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Blood, Vol. 93 No. 12 (June 15), 1999:
pp. 4109-4115
Final Height of Patients Who Underwent Bone Marrow Transplantation
for Hematological Disorders During Childhood: A Study by the
Working Party for Late Effects-EBMT
By
Amnon Cohen,
Attilio Rovelli,
Boudewijn Bakker,
Cornelio Uderzo,
Maria-Teresa van Lint,
Helene Esperou,
Alberto Gaiero,
Alison D. Leiper,
Roland Dopfer,
Jean Yves Cahn,
Franco Merlo,
Hans J. Kolb, and
Gerard Socié on behalf of the EBMT Late-Effects Working Party
From the University Department of Pediatrics, Gaslini Institute,
Children's Hospital, Genoa, Italy; the Clinica Pediatrica, San Gerardo
Hospital, Monza, Italy; the Department of Pediatrics, Leiden University
Medical Center, Leiden, The Netherlands; the Centro Trapianti di
Midollo, San Martino Hospital, Genoa, Italy; the Service
d'Hematologie-Greffe de Moelle, Hòpital Saint Louis, Paris,
France; the Department Of Haematology and Oncology, Great Ormond Street
Hospital for Children, NHS Trust, London, UK; the Department of
Pediatrics University Hospital, Tubingen, Germany; the Service
D'Hematologie Hospital Jean Minjoz, Besancon, France; the Department
of Environmental Epidemiology and Biostatistics, National Cancer
Institute, Genoa, Italy; and Medical Klinik III, Klinikum Grosshadern,
Munchen, Germany.
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ABSTRACT |
Few data are available on the long-term effect of bone marrow
transplantation (BMT) on growth. This study examines those factors that
play a role in the final height outcome of patients who underwent BMT
during childhood. Data on 181 of 230 patients with aplastic anemia,
leukemias, and lymphomas who had BMT before puberty (mean age, 9.8 ± 2.6 years) and who had reached their final height were analyzed. An
overall decrease in final height standard deviation score (SDS) value
was found compared with the height at BMT (P < 107) and with the genetic height (P < 107). Girls did better than boys, and the younger in age
the person was at time of BMT, the greater the loss in
height. Previous cranial irradiation + single-dose total
body irradiation (TBI) caused the greatest negative effect
on final height achievement (P < 104).
Fractionation of TBI reduces this effect significantly and conditioning
with busulfan and cyclophosphamide seems to eliminate it. The type of
transplantation, graft-versus-host disease, growth hormone, or steroid
treatment did not influence final height. Irradiation, male gender and
young age at BMT were found to be major factors for long-term height
loss. Nevertheless, the majority of patients (140/181) have reached
adult height within the normal range of the general population.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
THE SUCCESS OF bone marrow
transplantation (BMT) in treating malignant and nonmalignant
hematological disorders and the improvement of the sophisticated
techniques involved in this procedure have extended the indications for
transplantation and have increased the number of patients who survive
BMT.1,2 Nevertheless, one of the many negative effects that
these successfully treated children have to face is the endocrine
dysfunction associated with the chemotherapy, radiotherapy, and
immunosuppressive treatment they receive before and after marrow
transfusion, which could eventually induce growth delay.
To our knowledge, only two single-center studies have dealt with the
final height achievement of patients who had BMT during childhood.3,4 Because the BMT procedure is relatively
recent, making it difficult to include large numbers of patients who
have reached their final adult height, the statistical power of these two studies was frail. The European BMT Working Party for Late-Effects conducted this multicenter study with the aim of evaluating the final
height achieved by children who underwent BMT for hematological disorders and identifying those factors that influence the long-term growth in these patients.
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PATIENTS AND METHODS |
Study design.
The study is based on a retrospective survey using a
two-step-questionnaire approach, involving Centers that are part of the European-BMT group.
A first questionnaire was sent to 284 BMT Centers asking for the number
of patients with severe aplastic anemia (SAA), leukemia, and lymphomas
who underwent BMT before onset of puberty (breast stage 1 in girls and
testicular volume less than 4 mL in boys) and who had reached their
final adult height. Final height was defined either on a documented
closure of the hand, wrist, or iliac crest epiphyses or growth velocity
less than 1 cm/yr.5
One hundred of the 284 Centers (35%) completed and sent back the first
questionnaire form. Sixty-two centers (22%) confirmed that they did
not have cases that met the inclusion criteria. A second questionnaire
was sent to the remaining 38 centers that claimed to have patients
eligible for the study. Twenty-two of the 38 centers answered the
second questionnaire, providing data on a total of 230 patients.
The questionnaire included queries regarding the primary hematological
disorder, irradiation therapy used during first-line treatment (between
diagnosis and pre-BMT conditioning treatment), BMT-related data (age
and type of BMT, conditioning regimen, grading of acute and chronic
graft-versus-host disease [GVHD], and type and duration of
immunosuppression therapy), and endocrine-related data that included
parental height, patient's height and weight at BMT, final adult
height achieved, age at latest measurement, growth hormone treatment,
and sex hormone replacement therapy performed.
Patients' characteristics.
Of the 230 forms received, 49 patients were excluded from the study
either because the onset of puberty was before BMT or because of
insufficient key data necessary for a correct and comprehensive statistical analysis. BMT was performed between October 1973 and October 1993. The characteristics of the 181 patients who met the
inclusion criteria are summarized in Table
1. The type of irradiation applied to the patients in relation to the
primary disorder is shown in Table 2. Fifty
patients received cranial radiation therapy (CRT) as prophylaxis or
treatment of central nervous system involvement (<18 Gy in 4 patients, 18 Gy in 29 patients, 24 Gy in 16 patients, and 36 Gy in 1 patient). Irradiation during conditioning regimen included single-dose
total body irradiation (sTBI) in 52 patients at a median dose of 8 Gy
(range, 3 to 10 Gy; 3 SAA patients received 3 to 4 Gy, whereas the
remaining patients received 7 to 10 Gy); fractionated TBI (fTBI) in 73 patients (6 to 13.2 Gy) administered in 2 to 8 fractions;
thoraco-abdominal irradiation (TAI) in 17 patients (5 to 11 Gy); and
total lymphoid irradiation (TLI) in 2 patients (7.5 Gy). Seventeen
children with acute lymphoblastic leukemia (ALL) received a booster
dose of 4 to 10 Gy to the testicles.
Patients subjected to irradiation as part of the pre-BMT conditioning
regimen also received cyclophosphamide (Cy) alone or in combination
with other cytotoxic drugs (cytarabine, etoposide, and vincristine). Of
the 36 patients who did not receive irradiation, 10 children (7 acute
myeloid leukemia [AML], 2 chronic myeloid leukemia
[CML], and 1 SAA) were conditioned with busulfan and cyclophosphamide only (BuCy).
Steroid therapy for acute and/or chronic GVHD was administered in 87 patients for a median period of 4 months (range, 0.5 to 168 months); 62 of them stopped treatment within 12 months, whereas 14 patients had treatment for periods longer than 24 months. Cyclosporin-A was administered in 90 patients for a median period of
6.5 months (range, 2 to 84 months); 67 of them stopped
treatment within 12 months, whereas 11 patients had treatment for
periods longer than 24 months.
Sex hormone replacement therapy was administered to 55 patients (24 male and 31 female), starting at 14.0 ± 3.3 years of age (range, 12 to 18 years of age) in males and at 14.4 ± 1.8 years of age (range,
11 to 18.8 years of age) in females. Growth hormone (GH) treatment was
administered in 28 patients for a median period of 3.5 years (range,
0.3 to 7 years), starting at 13.2 ± 2.1 years of age (range, 9.8 to
17.9 years of age), 3.8 ± 2.0 years from BMT (range, 0.9 to 8.3 years).
Statistical analyses.
Height measurements of each patient both at the time of BMT and final
height were expressed as the standard deviation score (SDS) from the
mean of the normal population.5 The genetic height of each
patient was calculated as the mean of the mother's and the father's
height-SDS (genetic height = [mother's SDS + father's
SDS]/2).
The difference between the height-SDS value at BMT and that of the
final height was calculated for each patient and was regarded as the
delta-SDS value, expressing the gain (zero or positive values) or the
loss of height (negative values) after transplantation in terms of SDS.
Statistical analyses for the comparisons of delta-SDS values were
performed according to the type and age at BMT, gender, pretransplant
conditioning regimens, complications, and therapies applied. The
relationships between dependent and explanatory covariates were
investigated by using the analysis of variance and the  2
statistics for continuous and categorical covariates, respectively.
The association between delta-SDS, as dependent variable, with the type
of BMT, age at transplant, gender, radiotherapy, chronic GVHD severity,
and GH treatment were also investigated using the multiple logistic
regression analysis.6 This multivariable technique permits
identification of covariates that are associated with the probability
of the studied outcome and expresses each covariate association,
adjusted for the effect of the other covariates included in the
regression model, in terms of relative risk point estimates (RR) and
its confidence intervals.
To this aim, the dependent variable delta-SDS was dichotomized to
distinguish between subjects who had normal growth after transplant
(ie, delta-SDS value  0) and those who had growth failure (delta-SDS
<0). Patients were also divided into three groups to identify
subjects who received CRT (with or without TBI), subjects who received
radiation therapy that did not include CRT, and patients who have never
received any irradiation therapy (reference group, RR = 1). The age at
transplant (continuous covariate) was categorized into three levels
according to the 33rd (1.5 to 8.8 years) and the 66th percentile values
of its frequency distribution (8.8 to 11 years). Patients with age
greater than 11 years at transplantation were used as a reference (ie,
RR = 1).
The statistical analyses were performed using the SPSS statistical
software, version 8.0 (SPSS Inc, Chicago,
IL).7
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RESULTS |
Final height achievement was documented by closure of hand, wrist, or
iliac crest epiphyses in 9 patients who were 18.5 ± 2.4 years of age at latest evaluation and by growth velocity less than 1 cm/yr in the remaining patients, who were 19.1 ± 2.8 years of age.
Final height-SDS values of 140 of 181 were within normality for the
general healthy population (between  2.0 and +2.0 SDS). Three
patients achieved height values greater than +2.0 SDS, whereas the
remaining 38 are to be considered as short stature (below 2.0 SDS).
Considering the entire cohort of patients
(Fig 1), the height-SDS value at BMT
(0.15 ± 1.16) was significantly higher (paired Student's
t-test; P < 107) than the final
height-SDS value (1.09 ± 1.45), resulting in a mean decrease
of 0.94 ± 1.30 SDS from transplant to adulthood. Whereas the
height-SDS value at BMT was comparable to that of the genetic height
(0.22 ± 1.02 SDS), the final height-SDS value was
significantly lower (P < 107).
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| Fig 1.
Correlation between the genetic height, height-SDS at
BMT, and final height-SDS. Numerals indicate the number of cases
studied in each group. The dotted area indicates the height-SDS
distribution for the normal general population. (Box plot) The lower
line of the box indicates the 25th percentile, the upper line indicates
the 75th percentile, and the horizontal lines above and below the boxes
represent the 3rd and the 97th percentile, respectively. Statistical
analyses: paired Student's t-test.
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The mean delta-SDS value of the whole cohort was 0.94 ± 1.30 (range, 6.9 to +2.6). The 112 boys did worse than the 69 girls, having a mean delta-SDS value of 1.17 ± 1.34 compared with
0.56 ± 1.13, respectively (t-test; P < .002). Girls were younger at BMT compared with boys (8.9 ± 2.7 and
10.3 ± 2.4 years, respectively; P < .0005). Age was found
as an additional factor that influences growth, because the younger the
age at BMT the higher the delta-SDS value (linear regression analysis;
regression coefficient = 0.218; P < 107) and the
lower the final height-SDS (regression coefficient = 1.104; P = .01).
The type of BMT was found to have no effect on the delta-SDS value
(analysis of variance, one-way ANOVA); in fact, the 28 patients who
underwent autologous-syngeneic BMT (for statistical purposes, the 3 children who received a transplantation from a monozygotic twin were
considered as part of the autologous group) had a delta-SDS value of
0.95 ± 1.25 compared with that of 0.94 ± 1.31 in
the 153 cases who had allogeneic BMT.
Seven different groups were identified according to the type of
irradiation and chemotherapy applied (Table
3); the age at BMT was similarly distributed in these groups (analysis
of variance). As shown in Fig 2, the most
severe growth failure was found in patients who received CRT+sTBI (mean
delta-SDS value, 2.07 ± 0.91) followed, respectively, in
decreasing degree of severity by sTBI (1.37 ± 1.06),
CRT+fTBI (1.11 ± 1.61), fTBI (0.88 ± 1.25), and TAI/TLI (0.71 ± 0.72). The nonirradiated group
had virtually no growth deficit after BMT (0.07 ± 1.08). A
similar pattern was found when final Weight-SDS values were considered (Fig 3).
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| Fig 2.
Delta-SDS (final height-SDS minus SDS at BMT) in the
different irradiation groups. Numerals indicate the number of cases
studied in each group. (Box plot) The lower line of the box indicates
the 25th percentile, the upper line indicates the 75th percentile, and
the horizontal lines above and below the boxes represent the 3rd and
the 97th percentile, respectively.
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| Fig 3.
Final height-SDS achievement in the different irradiation
groups. Numerals indicate the number of cases studied in each group.
The dotted area indicates the height-SDS distribution for the normal
general population. (Box plot) The lower line of the box indicates the
25th percentile, the upper line indicates the 75th percentile, and the
horizontal lines above and below the boxes represent the 3rd and the
97th percentile, respectively.
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The delta-SDS value of the 10 nonirradiated patients conditioned with
BuCy (+0.05 ± 1.13) was not statistically different from the 26 nonirradiated SAA patients (0.12 ± 1.08).
Comparing the delta-SDS value among the patients divided into groups
according to diagnosis, no significant difference was found between the
ALL (73 cases; 1.26 ± 1.35), AML (46 cases; 0.96 ± 1.06), and CML groups (10 cases; 0.74 ± 1.98). The
delta-SDS found in the SAA group (48 cases; 0.43 ± 1.09) was significantly better than that of the ALL and AML groups.
Dividing the SAA group into nonirradiated (27 cases; 0.12 ± 1.06 delta-SDS) and irradiated (21 cases; 0.82 ± 1.01), a
significant statistical difference was found (Wilcoxon rank-sum test;
P < .03).
The severity of chronic GVHD (126 cases with no GVHD: 0.84 ± 1.20 delta-SDS; 37 cases with limited GVHD: 1.08 ± 1.30; and 18 cases with extended GVHD: 1.34 ± 1.85) did not
significantly influence the delta-SDS mean value (analysis of variance:
P = .22), even though an increasing severity of the chronic
GVHD showed a tendency toward worsening of delta-SDS.
On a long-term basis, cortisone treatment (87 treated patients
[1.03 ± 1.48 delta-SDS] v 84 not treated
[0.79 ± 1.07]) and cyclosporin-A treatment for GVHD (91 treated [0.84 ± 1.22] v 80 not treated
[0.99 ± 1.38]) were found to have no effect on delta-SDS values.
The 55 patients who received sex hormone replacement therapy reached a
similar final height-SDS (1.05 ± 1.53) compared with the
group of patients who started and completed pubertal development spontaneously (1.05 ± 1.35).
The mean delta-SDS found in the 28 patients treated with exogenous GH
(1.14 ± 1.24) was not statistically different from that of
the remaining 153 patients (0.90 ± 1.31) not treated with
exogenous GH. Because irradiation was the major factor in altering the
delta-SDS value in our cohort, this analysis was performed within the
same conditioning group. Twelve of 34 patients who received CRT+fTBI
and who were treated with GH (delta-SDS 0.75 ± 1.32) were
compared with the remaining 22 patients who did not receive GH
treatment (delta-SDS 1.31 ± 1.75); 8 of 13 patients who
received CRT+sTBI and who were treated with GH (delta-SDS 1.83 ± 0.71) were compared with the remaining 5 patients who did not receive GH treatment (delta-SDS 2.46 ± 1.13); and 7 of 39 patients who received sTBI and who were treated with
GH (delta-SDS 1.24 ± 1.38) were compared with the remaining
32 patients who did not receive GH treatment (delta-SDS
1.40 ± 1.0). None of the comparisons was found to
be statistically significant, but there seem to be a trend towards
better growth in the GH-treated group. We also failed to show
differences within the same gender, both between GH-treated (20;
1.21 ± 1.34 delta-SDS) and untreated boys (92; 1.77 ± 1.35) and between GH-treated (8; 0.99 ± 1.01) and
untreated girls (61; 0.50 ± 1.14 delta-SDS).
Multiple-logistic regression was used to model the relationship between
the dependent variable delta-SDS and the explanatory covariates
(gender, age at transplant, type of BMT, irradiation applied, chronic
GVHD severity, and GH therapy). Stepwise multiple logistic regression
identified irradiation, age at transplant, and gender as statistically
relevant explanatory covariates that significantly contributed to the
model that was fitted to the data
(Table 4). The role of each
covariate in determining a relevant growth deficiency (delta-SDS <0)
while accounting for the effect of the other covariates included in the
logistic regression model and the estimated effect size is reported as
relative risk point estimates with their 95% confidence intervals
(Table 4).
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Table 4.
Stepwise Regression Logistic Analysis Identifying
the Role of Each Covariate in Determining a Relevant Growth Deficiency
(Delta-SDS <0) While Accounting for the Effect of the Other
Covariates
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DISCUSSION |
The normal growth process during childhood reflects the child's
general well-being, and it is regulated by and depends on the
interaction between genetic, nutritional, metabolic, and hormonal factors. Nevertheless, growth is not always linear, especially in
children who have periods of chronic illnesses and/or undergo toxic
treatment procedures. The end result of growth is the final adult
height, which is used in this study as the long-term marker for
treatment-related toxicity in patients who underwent BMT during childhood.
Growth impairment in the short term has been repeatedly reported after
BMT,8-12 but data on final height achievement are scarce, and the only two published reports dealt with a limited number of
patients.3,4 This is the first multicenter study on final height with a large number of patients that takes into consideration the various potential risk factors that might affect growth after transplantation performed during childhood. Solid tumors and
hematological disorders in which short stature is a trait of the
disease itself (Fanconi's anemia, Thalassemia, inborn errors, etc)
were excluded.
Our data showed a similarity between the genetic height and the height
at BMT on one hand and a decreased value of final height-SDS compared
both with the genetic height and the patient's height-SDS at BMT on
the other, suggesting that the growth impairment in transplanted
patients occurred mostly during the period after transplantation (Fig
1).
The outcome of final height in this study did not change significantly
between the different types of hematological malignancies (ALL, AML,
and CML), suggesting that, in this cohort of patients, the primary
disease itself does not affect growth. This study confirms that
irradiation is the major contributor for long-term growth impairment
(final height achievement). Patients who were not irradiated had
virtually no decrease in final height-SDS compared both with the height
at BMT and the genetic height, underlining what was reported in smaller
series of patients.3,4 Among the different irradiation
settings, leukemia patients who received CRT during first-line
treatment and sTBI during pre-BMT conditioning had the most severe
long-term impairment of growth (Figs 2 and 3). Moreover, patients with
an identical primary disorder (SAA) who were treated with two different
conditioning regimens (Cy + irradiation v Cy only) presented
two completely different patterns of growth, with the most favorable
being the nonirradiated group.
Because the BuCy conditioning regimen has been more recently introduced
to reduce the detrimental effects of irradiation,13 the
number of the BuCy patients in this study is too small to draw
unequivocal conclusions regarding the effect of this regimen on the
long-term growth. Nevertheless, and notwithstanding these limitations,
final height achieved by these patients was similar to their predicted
final height, suggesting that, despite the known radio-mimetic effect
of busulfan,14 BuCy pre-BMT conditioning regimen has less
interference on the growth process than does irradiation. Published
data available on the effect of BuCy regimen on growth are discordant,
and report experience on the short-term growth, but not on final height
achievement. Whereas Wingard et al15 reported on the
similarity between the effect of BuCy and TBI, 2 years after
transplant, 8 of 24 patients in that study who were conditioned with
BuCy also received CRT during first line treatment. Other
studies16-18 found no harmful effect of BuCy on growth.
However, these three studies were based on a short-term follow-up (3 to
6 years), whereas the present study reports the final height outcome of
BuCy conditioning, albeit on a limited number of patients.
Unfortunately, although BuCy conditioning should be encouraged, at
least in pediatric patients, the attempt to substitute a TBI-based
conditioning regimen with BuCy was not found to be advantageous when
applied to patients with ALL.19
The type of BMT (autologous or allogeneic) did not influence final
height achievement. In this context, because chronic GVHD is a
relatively common complication in patients who receive allogeneic BMT20 and is not encountered after autologous BMT, the
severity of chronic GVHD and its treatment (steroids and cyclosporin-A) were also found to have no significant effect on growth, even though a
tendency toward worsening delta-SDS with increasing severity of chronic
GVHD was documented. Although steroids and severe chronic systemic
illness (ie, chronic GVHD) are known to induce growth impairment in
children, our study, however, despite being limited by a relatively
small sample size, suggests that children surviving after
transplantation have an adequate, although partial, capacity to
catch-up with growth in the long term.
Being younger at BMT, the female group was theoretically supposed to
experience a greater growth impairment than males. Nevertheless, the
loss in height-SDS was more profound in boys than in girls, although
the two groups were comparable for differences in genetic heights and
height at BMT, sex hormone replacement therapy, and age of commencement
of sex hormone treatment. This phenomenon therefore remains open for
further specific studies.
The loss in growth velocity in patients after BMT seems to be the
result of a complex interaction of different factors related to the
effect of irradiation and chemotherapy, such as lesions of bone,
cartilage, and the epiphyseal growth plate; gonadal damage; delayed or
precocious puberty; and hypothyroidism. Growth delay has also been
attributed to GH deficiency.8-12,18,21 Data on GH secretion
were not included in the questionnaire, and GH therapy was prescribed
by some of the BMT centers. Despite the relatively small number of
patients who received GH treatment in our cohort, the effect on the
final height outcome was less enthusiastic than that reported by
others. Thomas et al22 showed that growth impairment after
BMT in a homogeneous group of 49 children with leukemia who received
CRT and TBI resulted prevalently from severe spinal growth suppression
(reduced spinal height) that was unresponsive to GH treatment; also,
there was an inappropriate response with absent catch-up growth in
their legs. Even in children surviving brain tumors (a group with
florid radiation-induced GH deficiency), GH treatment increased the
short-term growth velocity but did not significantly improve the final
height.23 Furthermore, in our cohort, a reduced final
height was also observed in patients with SAA irradiated with TAI/TLI
only, ie, with irradiation fields not involving the skull and its
neuroendocrine structures. This observation is further emphasized by
the finding that patients who received CRT with or without TBI (high
cumulative irradiation dose to the hypothalamic-pituitary region) had
an equal relative risk for developing growth failure, as those patients
who had irradiation that did not include CRT (stepwise multiple
logistic regression analysis). GH deficiency, therefore,
does not seem to play a major role in growth impairment after BMT.
Because patients are already at high risk for secondary tumors after
BMT,24,25 and although available data on the safety of
GH-treatment in patients with a history of malignancies are
reassuring,26 we recommend caution in selecting patients as
candidates for GH treatment after BMT, especially because a positive
long-term effect of GH treatment on growth is not yet ascertained in
such patients. Furthermore, because we found that, in the long term,
140 of 181 patients who attained their final height reached normal
heights (within ±2 SDS for the general population), we also suggest
that growth should be clinically followed-up once every 6 months and
that only a few selected cases of severe and persistent growth
deficiency, observed after the interruption of the posttransplant
medication, be considered for GH treatment.
This study gathered data on patients who were transplanted during a
period when CRT was frequently used as prophylaxis treatment in the
majority of ALL patients and single-dose administration of irradiation
was widely used. At present, CRT is used in a small and selected group
of children, and irradiation schedules encourage fractionated TBI.
Because irradiation was found to have a significant role in long-term
growth impairment, especially in patients who received cranial
irradiation before transplant and received sTBI during pre-BMT
conditioning, we expect an improvement in the height prognosis in
children transplanted during the 1990s.
| |
APPENDIX |
Participating centers.
H. Lackner, Division of Pediatric Hematology-Oncology, University
Children's Hospital, Graz, Austria; J.Y. Cahn, Service D'hematologie Hospital Jean Minjoz, Besancon, France; H. Esperou, G. Socié, Service d'Hematologie-Greffe de Moelle, Hòpital Saint Louis, Paris, France; F. Freycon, Onco-hematologie pediatrique, Hospital Nord
Chru, Saint Etienne, France; F. Zintl, Department of Pediatrics University of Jena, Jena, Germany; R. Dopfer, Department of Pediatrics University Hospital, Tubingen, Germany; J. Sanders, Department of
Haematology, Canterbury Health Laboratory, Christchurch, New Zealand;
J. O'Riordan, Department of Hematology, St. James Hospital, Dublin,
Ireland; A. Cohen, A. Gaiero, University Department of Pediatrics,
Gaslini Institute Children's Hospital, Genoa, Italy; M.T. van Lint, A. Bacigalupo, Department of Hematology, Ospedale San Martino, Genoa,
Italy; C. Uderzo, A. Rovelli, Clinica Pediatrica, Ospedale San Gerardo,
Monza, Italy; S. Varotto, Centro Leucemie Infantili Clinica Pediatrica
I, Padova, Italy; W. Arcese, Università La Sapienza, Institute of
Hematology, Rome, Italy; J. Prtnar, Department of Hematology,
University Medical Center Ljubljana, Ljubljana, Slovenia; A.M.
Martinez-Rubio, Hospital Infantil La Paz, Madrid, Spain; A. Verdeguer,
Hospital infantil, Valencia, Spain; A. Fast, Department of Pediatrics,
East Hospital University of Goeteborg, Goeteborg, Sweden; N. Bekassy,
Department of Pediatrics, University Hospital, Lund, Sweden; W. Oostdijk, M. van Weel, J.M. Vossen, Department of Pediatrics, Leiden
University Medical Center, Leiden, The Netherlands; I. Roberts,
Department of Hematology, Royal Postgrade Medical School, Hammersmith
Hospital, London, UK; H.G. Prentice, Department of Hematology, Royal
Free Hospital, London, UK; and A.D. Leiper, Great Ormond Street
Hospital for Children, London, UK.
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ACKNOWLEDGMENT |
The authors thank the nonprofit "Associazione CRESCI, a cura e
sostegno della bassa statura" for their help in the accomplishment of this study and J. Upton for her technical assistance.
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FOOTNOTES |
Submitted September 2, 1998; accepted February 9, 1999.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Amnon Cohen, MD, University Department of
Pediatrics, Gaslini Institute, Children's Hospital, Largo Gaslini 5, 16147-Genoa, Italy; e-mail: cohen.amnon{at}pn.itnet.it.
| |
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ABSTRACT
INTRODUCTION