Incidence and risk factors for new overweight or obesity following hematopoietic cell transplantation for sickle cell disease

Abstract Longterm outcomes after curative allogeneic hematopoietic cell transplantation (HCT) for sickle cell disease (SCD) are being established, but preliminary data suggest a proportion become newly overweight or obese, likely reflecting metabolism change post-HCT. In a larger longitudinal cohort, we aimed to describe incidence of new overweight or obesity post-HCT for SCD and hypothesized that SCD and HCT factors will predict its development. In a single center retrospective study, SCD patients post 1st allogeneic or autologous (gene modified) HCT from 2010-2024 were eligible. Patients were excluded if no pre- or <1 yr post-HCT data (n=22), primary graft rejection (n=1), HCT for another reason (n=1), or died <1 yr post-HCT (n=2). Data were abstracted from the electronic medical record through their last visit. Height and weight measurements were cleaned using R growthcleanr package, with implausible values removed. BMI value, percentile, and z-score were calculated and categorized, using BMI percentile if <20 yrs and BMI if ≥20 yrs. All data was summarized and cumulative incidence (CI) of new post-HCT overweight or obesity was calculated. Amongst those newly overweight or obese, available lipid panel and fructosamine data were summarized. Statistical significance was set as p<0.05. Amongst 106 patients, median age at HCT was 9.0 yrs (range, 5.6-14.0) and post-HCT follow up was 5.1 yrs (1.1-12.1). Nearly all (96%) had HbSS or HbS/β0 genotype and 48% were female. All autologous recipients (n=8) had severe clinical phenotype with recurrent vaso-occlusive episodes (VOE). Amongst allogeneic recipients (n=98), 59% had severe clinical phenotype with indication of recurrent VOE in 59%, CNS complication in 49%, and recurrent acute chest syndrome in 46%; most received HU treatment pre-HCT (67%), while 21% received chronic RBC transfusions. Most allogeneic recipients received bone marrow (97%), from a matched sibling donor (89%), and myeloablative conditioning (84%). GVHD was rare - 5% developed grade III-IV acute and 9% severe chronic, at a median of 1.1 (range, 0.9-2.4) and 7.7 mo (6.9-10.4), respectively. One patient had poor allogeneic graft function with successful 2nd HCT, and one allogeneic recipient died 9.2 yrs post-HCT of giant cell myocarditis. Pre-HCT, only 15 patients (14%) were overweight (n=11) or obese (n=4), with most (86%) underweight (n=4) or normal weight (n=87). The proportion overweight or obese increased every yr post-HCT, such that by 3 yrs, it significantly increased from baseline (to 29%; p=0.026). The proportion overweight or obese peaked at 40% at yr 4 and remained steady at 41% to yr 5. While most patients (75%) increased BMI % by ≥5%, 62% did not increase in weight category (e.g. underweight→normal, normal→overweight, etc.). Amongst 38% increasing weight category, their donor was significantly more likely to have sickle trait (78% vs 56%; p=0.048). No significant differences in other characteristics or outcomes were seen between cohorts, including age at HCT, disease severity, or GVHD. Amongst those under or normal weight at baseline (n=91), 35% became newly overweight or obese post-HCT, half of whom became obese. All newly overweight/obese patients with available testing (n=31) had ≥1 abnormal lipid panel element – triglycerides were elevated in 45% and 26% each had low HDL or high LDL. Fructosamine levels (n=15 with testing) were pre-diabetic range in 73% and diabetic in 7%. At 1, 3, and 5 yrs post-HCT, CI of new overweight was 19% (95% CI: 11-27%), 30% (20-40%), and 38% (27-48%), respectively; at the same timepoints, CI of new obesity was 5% (2-10%), 8% (4-15%), and 16% (9-26%). At ≥2 yrs post-HCT, females had a higher CI of new overweight/obese status. In a large single center cohort of pediatric SCD patients, most increased BMI pre- to post-HCT, and a significant proportion develop new overweight or obese status. Further, a significant proportion with new overweight/obesity had an abnormal lipid panel or fructosamine level, which may contribute to metabolic syndrome. Age at HCT and recipient sex may be predictors of this outcome, but further analysis is ongoing, and validation will be necessary in a secondary cohort. As increasing numbers of patients are cured of their SCD, it will be critical to continue to assess their risk for these late effects which may increase risk for cardiovascular disease and to develop prevention strategies.