Samarasinghe Et Al-2012-British Journal of Haematology
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Transcript of Samarasinghe Et Al-2012-British Journal of Haematology
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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
32 2012 Blackwell Publishing LtdBritish Journal of Haematology, 2012, 157, 2640
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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