Safety and efficacy of enzyme replacement therapy in combination with hematopoietic stem cell transplantation in Hurler syndrome.
ABSTRACT Hurler syndrome is a debilitating genetic disease with a typical life span of 5 to 8 years. Early hematopoietic stem cell transplantation (HSCT) mitigates disease symptoms and improves survival. However, morbidity and mortality associated with HSCT can limit its success. We describe the initial experience with combined use of enzyme replacement therapy (ERT, laronidase) and HSCT in Hurler syndrome.
Thirteen transplants were performed in 12 patients. ERT was given at a standard dose of 0.58 mg/kg per week. Transplant conditioning regimen and donor graft source were determined by institutional protocol.
The median age at initiation of ERT was 12 months (range, 8 to 18 months). The median duration of pre-HSCT ERT was 12 weeks (range, 4 to 28). All but 1 patient tested showed decrease in urinary GAG excretion during ERT. ERT infusion-related toxicity was limited to mild reactions. Development of antibodies to laronidase did not correlate with infusion reactions or responses in urinary GAG excretion. ERT was given for a median of 7 weeks (range, 3 to 20) after HSCT. After transplantation, eight patients demonstrated complete donor engraftment and four suffered graft failure. Two patients required ventilator support and three developed acute GVHD. Eleven of the 12 patients are surviving with a median follow-up of 3 months (range, 1 to 7 months).
In children with Hurler syndrome, ERT with HSCT is feasible and well tolerated. Development of antibodies against exogenous enzyme does not appear to correlate with infusion reactions or response to ERT. A prospective study is needed to determine the effect of concomitant ERT on transplant outcomes.
- SourceAvailable from: Shunji Tomatsu[Show abstract] [Hide abstract]
ABSTRACT: Patients with mucopolysaccharidoses (MPS) have accumulation of glycosaminoglycans in multiple tissues which may cause coarse facial features, mental retardation, recurrent ear and nose infections, inguinal and umbilical hernias, hepatosplenomegaly, and skeletal deformities. Clinical features related to bone lesions may include marked short stature, cervical stenosis, pectus carinatum, small lungs, joint rigidity (but laxity for MPS IV), kyphoscoliosis, lumbar gibbus, and genu valgum. Patients with MPS are often wheelchair-bound and physical handicaps increase with age as a result of progressive skeletal dysplasia, abnormal joint mobility, and osteoarthritis, leading to 1) stenosis of the upper cervical region, 2) restrictive small lung, 3) hip dysplasia, 4) restriction of joint movement, and 5) surgical complications. Patients often need multiple orthopedic procedures including cervical decompression and fusion, carpal tunnel release, hip reconstruction and replacement, and femoral or tibial osteotomy through their lifetime. Current measures to intervene in bone disease progression are not perfect and palliative, and improved therapies are urgently required. Enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), and gene therapy are available or in development for some types of MPS. Delivery of sufficient enzyme to bone, especially avascular cartilage, to prevent or ameliorate the devastating skeletal dysplasias remains an unmet challenge. The use of an anti-inflammatory drug is also under clinical study. Therapies should start at a very early stage prior to irreversible bone lesion, and damage since the severity of skeletal dysplasia is associated with level of activity during daily life. This review illustrates a current overview of therapies and their impact for bone lesions in MPS including ERT, HSCT, gene therapy, and anti-inflammatory drugs. Copyright © 2014 Elsevier Inc. All rights reserved.Molecular Genetics and Metabolism 12/2014; · 2.83 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Mucopolysaccharidoses (MPSs) are a group of rare inherited metabolic diseases caused by genetic defects in the production of lysosomal enzymes. MPSs are clinically heterogeneous and are characterized by progressive deterioration in visceral, skeletal and neurological functions. This article aims to review the classification and pathophysiology of MPSs and discuss current therapies and new targeted agents under development. A Medline search through PubMed was performed for relevant articles and treatment guidelines on MPSs published in English for years 1970 to September of 2013 inclusive. The references listed in the identified articles, prescribing information of the drugs approved for the treatment of MPSs, as well as recent clinical trial information posted on Clinicaltrials.gov website, were reviewed. Until recently, supportive care was the only option available for the management of MPSs. In the early 2000s, enzyme replacement therapy (ERT) was approved by the United States Food and Drug Administration (FDA) for the treatment of MPS I, II and VI. Clinical trials of ERT showed substantial improvements in patients' somatic symptoms; however, no benefit was found in the neurological symptoms because the enzymes do not readily cross the blood-brain barrier (BBB). Haematopoietic stem cell transplantation (HSCT), another potentially curative treatment, is not routinely advocated in clinical practice due to its high risk profile and lack of evidence for efficacy, except in preserving cognition and prolonging survival in young patients with severe MPS I. In recent years, substrate reduction therapy (SRT) and gene therapy have been rapidly gaining greater recognition as potential therapeutic avenues. Enzyme replacement therapy (ERT) is effective for the treatment of many somatic symptoms, particularly walking ability and respiratory function, and remains the mainstay of MPS treatment. The usefulness of HSCT has not been established adequately for most MPSs. Although still under investigation, SRT and gene therapy are promising MPS treatments that may prevent the neurodegeneration not affected by ERT.Journal of Clinical Pharmacy and Therapeutics 02/2014; · 2.10 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Mucopolysaccharidosis type I can be classified as three clinical sub-types; Hurler syndrome, Hurler-Scheie syndrome and Scheie syndrome, with the scale of severity being such that Hurler syndrome is the most severe and Scheie syndrome the least severe. It is a rare, autosomal recessive disorder caused by a deficiency of alpha-L-iduronidase. Deficiency of this enzyme results in the accumulation of glycosaminoglycans within the tissues. The clinical manifestations are facial dysmorphism, hepatosplenomegaly, upper airway obstruction, skeletal deformity and cardiomyopathy. If Hurler syndrome is left untreated, death ensues by adolescence. There are more attenuated variants termed Hurler-Scheie or Scheie syndrome, with those affected potentially not presenting until adulthood. Enzyme replacement therapy has been used for a number of years in the treatment of Hurler syndrome, although the current gold standard would be a haemopoietic stem cell transplant in those diagnosed by 2.5 years of age. To evaluate the effectiveness and safety of treating mucopolysaccharidosis type I with laronidase enzyme replacement therapy as compared to placebo. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register, MEDLINE via OVID and EMBASE.Date of most recent search: 08 February 2013. Randomised and quasi-randomised controlled trials of laronidase enzyme replacement therapy compared to placebo. Two authors independently screened the identified trials. The authors then appraised and extracted data. One study of 45 patients met the inclusion criteria. This double-blind, placebo-controlled, randomised, multinational trial looked at laronidase at a dose of 0.58 mg/kg/week versus placebo in patients with mucopolysaccharidosis type I. All primary outcomes listed in this review were studied in this trial. The laronidase group achieved statistically significant improvements in per cent predicted forced vital capacity compared to placebo, MD 5.60 (95% confidence intervals 1.24 to 9.96) and in the six-minute-walk test (mean improvement of 38.1 metres in the laronidase group; P = 0.039, when using a prospectively planned analysis of covariance). The levels of urinary glycoaminoglycans were also significantly reduced. In addition, there were improvements in hepatomegaly, sleep apnoea and hypopnoea. Laronidase antibodies were detected in nearly all patients in the treatment group with no apparent clinical effect and titres were reducing by the end of the study. Infusion-related adverse reactions occurred in both groups but all were mild and none necessitated medical intervention or infusion cessation. The current evidence demonstrates that laronidase is effective when compared to placebo in the treatment of mucopolysaccharidosis type I. The included trial was comprehensive and of good quality, although there were few participants. The trial included all of the key outcome measures we wished to look at. It demonstrated that laronidase is efficacious in relation to reducing biochemical parameters (reduced urine glycosaminoglycan excretion) and improved functional capacity as assessed by forced vital capacity and the six-minute-walk test. In addition glycosaminoglycan storage was reduced as ascertained by a reduction in liver volume. Laronidase appeared to be safe and, while antibodies were generated, these titres were reducing by the end of the study. More studies are required to determine long-term effectiveness and safety and to assess the impact upon quality of life. Enzyme replacement therapy with laronidase can be used pre- and peri-haemopoietic stem cell transplant, which is now the gold standard treatment in those patients diagnosed under 2.5 years of age.Cochrane database of systematic reviews (Online) 11/2013; 11:CD009354. · 5.94 Impact Factor
Safety and efficacy of enzyme replacement therapy
in combination with hematopoietic stem cell
transplantation in Hurler syndrome
Satkiran S. Grewal, MD1, Robert Wynn, MD, MRCP2, Jose E. Abdenur, MD3, Barbara K. Burton, MD4,
Maged Gharib, MD2, Claudia Haase, MD5, Robert J. Hayashi, MD6, Shalini Shenoy, MD6, David Sillence, MD7,
George E. Tiller, MD8, Martha E. Dudek8, Annet van Royen-Kerkhof, MD9, James E. Wraith, MD10,
Paul Woodard, MD11, Guy A. Young, MD3, Nico Wulffraat, MD, PhD9, Chester B. Whitley, PhD, MD1, and
Charles Peters, MD1
Purpose: Hurler syndrome is a debilitating genetic disease with a typical life span of 5 to 8 years. Early
hematopoietic stem cell transplantation (HSCT) mitigates disease symptoms and improves survival. However,
morbidity and mortality associated with HSCT can limit its success. We describe the initial experience with
combined use of enzyme replacement therapy (ERT, laronidase) and HSCT in Hurler syndrome. Methods: Thirteen
transplants were performed in 12 patients. ERT was given at a standard dose of 0.58 mg/kg per week. Transplant
conditioning regimen and donor graft source were determined by institutional protocol. Results: The median age
at initiation of ERT was 12 months (range, 8 to 18 months). The median duration of pre-HSCT ERT was 12 weeks
(range, 4 to 28). All but 1 patient tested showed decrease in urinary GAG excretion during ERT. ERT infusion–related
toxicity was limited to mild reactions. Development of antibodies to laronidase did not correlate with infusion
reactions or responses in urinary GAG excretion. ERT was given for a median of 7 weeks (range, 3 to 20) after
HSCT. After transplantation, eight patients demonstrated complete donor engraftment and four suffered graft
failure. Two patients required ventilator support and three developed acute GVHD. Eleven of the 12 patients are
surviving with a median follow-up of 3 months (range, 1 to 7 months). Conclusions: In children with Hurler
syndrome, ERT with HSCT is feasible and well tolerated. Development of antibodies against exogenous enzyme
does not appear to correlate with infusion reactions or response to ERT. A prospective study is needed to
determine the effect of concomitant ERT on transplant outcomes. Genet Med 2005:7(2):143–146.
Key Words: Hurler syndrome, mucopolysaccharidosis, enzyme replacement therapy, laronidase, hematopoietic
stem cell transplantation.
Mucopolysaccharidosis type I (MPS I) is caused by an
inherited deficiency of the lysosomal enzyme ?-L-iduroni-
dase, which results in accumulation of partially degraded
glycosaminoglycans (GAGs) in lysosomes and their excre-
tion in urine.1Hurler syndrome (MPS IH) represents the
most severe phenotype of MPS I and is characterized by
progressive multisystem manifestations including obstruc-
tive airway disease, cardiac manifestations, hydrocephalus,
poietic stem cell transplantation (HSCT) can reverse the
airway obstruction, prevent certain aspects of the cardiac
disease, stabilize learning ability, and increase longevity.2–4
However, morbidity and mortality inherent to HSCT limit
its benefits. As a group, children with Hurler syndrome are
particularly susceptible to pulmonary complications in the
early period after HSCT.5,6
ble therapeutic option in MPS I.7,8Laronidase (recombinant
human ?-L-iduronidase) infusions reduce abnormal and ex-
hepatomegaly and urinary GAG excretion and improvements
in upper airway obstruction as well as lung function tests.7,8
However, a limitation of intravenous ERT is its inability to
the central nervous system directly.
From the1Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota;
2Royal Manchester Children’s Hospital, Manchester, United Kingdom;3Children’s Hospital
of Orange County, Orange, California;4Children’s Memorial Hospital, Chicago, Illinois;
5Children’s Hospital University, Jena, Germany;6St. Louis Children’s Hospital, St. Louis,
ics, Vanderbilt University Medical Center, Nashville, Tennessee;9Wilhelmina Children’s
Hospital, Utrecht, the Netherlands;10Willink Biochemical Genetics Unit, Manchester, UK;
and11St. Jude Children’s Research Hospital, Memphis, Tennessee.
Satkiran S. Grewal, MD, Pediatric Blood and Marrow Transplantation, University of Min-
nesota, 420 Delaware St. SE., MMC 477, Minneapolis, MN, 55455.
Received: July 23, 2004.
Accepted: November 4, 2004.
February 2005 ? Vol. 7 ? No. 2
b r i e f r e p o r t
Genetics IN Medicine
As ERT can mitigate airway and pulmonary manifestations
of MPS I, we hypothesized that ERT before and after HSCT
would decrease transplant-related complications in Hurler
children. We describe the initial multi-institution experience
using ERT and HSCT combination therapy in Hurler
We received data from nine institutions on 12 HSCTs in-
volving 11 children with Hurler syndrome. In addition, data
on one patient was captured from an abstract.10The diagnosis
of Hurler syndrome was established by clinical features and
deficient activity of leukocyte ?-L-iduronidase. Enzyme re-
placement therapy with laronidase was infused once a week at
a standard dose of 0.58 mg/kg. Preparative regimens for the
transplant procedure were determined by the participating
centers. Institutional review boards approved all treatment
Patient characteristics and transplant-related outcomes are
summarized in Table 1.
Enzyme replacement therapy
Infusion-associated reactions were seen in two patients
during the pre-HSCT infusion phase; these were limited to
flushing and hives in one patient and fever with vomiting in
another. The intensity of reactions did not increase with
subsequent infusions. An additional patient had a single
infusion-associated reaction only after HSCT (rash and hy-
potension), which did not recur. At baseline, titers of anti-
body against laronidase were negative in all five patients
evaluated. Follow-up evaluations were available in three of
these patients: two patients (patients 2 and 8) were subse-
quently tested for development of antibodies during ERT;
both developed positive titers, but neither had infusion-
associated reactions and both showed progressive decreases
in urinary GAG excretion. The third patient (Patient 1),
who did not develop any infusion-associated reactions, was
subsequently evaluated for antibodies 12 weeks after HSCT
and was found to have positive titers.
Baseline (before initiation of ERT) urinary GAGs were ele-
therapy were performed in seven patients. During the pre-
exception was Patient 4). In three of these six patients, the
levels of urinary GAG further declined to the normal range
Apnea/hypopnea index (by polysomnogram) or high-risk
Summary of patient, enzyme replacement, and transplant characteristics
Duration of ERT
regimen for HSCT
engraftment Acute GvHD
1. ND18 mo24 weeks Bu, CyR-BM 3 mo 12 weeksalive completeno nono
2.ND9 mo 12 weeksBu, Cy, FluU-BM 7 mo4 weeksalivecompleteYes, grade IIYes, for 12 daysno
3.ND8 mo 8 weeks
R-BM 1 mo3 weeks alivecomplete nono no
W402X, W402X15 mo10 weeks
bFlu, Cy, ATG
1 mo4 weeksDeadFailed
Yes, till death
13 mo6 weeks Bu, Cy, FluR-PBSC6 mo 20 weeksalivecompleteYes, grade II no no
6. ND 14 mo16 weeksBu, Cy, ATGU-BM3 mo8 weeksalivecompleteyesnono
9 mo12 weeks
U-BM1 mo12 weeksalivecompletenonono
8 mo12 weeks
R-BM4 mo12 weeks alivefailed nono no
9. ND 18 mo14 weeks Bu, Cy, FluU-BM 3 mo4 weeksalivecompleteNo datanono
10.ND16 mo24 weeksBu, Cy, ATGUCB5 moYesalivefailednonono
11.ND10 mo28 weeksBu, Cy, ATGU-BM1.5 moYesalivefailednono
12.A327P, W402X11 mo4 weeks
R-PBSC3 mo6 weeksalivecomplete nonono
aAge, age at initiation of ERT;bRepresents a reduced intensity conditioning regimen.
Abbreviations: ND, not done; mo, months; for donor graft: UCB, unrelated cord blood; U-BM, unrelated bone marrow; R-BM, related donor bone marrow;
ATG, anti-thymocyte globulin; Complete engraftment, ? 90% donor; failed engraftment, ? 10% donor. 4a and 4b represent the two transplants in patient 4.
Grewal et al.
Genetics IN Medicine
night time oxygen requirement) was noted in 8 of the 12 pa-
tients at presentation. Follow-up sleep apnea studies were
available in two patients. One child (Patient 1), who demon-
strated a sleep study without apnea or hypopnea, showed nor-
mal sleep studies when tested after 24 weeks of ERT, and
child (Patient 5) showed moderate obstructive sleep apnea at
baseline; a repeat study was done 6 months after HSCT, which
showed marked improvement. Cardiomyopathy was diag-
nosed in one patient before initiation of ERT, which resolved
after 14 weeks of ERT before HSCT.
Eleven patients received a single hematopoietic stem cell
1; in five patients, a reduced-intensity conditioning regimen
was used. The median time to recovery of neutrophil count to
Two of the four transplants with failed donor engraftment
were performed using reduced intensity conditioning regi-
mens; this included Patient 4, who subsequently engrafted
with donor cells after a second HSCT using a myeloablative
Two patients developed respiratory failure after HSCT. Pa-
tient 2, with an abnormal sleep study before initiation of ERT,
manifested respiratory failure 7 days after stem cell infusion,
which was diagnosed as a rapid engraftment pulmonary syn-
drome; the child required ventilator support for 12 days. Pa-
tient 4, who did not have a high-risk respiratory history, re-
quired ventilator support 6 days after second HSCT; major
post-HSCT complications at time of ventilator support in-
cluded venoocclusive disease and pulmonary hemorrhage; the
patient died 1 month after second HSCT due to multiorgan
HSCT can stabilize long-term neurocognitive function and
improve survival in children with Hurler syndrome.2–4,11
ity. Enzyme replacement therapy can significantly reduce ab-
normal GAG deposits in MPS I; however, as it does not pene-
term treatment in Hurler children. The rationale for the
combined use of ERT and HSCT in Hurler syndrome was
based on (1) the high risk of pulmonary complications with
HSCT in the early posttransplant period,5,6and (2) the symp-
tomatic benefit of ERT in terms of reducing upper airway ob-
struction as well as improving lung function in patients with
MPS I.7,8This led to the hypothesis that ERT in combination
ticularly pulmonary complications. We present the first mul-
ticenter report on the preliminary experience with ERT and
HSCT for Hurler syndrome.
In two previous trials of laronidase ERT in MPS I patients,
infusion-related toxicity was frequent but typically mild; reac-
tions during subsequent infusions usually became less com-
typically involved subjects with less severe clinical phenotypes
of MPS I (i.e., Scheie and Hurler-Scheie syndromes), and sug-
neutralizing and do not effect efficacy.12Similar to these data,
in our series of 12 patients with Hurler syndrome, infusion-
associated reactions were infrequent and mild. Three patients
had follow-up data on antibody titers after initiation of ERT;
all three developed positive titers against the enzyme. Interest-
ingly, none of these three patients developed hypersensitivity
reactions and all showed decline in urine GAG concentration.
of ERT on the donor engraftment. In this series, 4 of the 13
transplants were associated with failure of donor engraftment.
Of the three patients who developed positive antibody titers
Due to the different preparative regimes and donor sources
used in this series, it is not possible to conclude what effect, if
any, pretransplant ERT had on donor engraftment. However,
these data are consistent with engraftment results from larger
multi-institutional series of HSCT (without ERT) in Hurler
syndrome in which donor-derived engraftment varied from
63% after unrelated donor transplants to 72% after related
Children with Hurler syndrome are at higher risk for pul-
monary and airway related complications, especially in the
early period after HSCT. Data from a single center study of 74
children with Hurler syndrome undergoing HSCT showed a
31% incidence of ventilator intervention and 14% risk of seri-
ous pulmonary hemorrhage in the first 100 days after HSCT.5
Another center observed major pulmonary hemorrhage re-
quiring ventilatory support in 3 of 15 children with Hurler
syndrome in the first weeks after HSCT.6We speculated that
the addition of ERT would decrease the risk of pulmonary
ever, could not provide sufficient data to determine whether
ERT protected the patients from pulmonary complications.
In summary, the data from this multi-institutional series
nation with HSCT is feasible and relatively safe. The develop-
ment of antibodies did not affect efficacy of ERT in terms of
reduction of urinary GAG concentration. It is hypothesized
that ERT in the peritransplant period would reduce the trans-
plant-related morbidity and mortality in children with Hurler
ther study, preferably a multinational, multicenter collabora-
suggest that this study address the following issues: (1) should
Enzyme therapy with transplant in Hurler syndrome
February 2005 ? Vol. 7 ? No. 2
all patients affected with Hurler syndrome be candidates for
appropriate duration of ERT before transplant, (3) what is the
appropriate duration of ERT after stem cell infusion, and
should that duration be modified under any specific circum-
presence of acute graft vs. host disease); and (4) how can we
best evaluate outcomes associated with combined ERT and
HSCT, compared to HSCT, alone in patients with Hurler
1.Neufeld E, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly
WS, Valle D, eds. The metabolic and molecular bases of inherited disease. 8th Ed.
New York: McGraw-Hill, 2001:3421–3452.
of unrelated donor bone marrow transplantation in 40 children with Hurler syn-
drome. Blood 1996;87:4894–4902.
Peters C, Shapiro EG, Anderson J, Henslee-Downey PJ, Klemperer MR, Cowan MJ
et al. Hurler syndrome: II. Outcome of HLA-genotypically identical sibling and
HLA-haploidentical related donor bone marrow transplantation in fifty-four chil-
dren: The Storage Disease Collaborative Study Group. Blood 1998;91:2601–2608.
4. Staba SL, Escolar ML, Poe M, Kim Y, Martin PL, Szabolcs P et al. Cord-blood
Orchard PJ, Milla CE, Grewal SS, Braunlin EA, Defor TE, Krivit W et al. Determi-
nation of high-risk factors in allogeneic transplantation for Hurler syndrome [ab-
stract]. WORLD Lysosomal diseases research network symposium 2004:20.
Gassas A, Sung L, Doyle JJ, Clarke JT, Saunders EF. Life-threatening pulmonary
hemorrhages post bone marrow transplantation in Hurler syndrome. Report of
three cases and review of the literature. Bone Mar Trans 2003;32:213–215.
Kakkis ED, Muenzer J, Tiller GE, Waber L, Belmont J, Passage M et al. Enzyme-
replacement therapy in mucopolysaccharidosis I. N Engl J Med 2001;344:182–188.
Wraith JE, Clarke LA, Beck M, Kolodny EH, Pastores GM, Muenzer J et al. Enzyme
replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded,
placebo-controlled, multinational study of recombinant human alpha-L-iduroni-
dase (laronidase). J Pediatr 2004;144:581–588.
Shull RM, Kakkis ED, McEntee MF, Kania SA, Jonas AJ, Neufeld EF. Enzyme re-
placement in a canine model of Hurler syndrome. Proc Natl Acad Sci USA 1994;91:
(MPS IH): enzyme replacement therapy pre-bone marrow transplantation. Mol
Genet Metabol 2004;81:168–169.
Whitley CB, Belani KG, Chang P-N, Summers CG, Blazar BR, Tsai MY et al. Long-
term outcome of Hurler syndrome following bone marrow transplantation. Am J
Med Genet 1993;46:209–218.
Kakavanos R, Turner CT, Hopwood JJ, Kakkis ED, Brooks DA. Immune tolerance
after long-term enzyme-replacement therapy among patients who have mucopo-
lysaccharidosis I. Lancet 2003;361:1608–1613.
Grewal et al.
Genetics IN Medicine