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.