Discussion
Obesity represents a growing health risk in this country. Pediatric
patients with hematopoietic malignancies are no exception. In this
study, we demonstrate that pediatric patients experience an increase in
BMI after HCT. Prior to transplant, 40% of patients were overweight or
obese according to BMI, of which 17.8% qualified as obese. At the five
years post-transplant mark, 40.5% were overweight or obese, of which
24% were obese. While the total number of overweight and obese remained
constant, the number of obese patients increased, likely secondary to
overweight individuals becoming obese. Further, our longitudinal
analysis of BMI trends over time demonstrated the highest rate of BMI
increase in older patients. In the general US pediatric population, the
prevalence of overweight and obesity is 31.8%, with 16.9% obese.
Similarly, the prevalence is higher in older youth aged 12-19, with
34.5% overweight or obesity, of which 20.5% classify as
obese.22 In Los Angeles County, 23.0% of school-aged
children are obese.23 Despite the full-time support of
a registered dietician in both the inpatient and outpatient settings for
the UCLA pediatrics hematology and oncology service, our cohort
demonstrated similar rates of obesity compared with children in Los
Angeles county, and higher rates of obesity compared with the general US
pediatric population. This suggests that pediatric HCT patients have a
high predisposition for obesity in the years following transplantation,
with adolescents/young adults at highest risk.
Understanding the trends in BMI after HCT is critical, yet few
longitudinal reports of body composition in HCT patients exist and the
results are inconsistent. A European report characterized the trends in
BMI for both adult and pediatric patients after HCT, noting that BMI
remained stable in adults while it increased in
children.24 However, this study did not analyze BMI
using age-appropriate scales in children. A more recent report adjusted
BMI utilizing the same age conversion scales as we did. This study of
179 HCT recipients over a 10 year span demonstrated a drop in BMI after
transplantation due to a reduction in lean mass.17Conversely, it has been shown that childhood HCT recipients are at risk
of developing central obesity that is not adequately captured through
BMI measures.18 Our work contributes to this
understudied topic, suggesting that childhood HCT survivors experience
weight gain that disproportionately affects older patients.
There are several reasons that may contribute to this increased
predisposition for obesity. Complications after HCT, such as GVHD, are
frequently treated with steroids that can cause significant toxicity
including weight gain and central obesity.25 Sleep
disruption is also common among HCT recipients,26which may influence weight status.27 HCT recipients
may experience physical fatigue and poor functional status that can
persist for several years post-transplantation.28Further, chemotherapy can induce endothelial damage, causing capillary
leakage and fluid retention.29 While not all of these
directly reflect nutritional status and degree of adiposity, indirect
and direct factors that promote fatty deposition and sedentary
lifestyles are concerning. Excessive weight and obesity induce a chronic
low grade inflammatory state that predisposes to a wide variety of
conditions, including metabolic syndrome.30 The
impacts of obesity on HCT is complex, such that excess adiposity may
directly affect disease pathogenesis and alter pharmacodynamics, further
complicated by the often varying conditioning regimens for those who are
obese.31 While a consensus has not been reached
regarding the effects of obesity on HCT outcomes, many studies highlight
its negative effects. One report in both children and adults receiving
HCT demonstrated higher rates of non-relapse related mortality in obese
patients, likely due to acute and chronic GVHD, although with no
difference in overall survival.32 A meta-analysis
found that a high pre-transplant BMI was associated with an increased
risk for acute GVHD along with worsened survival.33 In
the pediatric literature, two studies revealed that high BMI
pre-transplantation led to lower overall survival and higher
mortality.16,34 While our post-transplant outcomes
analysis regarding GVHD, infection, platelet and neutrophil engraftment,
and overall survival were not statistically significant among weight
categories, our results do show trends towards higher rates of severe
acute GVHD and lower survival for overweight and obese patients. Thus,
further research is warranted to investigate the impacts of obesity on
HCT outcomes.
A notable trend in our analysis of BMI is that those who did not receive
TBI had a higher BMI increase from baseline, such that TBI demonstrated
a protective effect in weight gain. TBI may induce hypothalamic
pituitary lesions that disrupt the regulatory secretion of hormones that
contribute to height and nutritional status.35Further, it has been demonstrated that TBI may decrease GH secretion,
interrupt leptin regulation, and result in a persistently low BMI and
blunted adult height.36,37 We believe that the trends
in our weight analysis may be the result of similar hypothalamic
disruptions, where TBI may hinder growth in both height and weight that
precludes a BMI increase.
Regardless of the data on HCT outcomes, it is well established that
obesity is associated with a variety of comorbidities. Chronic
adaptations in cardiac structure and function in response to excess
adipose tissue accumulation increases risk of cardiovascular disease,
which can manifest as heart failure, coronary heart disease, and sudden
cardiac death.38,39 Given that many HCT patients
receive doxorubicin, an anthracycline with severe cardiotoxic side
effects,40 it is especially critical to optimize body
composition in this vulnerable population. A proactive approach by
maintaining a healthy BMI before treatment, and well after, may mitigate
the risk of adverse cardiovascular events later in life.
The idea that there is a close relationship among nutrition, HCT, and
oncology is not novel. Since the observation of the Warburg
effect,41 the literature has expanded with attempts to
better understand the relationship between nutrition and tumorigenesis.
There currently exists several proposed dietary regimens, including the
ketogenic diet,42 intermittent
fasting,43 and caloric restriction44as emerging approaches in cancer treatment. It is believed that an
avoidance of the Western diet,45 and an adaptation of
the Japanese diet,46 vegan diet,47or Mediterranean diet48 may decrease risk of
developing a wide variety of malignancies. Due to the possible
influences of nutrition on tumorigenesis and transplant outcomes,
optimization of body composition throughout the process of HCT is
essential.49
This is a comprehensive analysis of the HCT data from the pediatric
population at our institution. Nonetheless, our study, which is
retrospective in nature, is limited by the availability of patient data.
Thus, we were only able to include patients who received HCT from 2005
to 2018 since those who were transplanted prior to 2005 had incomplete
clinical data that were insufficient to include in our study. Further,
there may be potential confounders in the patient characteristics
affecting post-transplant outcomes; however, these do not affect our
overall observation of increased BMI after HCT. Another limitation is
our reliance on BMI to assign patients into the appropriate weight
categories. There is evidence to suggest that BMI may not adequately
represent body fat percentage and those who have central
obesity.18 Unfortunately, data on body fat percentage
is not available in our cohort, but may be a variable to be included in
future studies.