HLA-antibodies should be mea-
sured in case of inadequate increments post platelet transfusions
and HLA-matched single donor apheresis concentrates should be
used if HLA-antibodies have been detected.45 All blood products
for patients with AA should be irradiated to reduce the risk of
transfusion-associated GVHD and allo-sensitisation. Generally,
there is no need for cytomegalovirus (CMV)-negative products as
leukocyte-depleted blood products are considered to be suitable
for haematological patients including patients undergoing HSCT.
Exceptions are CMV-negative patients undergoing HSCT with a
CMV-negative donor, where most institutions choose to use
CMV-negative blood products.46
Prevention and treatment of infections
Patients with sAA are at high risk of developing invasive fungal
infections due to prolonged periods of severe neutropenia.47 Pro-
phylactic anti-fungals should be used in all patients with sAA,
posaconazole being considered more effective than fluconazole
for its extended mould species cover.48 Febrile neutropenia is a
E Furlong and T Carter
haematological emergency and is managed as per institutional
guidelines with broad spectrum antibiotics. Prolonged fever and
neutropenia should prompt investigations for a suspected fungal
infection such as galactomannan testing and computed tomogra-
phy scans, as well as broadening anti-fungal agents.
Although using myeloid growth factors has proven to be
ineffective in the overall treatment of AA, granulocyte-colony
stimulating factor is often used during episodes of prolonged
neutropenia and fever where a fungal infection is suspected
as it may temporarily increase the neutrophil count. In life-
threatening infections, the use of granulocyte transfusions
may be considered as an adjunctive therapy taking in consid-
eration limited evidence and potentially significant side
effects.49
There are no general recommendations for prophylaxis against
Pneumocystis jirovecii. Most centres use P. jirovecii prophylaxis post
IST as well as routinely in patients undergoing HSCT. Similarly,
many centres choose to use antiviral prophylaxis against CMV
and Epstein-Barr virus in patients post IST as per standard HSCT
guidelines.50
Psycho-social support
Despite significant advances in the understanding and manage-
ment of AA, the course of the condition remains difficult. Fre-
quent transfusions and hospital checks are required during the
time of establishing diagnosis and searching for suitable HSCT
donors as well as in recovery phase. Patients undergoing HSCT
might develop GVHD or other associated complications. Patients
post IST are at risk of not responding to the treatment or later
relapsing. Prolonged periods of neutropenia put patients at risk of
severe fungal infections requiring lengthy hospitalisations and
further provoking anxiety about the outcome.
Ongoing psycho-social support for patients with AA and their
families is an indispensable part of the disease management
within a multidisciplinary specialist centre facilitating communi-
cation, reassurance and comfort during the course of the disease
and long-term follow-up.
Summary
Recent advances in understanding the pathophysiology and
improved treatment strategies including HSCT have contributed
to a significantly increased survival of patients with AA, once an
inevitably fatal disease. Despite the progress, the medical and
psycho-social burden for patients with AA, their families and the
health system remain high due to the nature of the disease asso-
ciated with prolonged periods of hospitalisation, requirement for
ongoing supportive care and the possibility of treatment failure.
Modern molecular and genetic methods including next-
generation sequencing have undoubtedly improved our under-
standing of this heterogeneous group of conditions, and become a
powerful tool in establishing the diagnosis. Increased identification
of rare genetic mutations in patients with AA has brought a new
dimension to the complex decision-making regarding prognosis and
appropriate treatment for individual patients supported by limited
long-term experience of these very rare disorders.
The rarity and heterogeneity of AA highlights the necessity
of multidisciplinary approach supported by ongoing research,
Journal of Paediatrics and Child Health (2020)
© 2020 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)
Aplastic anaemia
well-established clinical trials and centralisation of data in
national and international registries.
Acknowledgements
The authors express their gratitude to Professor Catherine Cole
for her long-standing dedication to patients with AA and shared
knowledge; and to Dr Shanti Ramachandran who kindly
reviewed the summary of latest approach to AA and the role of
haematopoietic stem cell transplantation.
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