HSCT is being increasingly offered as a curative option for children with hematologic malignancies. Although survival has improved, the long-term morbidity ascribed to the HSCT procedure is not known. We compared the risk of chronic health conditions and adverse health among children with cancer treated with HSCT with survivors treated conventionally, as well as with sibling controls. HSCT survivors were drawn from BMTSS (N ‫؍‬ 145), whereas conventionally treated survivors (N ‫؍‬ 7207) and siblings (N ‫؍‬ 4020) were drawn from CCSS. Selfreported chronic conditions were graded with CTCAEv3.0. Fifty-nine percent of HSCT survivors reported > 2 conditions, and 25.5% reported severe/life-threatening conditions. HSCT survivors were more likely than sibling controls to have severe/ life-threatening (relative risk [RR] ‫؍‬ 8.1, P < .01) and 2 or more (RR ‫؍‬ 5.7, P < .01) conditions, as well as functional impairment (RR ‫؍‬ 7.7, P < .01) and activity limitation (RR ‫؍‬ 6.3, P < .01). More importantly, compared with CCSS survivors, BMTSS survivors demonstrated significantly elevated risks (severe/lifethreatening conditions: RR ‫؍‬ 3.9, P < .01; multiple conditions: RR ‫؍‬ 2.6, P < .01; functional impairment: RR ‫؍‬ 3.5, P < .01; activity limitation: RR ‫؍‬ 5.8, P < .01). Unrelated donor HSCT recipients were at greatest risk. Childhood HSCT survivors carry a significantly greater burden of morbidity not only compared with noncancer populations but also compared with conventionally treated cancer patients, providing evidence for close monitoring of this high-risk population. (Blood. 2011;118(5):1413-1420)

IMPORTANCE Frailty results in decreased physiological reserve and diminished resistance to stressors; approximately 10% of those in the elderly population (those ≥65 years) are frail. High-intensity treatments and complications after hematopoietic cell transplantation (HCT) injure normal tissues and may increase the risk of frailty even among nongeriatric HCT patients. OBJECTIVE To determine the prevalence of frailty in young adult HCT patients (18- to 64-year-olds) and siblings; and the impact of frailty on subsequent mortality in HCT survivors. DESIGN, SETTING, AND PARTICIPANTS This cohort study, conducted in August 2015 examined 998 HCT survivors, who underwent transplant procedures between 1974 and 1998, who have survived at least 2 years after HCT, and 297 frequency-matched siblings. The study was performed at City of Hope or University of Minnesota with participants completing surveys at home or in the clinic. Hematopoietic cell transplantation survivors and siblings participating in the Bone Marrow Transplant Survivor Study (BMTSS) completed a frailty survey between February 13, 1999 and June 15, 2005 (median time since HCT: 7.9 years); HCT survivors were followed for subsequent mortality (median: 10.3 years from survey). MAIN OUTCOMES AND MEASURES Prevalence and predictors of frailty; impact of frailty on subsequent mortality in HCT survivors. Frailty phenotype defined as exhibiting 3 or more of the following characteristics: clinically underweight, exhaustion, low energy expenditure, slow walking speed, and muscle weakness. The national Death Index, Social Security Death Index and medical records were used for mortality assessment as of December 21, 2011. RESULTS The 998 HCT survivors were a mean (SD) of 42.5 (11.6) years of age, and the 297 matched siblings were 43.8 (10.9) years of age. The prevalence of frailty among young adult HCT patients exceeded 8%. The HCT survivors were 8.4 times more likely to be frail than their siblings (95%CI, 2.0–34.5; P = .003). Among HCT recipients, allogeneic HCT recipients with chronic graft-vs-host disease (GvHD) were at increased risk of frailty compared with autologous HCT (OR,15.02; 95%CI, 6.6–34.3; P < .001); resolved chronic GvHD (OR, 2.7; 95% CI, 1.1–6.9; P = .04). Cumulative incidence of subsequent all-cause mortality was 39.3%and 14.7%at 10 years for HCT recipients with and without frailty, respectively (P < .001). Frailty was associated with a 2.76-fold (95%CI, 1.7–4.4; P < .001) increased risk of subsequent mortality after adjusting for relevant prognosticators. CONCLUSIONS AND RELEVANCE The prevalence of frailty among young-adult HCT survivors approaches that seen in the elderly general population. Frail HCT survivors are at increased risk of subsequent mortality when compared with nonfrail survivors. This study identifies vulnerable populations needing close monitoring to anticipate and manage morbidity and prevent mortality.

Long-term survival after hematopoietic cell transplantation (HCT) is now an expected outcome. The growing population of survivors is at risk of developing treatment-related complications, including cardiovascular events (CVD). A nested case-control design was used to identify clinical and treatment-related risk factors for development of late (1+ years after HCT) CVD. Cases were identified from a cohort of one+ year survivors transplanted at City of Hope between 1977 and 2006. Controls (HCT survivors without CVD) were matched on age, year of HCT, type of HCT, and length of follow-up. Sixty-three patients with late CVD were identified; 44 (69.8%) with coronary artery events, and 19 (30.2%) with cerebrovascular events. Median age at HCT was 49.0 years; median age at late CVD was 54.0 years; 66.7% had undergone autologous HCT. Multivariate logistic regression analysis revealed multiple cardiovascular risk factors (≥2 of the following: obesity, dyslipidemia, hypertension, and diabetes) after HCT to be associated with a 5.2-fold increased risk of late CVD (p<0.01); pre-HCT chest radiation was associated with a 9.5-fold risk of coronary artery disease (p=0.03). Pre-HCT exposure to chest radiation and presence of comorbidities are primarily responsible for the risk associated with late CVD after HCT. These data form the basis for developing predictive models for identifying high-risk individuals for targeted surveillance and aggressive management of comorbidities.

• We identified distinct groups of HCT survivors at low, intermediate, and high risk of developing late-occurring CVD.• The prediction model had good discrimination across outcomes and was validated in an external cohort of HCT survivors. 2) and 2.9-fold (95% confidence interval, 1.9-4.6) risk of developing CVD (referent group: low risk). These validated models provide a framework on which to modify current screening recommendations and for the development of targeted interventions to reduce the risk of CVD after HCT.

Background High intensity treatments such as hematopoietic cell transplantation (HCT) can be curative for patients with hematologic malignancies, but this needs to be balanced by the high risk of nonrelapse mortality (NRM) during the first 2 years after HCT. Sarcopenia (low muscle mass) is associated with physical disability and premature mortality in individuals with nonmalignant diseases and may be a predictor of NRM and poor overall survival in patients undergoing HCT. Methods This was a retrospective cohort study of 859 patients with acute leukemia or myelodysplastic syndrome who underwent a first HCT as adults (≥18 years) between 2007 and 2014. Sarcopenia was assessed from pre-HCT abdominal computed tomography scans. Two-year cumulative incidence of NRM was calculated, with relapse/progression considered as a competing risk event. Fine-Gray subdistribution hazard ratio estimates and 95% confidence intervals (CI) were obtained and adjusted for relevant covariates. Kaplan-Meier method was used to examine overall survival. All statistical tests were two-sided. Results Median age at HCT was 51 years (range = 18–74 years); 52.5% had a high [≥3] HCT-comorbidity index; 33.7% had sarcopenia pre-HCT. Sarcopenia was an independent predictor of higher NRM risk (hazard ratio = 1.58, 95% CI = 1.16 to 2.16) compared with patients who were not. The 2-year incidence of NRM approached 30% in patients with sarcopenia and high (≥3) HCT-comorbidity index. Patients with sarcopenia had on average a longer hospitalization (37.2 days vs 31.5 days, P < .001) and inferior overall survival at 2 years (55.2%, 95% CI = 49.5% to 61.0% vs 66.9%, 95% CI = 63.0% to 70.8%, P < .001). Conclusions Sarcopenia is an important and independent predictor of survival after HCT, with potential additional downstream impacts on health-economic outcomes. This information can be used to facilitate treatment decisions prior to HCT and guide interventions to decrease the risk of treatment-related complications after HCT.