Exercise during hematopoietic stem cell transplant hospitalization in children.

Abstract

The purpose of this controlled trial was to assess the effect of an approximately 3-wk intrahospital exercise intervention performed during inpatient hospitalization for pediatric allogeneic hematopoietic stem cell transplant (HSCT) on (i) immune cell recovery and (ii) body composition.
Immune (i.e., blood counts of leukocytes, monocytes, lymphocytes, and lymphocyte subpopulations) and anthropometric variables (i.e., body mass, body mass index, and estimated fat-free mass) were measured before and after (+15 and 30 d) HSCT. Seven children (5 boys and 2 girls; age (mean +/- SD) = 8 +/- 4 yr) with high-risk cancer performed an individualized training program (aerobic + resistance exercises) in their isolated hospital rooms. We also assessed a control group (n = 13; 9 boys and 4 girls; age = 7 +/- 3 yr) with similar medical conditions and following the same transplant protocol.
In both groups, the dendritic cell count decreased from pre-HSCT to +15 d post-HSCT and thereafter (up to +30 d) remained stabile; however, the posttransplant decrease was more abrupt in the control group than that in the intervention group (-87% vs -63%, respectively, from pre-HSCT to +15 d). The rest of the immune cell parameters measured showed a similar response from pre-HSCT to post-HSCT in both groups. We found a significant effect of the interaction group x time for all anthropometric variables (weight, body mass index, body fat, and fat-free mass), indicating an increase over the hospitalization period only in the intervention group, for example, body mass increased from 32.9 +/- 18.7 kg pre-HSCT to 35.4 +/- 18.6 kg at +30 d in the intervention group versus a decrease from 30.2 +/- 16.6 to 29.3 +/- 6.3 kg in the control group.
Our findings support the feasibility of exercise training interventions during hospitalization, including immunocompromised children.

Full text

Page 1

by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.Copyright @ 2010
Exercise during Hematopoietic Stem Cell
Transplant Hospitalization in Children
CAROLINA CHAMORRO-VIN˜A1, JONATAN R. RUIZ2, ELENA SANTANA-SOSA1,
MARTA GONZA´LEZ VICENT3, LUIS MADERO3, MARGARITA PE´REZ1, STEVEN J. FLECK4,
ANTONIO PE´REZ3, MANUEL RAMI´REZ3, and ALEJANDRO LUCI´A1
1European University of Madrid, Madrid, SPAIN;2Unit for Preventive Nutrition, Department of Biosciences and
Nutrition at NOVUM, Karolinska Institutet, Huddinge, SWEDEN;3Pediatric University Hospital Nin ˜o Jesu ´s, Madrid, SPAIN;
and4Department of Sport Sciences, Colorado College, CO
ABSTRACT
CHAMORRO-VIN˜A, C., J. R. RUIZ, E. SANTANA-SOSA, M. GONZA´LEZ VICENT, L. MADERO, M. PE´REZ, S. J. FLECK,
A. PE´REZ, M. RAMI´REZ, and A. LUCI´A. Exercise during Hematopoietic Stem Cell Transplant Hospitalization in Children. Med.
Sci. Sports Exerc., Vol. 42, No. 6, pp. 1045–1053, 2010. Purpose: The purpose of this controlled trial was to assess the effect of an
approximately 3-wk intrahospital exercise intervention performed during inpatient hospitalization for pediatric allogeneic hematopoietic
stem cell transplant (HSCT) on (i) immune cell recovery and (ii) body composition. Methods: Immune (i.e., blood counts of
leukocytes, monocytes, lymphocytes, and lymphocyte subpopulations) and anthropometric variables (i.e., body mass, body mass index,
and estimated fat-free mass) were measured before and after (+15 and 30 d) HSCT. Seven children (5 boys and 2 girls; age
(mean T SD) = 8 T 4 yr) with high-risk cancer performed an individualized training program (aerobic + resistance exercises) in their
isolated hospital rooms. We also assessed a control group (n = 13; 9 boys and 4 girls; age = 7 T 3 yr) with similar medical conditions
and following the same transplant protocol. Results: In both groups, the dendritic cell count decreased from pre-HSCT to +15 d post-
HSCT and thereafter (up to +30 d) remained stabile; however, the posttransplant decrease was more abrupt in the control group than
that in the intervention group (j87% vs j63%, respectively, from pre-HSCT to +15 d). The rest of the immune cell parameters
measured showed a similar response from pre-HSCT to post-HSCT in both groups. We found a significant effect of the interaction
group ? time for all anthropometric variables (weight, body mass index, body fat, and fat-free mass), indicating an increase over
the hospitalization period only in the intervention group, for example, body mass increased from 32.9 T 18.7 kg pre-HSCT to 35.4 T
18.6 kg at +30 d in the intervention group versus a decrease from 30.2 T 16.6 to 29.3 T 6.3 kg in the control group. Conclusion: Our
findings support the feasibility of exercise training interventions during hospitalization, including immunocompromised children.
Key Words: PHYSICAL ACTIVITY, PEDIATRIC CANCER, BONE MARROW TRANSPLANTATION, STRENGTH TRAINING
A
(HSCT), which includes both bone marrow transplanta-
tion (BMT) and peripheral blood stem cell transplantation.
Patients who undergo HSCT are at risk of suffering
treatment-related complications mostly associated with the
immune system (19). Graft-versus-host disease (GVHD),
infections, and delay in immune cell recovery are the major
sources of HSCT comorbidities as well as major limiting
factors to consolidate transplant success (19,22).
pproximately 10%–20% of children suffering he-
matological malignancies or refractory solid tumors
need hematopoietic stem cell transplantation
The health benefits of regular exercise training in cancer
patients or survivors including adult inpatients receiving
HSCT are promising and include increases in hemoglobin
levels (7), improved physical fitness (4,5,7), improved vigor
(6), and fatigue stabilization (6). In outpatient children with
acute lymphoblastic or myeloid leukemia who received
HSCT, an 8-wk supervised exercise intervention induced a
significant improvement in functional capacity and quality
of life (26). Kim and Kim (16) reported that in-room (bed)
exercise during hospitalization of adults for HSCT in-
creased total lymphocyte count without deteriorating cel-
lular subpopulations (CD3+, CD4+, and CD8+ or CD4+/
CD8+ ratio) (16).
Intervention studies examining the effects of regular
exercise training on the immune system in pediatric cancer
patients or survivors are scarce. It is known that bed rest
aggravates the already low functional capacity as well as
the muscle atrophy induced by immunosuppressive therapy
in children receiving HSCT (21). A preliminary report by
Shore and Shepard (28) showed that a 12-wk aerobic ex-
ercise training program decreased CD3+, CD4+, and CD8+
counts in three children with acute lymphoblastic leukemia
Address for correspondence: Alejandro Lucı ´a, M.D., Ph.D., Universidad
Europea de Madrid, 28670 Villaviciosa de Odo ´n, Madrid, Spain; E-mail:
alejandro.lucia@uem.es.
Submitted for publication July 2009.
Accepted for publication October 2009.
0195-9131/10/4206-1045/0
MEDICINE & SCIENCE IN SPORTS & EXERCISE?
Copyright ? 2010 by the American College of Sports Medicine
DOI: 10.1249/MSS.0b013e3181c4dac1
1045
CLINICAL SCIENCES

Page 2

by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.Copyright @ 2010
receiving chemotherapy; however, the training-induced
changes were not of sufficient magnitude to be a health
concern. More recently, Ladha et al. (17) reported no del-
eterious acute effect of a single 30-min bout of aerobic
exercise on immune parameters in children receiving main-
tenance therapy against acute lymphoblastic leukemia.
Although these studies concerned children being treated for
cancer, the findings cannot be extrapolated to children while
undergoing HSCT hospitalization.
The purpose of the present controlled trial was to assess the
effect of a È3-wk exercise intervention performed during
inpatient stay for HSCT on immune cell recovery, that is,
blood counts of leukocytes, monocytes, and lymphocytes and
main lymphocyte subpopulations (T lymphocytes, natural
killer cells (NK), NK T, CD4+, and CD8+) and dendritic
cells. We also assessed the effect of this intervention on
patients’ body mass, body mass index (BMI), and estimated
fat-free mass because body composition seems to be affected
in patients undergoing HSCT and has a prognostic value in
this population (8,10,18).
MATERIALS AND METHODS
Patients
Eligibility criteria. A preliminary screening for children
selection was performed in the medical database of the Onco-
Hematology Department at Children’s Hospital Universitario
Nin ˜o Jesu ´s (Madrid, Spain). The children were eligible for
participating in the study if they met the following criteria: (i)
being a pediatric patient (G16 yr) with high-risk cancer
needing HSCT; (ii) receiving manipulated allogeneic HSCT
and nonmyeloablative conditioning therapy in the aforemen-
tioned hospital; (iii) receiving the same type of medical
treatment (conditioning regimen), including antibiotic pro-
phylaxis if needed; (iv) no evidence of cardiac or pulmonary
failure associated with treatment; and (v) being in an isolated
unit during the neutropenic phase of their hospital stay with
high-efficiency particulate air (HEPA) filter and room
positive pressure.
Before entering the study, one parent or legal guardian
provided written informed consent. The study procedures
were explained verbally to all children, and all gave verbal
consent to participate in the study. The research protocol was
approved by the institutional review board of Children’s
Hospital Universitario Nin ˜o Jesu ´s. In addition, the treating
oncologist’s approval was required before a child entered
the training group.
Intervention and control groups. Because of the low
number of hospitalized children with cancer, it was not pos-
sible to perform a randomized controlled trial. Instead, we
performed a controlled trial using a ‘‘historical’’ control group
whose medical conditions were comparable to those of the
intervention group. Because the groups were closely matched,
we believe that lack of randomization in group assignment
did not materially affect the results.
The exercise program was performed during 2007–2008. A
total of 14 children met the aforementioned criteria to par-
ticipate in the intervention study. Of these, nine patients
entered the study. Two of them had very severe medical com-
plications at the start of the training program, before HSCT
(one patient had respiratory insufficiency, and the other child
suffered bacteremia for Staphilococus hominis and urinary
infection by Escherichia coli with a high fever). The oncol-
ogist did not recommend these children to enroll in any type
of exercise program. Thus, we reported data from seven
children (5 boys and 2 girls; age (mean T SD) = 8 T 4 yr) in
the intervention group.
During the intervention phase of the study, a researcher
blinded to the immune and anthropometric results of the
intervention group was in charge of gathering the control
inpatients from medical records (corresponding to the period
January to December 2006) of the same hospital. Children
were selected as controls if we obtained their parents’ consent
to use their child’s data for research purposes, if they met
all the eligibility criteria (see previous section), and if there
were available data on the same immune and anthropometric
parameters at the same time points used for the exercise
group. A control group of 13 children (9 boys and 4 girls;
age = 7 T 3 yr) met all inclusion criteria. Characteristics of
study participants are shown in Table 1. They were all treated
by the same medical staff (physicians and nurses) of the
onco-hematology department. This staff has not changed
since year 2005.
Transplantation Protocol and Hospitalization
The HSCT protocol and the study design are presented in
Figure 1. The training protocol started at the beginning of
the conditioning phase (pretransplant) and lasted until the
end of the neutropenic phase (i.e., mean of È3 wk). Patients
were closely supervised and clinically evaluated on a daily
basis. During hospitalization, prophylactic therapy was given
to all patients with acyclovir to prevent herpes simplex virus
and cytomegalovirus reactivation infection and with cyclo-
sporine and methotrexate to prevent GVHD. The condition-
ing regimen preceding HSCT included the following drugs
in all patients: thiotepa (daily), fludarabine (daily), dexa-
methasone (daily), and busulphan (for 2 d). Standard
prophylactic antibiotics were administered if the absolute
neutrophil count was G0.5 ? 109Lj1and fever 938-C devel-
oped and were maintained until neutropenia resolved. The
neutropenic phase ended with neutrophil engraftment, which
was defined to occur the first day that absolute neutrophil
count was higher than 0.5 ? 109Lj1.
Outcome Variables
Immunology assessment. We prepared six cytometry
tubes with six monoclonal antibodies marked with six dif-
ferent fluorochromes to study leukocyte subpopulations in
patients’ peripheral (venous) blood. We incubated 100 KL of
blood in each tube during 20 min at room temperature in the
dark and treated red blood cells with a 1-mL lysis solution
http://www.acsm-msse.org
1046
Official Journal of the American College of Sports Medicine
CLINICAL SCIENCES

Page 3

by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.Copyright @ 2010
for 10 min. The different white blood cell population counts
(leukocytes, monocytes, and lymphocytes) were measured
with a hematology analyzer (Advia 120 Hematology System;
Bayer Corporation, Tarrytown, NY). The different lympho-
cytesubpopulations(lymphocytesT(CD45+CD3+CD56j),
NK (CD45+ CD3j CD56+), NKT (CD45+ CD3+ CD56+),
CD4+ (CD3+ CD4+ CD8j), and CD8+ (CD3+ CD4j
CD8+)) and dendritic cells (CD45+ lineage HLA-DRhigh)
were assessed by flow cytometry (FACS Canto II flow
cytometer; BD Bioscience, Franklin Lakes, NJ). The cell
count of each of the lymphocyte subpopulations was
calculated by multiplying total leukocyte count by the
percentage of each subpopulation.
All immunological variables were assessed before (before
the conditioning regimen) and after HSCT (+15 and +30 d
post-HSCT, respectively) (Fig. 1).
Anthropometry assessment. We measured standing
height to the nearest 0.1 cm with a clinical stadiometer
(Asimed T2, Barcelona, Spain) while children were standing
barefoot. We determined body mass to the nearest 0.05 kg
using a balance scale (Ano Sayol S.L., Barcelona, Spain)
with the subjects in their underwear. We calculated body
mass index (BMI) as weight height (kgImj2). We estimated
children’s fat-free mass (FFM) from the following equation
(1): FFM = body mass j fat mass (FM), where FM = 4.95
body density (BD) ? body mass. Children’s BD was in turn
estimated from skinfold thickness at the triceps, biceps, sub-
scapular, and suprailiac area at the left side of the body ac-
cording to the criteria described by Lohman et al. (20) using
different equations depending on children’s age and gender:
BD = 1.169 j 0.0788log 3 4 skinfolds and BD = 1.2063 j
0.0999log 3 4 skinfolds (for boys and girls, respectively,
aged e12 yr) (1) and BD = 1.1533 j 0.0643log 3 4
skinfolds and BD = 1.1369 j 0.0598log 3 4 skinfolds (for
boys and girls, respectively, aged Q13 yr) (9).
TABLE 1. Main cancer and transplant characteristics of each participant.
Tumor Remission at
Moment of Transplant?
MolecularHematological
Group/PatientPrimary CancerType of Allogeneic HSCT Age (yr) GenderType of DonorMetastasis Total No. of Transplantsa
Exercise
1
2
3
4
5
6
7
Control
8
9
10
11
12
13
14
15
16
17
18
19
20
Rhabdomyosarcoma
B-cell ALL
B-cell ALL
Neuroblastoma
B-cell ALL
B-cell ALL
T-cell ALL
PBSCT
PBSCT
PBSCT
PBSCT
BMT
PBSCT
PBSCT
5
6
9
Girl
Boy
Girl
Boy
Boy
Boy
Boy
HLA-MSR
HLA-MSU
HLA-MR
HLA-MSR
HLA-MU
HLA-MU
HLA_MSR
Lungs
CNS
–
Bone
–
–
–
1
1
1
2
2
1
1
Yes
Yes
Yes
No
Yes
No
No
Yes
Yes
Yes
No
Yes
Yes
Yes
16
5
7
9
B-cell ALL
AML
AML
AML
B-cell ALL
AML
B-cell ALL
B-cell ALL
B-cell ALL
B-cell ALL
B-cell ALL
AML
B-cell ALL
PBSCT
PBSCT
PBSCT
PBSCT
PBSCT
PBSCT
PBSCT
PBSCT
PBSCT
PBSCT
PBSCT
PBSCT
PBSCT
6Boy
Boy
Girl
Girl
Boy
Boy
Boy
Boy
Girl
Boy
Boy
Boy
Girl
HLA-MSR
HLA-MSR
HLA-MR
HLA-MSR
HLA-MR
HLA-MSU
HLA-MSR
HLA-MSR
HLA-MSR
HLA-MR
HLA-MU
HLA-MU
HLA-MSU
–
–
–
–
–
–
–
–
–
1
2
1
1
1
1
2
2
1
1
1
1
1
Yes
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
10
10
7
4
4
7
7
4
12LN
–
–
–
6
13
5
aIncluded the one during the study.
ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia marrow transplant; HSCT, hematopoietic stem cell transplant; BMT, bone marrow transplantation; PBSCT, peripheral
blood stem cell transplantation; HLA-MR, HLA-matched related; HLA-MSR, HLA-mismatched related; HLA-MU, HLA-matched unrelated; HLA-MSU, HLA-mismatched unrelated; CNS,
central nervous system; LN, lymph nodes.
FIGURE 1—Scheme of the transplant protocol, together with the
study design. HSCT, hematopoietic stem cell transplant; ANC,
absolute neutrophil count; GVHD, graft-versus-host disease.
EXERCISE AND CHILDHOOD CANCERMedicine & Science in Sports & Exercised
1047
CLINICAL SCIENCES

Page 4

by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited. Copyright @ 2010
Anthropometry was assessed before (prior to the condi-
tioning regimen) and 30 d post-HSCT (Fig. 1). Because of
logistic problems, it was not possible to assess these
parameters 15 d post-HSCT.
Training Intervention in Each Isolated Room
The intervention group trained from the beginning of the
conditioning regimen until neutrophil engraftment, that is,
the end of the neutropenic phase (Fig. 1). A mean of È22
training sessions would have been completed by each child
if they all had a 100% adherence to the training program.
The total number of planned training sessions was not the
same for all children (range = 17–23) as there were indi-
vidual variations in the duration of the neutropenic phase.
We used a combined (aerobic + resistance) training design
on the basis of our previous experience with children (out-
patients, G16 yr of age) who received HSCT within the
previous 12-month period (26). Due to the unique setting
characteristics (with each patient living in his room and
within an isolation unit with HEPA and positive room pres-
sure during the entire neutropenic phase), group training was
not possible. Thus, each training session was individually
supervised (one fitness instructor per patient). During the
neutropenic phase, all training equipment (including cycle
ergometers) was sterilized before each training session, and
the instructors wore face masks during the sessions.
The training program for the exercise group was planned to
include five weekly È50-min sessions, that is, three sessions
including aerobic exercises only and two sessions including
both aerobic and resistance exercises. Only those exercises
such as bench (chest) press that had to be performed in the
supine position were performed while children were lying in
bed. All sessions started and ended with articular motion (hip,
knees, and shoulders) and stretching exercises involving all
major muscle groups at the start and end of session, respec-
tively. Aerobic training corresponded to low- to moderate-
intensity cycle ergometry (Rhyno Magnetic H490; BH
Fitness Proaction, Victoria, Spain), averaging a total mean
duration of 25–30 min per session and ranging from 10 to 40
min per session, depending on the physical status of each
child. When needed, participants took short 1- to 2-min rest
periods during the aerobic part of the sessions to allow com-
pletion of the target total training time. All participants wore a
portable heart rate monitor (Xtrainer Plus; Polar Electro OY,
Kempele, Finland) during the sessions to allow maintaining
aerobic exercise intensity between 50% and 70% of age-
predicted maximum heart rate, depending on the physical
status of each child.
Patients also performed twice a week strength exercises
engaging the major muscle groups (arm curl, elbow exten-
sion, bench press, leg extension, half squat, abdominals, su-
pine bridge, and rowing). They performed one set of 12–15
repetitions per exercise. As for loads, we used (i) their own
body weight (e.g., for abdominal crunches); (ii) Therabands
(usually for the youngest children) with resistance gradually
increasing over the program, that is, from low (yellow color)
to medium (red) or high resistance (green); (iii) 1.5- to 3-kg
barbells (for the oldest ones); or (iv) both body weight and
barbells (e.g., for half squats by the end of the program). A
session was cancelled ifa child had fever 938-C,hemorrhage,
severe muscle pain, or extreme fatigue.
Data Analysis
To assess the effect of the training intervention on immune
and anthropometric variables, we used a two-factor (group
(exercise and control) ? time (pre-HSCT, +15, or +30 d post-
HSCT)) ANCOVA with repeated measures for time. The
analyses were adjusted for multiple comparison (14). Age
was initially introduced in the model as a covariate. For each
variable, we reported the P value corresponding to the main
group (between-patient) and time (within-patient) interaction
(group ? time) effects. Since there was no interaction be-
tween sex, training, and any of the outcome variables (all
P 9 0.2), all the analyses were performed for boys and girls
together, and sex was included in the model as a covariate.
We applied a Mann–Whitney’s U test to compare between
the two groups the duration (in days) of the conditioning
phase, neutropenic phase, and severe myelosupression as
well as the number of erythrocyte and platelet concentrate
transfusions needed. To assess the efficacy of the training
program in improving children’s fitness, we compared indi-
cators of aerobic (resting heart rate) (25) and muscle fitness
(resistance loads) between the start and the end of the
intervention using a Mann–Whitney’s U test.
All statistical analyses were performed using the Statistical
Package for the Social Sciences for Windows (Version 16.0;
SPSS Inc., Chicago, IL), the level of significance was set
to e0.05, and all data are expressed as mean T SD, unless
otherwise indicated.
RESULTS
There were no protocol deviations from the study as
planned. The final number of participants included as valid
study participants in the intervention group, that is, with a
100% return for follow-up over the assessment period (pre-
HSCT and up to +30 d post-HSCT), equaled seven.
TABLE 2. Main transplantation characteristics and outcomes by group.
Control
(n = 13)
Exercise
(n = 7)
Conditioning regimen (d)
Myelosupression (d)
Neutropenic phase (d)
Time between HSCT and hospital discharge (d)
Amount of CD34+ lymphocytes infused in the HSCT
(cellsI106kgj1)
No. erythrocyte concentrate transfusions needed
No. platelet concentrate transfusions needed
5 T 1
9 T 4
13 T 2
16 T 6
8.9 T 9.8
5.0 T 0
10 T 2
13 T 2
16 T 4
7.6 T 6.8
1.6 T 1.7
2.1 T 2.3
2.0 T 1.1
2.7 T 2.2
Data are presented as mean T SD.
All P 9 0.05 for group comparisons.
HSCT, hematopoietic stem cell transplantation.
http://www.acsm-msse.org
1048
Official Journal of the American College of Sports Medicine
CLINICAL SCIENCES

Page 5

by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.Copyright @ 2010
Transplant outcome. We observed no significant dif-
ferences (P 9 0.05) between groups in main transplant char-
acteristics (Table 2).
Only one study participant (in the control group) received
no antibiotic prophylaxis. As for transplant-related toxicities,
all but one control subject (92%) had one or more of such
toxicities, including oropharyngeal mucositis (n = 3),
intestinal mucositis (n = 3), liver toxicity (n = 7), diarrhea
(n = 6), and cyclosporine-induced hypertension (n = 1). In
the exercise group, five patients (71% of total) had transplant
toxicities, including oropharyngeal mucositis (n = 2), kidney
(n = 2) and liver toxicity (n = 2), diarrhea (n = 2), and
cyclosporine-induced hypertension (n = 1). Six (46%) and
two (29%) children in the control and exercise group,
respectively, had acute GVHD after HSCT. In the control
group, seven patients (54%) had no fever during hospitali-
zation, and the rest of the control patients had fever during 1
(n = 3), 2 (n = 2), or 4 d (n = 1). In the exercise group, two
children (15%) had no fever during hospitalization, whereas
the rest of children had fever during 1 (n = 2), 4 (n = 2), or
9 d (n = 1).
Training. The training characteristics for each child in
the exercise group are shown in Table 3. Mean adherence
to training was high (i.e., 990%), and we observed no major
adverse effect or health problems induced by exercise
during or after the training sessions. Reasons for lacking
one or more sessions were lack of motivation (one patient),
coincidence with transplant day (n = 1), feeling bad or
weak (n = 3), fever (n = 2), and diarrhea (n = 1). One
patient in the intervention group was missing the lower part
of a leg and thus performed one-legged cycle ergometry
and strength exercises. The training program improved
children’s functional capacity, that is, increase over the
intervention period in (i) aerobic fitness, as reflected by
significant decreases in resting heart rate, and (ii) muscle
strength, as reflected by significantly augmenting resistance
loads (Table 4).
Anthropometric variables. Mean levels of anthropo-
metric variables by group are shown in Table 5. There were
no differences between groups before HSCT. We observed
no significant group (between-patient) effect for any of the
variables (all P 9 0.1). We found a significant effect of the
interaction group ? time for all anthropometric variables
(weight, BMI, body fat, and fat-free mass), indicating an
increase over the hospitalization period only in the inter-
vention group. The effect of the interaction group ? time on
fat-free mass became nonsignificant after adjusting for mul-
tiple comparisons. All the anthropometric variables tended
to slightly decrease from pretransplant to posttransplant con-
ditions in the control group.
Immune cell recovery. Mean levels of white blood cell
subpopulations by group are shown in Table 6. There were
no differences between groups before transplantation. We
observed no significant group (between-patient) effect for
any of the variables (all P 9 0.1). We only found a time
(within-patient) effect for lymphocytes T, CD4+, and den-
dritic cells, which became nonsignificant after adjustment
for multiple comparisons. Further, we only observed a signif-
icant effect of the interaction group ? time, that is, an effect
actually attributable to the exercise intervention versus the
TABLE 3. Training characteristics of each patient of the intervention group.
Total No. Sessions
Aerobic
Mean Duration of Aerobic
Exercise/Session (min)
Mean Intensity of Aerobic
Exercise/Session (%HRmax)
71.6
65.6
71.0
72.4
62.4
71.8
69.0
69 T 4
PatientResistanceAdherence (% Total Planned Sessions)
1
2
3
4
5
6
7
Mean T SD
17
16
22
18
20
19
18
7
7
9
7
8
8
7
100
85.5
95.5
94.4
80.0
89.5
100
92 T 8
31
32
26
28
25
25
28
19 T 28 T 1 28 T 3
TABLE 4. Changes in fitness level of the intervention group over the training program.
RHR Pre (beatsIminj1)
1 (5 yr, 21 kg)c
119
2 (6 yr, 20 kg) 101
3 (9 yr, 44 kg)103
4 (16 yr, 71 kg)90
5 (5 yr, 25 kg)135
6 (7 yr, 24 kg) 87
7 (9 yr (25 kg)94
32.9 T 18.7104 T 17
Patient
RHR Post (beatsIminj1)Bench Press Prea
Bench Press Posta
Half Squat Pre (kg)b
Half Squat Post (kg)b
23.4a
22.0
46.5
77.0
31.1
27.1
28.6
36.5 T 19.6**
110
98
96
91
119
86
91
Low
Medium
1.5
2.0
Low
1.0
1.0
High
High
2.3
3.3
High
1.8
2.0
21.4
20.0
43.8
71.3
25.0
23.9
24.7
99 T 12* 32.8 T 18.7
aKilogram or Theraband resistance.
bThe load for half squat includes the body mass of each children.
cBody mass (kg) corresponding to the start of the program.
* P = 0.034 for Pre vs Post.
** P = 0.018 for Pre vs Post.
RHR, resting heart rate; Pre, start (first session) of training program; Post, end (last session) of training program.
EXERCISE AND CHILDHOOD CANCERMedicine & Science in Sports & Exercised
1049
CLINICAL SCIENCES

Page 6

by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.Copyright @ 2010
control condition, for dendritic cells (P = 0.045), which also
became nonsignificant after adjustment for multiple compari-
sons. The dendritic cell count decreased from pretransplant
to +15 d posttransplant in both groups and thereafter re-
mained stable, yet the posttransplant decrease was more
abrupt in the control group.
DISCUSSION
The main finding of our study was that, overall, moderate-
intensity exercise training (19 sessions on average, including
both aerobic and light resistance exercises) during inpatient
stay for HSCT did not affect immune cell recovery in very
young children with high-risk cancer. Further, this interven-
tion contributed to increase patient’s body mass and BMI, an
effect that was partly mediated by an increase in fat-free mass.
A limitation of our study stems from the small population
sample and the fact that we did not randomize group as-
signment. We believe that the limited sample size is justifi-
able given the low number of children undergoing HSCT, and
the lack of randomization did not significantly influence the
results as both groups were closely matched for age and type
of treatment. In addition, we did not access dietary intake, and
further research is necessary assessing dietary intake during
HSCT hospitalization. This is an important consideration as
HSCT and its related complications can cause gastrointesti-
nal side effects (e.g., mucositis, diarrhea), leading to poor nu-
trition in children (25). Future research might determine if
increased daily energy expenditure associated with exercise
training can increase young children’s appetite and energy
intake, leading to favorable changes in body composition
(increased body mass and BMI) as the ones observed here.
Although the present findings do not rule out that nutritional
status did not affect some variables, it appears that children’s
nutrition was sufficient to allow an increase in body mass
and strength to occur. Our findings on body composition
were limited by the fact that we used estimation equations to
assess muscle and fat mass. It is likely that the use of more
advanced and accurate techniques to quantify body compo-
sition (e.g., dual-energy x-ray absorptiometry) may help to
better elucidate the effect of an exercise intervention on
the patients’ body composition. Unfortunately, because of
logistic reasons (patients were confined to their rooms), this
option was not possible in the present study. Body mass and
BMI per se are nonetheless prognostic indicators of HSCT
success (8,10,18). Finally, further research is necessary to
determine the effect of exercise interventions during HSCT
not only in immune cell subpopulations as we did here but
also on immune function, for example, neutrophil oxidative
capacity (17), cytolytic activity, or mitogen-induced lympho-
cyte proliferation (28).
The novelty of our data and the special population studied,
made up of very young children (mean age = 7–8 yr) with
TABLE 5. Body composition before and after 30 d of hematopoietic stem cell transplantation (HSCT) in control (n = 13) and intervention groups (n = 7).
Variable GroupPre-HSCT +30 d Post-HSCTP (Group)P (Time)P (Group ? Time)
G0.001 Body mass (kg)Control
Intervention
Control
Intervention
Control
Intervention
Control
Intervention
30.2 (16.6)
32.9 (18.7)
18.3 (4.1)
17.8 (4.3)
7.9 (6.2)
8.5 (9.7)
22.4 (10.8)
24.3 (9.3)
29.3 (16.3)
35.4 (18.6)
17.7 (4.2)
19.4 (4.6)
7.6 (5.9)
9.7 (9.7)
21.7 (10.9)
25.7 (9.0)
0.5960.013
BMI (kgImj2) 0.7900.031
G0.001
Body fat (kg)0.6970.055 0.006
Fat-free mass (kg) 0.545 0.4570.021
Values are presented as mean (SD).
TABLE 6. White blood cell subpopulations before and after 15 and 30 d of hematopoietic stem cell transplantation (HSCT) in control (n = 13) and intervention groups (n = 7).
Cell Type (cellsImmj3)GroupPre-HSCT15 d Post-HSCT30 d Post-HSCTP (Group)P (Time)P (Group ? Time)
0.181Leukocytes Control
Intervention
Control
Intervention
Control
Intervention
Control
Intervention
Control
Intervention
Control
Intervention
Control
Intervention
Control
Intervention
Control
Intervention
2314.7 (2398.3)
2386.0 (2519.6)
1188.5 (816.5)
1911.1 (2477.8)
419.5 (310.5)
631.3 (186.9)
932.9 (700.3)
1269.0 (1594.6)
202.9 (148.9)
200.0 (177.2)
9.3 (11.0)
12.7 (17.3)
397.1 (367.4)
643.2 (885.2)
532.4 (545.5)
529.3 (648.1)
10.6 (8.7)
5.4 (2.4)
863.0 (1155.9)
1270.3 (1851.9)
155.1 (217.2)
231.0 (305.0)
518.8 (513.5)
620.4 (308.3)
77.6 (96.1)
92.0 (117.9)
95.1 (133.5)
218.4 (167.5)
1.9 (2.7)
2.4 (3.2)
46.7 (70.5)
41.0 (51.6)
27.2 (36.2)
48.4 (71.8)
1.4 (2.3)
2.0 (2.2)
2149.2 (2853.9)
5158.3 (4083.7)
783.3 (8600.6)
571.1 (282.2)
733.5 (1102.1)
857.6 (596.0)
403.0 (325.4)
305.6 (206.5)
334.7 (357.4)
368.7 (227.7)
7.7 (16.1)
4.6 (6.6)
177.3 (169.4)
78.6 (31.8)
200.7 (177.8)
153.7 (161.5)
1.7 (4.1)
2.6 (1.6)
0.1810.158
Lymphocytes0.4900.058 0.498
Monocytes 0.4080.5750.887
Lymphocytes T0.583 0.040 0.523
NK0.539 0.637 0.375
NK T 0.8920.838 0.791
CD4+
0.5820.0320.422
CD8+
0.975 0.2300.794
Dendritic0.4970.001 0.045
Values are presented as mean (SD).
NK, natural killer.
http://www.acsm-msse.org
1050
Official Journal of the American College of Sports Medicine
CLINICAL SCIENCES

Page 7

by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited. Copyright @ 2010
high-risk cancer, are strong aspects of our study. In addition,
we performed an individually supervised training interven-
tion in a difficult, unusual setting, that is, isolated hospital
rooms requiring sterilization of all training materials. Unique-
ness of training conditions together with the high adherence
to the program (in spite of the numerous drug toxicities
suffered by the children and their poor functional status) also
make the data unique. These aspects give support to the
notion that exercise training can be a feasible therapeutic
intervention even in the most debilitated and immune-
compromised patient groups. Although keeping in mind that
the total safety of exercise training during inpatient stay for
pediatric HSCT remains to be determined in future trials with
much larger population samples, we believe that our inter-
vention is applicable worldwide. Besides the fact that all
training materials must be sterilized and caution is needed
when prescribing training loads in these very young, weak
patients, no expensive equipment is needed, and children
have high time availability for training during room isolation.
The fact that adherence to training was very high concurs
with previous intrahospital training trials in pediatric cancer
patients (26,27) and supports the applicability of exercise
interventions during hospitalization for cancer treatment.
Further, intrahospital settings provide the best possible envi-
ronment in the event of health problems occurring during
training sessions.
The training-induced gains we showed in body mass/BMI
over the hospitalization period in the intervention group,
associated with an approximately 1-kg gain in fat-free mass,
are clinically relevant. These anthropometric parameters have
prognostic value after HSCT over a wide range of patients’
age (8,10,18). In adult patients who received allogeneic
HSCT, a low BMI (G20 kgImj2) was significantly correlated
with increased transplant-related mortality, decreased sur-
vival, and relapse-free survival (18). Maintenance of skeletal
muscle protein is crucial in immunocompromised children
(24), including those receiving HSCT (30). Avoiding losses
in body mass during pediatric HSCT is of paramount
importance because children undergoing this intervention
are at particular high risk of malnutrition (34), and their
muscle weakness is further aggravated by transplant-related
problems, that is, bed rest and drug toxicities including
among others oral intestinal mucositis and diarrhea (8,33).
Because of the novelty of our design and the type of pop-
ulation, it is not possible to directly compare the present
findings on anthropometric data with those reported in pre-
vious research. We recently reported no significant changes
in body mass in outpatients who underwent HSCT within the
previous 12 months after an 8-wk training program combin-
ing aerobic and resistance exercises (27). It is important to
note that the physical status was less deteriorated than that in
the present subjects, making comparisons difficult. Although
there is some controversy (3,35), our findings seem to be in
agreement with previous research on adult outpatients
showing the overall efficacy of exercise training interventions
for preserving patients’ muscle mass after HSCT (2,3,11).
In a home-based 6-month aerobic and resistance training
intervention performed by adults receiving BMT, Coleman
et al. (2) found that control patients lost body mass whereas
intervention participants increased in body mass and fat-free
mass. Similarly, Hayes et al. (11) reported increased fat-free
mass in adults who received HSCT after a 3-month inter-
vention of aerobic and resistance training.
There is evidence supporting the beneficial effects of
physical exercise in the distribution and function of the cel-
lular components of the immune system in healthy children
(31). Up to date, however, the feasibility and the safety of
exercise interventions in immunocompromised children as
those studied here remain to be determined. Overall, exercise
training was shown to be a safe intervention in our inpatients,
that is, not compromising immune cell recovery over the
hospitalization period. This preliminary finding is promising
and clinically relevant, especially when considering that the
largest part of the exercise intervention took part during the
neutropenic phase, that is, while the absolute neutrophil count
was below 0.5 ? 109Lj1. Patients were not neutropenic in
any of the two previous studies assessing the immune cell
acute responses (17) or adaptations to exercise in children
withacutelymphoblasticleukemia(28). Both pioneer studies
reported no health-threatening effects of exercise on immune
cells, which concurs with our results. Our findings are also
in agreement with those previously reported by Hayes et al.
(12) in adult patients who received HSCT and whowerealso
immunocompromised.Theycarriedoutacombined(aerobic+
resistance) moderate-intensity exercise training program
during the first 3 months posttransplantation that showed
no significant effect on immune cell recovery posttransplant.
Dimeo et al. (6) reported shorter duration of the neutropenic
phase after bed endurance training, and Kim and Kim (16)
reported increases in total lymphocyte count with no de-
creases in lymphocyte subpopulations (CD3+, CD4+, and
CD8+ or CD4+/CD8+ ratio). Taken together, these findings
support the notion that physical exercise is a promising ad-
juvant therapeutic intervention during HSCT hospitalization
inbothchildrenandadults.
We only observed a significant effect of the interaction
group ? time (which became nonsignificant after adjusting
for multiple comparisons) for one of the immune cell
populations, that is, dendritic cells. The dendritic cell count
decreased from pretransplant to +15 d posttransplant in both
groups and thereafter remained stabile with the posttransplant
decrease being more abrupt in the control group, that is,
j87% versus j63% compared with the intervention group.
Whether this finding is of clinical relevance remains to be
determined, yet it deserves some attention given the pivotal
immune role played by dendritic cells. These cells are the
most potent antigen-presenting cells of the immune system
(15). They play a central modulator role in allogeneic HSCT
(23) and are excellent candidates for immunotherapy in
pediatric cancer patients (15). The content of donor’s den-
dritic cells associated with decreased risk of GVHD (32), and
dendritic cell recovery at 30 d post-HSCT is associated with
EXERCISE AND CHILDHOOD CANCERMedicine & Science in Sports & Exercised
1051
CLINICAL SCIENCES

Page 8

by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.Copyright @ 2010
the clinical outcome after allogeneic HSCT (29). Ho et al.
(13) reported an increase in dendritic cell count after acute
(treadmill) exercise that paralleled that of monocytes. Their
study showed that exercise is one of the main stressor stimuli
able to trigger dendritic cell increases in blood.
In summary, moderate-intensity exercise training during
inpatient stay for HSCT (È3-wk training period) does not
negatively affect immune cell recovery in children with
high-risk cancer while contributing to increase body mass
and BMI. These findings together with the multiple health
benefits associated with exercise training in cancer patients
support the feasibility of training interventions during hos-
pitalization, including immune-compromised children. Future
studies using randomized controlled designs in larger pop-
ulation samples are nonetheless necessary, especially to
corroborate the total safety of this type of intervention.
This study was funded by a grant from the Fondo de Inves-
tigaciones Sanitarias (grant Nos. P1061183 and PS09/00194), from
the Fundacio ´n Blas Ponce Para El Nin ˜o Oncolo ´gico, and from the
Spanish Ministry of Education (EX-2007-1124).
The authors state that the results of the present study do
not constitute endorsement by the American College of Sports
Medicine.
This study was awarded with Segundo Premio Nacional de
Investigac ´ion en Medicina del Deporte, Escuela de Medicina del
Deporte, Oviedo (Spain).
REFERENCES
1. Brook CG. Determination of body composition of children from
skinfold measurements. Arch Dis Child. 1971;46:182–4.
2. Coleman EA, Coon S, Hall-Barrow J, Richards K, Gaylor D,
Stewart B. Feasibility of exercise during treatment for multiple
myeloma. Cancer Nurs. 2003;26:410–9.
3. Cunningham BA, Morris G, Cheney CL, Buergel N, Aker SN,
Lenssen P. Effects of resistive exercise on skeletal muscle in
marrow transplant recipients receiving total parenteral nutrition.
JPEN J Parenter Enteral Nutr. 1986;10:558–63.
4. Decker WA, Turner-McGlade J, Fehir KM. Psychosocial aspects
and the physiological effects of a cardiopulmonary exercise pro-
gram in patients undergoing bone marrow transplantation (BMT)
for acute leukemia (AL). Transplant Proc. 1989;21:3068–9.
5. Dimeo F, Bertz H, Finke J, Fetscher S, Mertelsmann R, Keul J.
An aerobic exercise program for patients with haematological
malignancies after bone marrow transplantation. Bone Marrow
Transplant. 1996;18:1157–60.
6. Dimeo FC, Stieglitz RD, Novelli-Fischer U, Fetscher S, Keul J.
Effects of physical activity on the fatigue and psychologic sta-
tus of cancer patients during chemotherapy. Cancer. 1999;85:
2273–7.
7. Dimeo FC, Tilmann MH, Bertz H, Kanz L, Mertelsmann R,
Keul J. Aerobic exercise in the rehabilitation of cancer patients
after high dose chemotherapy and autologous peripheral stem cell
transplantation. Cancer. 1997;79:1717–22.
8. Duggan C, Bechard L, Donovan K, et al. Changes in resting
energy expenditure among children undergoing allogeneic stem
cell transplantation. Am J Clin Nutr. 2003;78:104–9.
9. Durmin JV, Rahaman MM. The assesment of the amount of fat
in the human body from measurments of skinfolds thickness.
Br J Nutr. 1967;21:681–9.
10. Hadjibabaie M, Iravani M, Taghizadeh M, et al. Evaluation of
nutritional status in patients undergoing hematopoietic SCT. Bone
Marrow Transplant. 2008;42:469–73.
11. Hayes S, Davies PS, Parker T, Bashford J. Total energy ex-
penditure and body composition changes following peripheral
blood stem cell transplantation and participation in an exercise
programme. Bone Marrow Transplant. 2003;31:331–8.
12. Hayes SC, Rowbottom D, Davies PS, Parker TW, Bashford J.
Immunological changes after cancer treatment and participa-
tion in an exercise program. Med Sci Sports Exerc. 2003;35(1):
2–9.
13. Ho CS, Lopez JA, Vuckovic S, Pyke CM, Hockey RL, Hart DN.
Surgical and physical stress increases circulating blood dendritic
cell counts independently of monocyte counts. Blood. 2001;98:
140–5.
14. Holm S. A simple sequentially rejective multiple test procedure.
Scand J Statist. 1979;6:65–70.
15. Jacobs JF, Hoogerbrugge PM, de Rakt MW, et al. Phenotypic and
functional characterization of mature dendritic cells from pediatric
cancer patients. Pediatr Blood Cancer. 2007;49:924–7.
16. Kim SD, Kim HS. A series of bed exercises to improve lympho-
cyte count in allogeneic bone marrow transplantation patients. Eur
J Cancer Care (Engl). 2006;15:453–7.
17. Ladha AB, Courneya KS, Bell GJ, Field CJ, Grundy P. Effects of
acute exercise on neutrophils in pediatric acute lymphoblastic
leukemia survivors: a pilot study. J Pediatr Hematol Oncol. 2006;
28:671–7.
18. Le Blanc K, Ringden O, Remberger M. A low body mass index is
correlated with poor survival after allogeneic stem cell transplan-
tation. Haematologica. 2003;88:1044–52.
19. Little MT, Storb R. History of haematopoietic stem-cell trans-
plantation. Nat Rev Cancer. 2002;2:231–8.
20. Lohman TG, Roche AF, Martorell R. Anthropometric Standard-
ization Reference Manual. Champaign (IL): Human Kinetics;
1991. p. 55–70.
21. Lucia A, Ramirez M, San Juan AF, Fleck SJ, Garcia-Castro J,
Madero L. Intrahospital supervised exercise training: a comple-
mentary tool in the therapeutic armamentarium against childhood
leukemia. Leukemia. 2005;19:1334–7.
22. Mello M, Tanaka C, Dulley FL. Effects of an exercise program on
muscle performance in patients undergoing allogeneic bone mar-
row transplantation. Bone Marrow Transplant. 2003;32:723–8.
23. Mohty M. Dendritic cells and acute graft-versus-host disease after
allogeneic stem cell transplantation. Leuk Lymphoma. 2007;48:
1696–701.
24. Neumann CG, Lawlor GJ Jr, Stiehm ER, et al. Immunologic
responses in malnourished children. Am J Clin Nutr. 1975;28:
89–104.
25. Rodgers C, Walsh T. Nutritional issues in adolescents after bone
marrow transplant: a literature review. J Pediatr Oncol Nurs.
2008;25:254–64.
26. San Juan AF, Chamorro-Vina C, Moral S, et al. Benefits of intra-
hospital exercise training after pediatric bone marrow transplan-
tation. Int J Sports Med. 2008;29:439–46.
27. San Juan AF, Fleck SJ, Chamorro-Vina C, et al. Effects of an
intrahospital exercise program intervention for children with
leukemia. Med Sci Sports Exerc. 2007;39(1):13–21.
28. Shore S, Shepard RJ. Immune responses to exercise in children
treated for cancer. J Sports Med Phys Fitness. 1999;39:240–3.
29. Talarn C, Urbano-Ispizua A, Martino R, et al. Kinetics of recov-
ery of dendritic cell subsets after reduced-intensity conditioning
http://www.acsm-msse.org
1052
Official Journal of the American College of Sports Medicine
CLINICAL SCIENCES

Page 9

by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited. Copyright @ 2010
allogeneic stem cell transplantation and clinical outcome. Haema-
tologica. 2007;92:1655–63.
30. Taskinen M, Saarinen UM. Skeletal muscle protein reserve
after bone marrow transplantation in children. Bone Marrow
Transplant. 1996;18:937–41.
31. Timmons BW. Paediatric exercise immunology: health and
clinical applications. Exerc Immunol Rev. 2005;11:108–44.
32. Waller EK, Rosenthal H, Sagar L. DC2 effect on survival fol-
lowing allogeneic bone marrow transplantation. Oncology. 2002;
16:19–26.
33. White AC, Terrin N, Miller KB, Ryan HF. Impaired respiratory
and skeletal muscle strength in patients prior to hematopoietic
stem-cell transplantation. Chest. 2005;128:145–52.
34. White M, Davies P, Murphy A. Validation of percent body fat
indicators in pediatric oncology nutrition assessment. J Pediatr
Hematol Oncol. 2008;30:124–9.
35. Wilson RW, Jacobsen PB, Fields KK. Pilot study of a home-based
aerobic exercise program for sedentary cancer survivors treated
with hematopoietic stem cell transplantation. Bone Marrow
Transplant. 2005;35:721–7.
EXERCISE AND CHILDHOOD CANCER Medicine & Science in Sports & Exercised
1053
CLINICAL SCIENCES