Pediatric Hematology and Oncology, 30:6170, 2013

ISSN: 0888-0018 print / 1521-0669 online

DOI: 10.3109/08880018.2012.762076

REVIEW

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Gauchers DiseaseA Reappraisal of Hematopoietic

Stem Cell Transplantation
Sawa Ito and A. John Barrett
Hematology Branch, NHLBI, National Institutes of Health, Bethesda, Maryland, United
States

Hematopoietic stem cell transplantation (HSCT), rst performed in 1984, was the rst treatment
approach for Gauchers disease (GD) which had curative intent. The early successes in HSCT were
soon eclipsed by the introduction of a highly eective enzyme replacement therapy (ERT), which
has remained the single most widely used treatment. Experience with HSCT is limited to about 50
reported cases, mainly performed in the last century, with an overall survival around 85%. HSCT
typically achieves complete correction of visceral and bony changes and can fully stabilize neurological features in otherwise progressive type II and III GD. ERT, in contrast, is completely safe and
eective, but is limited by cost, incomplete resolution of visceral, hematological, and bony features in some patients, and lack of neurological correction in type II and III disease. In this review,
we summarize and compare HSCT and ERT. With 20 years of experience of ERT, its limitations as
well as its advantages are now well delineated. Meanwhile progress in HSCT over the last decade
suggests that transplantation would today represent a very safe curative approach for GD oering one time complete correction of the disease, contrasting with the lifelong need for ERT with
its associated expense and dependence on sophisticated drug manufacture. Additionally, unlike
ERT, HSCT can be benecial for neurological forms of GD. We conclude that the time has come to
re-evaluate HSCT in selected patients with GD where ERT is less likely to fully eradicate symptoms
of the disease.
Keywords ERT, Gauchers disease, hematology (nonmalignant), HSCT

INTRODUCTION
Gauchers disease (GD) arose in Ashkenazy Jews from mutations that may have conferred protection against malaria [13]. Unfortunately, the homozygous mutation in glucocerebrosidase leads to a debilitating storage disease with massive accumulation
of -glucocerebrosides in monocyte-derived cells, producing the diagnostic foamy
macrophages (Gaucher cells) seen on bone marrow and liver biopsy. The major target
organs affected by accumulation of -glucocerebrosides are the reticulo-endothelial
system, the bones, and the brain. The most common type is a non-neuropathic form,
type I, presenting in childhood up to adulthood depending on severity. The majority of the patients have N370S allele mutation and the disease is manifest by hepatosplenomegaly, cytopenia, chronic bone pain with intermittent pain crises, and
bony fractures. Type II and III GD have an N444P and other -glucocerebrosides
Received 20 December 2012; accepted 20 December 2012; published online 30 January 2013.
This article is not subject to United States copyright law.
Address correspondence to Sawa Ito, NHLBI, National Institutes of Health, Hematology Branch,
Center Drive Building 10, 20892 Bethesda, USA. E-mail: itos2@nhlbi.nih.gov

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S. Ito and A. J. Barrett

allele mutations which confers neurological involvement [4, 5]. Type II presents in
infancy with major neuropathy, hypertonia, convulsions, and mental retardation.
Death by the age of 2 is common. Type III GD (Norbottnian variant) occurs mainly
in Sweden causing similar severe neurological defects with motor problems and early
death. Beyond supportive care, and splenectomy for hypersplenism, all definitive
treatments aim to correct the clinical manifestations of the disease by replacing the
defective enzyme. Three approaches are possible: (1) allogeneic hematopoietic stem
cell transplantation (HSCT) from a healthy donor which replaces the defective monocytes with hematopoietic stem cells that produce -glucocerebrosidase; (2) enzyme
replacement with intravenous recombinant enzyme linked to mannose to target the
Gaucher cell; and (3) gene therapycorrection of the defect by gene insertion into
hematopoietic stem cells. The first attempts to correct GD in the 1980s used allogeneic
bone marrow transplants as a stem cell source of normal enzyme-competent monocytes, macrophages, and microglia. Subsequently, enzyme replacement therapy (ERT)
was instituted and by the 1990s became the standard treatment approach. General
treatment of GD has been recently reviewed by several authors based on almost 20
year experiences of ERT [68].Gene therapy has not been successfully introduced yet
in GD [9, 10] and is not further discussed here.

ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION

The first successful correction of an inborn error of metabolism by HSCT, in
iduronidase deficiency (Hurlers type 1a), was reported in 1981 [11]. Shortly, afterward,
an unsuccessful attempt of HSCT was made to correct advanced type 3 GD HSCT by
Rappeport et al. in 1984 [12]. Ringden and colleagues at the Karolinska Institute in
Sweden were first to successfully correct a child with type 1 GD by HSCT in 1984 [13].
Subsequently, several groups in Europe reported a small series of HSCT for GD mainly
from matched sibling donors [1417]. Collected HSCT data on eight patients reported
to the European Group for Blood and Marrow Transplantation (EBMT) registry was
summarized in 1995 [16]. Since that time, following the introduction of ERT there have
been only sporadic single case reports of HSCT for GD. The Center for International
Blood and Marrow Transplantation Research (CIBMTR) currently has data on only 50
HSCT for GD (31 Human Leukocyte Antigen (HLA) identical sibling, 9 family members, and 10 unrelated) between 1983 and 2009 with only 7 reported this century. The
majority of patients transplanted were under the age of 10. Conditioning regimens
have mainly used busulfan and cyclophosphamide combinations with cyclosporine
and methotrexate given as graft-versus-host disease (GVHD) prophylaxis (Table 1).
Although the data on HSCT for GD remains scanty these published reports allow us
to draw some general conclusions about the correction of disease manifestations as
summarized below.

Hematological Features
Full engraftment is associated with complete hematological correction of GD with
a progressive loss of GD cells in marrow and liver, a process which may take many
months before the last foamy macrophage is eliminated [13]. While hematological engraftment has been rapid in splenectomized patients, transplantation in patients with
intact spleens can result in prolonged pancytopenia, which contributed to the death
of one patient [15]. Subsequent to this event, Hobbs et al. recommended splenectomy
prior to HSCT.

Pediatric Hematology and Oncology

Author
Rappeport

Hobbs

Hoogerbrugge

Tsai

Chan

Year
1984

1989

1991

1992

1994

Canada

EBMT

USA

N
1

UK

Country
USA

I (1)

III (1)

I (8)

I (6)

Type
of disease
(n)
III (1)
Donor
type
MRD

2.5

0.69.7

MRD

MRD

N/A

10.5
MRD (6)
(5.516)

Median
age, year
(range)
8

BM

BM

N/A

BM

Stem cell
source (n)
BM

Median
follow-up,
Conditioning
GVHD
year
Biochemical
regimen
prophylaxis Engraftment GVHD (n) (range)
response
Clinical response
Bu/Cy/ATG
MTX
Engrafted Minimal
1
Normalized
No change in
aGVHD
enzyme
hepatomegaly,
activity by day
no change in
28
Gauchers
complications
Bu/Cy
CSA
5 engrafted, Mild skin
1.5 (0.15 All 5 engrafted
All 5 engrafted
1 not
aGVHD
3.3)
patients had
patients had
evaluable
(5),
normalized
full active life,
mild
enzyme
resolved bone
skin
activity in 6
pain and
cGVHD
months
hepatomegaly
(2)
N/A
N/A
N/A
N/A
0.210.2 Evaluable 3
All resolved
patients had
hepatomegaly,
normalized
bone pain, and
enzyme
improved
activity
growth delay
Bu/Cy/ATG
MTX
Engrafted
No
2
Plasma enzyme
No change in
activity
developmental
normalized by
quotient and
day 150;
strabismus but
however, the
EEG irritable
brain tissue
pattern
enzyme
disappeared
activity was
low on autopsy
Bu/Cy
CSA+MTX Delayed
No
2
Enzyme activity
Bone pain
graft
normalized in
resolved,
failure
3 months, but
normal activity
back to
and
baseline in 9
accelerated
months
physical
growth

TABLE 1 Published Case Series of Hematopoietic Stem Cell Transplantation for Gauchers Disease and CIBMTR Report

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14

21

16

11

(Continued on next page)

Survived

Died from S
pneumonia
sepsis 24
months
posttransplant

N/A

5 survived, 1 died
from
aspergillosis

Survival
Reference
Died from sepsis
12
early
posttransplant

UK

Sweden

CIBMTR

Young

Ringden

CIBMTR

1997

2006

2012

50

N
6

N/A

N/A

I (5),
III
(3)

N/A

N/A

N/A

N/A

4 (<138) MRD (31), BM (45), CB

MUD
(4), PBSC
(10),
(1)
Other
related
(9)

N/A

7.6
(1.716.5)

Donor
Stem cell
type
source (n)
MRD (4),
BM
5/6MRD(1),
7/8
MUD(1)

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

Clinical response
Survival
All 5 engrafted
All survived
patients had
marked
growth spurt,
decreased liver
size, favorable
psychological
development
8.1
Plasma
All 5 type 1
All survived
(5.512)
chitotriosidase
patients are
activity fell by
well and
9398% by
asymptomatic.
2 years in 7
One type 3 had
patients < 500
residual
nmol/h
skeletal
problem
1422
Two being well,
Four survived
one BO and
seizure, one
seizure
N/A
N/A
N/A
N/A

Median
follow-up,
Conditioning
GVHD
year
Biochemical
regimen
prophylaxis Engraftment GVHD (n) (range)
response
Cy/TBI or
CSA or CSA Five enI-aGVHD
2-i11
All 5 engrafted
Bu/Cy
+ MTX
grafted,
(4),
patients
ATG
one
Mild
normalized
rejection
skin
enzyme
cGVHD
activity by 1
(1)
year

18

23

17

Reference
13

Data including the cohort from Hobbs and Ringden.

Data including the cohort from Hobbs.

Follow-up data from the same cohort reported by Ringden in 1995.

The data presented here are preliminary and were obtained from the Statistical Center of the Center for International Blood and Marrow Transplant Research. The
analysis has not been reviewed or approved by the Advisory or Scientific Committee of the CIBMTR.
Abbreviations: MRD, matched related donor; MUD, matched unrelated donor, BM, bone marrow; CB, cord blood; PBSC, peripheral blood stem cell; Bu, busulfan; Cy,
cyclophosphamide; MTX, methotrexate; ATG, antithymocyte globulin; TBI, total body irradiation. CSA, cyclosporine; aGVHD, acute graft-versus-host disease; cGVHD,
chronic graft-versus-host disease.

Country
Sweden

Author
Ringden

Year
1995

Type
of dis- Median
ease
age, year
(n)
(range)
I (2),
2.5 (29)
III
(4)

TABLE 1 Published Case Series of Hematopoietic Stem Cell Transplantation for Gauchers Disease and CIBMTR Report (Continued)

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Gauchers DiseaseA Reappraisal of Hematopoietic Stem Cell Transplantation

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Biochemical Changes
Several reports attest to the rapid normalization of -glucocerebrosidase and disappearance of -glucocerebrosides breakdown compounds and a long-term normalization of chitotriosidase in eight patients studied [17].
Bony Manifestations of Disease
A remarkable and recurrent finding is the extensive bony remodeling that can be
achieved after HSCT with complete normalization of long-bone defects and a disappearance of painful crises and bone fractures. Most notable in the study by Starer et al.
[18] was the rapid improvement in performance status, with early loss of bone pain
leading to increased mobility, decrease in hepatomegaly occurring over the first 612
months posttransplant and finally a slower but complete resolution of radiological
bony changes. The complete correction of the defect was reflected by normalization
of enzyme levels. Some patients, however, with preexisting kyphosis have not shown
complete remodeling [13, 15].
Neurological Forms of GD
Patients with type II and III GD can benefit from HSCT provided the transplant is given
before irreversible neurological deficit occurs. Early splenectomy in the Norbottnian
form of GD leads to rapid neurological deterioration. Nevertheless, HSCT was shown
to be successful in at least stabilizing, and in some cases, completely correcting neurological changes in four patients [13, 17, 19]. Against these impressive clinical outcomes
is the observation from an autopsy of a patient who died 24 months post HSCT who
showed low -glucocerebrosidase level in the brain tissue (despite no progression of
neurological symptoms) [20]. In the absence of larger studies, we conclude that the
role of HSCT in type II and II GD remains to be fully evaluated.
Transplant-related Mortality
Of reported deaths one was due to pancytopenia [12], and two from septicemia [15,
20]. Notably, there were no deaths from acute or chronic GVHD. Overall survival in
reports complied from institutes throughout Europe, reported to the EBMT was 85%
[16]. These results are comparable to the outcome for large series of contemporaneous patients with beta thalassemia transplanted in the last century where (depending
on risk category) survivals in the region of 7595% were achieved in children using
comparable transplant regimens and HLA identical sibling donors [21].
Long-term Outcomes and Quality of Life
The two largest series from Sweden [13, 22] and UK [15] report four of five and five of six
engrafted patients, respectively, becoming long term survivors. The longest follow-up
reported following HSCT for GD was 22 years [22]. Patients with full chimerism show
no recurrence of GD features and are reported in at least 2 studies to have excellent
quality of life with no long-term sequelae, or complications from GVHD.
ERT
The concept of ERT for GD was introduced by Brady et al. in 1974 [23]. The single infusion of placenta derived gluco-glucocerebrosidase significantly decreased
biomarkers in two patients. In 1991, placenta-derived, macrophage-targeted glucocerebrosidase, alglucerase, was approved by U.S. Food and Drug Administration (FDA) as the first ERT for GD based on the small case series of 12 patients who
demonstrated clinical efficacies measured by improvements of anemia and thrombocytopenia and reductions of hematosplenomegaly [24]. Soon afterward, Imiglucerase,

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S. Ito and A. J. Barrett

the Chinese hamster ovary cell-derived recombinant -glucocerebrosidase was approved by FDA in 1994 [25] after showing the comparative efficacy and safety to those
of alglucerase in randomized controlled study. Subsequent confirmation of long-term
efficacy and safety [2628] made ERT as a standard, first line therapy for the patient
with symptomatic type I GD. The established therapeutic efficacy of ERT includes (1)
improvement of anemia and thrombocytopenia (with intact spleen) in 612 months,
(2) decrease in size of liver by 3040% and spleen by 5060% in 25 years, (3) normalization of growth patterns in children [29]. Although the bone pain and pain crisis was
significantly reduced after ERT [27, 30], the morphological changes in bones persist
even several years after ERT. Indeed 3948% patients still reported bone pain after ERT.
Bone mineral density slowly normalizes in a dose dependent manner after 8 years of
ERT [31]. Two quality of life studies [32, 33] reported up to 25% of patients had persistent physical activity limitation and low health-related quality of life (HRQOL) even
after full adherence to ERT especially those with irreversible skeletal disease. These results contrast with another study which reported normalization of HRQOL and physical component summary 2 years after HRT [27]. Although ERT in GD is well tolerated
with minimal side effects, the life-long dependency on frequent intravenous drug and
the substantial cost of imiglucerase creates socio-economical challenges in both patients and health care providers. Furthermore, an unforeseen shortage of imiglucerase
in June 2009 due to the viral contamination of manufacturing plants caused a significant reduction of the drug supply to the patients [34]. The crisis highlighted the risk
of reliance on a single treatment agent in the absence of alternative therapies. After
the crisis, a new generation ERT, velaglucerase alfa derived from a human cell line
was approved with accelerated access in 2010, based on one phase I/II open label
trial [35, 36]. Another new ERT, plant derived-taliglucerase achieved both hematological response and spleen/liver size reduction, especially with higher dose 60 IU/kg in
a phase 3 randomized parallel dose comparison trial, and was recently approved by
FDA. The oral substrate reduction agent, miglustat is not as effective as ERT, but may
play a role in maintenance after intensive ERT achieves stable disease [37, 38]. Since
both recombinant enzyme and substrate reduction therapy (SRT) are unable to penetrate the blood brain barrier, ERT and SRT are not effective for the neuropathic type
of GD [4, 5].
HSCT VERSUS ERT
There have been no trials controlled, randomized, or quasirandomized trials describing long-term outcome of HSCT in GD [39, 40] and with almost no contemporaneous
data on HSCT for GD, comparisons of these radically different methods to correct GD
are difficult. On the one hand, HSCT appears to have the advantage over ERT in being a
single lifelong solution to the disease offering complete normalization of hematological, bony, and also neurological features. In contrast, ERT shows a spectrum of efficacy
with great individualization in the frequency of enzyme replacement needed and degree of correction. Furthermore, ERT is ineffective against neurological forms of GD.
There are also cost considerations; HSCT representing a single large up-front expenditure, contrasting with the annual cost of expensive therapy given for life. A hiatus in
the availability of ERT led to periods of deterioration and symptom recurrence in GD
patients and some countries can less easily afford ERT and provide it on a regular basis.
A recent study from the UK estimated the cost of ERT treatment at around 120,000 to
180,000 ($200,000$300,000) per annum [41]. A stem cell transplant in the UK is estimated to cost around 100,000. Comparability of cost to the health provider would,
therefore, be reached within a year posttransplant. Against these constraints is the
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Gauchers DiseaseA Reappraisal of Hematopoietic Stem Cell Transplantation

almost guaranteed safety of ERT, which was the prime motivator for the rapid fall off in
enthusiasm for HSCT with its perceived high mortality, when ERT became available.
Thus, most reviews on GD treatment have largely avoided discussion of HSCT [8, 29,
38], although conservatively others have recommended HSCT to be considered in
neurological forms of GD and in those failing enzyme treatment, or patients unable
to obtain ERT in their country of origin [42, 43].
In the last decade new data has become available that makes it important to reconsider the relative roles of HSCT and ERT. Firstly, HSCT has become safer. Given
the historically remarkably low complication rates of HSCT for GD, it seems likely
that an 85% overall survival could be readily surpassed today. In the absence of sufficient direct data, we must turn to other large groups of HSCT for nonmalignant disorders to provide estimates of outcome in the modern era. Recently, the CIBMTR
reported long-term survival data of 348 patients with inborn errors of metabolism
who survived 2 years after HSCT [44]. Although there is significant diversity of disease types, the 7-year overall survival was 90% (95% CI, 8693%) and active chronic
GVHD beyond 2 years after transplantation was only reported in 12% of the patients.
Furthermore, most enzyme defects occur widely throughout the body involving not
only cells of hematopoietic origin but nonhematopoietic cells which are not replaced
following HSCT. GD represents a special case where the enzyme defect is confined to
cells of hematopoietic origin and substitution of a healthy marrow can completely replace all the defective cells. Because many more patients have been transplanted for
hemoglobinopathies than for inborn errors, we have chosen HSCT for -thalassemia
as the yardstick for potential success of HSCT for GD in the twenty-first century. Over
the last 30 years, outcome of HSCT for -thalassemia has improved to reach survival rates of 93% [45, 46]. Furthermore, comparable outcomes to HLA identical sibling transplants can now be achieved from unrelated donors or from umbilical cord
blood [4749]. Success in -thalassemia HSCT has now encouraged an increasing
number of centers to explore HSCT in sickle cell anemia, notably in adults with preexisting tissue damage [50, 51]. New transplant regimens which achieve only mixed
chimerism have almost no mortality, even in patients with multisystem failure. Results of HSCT for GD in the last century were very encouraging and it is reasonable
to assume that current survival rates with a wider range of donor types as used for
HSCT for hemoglobinopathies should be reproducible in similar modern HSCT approaches for GD. Furthermore, the apparent low rate of GVHD in GD HSCT raises
the question whether the GD foamy macrophage is defective not only in inflammatory function but also as an antigen presenting cell (APC) to the donors immune system [52]. Animal data indicates that host marrow-derived APC are central to the initiation of GVHD being the principle route for alloantigen presentation and recognition by incoming host cells [53, 54]. It is possible that the metabolic abnormalities
of GD APC lead to defective antigen presentation leading to a lower risk of GVHD.
This possibility deserves exploration in in vitro studies. Secondly, mature data is now
available on the long term outcomes of ERT [26, 27, 37, 41, 55]. It is now clear that
there is a wide range of the degree of correction achieved. Thus, some patients continue to have a diminished quality of life, despite maximum optimization of their
therapy. Long-term complications associated with persisting incomplete correction
are emerging such as Parkinsons disease [5658], aseptic necrosis, and continuing
risk from bony fractures [59]. In contrast, complications from HSCT are largely in
the first few years. Beyond 5 years, most survivors have lost any features of cGVHD,
and have a high QOL. Cardiovascular disease, however, may be an increasing risk in
1020 year survivors [6062]. From what we know about long-term outcomes from
HSCT in nonmalignant disorders, late effects are less frequent and second cancers

S. Ito and A. J. Barrett

in the absence of TBI are not clearly more frequent than that expected in the general
population [63].

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MOVING FORWARD
While some authorities suggest that HSCT could be offered to patients failing ERT and
those with neurological defects, the very low number of reports of HSCT for GD implies that these suggestions are not being followed. We, therefore, propose a reevaluation of HSCT in GD in the context of a prospective clinical trial comparing the two approaches. HSCT should be modeled on successful treatment of hemoglobinopathies
and conservatively could be restricted to children under the age of 10 (who have the
best outcomes for HSCT) and those who show incomplete responses to ERT. The treatment options today for GD are strongly reminiscent of the situation for -thalassemia
patients in the 1980s where expensive but effective transfusion/chelation therapy was
strongly balanced against the rapid correction at a risk offered by the transplant approach. Eventually the more conservative transfusion/chelation approach gave way
to more widespread use of HSCT. The time has come to open a similar debate for the
treatment of GD.
Declaration of Interest
The authors report no conflicts of interest. The authors alone are responsible for the
content and writing of the paper.
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