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Blood, Vol. 91 No. 7 (April 1), 1998:
pp. 2601-2608
Hurler Syndrome: II. Outcome of HLA-Genotypically Identical
Sibling and HLA-Haploidentical Related Donor Bone Marrow
Transplantation in Fifty-Four Children
By
Charles Peters,
Elsa G. Shapiro,
James Anderson,
P. Jean Henslee-Downey,
Martin R. Klemperer,
Morton J. Cowan,
E. Fred Saunders,
Pedro A. deAlarcon,
Clare Twist,
James B. Nachman,
Gregory A. Hale,
Richard E. Harris,
Marta K. Rozans,
Joanne Kurtzberg,
Guy H. Grayson,
Thomas E. Williams,
Carl Lenarsky,
John E. Wagner,
William Krivit, and
the members of The Storage Disease Collaborative Study
Group
From The Storage Disease Collaborative Study Group, Department of
Pediatrics, Division of Bone Marrow Transplant, University of
Minnesota, Minneapolis.
 |
ABSTRACT |
Untreated patients with Hurler syndrome (MPSIH) experience
progressive neurologic deterioration and early death. Allogeneic bone
marrow transplantation (BMT) ameliorates or halts this course. The
Storage Disease Collaborative Study Group was formed to evaluate the
effectiveness and toxicity of BMT. Effectiveness was defined as
engrafted survival with continuing cognitive development. Fifty-four patients deficient in leukocyte  -L-iduronidase enzyme
activity (median age, 1.8 years; range, 0.4 to 7.9) received high-dose chemotherapy with or without irradiation and BMT from HLA-genotypically identical sibling (GIS) or HLA-haploidentical related (HIR) donors between September 16, 1983 and July 14, 1995; all children were included in this report. Thirty-nine of 54 patients (72%) engrafted following the first BMT. The probability of grade II to IV acute graft-versus-host disease (GVHD) at 100 days was 32% for GIS and 55%
for HIR patients. The probability of extensive chronic GVHD was 0% for
GIS and 24% for HIR patients. The actuarial probability of survival at
5 years was 64% for all patients, 75% for GIS patients, 53% for HIR
patients, and 53% for patients with donor marrow engraftment. The
baseline Mental Developmental Index (MDI) was examined both for
children less than and greater than 24 months of age at BMT. Children
transplanted before 24 months had a mean baseline MDI of 78, while
those transplanted after 24 months had a mean baseline MDI of 63 (P = .0002). Both baseline and post-BMT neuropsychologic data were available for 26 of 30 engrafted survivors. Of 14 patients transplanted before 24 months of age, nine demonstrated developmental trajectories that were normal or somewhat slower than normal. In
contrast, of 12 patients transplanted after 24 months of age, only
three showed developmental trajectories that were normal or somewhat
slower than normal (P = .01). For children with a baseline
MDI greater than 70, there was a significant correlation between the
MDI at follow-up study and leukocyte -L-iduronidase enzyme activity (P = .02). Children were more likely to
maintain normal cognitive development if they were fully engrafted
following BMT from a donor with homozygous normal leukocyte
-L-iduronidase enzyme activity. Children who developed
acute GVHD of grade II or worse had significantly poorer cognitive
outcomes (P < .009). No difference in the post-BMT MDI was
observed between patients whose preparative therapies did (n = 10;
radiation dose, 300 to 1,400 cGy) or did not (n = 16) include
radiation. We conclude that MPSIH patients, particularly those less
than 24 months of age with a baseline MDI greater than 70, can achieve
a favorable long-term outcome with continuing cognitive development and
prolonged survival after successful BMT from a related donor with
homozygous normal enzyme activity.
| |
INTRODUCTION |
HURLER SYNDROME (MPSIH) is an autosomal
recessive inborn error of metabolism due to a deficiency of
-L-iduronidase enzyme activity, which results in
accumulation of heparan sulfate and dermatan sulfate substrates.
Progressive hepatosplenomegaly, cardiac disease, severe skeletal
abnormalities, hydrocephalus, and mental retardation result in
substantial morbidity and early death, often by 5 years of
age.1
Hematopoietic stem cell transplantation corrects enzymatic deficiencies
in selected lysosomal and peroxisomal disorders.2 While
hundreds of children with storage diseases, including nearly 200 patients with MPSIH, have received allogeneic bone marrow transplantation (BMT) worldwide, reports have described relatively small cohorts of patients.3-7 Recently, The Storage Disease
Collaborative Study Group described its experience using unrelated
donor (URD) BMT in MPSIH patients.8 We now report our
experience with HLA-genotypically identical sibling (GIS) and
HLA-haploidentical related (HIR) donor BMT in 54 MPSIH patients. The
Storage Disease Collaborative Study Group's data on these and 40 URD
BMT patients represent the largest such collective experience in MPSIH.
| |
SUBJECTS AND METHODS |
Patients, preparative regimens, and transplantation.
Children deficient in leukocyte -L-iduronidase enzyme
activity received GIS or HIR donor BMT with preparative regimens
determined by the transplant centers. Patient characteristics are
summarized in Table 1. Parental consent was obtained for
all patients, and protocols were approved by the institutional review
boards. Forty-six of these patients (23 GIS and 23 HIR) have been
briefly described in a previous publication.5 Furthermore,
11 of these 23 GIS patients were also reported by Whitley et
al.4
Prophylaxis and grading of graft-versus-host disease.
Bone marrow grafts were depleted of T lymphocytes (TLD) ex vivo by a
variety of methods for 14 of 26 HIR BMTs (Table 1).9-13 Various drugs were used for graft-versus-host disease (GVHD)
prophylaxis (Table 1). The severity of acute GVHD was diagnosed and
graded according to Glucksberg et al,14 and the severity of
chronic GVHD was diagnosed and graded according to Shulman et
al.15 Moderate to severe acute GVHD was defined as acute
GVHD of at least grade II. Patients were considered assessable for
acute GVHD if they survived 42 days and for chronic GVHD if they
survived 100 days following BMT.
Engraftment.
If the patient survived 21 days, engraftment was assessable by
leukocyte -L-iduronidase enzyme activity, sex chromosome
analysis, and/or semiquantitative restriction fragment length
polymorphism (RFLP) evaluation of monocytes and/or
neutrophils.16-18 Engraftment was deemed to be permanent at
1 year following GIS or HIR BMT. Complete donor chimerism was defined
as greater than 90% donor enzyme activity and/or greater than
90% donor cells by RFLP analysis. Leukocyte
-L-iduronidase enzyme activity is 100% in a homozygous normal donor; it is approximately 50% of normal in a heterozygous carrier donor. Mixed donor-recipient chimerism was defined as 10% to
90% donor enzyme activity and/or 10% to 90% donor cells by
RFLP analysis. Autologous recovery was defined as less than 10% donor
enzyme activity and/or less than 10% donor cells by RFLP
analysis.
Neuropsychologic testing.
A battery of standardized neuropsychological tests were used to assess
the child's developmental or intellectual level, adaptive behavior,
academic readiness or performance, neuropsychologic functioning in
several domains (language, perception, memory, attention, and executive
functions), and emotional and social functioning as described
previously.8 Testing performed within 6 months prior to BMT
served as a baseline; subsequent age-appropriate tests were
administered annually after BMT. For this report, only the results of
developmental and intelligence tests are reported. Baseline Mental
Developmental Indices (MDIs) from the Bayley Scales of Infant
Development were calculated from normative tables for all
children.19 At follow-up study, the children were
administered tests appropriate for their age (eg, Bayley Scales of
Infant Development, Stanford Binet Intelligence Scale, and Wechsler
Scales). Age-equivalent scores were used for monitoring developmental
and intelligence status. These scores provided a mechanism for
comparing results across developmental tests and information about
whether a child was losing mental ability, plateauing in learning,
gaining more slowly than normally expected, or progressing at an
appropriate rate. Because some children had a MDI below the lower limit
of the normative tables (MDI < 50), MDIs could not be used for
longitudinal assessment.
Statistical analysis.
Survival curves were calculated by the method of Kaplan and
Meier.20 Statistical comparisons of categoric data were
performed by  2 analysis. Correlation coefficients were
assessed by Spearman's rank order. Nonparametric comparisons of
neuropsychologic outcome according to severity of GVHD were performed
using the Mann-Whitney U statistic. Vital status was
ascertained for all patients on July 29, 1997.
| |
RESULTS |
From September 16, 1983 to July 14, 1995, 54 children with leukocyte
-L-iduronidase enzyme deficiency underwent GIS or HIR BMT at a median age of 1.8 years (range, 0.4 to 7.9) at 13 centers in
North America: 7 centers (54%) each cared for 1 child, 4 centers (31%) cared for 3 to 5 children, and 2 centers (15%) cared for 12 or
21 children. Twenty-six patients received marrow from GIS donors, and
26 children received marrow from HIR donors. Two children who were to
receive GIS donor BMT died during preparative therapy. The median
follow-up period for all GIS BMT patients is 7.3 years. The median
follow-up period for all HIR BMT patients is 4.6 years.
Transplant-related toxicity and GVHD.
Outcomes for MPSIH patients undergoing GIS and HIR BMT are
presented in Table 2. Transplant-related
complications included cardiopulmonary arrest, acute and chronic GVHD,
infection, hemorrhage, organ failure, and pneumonitis. Of 28 patients
scheduled to receive a GIS BMT, 2 died of cardiopulmonary arrest during
preparative therapy. Moderate to severe acute GVHD developed in 8 of 25 patients (32%; 95% confidence interval [CI], 15% to 49%)
following GIS BMT and in 12 of 22 patients (55%; 95% CI, 33% to
77%) following HIR BMT (P = .15). Acute GVHD could not be
assessed because of early death for 1 GIS BMT patient and 4 HIR BMT
patients. Moderate to severe acute GVHD occurred in 4 of 11 BMTs using
cyclosporin and corticosteroid with or without ATG for GVHD prophylaxis
and in 4 of 15 BMTs using other GVHD prophylaxis regimens following GIS
BMT. Moderate to severe acute GVHD occurred in 5 of 10 BMTs using
anti-CD5 ricin A chain-conjugated immunotoxin and corticosteroid for
GVHD prophylaxis and in 7 of 16 BMTs using other GVHD prophylaxis regimens following HIR BMT. The probability of extensive chronic GVHD
was 0% (95% CI, 0% to 14%) for GIS patients and 24% (95% CI, 4%
to 44%) for HIR patients (P = .0003). The primary cause of
death was cardiopulmonary arrest or failure (6 patients) and GVHD (6 patients).
The rates for survival and engrafted survival were comparable for
children who received GIS or HIR BMT during the periods 1983 to 1987, 1988 to 1990, and 1991 to 1995 (P = .70). On September 1, 1991, the 5-year National Institutes of Health, National Institute of
Neurological Disorders and Stroke (NINDS)-supported clinical trial of
the value of BMT for storage diseases started.
Engraftment.
Twenty-two of 26 GIS BMT patients engrafted. Fifteen patients
experienced complete donor engraftment, 7 achieved mixed
donor-recipient chimeric grafts, and 2 died of transplant-related
causes following engraftment. Thus, 20 of 28 patients survived
engrafted following the first GIS BMT.
Four patients failed to engraft following the initial GIS BMT. One
patient died of sepsis; the remaining 3 received a second GIS BMT. One
child is alive with engraftment 12.4 years following the second BMT.
Thus, 21 of 28 GIS BMT patients are alive and engrafted, 20 following
the first BMT and 1 following the second BMT. Durable complete
chimerism was observed in 15 of these 21 survivors of GIS BMT, with
mixed chimerism in 6.
Of 26 patients receiving a HIR BMT, 17 patients engrafted; 8 of these
17 died of transplant-related causes following engraftment. All but 1 of the 17 HIR BMT patients who engrafted had complete donor
engraftment. Nine patients failed to engraft following the initial HIR
BMT. One patient underwent a second HIR BMT and died unengrafted. Two
patients died of transplant-related causes. One patient died of
cardiopulmonary arrest 2.1 years from BMT. Five patients are alive but
auto-engrafted. Thus, 9 of 26 HIR BMT patients are alive and engrafted.
Durable complete chimerism was observed in 8 and mixed chimerism in one
of 14 survivors of HIR BMT; five survivors had autologous marrow
recovery.
Leukocyte -L-iduronidase enzyme activity measured 0.7 to
10.9 years following BMT was available for 20 of 21 engrafted GIS BMT
patients and 8 of 9 HIR BMT patients surviving 1 year. Six of 10 patients who received grafts from homozygous normal donors achieved a
normal level of enzyme activity. Of the remaining 4 patients, three had
enzyme levels consistent with carrier status and one had an enzyme
level below 25% of normal. Fifteen of 18 patients who received grafts
from heterozygous carrier donors achieved a carrier level of enzyme
activity. The remaining 3 patients had enzyme levels in the lower limit
of the carrier range.
Survival.
Thirty-five of 54 patients are alive 2.0 to 13.9 years post-BMT. The
overall actuarial probability of survival at 5 years was 64% (95% CI,
51% to 77%) for all patients (Fig 1A).The overall actuarial probability of survival at 5 years was 75% (95%
CI, 59% to 91%) for GIS BMT recipients and 53% (95% CI, 34% to
73%) for HIR BMT recipients (Fig 1B; P = .16). For patients
with donor cell engraftment, the actuarial probability of survival at 5 years was 53% (95% CI, 40% to 67%; Fig 1C). The overall actuarial
probability of survival at 5 years was 71% (95% CI, 55% to 88%) for
GIS BMT recipients with donor cell engraftment and 34% (95% CI, 15%
to 52%) for HIR BMT recipients with donor cell engraftment (Fig 1D; P = .03). Twenty-nine of 35 surviving patients engrafted
after the first BMT. Four patients received a second BMT because of graft rejection or failure; one patient is an engrafted survivor.
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| Fig 1.
(A) Overall actuarial probability of survival ( ) of 54 MPSIH patients treated with related-donor BMT. (B) Overall actuarial probability of survival of MPSIH patients treated with GIS () or HIR
(--) donor BMT. (C) Overall actuarial probability of survival () of
MPSIH patients with donor cell engraftment following related-donor BMT.
(D) Overall actuarial probability of survival of MPSIH patients with
donor cell engraftment following GIS () or HIR (--) donor BMT.
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Neuropsychologic function.
Twenty-one children who received a GIS BMT and 9 who received a HIR BMT
are alive and engrafted. Baseline and follow-up neuropsychologic data
are available for 18 of 21 GIS BMT and 8 of 9 HIR BMT children. Developmental trajectories derived from age-equivalent scores of serial
neuropsychologic tests were calculated for each child. We found no
statistical differences in the slope of the developmental trajectories
between the GIS and HIR groups (mean, 0.50 and 0.40, respectively).
Data were analyzed to examine the trajectories of cognitive development
in children transplanted before or after 24 months of age. Fourteen of
26 children with neuropsychologic data were transplanted before 24 months of age (Fig 2A). Of these 14, nine demonstrated relatively normal development (slope  .50); five had
slower than expected developmental gains (slope .25 to .49), and no
child has plateaued (slope < .25).
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| Fig 2.
(A) Mental age-equivalent scores of MPSIH patients
receiving related-donor BMT before 24 months of age (normal, ;
slope .50,  ; slope .25 to .49,  ; solid symbol denotes most
recent neuropsychologic evaluation). (B) Mental age-equivalent scores
of MPSIH patients receiving related-donor BMT after 24 months of age
(normal, ; slope .50, ; slope .25 to .49, ;
slope < .25,  ; solid symbol denotes most recent neuropsychologic
evaluation). *Latest neuropsychologic evaluation at 159 months of age
and a mental age-equivalent score of 108 months.
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Of the 12 children with neuropsychologic data transplanted after 24 months of age, only three showed relatively normal developmental trajectories. Four children acquired skills more slowly than normal. Five children have plateaued (Fig 2B). The mean difference in the
slopes of the developmental trajectories between children transplanted
before and after 24 months was significant (mean, .58 and .34, respectively, t = 2.5, P = .02). A Spearman
rank-order correlation of  .51, (P = .01) between the age
at BMT and the slope of the line approximating the developmental
trajectory was found.
The baseline MDI was examined for both children less than and greater
than 24 months of age at the time of BMT. Children transplanted before
24 months had a mean baseline MDI of 78, while those transplanted after
24 months had a mean baseline MDI of 63. A Spearman rank-order correlation of .77 (P = .0002) between the baseline MDI and
slope of the line approximating the developmental trajectory was found.
Further analysis to determine the effect of donor enzyme status on
neuropsychologic outcome was limited to the 15 children who had a
baseline MDI over 70. -L-Iduronidase enzyme activity levels were normalized for comparison across laboratories. The correlation of the normalized -L-iduronidase enzyme
activity levels with the latest MDI scores for these 15 children was
.59 (P = .02). No child whose ultimate enzyme activity level
was low (ie, in the carrier range) due to either a heterozygous carrier donor or partial engraftment from a homozygous normal donor had normal
mental functioning at follow-up study. Three children whose MDIs were
normal (ie, >80) at follow-up study received BMTs from homozygous
normal donors and fully engrafted. The enzyme activity levels in these
three children at follow-up study were completely normal. There were
seven children whose MDIs at follow-up evaluation were greater than 60 but less than 80; four had homozygous normal donors and three had
heterozygous carrier donors. All of these children had an enzyme level
at least 1.6 SD from normal. Finally, five children had follow-up MDIs
of at least 48 but less than 60; two had homozygous normal donors, with
one partially engrafted, and three had heterozygous carrier donors,
with one fully engrafted, one partially engrafted, and one with very
low enzyme activity (ie, <25% of normal).
The effect of acute GVHD on neuropsychologic function was examined.
Acute GVHD was assigned a score according to severity: 1 for grade 0 or
I and 2 for grades II to IV. Cognitive outcomes were significantly
poorer (t = 2.81, P < .009) in children with the
higher acute GVHD rating (mean MDI, 46 ± 12, n = 9) compared with
children with the lower acute GVHD rating (mean MDI, 64 ± 19, n = 19). For children whose baseline MDI pre-BMT was over 70, only
two patients had grade II or III acute GVHD (post-BMT MDI, 48 and 50).
There were 14 patients with grade 0 or I acute GVHD (mean post-BMT MDI,
70 ± 15). The result of nonparametric Mann-Whitney U
testing was significant (P < .006).
No difference in post-BMT MDIs was observed between patients whose
preparative therapies did (slope of developmental trajectory: median,
.49; range, .00 to .69; n = 10; radiation dose range, 300 to 1,400 cGy) or did not (slope of developmental trajectory: median, .49; range,
.18 to 1.04; n = 16) include radiation.
| |
DISCUSSION |
This report represents the largest, most comprehensive related-donor
BMT experience for MPSIH patients. Long-term adoptive enzyme
replacement has occurred in patients successfully engrafted following
BMT.3 Substrate reduction in the liver, tonsils, conjunctiva, and urine occurs due to enzyme
replenishment.3,21-24 Central nervous system substrate
reduction is measured in CSF and by magnetic resonance imaging and
computed axial tomography.4,25 These imaging modalities
demonstrate a reduction of glycosaminoglycans in the Virchow-Robin
spaces and an arrest of the pathologic process leading toward
hydrocephalus. Auditory improvements occur following successful
BMT.26 Cardiac manifestations including heart failure, coronary artery narrowing, and tachyarryhthmias are eliminated 1 year
after successful BMT.27,28 However, despite engraftment, skeletal deformities and some ophthalmologic abnormalities persist and
often progress.29,30
Failure to achieve stable engraftment in MPSIH patients was a major
obstacle following HIR BMT, as it was following URD BMT.8 A
consensus regarding optimal myeloablative and immunosuppressive preparation for BMT in MPSIH was not established from this study. In
the absence of a common protocol, the transplant centers determined the
preparative regimen: 88% (23 of 26) of GIS BMTs and 31% (8 of 26) of
HIR BMTs for MPSIH used busulfan and cyclophosphamide without
irradiation ([BU/CY] busulfan 12 to 25 mg/kg in divided doses every 6 hours over 4 days/cyclophosphamide 200 to 240 mg/kg in four divided
doses over 4 days with or without antithymocyte globulin; Table 1).
Engraftment occurred in only 65% of patients surviving at least 1 year
from the first HIR BMT. This differs from the 95% engraftment in
patients surviving at least 1 year from the first GIS BMT for MPSIH in
this study. While manipulation of marrow grafts with TLD has reduced
the incidence and severity of GVHD,13,15,31-35 there has
been an increase in rejection in patients with
leukemia.36,37 However, the consortium experience has shown
that TLD of the marrow apparently did not compromise either the rate of
engraftment or survival at 1 year. In fact, survival at 1 year for
patients receiving TLD marrow was 69%, and it was only 46% for those
not receiving TLD marrow. Of note, busulfan clearance can be
accelerated in children38,39; however, systematic
evaluation of busulfan pharmacokinetics was not performed in this
retrospective study. We speculate that insufficient myeloablative
and/or immunosuppressive therapy was the principal cause of
graft failure (ie, autologous recovery). The deposition of
glycosaminoglycan in the hematopoietic microenvironment may also
contribute to the high rate of autologous recovery.
Using the extensive array of BMT preparative and GVHD prophylactic
therapies, BMT-related mortality was 18% for GIS BMT and 44% for HIR
BMT in MPSIH patients. The overall actuarial survival at 5 years
following BMT in these 54 patients was 64%: 75% for patients
receiving GIS BMT and 53% for patients receiving HIR BMT. The two
leading causes of death were cardiopulmonary arrest or failure and GVHD
(six deaths each). These causes of death reflect the need to reduce
GVHD severity and to closely monitor the underlying pathophysiology in
MPSIH patients. The rates of survival and engrafted survival were
comparable for children who received GIS or HIR BMT before or after
September 1, 1991, the initiation of the 5-year NIH NINDS-supported
clinical trial of the value of BMT for storage diseases.
There are 35 survivors of related-donor BMT for MPSIH. Of these, 30 are
engrafted. Long-term enzyme determinations were available in 28. Six
patients who received marrow from a donor with homozygous normal
leukocyte -L-iduronidase enzyme activity demonstrated normal levels of enzyme activity up to 10.4 years post-BMT, while 18 patients demonstrated carrier enzyme levels up to 10.9 years following
BMT. These data support the notion that successful BMT is a means of
achieving long-term adoptive enzyme therapy. The decrease in enzyme
activity that can be observed following replacement by BMT suggests
that alternate donors (eg, URD bone marrow or umbilical cord blood)
with higher enzyme activity may be preferable to achieve optimal enzyme
activity.
The impact of bone marrow cell dose in providing optimal enzyme
replacement is also incompletely understood. While a bone marrow cell
dose of at least 3.5 × 108 cells/kg was associated with a
higher rate of engraftment and better long-term survival in MPSIH
recipients of URD BMT,8 such an association was not
observed in recipients of GIS and HIR donor BMT. Additional study is
needed to determine whether the cell dose is a critical factor in
achieving engraftment and long-term survival.
While neuropsychologic capabilities vary widely after matched-sibling
BMT, selected patients have maintained their rate of learning with
low-normal intelligence.40 Previous research has shown that
children with MPSIH transplanted after 24 months of age demonstrate a
different and less favorable trajectory of development than children
transplanted before 24 months.8 These data formed the
rationale for examining the cognitive development of children transplanted before or after 24 months of age. Hence, in addition to
examining the long-term neuropsychologic outcome of children transplanted with either a GIS or HIR donor, an additional goal of this
study was to analyze the developmental outcome of children transplanted
before or after 24 months of age.
Baseline and follow-up neuropsychologic data were available for 18 survivors of GIS BMT and eight survivors of HIR BMT. There were no
significant differences between GIS and HIR BMT groups with respect to
follow-up neuropsychologic status up to 159 months post-BMT. However,
we did find that the developmental outcome following BMT was strongly
associated with the age at BMT. Children transplanted before 24 months
of age showed a significantly better developmental trajectory compared
with children transplanted after 24 months of age. Thus, the older the
child was at BMT, the higher the likelihood of poor neuropsychologic
outcome. As reflected in the Figures, many of the children transplanted
after 24 months of age (Fig 2B) received BMT earlier in the
consortium's experience and hence have longer follow-up periods than
children transplanted before 24 months of age (Fig 2A).
During the 12 years that the 54 children with MPSIH described in this
report were transplanted, there was a growing awareness of the factors
that could affect outcomes. On September 1, 1991, the Storage Disease
Collaborative Study Group received a 5-year grant from the NIH NINDS to
conduct the study, "Control Study of Value of BMT for Storage
Diseases." In the eligibility criteria, it was recommended that
MPSIH patients be less than 24 months of age with a MDI of 75 or
greater when preparation for BMT was initiated. There has been a trend
toward transplanting children with MPSIH at younger ages. After 1991, the median age at BMT for GIS and HIR MPSIH patients decreased from 1.9 to 1.3 years, while the median age at BMT for URD MPSIH patients
decreased slightly from 1.8 to 1.7 years.
We found a significant association between the age at BMT and the
baseline MDI. A correlation of .82 between the age and MDI in
untransplanted children has been reported previously.40 Children transplanted before 24 months of age had a mean baseline MDI
that was significantly higher than in children transplanted after 24 months of age. In addition, there was a significant association between
the baseline MDI and long-term developmental outcome. As expected,
children transplanted with a MDI less than 70 experienced more
compromise in neuropsychologic functioning following BMT than children
transplanted with a baseline MDI above 70. Thus, if there was
significant developmental delay pre-BMT, there was an increased
likelihood of poor neuropsychologic outcome post-BMT. These results
suggested that the optimal neuropsychologic outcome following BMT for
MPSIH would occur when the child was less than 24 months of age and had
a baseline MDI greater than 70. While the two variables age at BMT and
baseline MDI were highly correlated, there were children with an MDI
greater than 70 despite an age over 24 months, as well as children with
a MDI less than 70 at an age less than 24 months. These cases emphasize
the variability in disease progression and its importance in clinical
decision-making.
We analyzed the effect of donor enzyme level on neuropsychologic
outcome in the 15 children who had a baseline MDI over 70. The
correlation of the normalized -L-iduronidase enzyme
activity level with the latest MDI score for these 15 children was
significant. However, it was difficult to assess this effect because of
differences in our patients pre-BMT. Specifically, a significant
correlation between the enzyme status (ie, homozygous normal v
heterozygous carrier) of the donor and the baseline MDI was found.
Children with homozygous normal donors had a significantly higher
baseline MDI and were also significantly younger at the time of BMT.
Due to the small sample size, we were unable to assess the contribution of these various factors independently. However, we did observe a
significant correlation between the donor enzyme status and the MDI at
follow-up study in children whose baseline MDI was over 70. We also
noted that children who retained fully normal intelligence (defined as
MDI >80) were all completely engrafted from a donor with homozygous
normal enzyme activity and therefore demonstrated normal
-L-iduronidase enzyme activity levels at follow-up
study. This observation should be considered when selecting a potential
donor. Achieving a normal -L-iduronidase enzyme activity level following BMT contributes favorably to the ultimate
neuropsychologic function of the child. Such an enzyme activity level
is achievable only if the donor has a homozygous normal enzyme activity
and engraftment is complete.
We also analyzed the effect of GVHD on neuropsychologic outcome in the
15 children who had a baseline MDI over 70. The development of moderate
to severe acute GVHD (ie, grade II to IV) was correlated with a poorer
ultimate neuropsychologic outcome. However, because the incidence of
acute GVHD was higher in children undergoing HIR BMT and since almost
all of these children received marrow from heterozygous carrier donors,
the relationship between acute GVHD and cognitive outcome could be
confounded by the lower (ie, carrier) enzyme status of the donor.
There were 20 children who received a radiation-containing preparative
regimen; pre- and post-BMT neuropsychologic data are available for 10 survivors (total-body irradiation dose, 300 to 1,400 cGy). There were
31 children whose preparative regimen did not include radiation; pre-
and post-BMT neuropsychologic data are available for 16 survivors. The
median slopes of the neuropsychologic developmental trajectories for
the 10 children who received a radiation-containing preparative regimen
and the 16 children whose preparative regimen did not include radiation
were identical (ie, .49). We conclude that radiation-containing
preparative regimens do not adversely affect the long-term
neuropsychologic development of MPSIH children undergoing BMT.
Only by pooling international patient resources can The Storage Disease
Collaborative Study Group make substantial progress. We anticipate that
an international study could accrue 75 to 100 MPSIH patients per year
and thus afford the Group the opportunity to conduct randomized phase
III clinical trials. Such studies would address questions such as the
impact of radiation on the ultimate neuropsychologic outcome in these
patients and how to optimize engraftment and decrease GVHD in patients
with MPSIH. At a recent consortium meeting, members unanimously
supported the concept of an international randomized trial designed to
evaluate preparative therapies and long-term neuropsychologic outcomes in transplanted MPSIH patients.
Stable, life-long normalization of -L-iduronidase enzyme
activity can be achieved by BMT in MPSIH patients. While research continues in the areas of gene transfer and genetically engineered enzyme therapy, BMT currently remains the only proven therapeutic modality for many lysosomal and peroxisomal storage diseases, including
MPSIH.
| |
FOOTNOTES |
Submitted April 22, 1997;
accepted November 12, 1997.
Supported in part by National Institutes of Health Grant No. NS29099.
Address reprint requests to Charles Peters, MD, The Storage Disease
Collaborative Study Group, University of Minnesota, Department of
Pediatrics, Division of Blood and Bone Marrow Transplant, Box 477, Room
D-548, Mayo Memorial Building, 420 Delaware St SE, Minneapolis, MN
55455.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
The contributors to this study are as follows: principal author,
Charles Peters; statistician, James Anderson; bone marrow transplanters, Charles Peters, P. Jean Henslee-Downey, Martin R. Klemperer, Morton J. Cowan, E. Fred Saunders, Pedro A. deAlarcon, Clare
Twist, James B. Nachman, Gregory A. Hale, Richard E. Harris, Marta K. Rozans, Joanne Kurtzberg, Guy H. Grayson, Thomas E. Williams, Carl
Lenarsky, John E. Wagner, and William Krivit; neuropsychologists, Elsa
G. Shapiro, Michael Balthazor, Valerie A. Cool, and Mary Crittenden;
geneticists, Joe T.R. Clarke, Seymour Packman, and Emmanuel Shapira;
neurologist, Lawrence A. Lockman; and radiation therapist, Kathryn
Dusenbery. The following centers participated in The Storage Disease
Collaborative Study Group, cared for patients, and contributed to this
report: the Departments of Pediatrics (C.P., W.K., and J.E.W.),
Neurology (E.G.S., M.B., and L.A.L.), and Therapeutic Radiology (K.D.),
University of Minnesota School of Medicine; Department of Preventive
and Societal Medicine, University of Nebraska (J.A.); University of
Kentucky School of Medicine (P.J.H.-D. and G.A.H.); University of South
Florida (M.R.K.); University of California, San Francisco (M.J.C.,
M.C., and S.P.); University of Toronto (E.F.S. and J.T.R.C.);
University of Iowa College of Medicine (P.A.D. and V.A.C.); Harvard
University Medical School (C.T.); University of Chicago (J.B.N.);
University of Cincinnati (R.E.H.); Tulane University (M.K.R. and E.S.);
Duke University (J.K.); University of Texas, San Antonio (G.H.G. and
T.E.W.); and University of Southern California (C.L.).
The Storage Disease Collaborative Study Group recognizes the excellent
clinical care provided to these patients by the nurses, physician
assistants, pediatric housestaff, and fellows. The authors also thank
Robert Zajac, principal data coordinator, the BMT center data managers,
secretarial staff, and Dr W. Dobyns for a critical review of the
manuscript.
| |
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Introduction
Abstract