samarasinghe et al-2012-british journal of haematology

How I manage aplastic anaemia in children

Sujith Samarasinghe1 and David K. H. Webb2

1Paediatric Haematopoietic Stem Cell Transplant Unit, Department of Adolescent and Paediatric Haematology and Oncology, Great

North Childrens Hospital, Royal Victoria Infirmary, Newcastle Upon Tyne, UK and 2Department of Haematology, Great Ormond

Street Hospital, London, UK

Summary

Aplastic anaemia (AA) is a rare heterogeneous condition in

children. 1520% of cases are constitutional and correct

diagnosis of these inherited causes of AA is important for

appropriate management. For idiopathic severe aplastic anae-

mia, a matched sibling donor (MSD) haematopoietic stem

cell transplant (HSCT) is the treatment of choice. If a MSD

is not available, the options include immunosuppressive ther-

apy (IST) or unrelated donor HSCT. IST with horse anti-

thymocyte globulin (ATG) is superior to rabbit ATG and has

good long-term results. In contrast, IST with rabbit ATG has

an overall response of only 3040%. Due to improvements

in outcome over the last two decades in matched unrelated

donor (MUD) HSCT, results are now similar to that of MSD

HSCT. The decision to proceed with IST with ATG or MUD

HSCT will depend on the likelihood of finding a MUD and

the differing risks and benefits that each therapy provides.

Keywords: paediatric aplastic anaemia, inherited bone mar-

row failure syndrome, transplantation in aplastic anaemia,

anti-thymocyte globulin.

Definition

Aplastic anaemia (AA) is defined as pancytopenia with a hyp-

ocellular bone marrow in the absence of an abnormal infil-

trate or marrow fibrosis. To diagnose AA, there must be at

least two of the following: (i) haemoglobin

& Alter, 2010). This triad however is typically absent in early

life and may remain absent even in a subset of adults.

Investigations

To confirm the diagnosis, assess severity and confirm/exclude

constitutional AA, the following investigations are recom-

mended (see Table III). The FBC typically shows pancytope-

nia, although isolated thrombocytopenia may occur early on.

A macrocytic anaemia with reticulocytopenia is normally

present. A bone marrow aspirate shows hypocellular particles,

with increased fat cells, macrophages, mast cells, and plasma

cells. Erythrocytes, megakaryocytes and granulocytes are

reduced or absent. Dyserythopoeisis is very common (Marsh

et al, 2009) but dysplastic megakaryocytes and granulocytes

are not seen in AA. A bone marrow trephine is required to

exclude abnormal fibrosis or an abnormal infiltrate. Baseline

immunological investigations are required as some IBMFS are

associated with immunodeficiency (Dokal, 2000; Dror et al,

2001; Knudson et al, 2005; Filipovich et al, 2010).

Screening for IBMFS

A diagnosis of FA can be confirmed by demonstration of

increased chromosomal breakage following exposure of periph-

eral blood lymphocytes to clastogens, such as mitomycin C or

diepoxybutane (Table IV). All children with AA should have

a clastogen stress test. Somatic reversion of the FA gene

mutation can result in a false negative test (found in at least

10%; Lo Ten Foe et al, 1997). Where there is a high clinical

suspicion, but a negative stress test, the diagnosis of FA can

be confirmed by testing skin fibroblasts for increased chro-

mosomal breakage. Complementation group and mutation

analysis facilitates genetic counselling.

Table II. Classification of aplastic anaemia based on aetiology.

Constitutional

Fanconi anaemia (FA)

Dyskeratosis congenita (DKC)

ShwachmanDiamond syndrome (SDS)

Congenital amegakaryocytic thrombocytopenia (CAMT)

Acquired

Radiation

Drugs and chemicals e.g. chloramphenicol, benzene,

anti-epileptics, chemotherapy

Viruses e.g. Hepatitis (non-A,-B,-C,-E or -G), EpsteinBarr virus

Graft-versus-host disease (GVHD)

Paroxysmal nocturnal haemoglobinuria (PNH)

Immune-systemic lupus erythematous (rare)

Idiopathic

Table I. Classification of aplastic anaemia based on severity.

Severe aplastic anaemia (SAA)

Marrow cellularity

Tab

leIV

.Characteristicsofinherited

bonemarrowfailure

syndromes

that

predispose

toaplasticanaemia.

Syndrome

Age

atpresentation

(years)

Haematologicalfeatures

Nonhaematologicalfeatures

Genemutation/Inheritance

Screening/Diagnostictests

Fanconianaemia

(FA)

Medianage65

(range

049)1

M=F

Progressive

thrombocytopenia

followed

byAA.Macrocytosis

Increasedrisk

ofMDS/AML

Lim

b/thumbabnorm

alities,

cafe-au-laitspots,shortstature,

microcephaly,urogenital

anomalies

Solidtumours

(cumulative

probabilityofmalignancy

by

50years85%)

15genes

(AR/X-linked)

(FANCA,FANCB,FANCC,

BCRA2(FANCD1),FANCD2,

FANCE,FANCF,FANCG,

FANCI,BRIP1(FANCJ),

FANCL,FANCM,PALB2

(FANCN),RAD15C(FANCO)

andSL

X4(FANCP)2

Increasedchromosomal

breakagebyDNAcross

linkers

inhaematopoieticcells(90%

)

orfibroblasts(100%)

Dyskeratosis

Congenita(D

KC)

Medianage14

(range

075)

M>F

AA,macrocytosis,

MDS/AML

90%

developAAbythird

decade

Dystrophicnails,lacy

reticular

pigmentation,oralleucoplakia,

solidtumours,pulm

onary

fibrosis,osteoporosis,cirrhosis

8genes

(AD/AR/X-linked)

Flow-FISH

fortelomerelength

MolecularanalysisofDKC1,

TERC,TERT,NOP10,NHP2,

TIN

F2,C16orf57andWRAP53

(TCAB1)

3

Shwachman

DiamondSyndrome

(SDS)

Range

011

M:F

Neutropenia

(77100%

),

pancytopenia

(1044%),

MDS/AML(1333%)4

Excocrinepancreaticfailure,

metaphysealdysostosis,short

stature

SBDS(90%

)

AR

Decreased

serum

trypsinogen/

isoam

ylase

Reducedstoolelastase

Imagingforfattypancreas

MolecularanalysisofSB

DSgene

Congenital

Amegakaryocytic

Thrombocytopenia

(CAMT)

Range

05

M:F

Thrombocytopenia

with

absentmegakaryocytesin

bonemarrow

Followed

byAAin

majority

5

Usually

nosomatic

abnorm

alities

MPL(thrombopoeitinreceptor

gene)

AR

MolecularanalysisofMPLgene

(However

notallpatientshave

MPLmutations)

M,male;F,female;AA,aplasticanaemia;MDS,

myelodysplasticsyndrome;AML,acute

myeloid

leukaem

ia;AD,autosomaldominant;AR,autosomalrecessive.

1Shim

amura

andAlter

(2010),

2Crossan

andPatel(2012),

3DokalandVulliamy(2010),Walneet

al(2010),Zhonget

al(2011),

4Sm

ithet

al(1996),

5Ballm

aier

andGermeshausen(2009).

28 2012 Blackwell Publishing LtdBritish Journal of Haematology, 2012, 157, 2640

Review

Testing for other IBMFS depends on clinical suspicion.

DKC is typically characterized by the detection of very

short telomeres in blood leucocytes (typically less than the

1st centile for age; Alter et al, 2007). Flow cytometry with

fluorescent in situ hybridization (Flow-FISH) can be used

to screen for abnormal telomere length. However this test

is not currently available as a routine clinical service. Fur-

thermore, not all patients with DKC have short telomeres

(Walne et al, 2010). Alternatively, blood can be sent for

mutation screening but there are probably many unidenti-

fied mutations (Dokal & Vulliamy, 2010). Thus a negative

genetic screen is insufficient to exclude DKC. Children with

mutations in TERC, TINF2 and TERT can present with just

AA, without the other manifestations of DKC; thus it is

reasonable to screen all children with idiopathic AA for

these mutations if the FA screen is negative. The other

genes can be screened for if there are additional features of

DKC (personal communication Inderjeet Dokal, Centre for Pae-

diatrics, Blizard Institute of Cell and Molecular Science, Barts

and The London School of Medicine and Dentistry, London).

If there is a clinical suspicion of ShwachmannDiamond

Syndrome (SDS), exocrine pancreatic insufficiency can be

screened for, though pancreatic function tends to improve

with age. Molecular analysis of the SBDS gene can help con-

firm the diagnosis, though 10% of children with SDS do not

have a mutation in the SBDS gene (Boocock et al, 2003).

Congenital amegakaryocytic thrombocytopenia (CAMT) is

usually diagnosed on clinical features and confirmed by

molecular analysis of the MPL gene (Ihara et al, 1999; Ball-

maier & Germeshausen, 2009).

Differential diagnosis

Around 12% of childhood lymphoblastic leukaemia (ALL)

cases are preceded by a period of pancytopenia, often with a

hypocellular marrow, which subsequently develops into overt

ALL around 19 months later (Breatnach et al, 1981). Dys-

plastic granulopoeitic or megakaryocytes, increased reticulin,

abnormal localization of immature precursors and increased

blasts are seen in hypoplastic myelodysplastic syndrome

(MDS) and not in AA (Bennett & Orazi, 2009). The detec-

tion of monosomy 7 or 5q- should be considered as MDS

(Marsh et al, 2009). The presence of isolated thrombocytope-

nia can make distinguishing between ITP and AA (especially

CAMT) difficult. ITP rather than AA is suggested by the

presence of normal or increased numbers of megakaryocytes

and increased reticulated platelet count.

Key points

AA is a rare disorder. About 7080% of cases are idio-

pathic.

Other potential causes of pancytopenia should be

excluded.

It is important to exclude IBMFS. Their presentation is

heterogeneous and management different to idiopathic

severe aplastic anaemia (SAA).

All children should be screened for FA.

Screening for other IBMFS will depend on clinical suspi-

cion.

Children with SAA and their families should be tissue

typed at diagnosis. If there is no matched family member,

an unrelated donor search should be undertaken.

Management

Transfusional support

Red cell transfusions should be used only to treat definite

symptoms/signs rather than maintain an arbitrary level. Leu-

codepleted blood products (routine in the UK) should be

given to reduce the risk of human leucocyte antigen (HLA)

sensitization. Cytomegalovirus (CMV)-negative blood prod-

ucts should be given until the patients CMV status is

known. The European Bone Marrow Transplant Severe

Aplastic Anaemia Working Party (EBMT SAAWP) currently

recommends that children should receive irradiated blood

products following immunosuppressive therapy (IST) and

that this should continue for as long as they receive ciclospo-

rin (Marsh et al, 2010). Repeated transfusions will lead to

secondary iron overload. Iron chelation should be considered

when the liver iron is >7 mg/g dry weight or when the totalred cell transfusion volume is >200 ml/kg. If liver iron mea-surement is not available, a persistently elevated ferritin level

>1000 lg/l may be used as a surrogate marker of iron over-load, though this is a non-specific marker (Marsh et al,

2009). Deferiprone should be avoided because of the risk of

agranulocytosis. Desferrioxamine or deferasirox are however

suitable iron chelators, the latter having the advantage of oral

administration (Lee et al, 2010). Following successful treat-

ment with IST or HSCT, venesection should be used to

remove excess iron.

Platelet transfusions can be given when the platelet count

is

Infection prevention and treatment

Anti-fungal prophylaxis should be given when the neutrophil

count is

Predictors of response to IST

Good prognostic factors that increase the likelihood of

response to IST include severity [very severe aplastic anaemia

(vSAA) better than SAA; Fuhrer et al, 2005], younger age,

higher pre-treatment reticulocyte count and lymphocyte count

(Scheinberg et al, 2008), male gender, and a leucocyte count

suppression. As late graft rejection is a characteristic com-

plication of HSCT for SAA, ciclosporin should be contin-

ued for at least 9 months, even in the absence of GVHD

and tailed over the following 3 months. Chimerism should

be monitored at 1, 3, 6 and 12 months post-HSCT and

during tapering of immunosuppression. If there is an

increase in recipient cells during this time period, ciclospo-

rin should be increased to maintenance levels and a further

attempt at withdrawal 3 months later (Lawler et al, 2009).

Stable mixed chimerism is associated with very low rates of

chronic GVHD and excellent outcome (McCann et al,

2007). Late effects remain a potential concern. In a single

centre analysis, fertility was preserved in 8090% of females

and c. 60% of males with normal growth (Sanders et al,

2011). Malignancy was reported in 713% on long-term

follow up (Kahl et al, 2005; Sanders et al, 2011). Chronic

GVHD and use of total body irradiation (TBI) regimens

remain the major risk factors for the development of malig-

nancy post-MSD HSCT.

The conditioning regimen for MSD HSCT favoured to

date in the UK is:

1 Cyclophosphamide 50 mg/kg per d 5 to 2 (total dose200 mg/kg).

2 Serotherapy is optional. If serotherapy is used, ale-

mtuzumab is the preferred option, 03 mg/kg per d 6 to4 (total dose 09 mg/kg).

3 Ciclosporin and methotrexate for GVHD prophylaxis.

Methotrexate may be omitted if alemtuzumab is used.

In view of the potential for impaired fertility seen with

high dose cyclophosphamide, an alternative approach is a

fludarabine-based regimen but using a lower dose of cyclo-

phosphamide (fludarabine 150 mg/m2, cyclophosphamide

120 mg/kg and alemtuzumab 09 mg/kg). A small seriesusing a similar approach showed promising results (Resnick

et al, 2006).

Key points

MSD HSCT is first-line therapy for idiopathic SAA.

Serotherapy is optional.

GVHD prophylaxis consists of ciclosporin and methotrex-

ate. Methotrexate may be omitted if alemtuzumab is used.

Serial chimerism should be monitored post-HSCT.

Unrelated donor HSCT

Children who fail IST are eligible for a MUD HSCT. Out-

comes over the last two decades have improved dramatically

for MUD HSCT in SAA (Perez-Albuerne et al, 2008; Viollier

et al, 2008), mainly due to the use of leucodepleted blood

products, improvements in tissue typing donor/recipient and

development of improved conditioning regimens (Maury

et al, 2007). There are currently two approaches to condition-

ing in MUD HSCT: a conditioning regimen incorporating

low dose TBI (2 Gy; Deeg et al, 2006) and a radiation-free

regimen using fludarabine (Bacigalupo et al, 2010). Deeg et al

(2006) demonstrated improved outcomes using a regimen of

2 Gy TBI, cyclophosphamide and ATG compared to higher

doses of TBI. With this regimen, children who were trans-

planted within a year of diagnosis had an 85% survival. The

aim of the low dose TBI regimen was to optimize engraftment

but minimize the long-term side effects associated with irradi-

ation. There was however a relatively high incidence of acute

GVHD (Grade IIIV 70%) and chronic GVHD (62%). The

high levels of GVHD may be partly due to the pro-inflamma-

tory effects of TBI. Administration of TBI also remains a

long-term concern in children because of the effects on fertil-

ity, growth, endocrine problems and potential for malignancy.

This is all the more worrying because of the inherent risk in

SAA to develop malignancy. In order to minimize these long-

term side effects, a radiation-free regimen was developed by

the EBMT (fludarabine 120 mg/kg, low dose cyclophospha-

mide 1200 mg/m2 and rATG 15 mg/kg; Bacigalupo et al,

2005). However this regimen has been complicated by rela-

tively high rates of graft failure in older children (5%

14 years, 32% if 15 years), post-transplant lymphopro-liferative disease (PTLD) and GVHD (Bacigalupo et al, 2005,

2010). In view of these complications, a modified EBMT pro-

tocol is now proposed (aged 14 years and not sensitized,fludarabine 120 mg/kg, cyclophosphamide 120 mg/kg, rATG

75 mg/kg and prophylactic rituximab; 2 Gy TBI is added tothe aforementioned regimen for those patients aged

15 years or sensitized; Kojima et al, 2011).In the UK, there has been considerable enthusiasm for

using alemtuzumab (campath-1H), a monoclonal anti-CD52

antibody. A retrospective analysis of 44 consecutive children

who received HLA-A, -B, -C, -DRB1, -DQ matched unrelated

donor HSCTs using a fludarabine (150 mg/kg), cyclophos-

phamide (120 or 200 mg/kg) and alemtuzumab regimen (091 mg/kg; FCC regimen) demonstrated excellent outcome.

There were no cases of graft failure, with an estimated 5 year

OS/FFS of 95% (Samarasinghe et al, 2012). At a median of

29 years follow up, there was a low rate of severe acuteGVHD (grades IIIIV 23%) and chronic GVHD (68%). Thelow rates of chronic GVHD are similar to other groups who

have also used alemtuzumab-based conditioning regimens

(Marsh et al, 2011). There were no cases of PTLD although

two children did require rituximab because of EpsteinBarr

Virus reactivation. This data, along with that reported by

others (Kennedy-Nasser et al, 2006), suggests that outcomes

following MUD HSCT (10/10 by high resolution typing) for

paediatric SAA are similar to that of MSD. As excellent

engraftment can be achieved in the absence of TBI, the best

approach would involve a radiation-free regimen (such as the

FCC regimen) in an attempt to minimize long-term side

effects. However until long-term data is available, it is difficult

to be certain whether radiation-free regimens will prevent


Review

long-term side effects. Therefore, post-pubertal males receiv-

ing a HSCT should have sperm cryopreserved.

The conditioning regimen recommended by the UK Pae-

diatric BMT group for 10/10 (HLA-A, -B, -C, -DRB1, -DQ

matched by high resolution) MUD HSCT is (FCC regimen):

1 Fludarabine 30 mg/m2 per d for 5 d: days 6 to 2(Total dose 150 mg/m2).

2 Cyclophosphamide 60 mg/kg per d for 2 d: days 3 to2 (Total dose 120 mg/kg).

3 Alemtuzumab 03 mg/kg per d for 3 d: days 6 to 4(Total dose 09 mg/kg: cap dose at 50 mg).With ciclosporin prophylaxis.

Data on mismatched unrelated donor HSCT and unre-

lated donor umbilical cord HSCT in idiopathic SAA is lim-

ited. Retrospective data suggest that single allele mismatched

unrelated donor (MMUD) HSCT have a reasonably good

outcome (78% 2-year OS for 8/8 vs. 60% for 7/8; Eapen &

Horowitz, 2010). Furthermore, with the advent of high reso-

lution typing, single antigen/allele MMUD may have a simi-

lar outcome to MUD HSCT (Yagasaki et al, 2011). Due to

the low cell dose in umbilical cord donations, initial reports

of using unrelated donor umbilical cord HSCT for idiopathic

SAA have been discouraging because of the high graft failure

rate and treatment-related mortality (TRM). OS in the two

largest retrospective analyses to date have ranged from 30%

to 40% (Yoshimi et al, 2008; Peffault de Latour et al, 2011).

Improved results were seen with higher total nucleated cell

(TNC) doses (OS was 45% for TNC > 39 9 107/kg vs. 18%for TNC 39 9 107/kg; Peffault de Latour et al, 2011).An impressive OS was seen in a small series of adults who

received unrelated umbilical cord HSCT using a fludarabine,

melphalan and 4 Gy TBI conditioning regimen (3-year OS of

83%), but these results will need to be confirmed in further

studies (Yamamoto et al, 2011). Selecting units to which the

recipient does not have anti-HLA antibodies may also

improve outcomes (Takanashi et al, 2010).

Key points

MUD HSCT (a HLA-A, -B, -C, -DRB1, -DQ matched

donor on high resolution typing) has an excellent outcome

in idiopathic SAA.

Radiation-free conditioning regimens are favoured in Eur-

ope.

Alemtuzumab-based conditioning regimens have low rates

of chronic GVHD.

Stem cell choice

The recommended stem source is bone marrow. PBSCs lead

to an increased risk of chronic GVHD and inferior outcome

(Schrezenmeier et al, 2007; Eapen et al, 2011). However, use

of alemtuzumab-based conditioning regimens may minimize

the effect of PBSCs on chronic GVHD (Marsh et al, 2011;

Shaw et al, 2011). Umbilical cord stem cells from a MSD are

also acceptable though rarely available.

Key points

Bone marrow is stem cell of choice.

Algorithm for idiopathic paediatric SAA

A recent algorithm for childhood SAA (Marsh et al, 2009)

states that a MSD HSCT is the treatment of choice. Those

children lacking a MSD should receive IST with ATG/ciclo-

sporin as second choice. Should they fail IST (response

assessment at 34 months), then they should proceed with

MUD HSCT as third choice. However, with recent data

demonstrating the low efficacy of rATG and the steady

improvement in MUD HSCT, a new algorithm is proposed

(see Fig 1). In the proposed algorithm, MSD HSCT remains

the first choice. Whether IST or MUD HSCT should how-

ever be second choice is contentious. Advantages of IST

with hATG include excellent long-term survival and low

TRM. However, IST has a significant RR (at least 10%; Sar-

acco et al, 2008), and a 10-year risk of developing a clonal

disorder of between 10% and 15%. Furthermore, IST takes

at least 34 months for cellular recovery, which is particu-

larly relevant if a child develops infectious complications.

MUD HSCT now has an excellent outcome with a much

quicker neutrophil recovery and a marked reduction in

development of secondary clonal disorders and relapse com-

pared to IST (Socie et al, 1993). Although MUD HSCT car-

ries a higher risk of early mortality, the subsequent survival

curve is stable. In contrast, due to the increased risk of sec-

ondary clonal disorders, no such plateau in survival is seen

following IST. Historically, HSCT was associated with the

upfront toxicities of GVHD, graft failure and infectious

complications. With improvements in supportive care, tis-

sue typing and conditioning regimens, the TRM for a

MUD HSCT in children is similar to that of MSD. The dis-

advantage with MUD HSCT includes the time taken to find

a suitable donor (typically 3 months before HSCT can pro-

ceed) and the difficulty finding a MUD in children with

more rare HLA haplotypes.

In those countries where hATG is available, the choice

between IST and MUD HSCT (when a 10/10 MUD donor

exists) will require a careful discussion between the physician

and family regarding the different risks. To help determine

whether one should proceed with hATG or MUD HSCT,

urgent tissue typing should be done and a judgement on the

likelihood of finding a MUD can then be made. Should IST

fail with hATG, the child should proceed directly to MUD

HSCT (see Fig 1). Horse ATG (ATGAM) is not currently

available in Europe, though the EBMT SAAWP is urgently

trying to change this. Until then, in Europe due to the disap-

2012 Blackwell Publishing Ltd 33British Journal of Haematology, 2012, 157, 2640

Review

pointing results with rATG, a MUD HSCT should be consid-

ered as the second choice (where a suitable donor exists).

The EBMT SAAWP have issued similar guidance (EBMTG

SAAWP, 2011).

In the proposed algorithm, IST with rATG/ciclosporin

would be the third choice. The EBMT SAAWP have sug-

gested that rATG be used at 25 mg/kg per d for 5 d ratherthan 375 mg/kg per d for 5 d (http://www.bcshguidelines.com/documents/Use_of_rabbit_ATG_July_2011.pdf) as rATG

is more immunosuppressive than hATG. Single allele/antigen

MMUD may be considered a suitable alternative to IST with

rATG. For those children lacking a suitable unrelated donor

(10/10 or 9/10) and failing IST, possible options include a

second course of ATG, an alternative IST or umbilical cord/

haploidentical HSCT. Alternative IST options include high

dose cyclophosphamide (Brodsky et al, 2010) or ale-

mtuzumab (Risitano et al, 2010). However further studies

are required in children to determine their long-term efficacy

and optimal dosing.

Non-severe aplastic anaemia (NSAA)

Transfusion-independent children with a neutrophil count

above 05 9 109/l should be observed. If they are transfu-sion-dependent, or have a neutrophil count

conditioning regimens were associated with high TRM. As

such, Gluckman et al (1984) proposed the use of a condi-

tioning regimen of low dose cyclophosphamide (2040 mg/

kg) combined with 400600 cGy of thoraco-abdominal irra-

diation or TBI with ciclosporin for GVHD prophylaxis. OS

rates of between 80% and 90% have been reported using this

approach (Dufour et al, 2001; Farzin et al, 2007). FA patients

demonstrate increased propensity to severe GVHD (Guardi-

ola et al, 2004). The occurrence of severe acute GVHD

(grades IIIV) and chronic GVHD strongly increased the risk

of oropharngeal/anogenital squamous cell carcinomas in

long-term FA survivors, with a 15-year incidence of head

and neck cancers of 53% in one series (Guardiola et al,

2004). There is no evidence currently that low dose chemora-

diotherapy conditioning regimens used in FA HSCTs increase

the risk of long-term malignancy. However there has been a

move to avoid irradiation-based conditioning regimens and

incorporate T-cell depletion to minimize the risk of GVHD,

with the aim of reducing the risk of malignancy. A retrospec-

tive comparison of irradiation-based regimens with radia-

tion-free regimens showed no difference in OS (Pasquini

et al, 2008). Prior use of androgens, age >10 years and CMVpositivity in either donor/recipient were adverse factors.

The optimal radiation-free conditioning regimen is

unknown. The favoured conditioning regimen for FA within

the UK incorporates fludarabine and low dose cyclophospha-

mide with serotherapy (de la Fuente et al, 2003). Whether

such regimens can reduce late effects will require long-term

follow up. All matched family donors should be screened

very carefully for FA even if they do not show features of the

disorder. Bone marrow rather than PBSCs is the stem cell of

choice.

Current indications for a MSD HSCT in FA are (please

see www.fanconi.org.uk/clinical-network/standards-of-care/):

1 Significant cytopenia/moderate BMF (haemoglobin

Dyskeratosis congenita (DKC)

Dyskeratosis congenita is an inherited disorder of telomere

maintenance characterized by mucocutaneous abnormalities,

BMF and increased predisposition to malignancy. There is

considerable genetic and phenotypic heterogeneity, which

can make diagnosis difficult (Vulliamy et al, 2006). For a

review of the genetics please see recent article (Dokal & Vul-

liamy, 2010). BMF/immunodeficiency is the major cause of

death, followed by pulmonary complications and malignancy

(Walne & Dokal, 2009). Allogeneic HSCT is the only curative

option for patients with BMF. However, high TRMs were

encountered using myeloablative conditioning regimens. To

counter this, reduced-intensity conditioning (RIC) regimens

have successfully been used (Dietz et al, 2011). However, the

numbers are too small to make any recommendations

regarding the optimal RIC regimen.

For those who lack a MSD or MUD, oxymetholone or

growth factors can be used. The same caveats that guide use

of androgens in FA apply in DKC. GCSF should not be used

with oxymethalone because of the risk of splenic rupture

(Shimamura & Alter, 2010).

ShwachmannDiamond syndrome (SDS)

ShwachmannDiamond syndrome is an autosomal recessive

disorder characterized by exocrine pancreatic insufficiency,

BMF and other somatic abnormalities (especially metaphyseal

dysostosis). A trial of GCSF may be considered to ameliorate

infection or prevent recurrent sepsis. The lowest possible

dose that maintains adequate levels of neutrophils should be

used. No association between GCSF administration and

malignancy has been demonstrated (Rosenberg et al, 2006).

Indications for HSCT include significant cytopenias, transfu-

sion dependence and severe recurrent sepsis secondary to

persistent neutropenia (Burroughs et al, 2009). However,

HSCT in SDS using myeloablative conditioning is associated

with increased TRM. The optimal conditioning regimen is

unknown but small case series have demonstrated the efficacy

of a RIC approach (Bhatla et al, 2008).

Congenital amegakaryocytic thrombocytopenia(CAMT)

This is an autosomal recessive IBMFS characterized by severe

thrombocytopenia at birth with a lack of or absence of

megakaryocytes in the bone marrow. The disorder is charac-

terized by a mutation in the thrombopoeitin receptor (MPL

gene). The diagnosis is one of exclusion; please see the recent

review by Ballmaier and Germeshausen (2009). HSCT from a

MSD after development of SAA has a good outcome (Ball-

maier & Germeshausen, 2009). CAMT patients do not show

increased TRM like FA or DKC patients following myeloab-

lative regimens. Increasing success has also been seen using

unrelated donor HSCTs with RIC regimens, although num-

bers remain small (Tarek et al, 2011).

Acknowledgements

The authors are grateful for Professor Irene Roberts and Dr.

Rod Skinner for reviewing the script.

Author contributions

SS and DW wrote and edited the review.

Financial disclosures

There are no financial disclosures.

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