Baseline Body Mass Index Among Children and Adults Undergoing Allogeneic Hematopoietic Cell Transplantation: Clinical Characteristics and Outcomes

Abstract

Obesity is a serious public health problem accompanying changes in diet and physical activity. The rising prevalence of obesity may influence the outcomes of hematopoietic cell transplantation (HCT). We studied 898 children and adults receiving first-time allogeneic bone marrow or peripheral blood stem cell transplants between 2004 and 2012 at the University of Michigan. Pre-transplant body mass index (BMI) was calculated using height and weight measurements and treated as a continuous variable. Recipients were then classified as underweight, normal weight, overweight, or obese according to BMI for adults using the World Health Organization classification system, or age-adjusted BMI percentiles for children based on Center for Disease Control and Prevention charts. The study population was predominantly Caucasian, and the median age was 51 years (5 months – 73 years). The cumulative 3-year incidence of non-relapse mortality (NRM) in underweight, normal weight, overweight, and obese patients was 20%, 19%, 20%, and 33% (p=0.04) (Figure 1A). Major causes of NRM were acute and chronic graft-versus-host disease (GVHD) (Figure 1B). The corresponding incidence of relapse was 30%, 41%, 37%, and 30% (p=0.002) (Figure 1C). Three-year overall survival was 59%, 48%, 47%, and 43% (p=0.55) (Figure 1D). Multivariate analysis showed that obesity was associated with higher NRM (hazard ratio [HR] 1.43, p=0.04), and lower relapse (HR 0.65, p=0.002) (Table 1). Pre-transplant plasma levels of ST2 and TNFR1 biomarkers were significantly higher in obese than in normal weight patients (p=0.04 and p=0.05, respectively) (Table 2). The increase in NRM observed in obese patients was partially offset by lower incidence of relapse, resulting in no significant difference in overall survival. Figure 1. Transplant outcomes according to BMI categories. Cumulative incidence of NRM (A), chronic GVHD (B), relapse (C), and probability of overall survival (D) according to BMI groups. N = 20 underweight (UW), 290 normal weight (NW), 287 overweight (OW), 301 obese (OB). Figure 1. Transplant outcomes according to BMI categories. Cumulative incidence of NRM (A), chronic GVHD (B), relapse (C), and probability of overall survival (D) according to BMI groups. N = 20 underweight (UW), 290 normal weight (NW), 287 overweight (OW), 301 obese (OB). Table 1. Results of multivariate regression analysis by BMI category. NRM Acute GVHD Chronic GVHD Relapse Overall survival Hazard ratio (95% confidence intervals), p value Normal weight 1.00 1.00 1.00 1.00 1.00 Underweight 1.74 (0.76−4.01), 0.19 1.11 (0.56−2.21), 0.76 0.99 (0.46−2.12), 0.98 0.70 (0.32−1.50), 0.36 1.02 (0.54−1.95), 0.95 Overweight 0.95 (0.65−1.37), 0.77 1.03 (0.78−1.35), 0.85 1.07 (0.83−1.38), 0.60 0.79 (0.61−1.03), 0.08 0.85 (0.68−1.07), 0.17 Obese 1.43 (1.02−2.01), 0.04 1.15 (0.89−1.50), 0.29 1.21 (0.94−1.55), 0.14 0.65 (0.49−0.86), 0.002 0.93 (0.75−1.16), 0.55 Other covariates Continuous age 1.01 (1.00−1.02), 0.18 1.00 (0.99−1.00), 0.37 1.00 (0.99−1.01), 0.69 1.00 (1.00−1.01), 0.36 1.01 (1.00−1.02), 0.003 Malignancy Non−malignant 1.00 1.00 1.00 1.00 1.00 Malignant 0.37 (0.10−1.33), 0.13 1.73 (0.82−3.68), 0.15 1.29 (0.72−2.31), 0.38 26.50 (3.49−201.02), 0.002 2.05 (0.92, 4.58), 0.08 Relatedness Related 1.00 1.00 1.00 1.00 1.00 Unrelated 2.20 (1.65−2.94), <0.001 1.88 (1.50−2.35), <0.001 1.13 (0.92−1.39), 0.23 0.61 (0.48−0.77), <0.001 1.24 (1.03−1.49), 0.02 Transplant type Peripheral blood 1.00 1.00 1.00 1.00 1.00 Bone marrow 0.23 (0.09−0.58), 0.002 0.66 (0.44−0.99), 0.04 0.91 (0.61−1.36), 0.65 1.09 (0.72−1.66), 0.68 0.56 (0.38−0.82), 0.003 HLA match Matched 1.00 1.00 1.00 1.00 1.00 Mismatched 1.59 (1.16−2.22), 0.004 1.69 (1.30−2.17), <0.001 0.95 (0.73−1.25), 0.73 0.83 (0.60−1.18), 0.29 1.41 (1.12−1.79), 0.003 Conditioning Myeloablative 1.00 1.00 1.00 1.00 1.00 Reduced 1.02 (0.76−1.35), 0.91 1.19 (0.94−1.49), 0.14 1.02 (0.82−1.27), 0.82 0.90 (0.69−1.16), 0.42 0.89 (0.74−1.09), 0.24 Year of transplant 2004−2008 1.00 1.00 1.00 1.00 1.00 2009−2013 0.79 (0.60−1.05), 0.10 0.76 (0.61−0.95), 0.02 0.96 (0.79−1.17), 0.70 0.76 (0.60−0.95), 0.02 0.78 (0.65−0.94), 0.01 Table 2. Baseline levels of plasma biomarkers suppression of tumorigenicity 2 (ST2) and tumor necrosis factor receptor 1 (TNFR1) by BMI category. ST2 TNFR1 BMI category N Median concentration (IQR), pg/ml p value N Median concentration (IQR), pg/ml p value Normal weight 115 131 (0-628) − 88 2129 (1486-3232) − Underweight 7 256 (82-659) 0.51 7 1596 (1467-2971) 0.57 Overweight 115 208 (0-845) 0.22 81 2266 (1708-3725) 0.32 Obese 110 257 (0-1045) 0.04 99 2644 (1922-3395) 0.05 Disclosures No relevant conflicts of interest to declare.

Changes in protein serum levels during stem cell transplantation

“…ST2 was also included in a biomarkers panel predictive for cGvHD development, GvHD severity and TRM [24]. Finally, pretransplant ST2 levels were reported being higher in obese patients as compared to normal weight patients [25]. Our result displayed that soluble ST2 levels increased from baseline to both aGvHD and cGvHD onset, but no differences were seen in terms of response to treatment.…”

Impact of Body Mass Index on Outcomes of Hematopoietic Stem Cell Transplantation in Adults

“…Gleimer et al [2] analyzed the effect of BMI in 898 children and adults after a first allogeneic HCT. Outcomes evaluated included overall survival, NRM, relapse, and cumulative incidences of acute and chronic GVHD.…”

“…Since that time, several single and multicenter analyses have assessed the effect of additional measures of body habitus, including body mass index (BMI), body surface area (BSA), and weight loss during transplantation, on transplantation outcomes. These studies, summarized in a recent review, had varying results and sometimes reached disparate conclusions [2]. Comparing the results of these studies is difficult because of the diversity of patient populations studied, differing duration of follow-up, small patient numbers, and diagnosis-or conditioning regimen-restricted patient groups.…”

Preclinical modeling of hematopoietic stem cell transplantation – advantages and limitations

“…Similarly, as the obesity epidemic continues, it may be assumed that the increased visceral fat composition and associated metabolic inflammation observed in obese recipients probably also contributes to increased GVHD severity in these patient populations. Epidemiological studies have reported that obese patients often experience a higher risk of both acute and chronic GVHD [6]. However, the vast majority of HSCT and cancer preclinical studies use relatively young, lean mice (sometimes equivalent to healthy, early-adolescent humans), despite the fact that cancer is predominantly a disease of the elderly and obese.…”