This study found that overweight children (age-adjusted BMI >95th percentile) with severe aplastic anemia experienced worse survival outcomes after allogeneic hematopoietic cell transplantation compared to patients who were not overweight. This demonstrates that obesity in this homogenous population has a significant negative impact on survival and possibly on complications post HCT. Overweight children with severe aplastic anemia have no apparent increase in rates of aGVHD III-IV in that region.
The effect of body weight on transplant outcomes is the topic of several studies. The results, however, vary depending on the transplant indication, type of transplant and patient population. This question was addressed initially in recipients of autologous HCT for malignant diseases. Obese adults, defined according to BMI, experienced higher mortality rates after autologous HCT for non-Hodgkin’s lymphoma and acute myeloid leukemia (AML) (4
). Subsequent studies using the CIBMTR database addressed this question in 4,681 adult recipients of autologous HCT for lymphoma. Obese patients experienced similar survival outcomes compared to overweight patients and to patients in the normal weight range. Transplant-related mortality was 2.5 times greater for patients in the underweight group compared to all the other weights (5
). Similar results, i.e. comparable survival outcomes of obese and non-obese patients and shortened survival in underweight patients, were demonstrated in patients with AML receiving HCT (20
). Despite these observations in large cohort of patients, obesity was identified as an independent prognostic factor for non-relapse mortality after HCT and is a component of the HCT-Comorbidity Index (21
The results from obesity studies in the adult population might not directly apply to children. The definition of obesity in adults utilizes a single BMI measurement at time of transplant. In children, age adjustments are necessary for defining weight groups and it is uncertain whether BMI in adults or age-adjusted BMI in children have the same prognostic impact. Chemotherapy dose adjustments based on weight to minimize toxicity are likely to be different between children and adults(10
). Children with leukemia at the opposite ends of the weight scale, overweight and underweight, suffer from higher mortality during standard chemotherapy induction treatments (9
). Studies on the impact of weight on post transplant outcomes in the pediatric population are scant. One single-institution study analyzed 54 children with BMI ≥ 95th
among a cohort of 325 recipients of allogeneic HCT for treatment of several diseases. Five-year overall survival probabilities were 47% in the overweight group compared to 70% in the non-overweight group (p=0.02)(22
The effect of obesity on aGVHD is less clear. Univariate analysis in our study demonstrated a higher rate of aGVHD III-IV in the overweight group, which was likely related to the higher proportion of recipients of URD recipients in this group. After adjusting the analysis for donor type and other variables, this effect of weight and aGVHD III-IV disappeared.
A study from the Japanese group also demonstrated a strong relationship between weight at time of transplant and GVHD (8
). This study analyzed patients of all ages with malignant diseases. Although the univariate analysis in the Japanese study demonstrated a strong association between weight and both acute and chronic GVHD, this association disappeared in multivariate analysis. In our analysis, other factors were strongly associated with development of aGVHD III-IV in patients with severe aplastic anemia. As expected, URD recipients and HLA disparity were associated with higher rates of aGVHD III-IV. Recipients from Asia experienced less frequent aGVHD III-IV, which could also be attributed to lower rates of aGVHD in URD recipients in Asia, due to less HLA gene variability in the region.
Race and region also were associated with survival outcomes. Interestingly, there was higher rate of mortality among African American compared to Caucasian children in the U.S. No data on socio-economic status was collected for these patients, which could impact outcomes along with access to care. Improvements in survival outcomes in the later periods are attributed to improvements in donor and patient selection, and have also been described in other studies (23
). The effect of conditioning regimen was analyzed separately in Sibs and URD HCT. The use of busulfan in Sibs recipients was associated with worse survival. There was no effect of conditioning regimens and survival outcomes in URD HCT.
This is the largest study ever done to assess the effect of weight on allogeneic transplant outcomes in children with severe aplastic anemia. However, this is a retrospective study, utilizing registry data that spans a 15-year period. The decision to proceed to transplantation was made by individual transplant physicians as part of center-specific protocols or as standard of care. Despite the number of cases, some variables such as dose-adjustment practices and detailed prior treatment, including transfusion, were not present in all patients and could not be formally examined. Another limitation of this study was the definition of obesity. The weight charts in which the age-adjusted BMIs were calculated are normalized to the U.S. population, but the study utilized children outside the U.S. This might explain the higher number of patients from Asia, South American and Europe in the underweight groups, which could clarify why this group did not experience poorer survival rates, as other studies on underweight children have shown. Small numbers of underweight children in the U.S. did not allow for a meaningful subset analysis to answer this question.
In conclusion, our study indicates that obese children with severe aplastic anemia have higher mortality rates following allogeneic HCT compared to normal weight children. There was no impact of weight on development of aGVHD III-IV in this population. Obesity is not an easily modifiable risk factor, and optimizing nutrition and weight pretransplant is difficult to achieve due to the urgency of the procedure. The impact of obesity on transplant outcomes for this disease should be discussed during pre-transplant counseling. Prospective studies with a better definition of obesity, using anthropometrics in children, are important to further understanding the association between obesity and post-transplant outcomes.