Association Between Body Composition and Development of Glucose Intolerance after Allogeneic Hematopoietic Cell Transplantation.

2022

OF1-OF7

07/2022

1538-7755

BACKGROUND: Allogeneic hematopoietic cell transplantation (HCT) recipients have increased risk of developing glucose intolerance and diabetes mellitus (DM). The strongest risk factor for glucose intolerance is being overweight/obese, as determined by body mass index (BMI), which does not account for differences in body composition. We examined the association between body composition measures from pre-HCT CT and early-onset (≤30 days) de novo glucose intolerance after HCT, and determined its impact on nonrelapse mortality (NRM).

METHODS: This study included 749 patients without pre-HCT DM. Skeletal muscle loss [abnormal skeletal muscle gauge (SMG)] and abnormal visceral adiposity (VA) were defined by sex-specific tertiles. Fine-Gray proportional subdistribution HR estimates and 95% confidence intervals (CI) were obtained to determine the association between muscle loss and VA and development of glucose intolerance. 1 year NRM was calculated for patients alive at day 30.

RESULTS: Median age at HCT was 50.2 years. By day 30, 8.1% of patients developed glucose intolerance and 731 remained alive. In multivariable analysis, abnormal SMG was associated with increased risk of glucose intolerance in nonoverweight (BMI < 25 kg/m2) patients (HR = 3.00; 95% CI, 1.15-7.81; P = 0.024); abnormal VA was associated with increased risk of glucose intolerance in overweight/obese patients (HR = 2.26; 95% CI, 1.24-4.12; P = 0.008). Glucose intolerance was independently associated with NRM (HR = 1.88; 95% CI, 1.05-3.39; P = 0.035).

CONCLUSIONS: Abnormal SMG and VA were associated with glucose intolerance in nonoverweight and overweight/obese patients, respectively, which contributed to increased risk of 1 year NRM.

IMPACT: This information may guide personalized interventions to decrease the risk of adverse outcomes after HCT.

10.1158/1055-9965.EPI-21-1449

Cancer Epidemiol Biomarkers Prev

35797113

Exercise training and NR supplementation to improve muscle mass and fitness in adolescent and young adult hematopoietic cell transplant survivors: a randomized controlled trial {1}.

2022

795

07/2022

1471-2407

BACKGROUND: Advances in hematopoietic cell transplantation (HCT) have led to marked improvements in survival. However, adolescents and young adults (AYAs) who undergo HCT are at high risk of developing sarcopenia (loss of skeletal muscle mass) due to the impact of HCT-related exposures on the developing musculoskeletal system. HCT survivors who have sarcopenia also have excess lifetime risk of non-relapse mortality. Therefore, interventions that increase skeletal muscle mass, metabolism, strength, and function are needed to improve health in AYA HCT survivors. Skeletal muscle is highly reliant on mitochondrial energy production, as reflected by oxidative phosphorylation (OXPHOS) capacity. Exercise is one approach to target skeletal muscle mitochondrial OXPHOS, and in turn improve muscle function and strength. Another approach is to use "exercise enhancers", such as nicotinamide riboside (NR), a safe and well-tolerated precursor of nicotinamide adenine dinucleotide (NAD), a cofactor that in turn impacts muscle energy production. Interventions combining exercise with exercise enhancers like NR hold promise, but have not yet been rigorously tested in AYA HCT survivors.

METHODS/DESIGN: We will perform a randomized controlled trial testing 16 weeks of in-home aerobic and resistance exercise and NR in AYA HCT survivors, with a primary outcome of muscle strength via dynamometry and a key secondary outcome of cardiovascular fitness via cardiopulmonary exercise testing. We will also test the effects of these interventions on i) muscle mass via dual energy x-ray absorptiometry; ii) muscle mitochondrial OXPHOS via an innovative non-invasive MRI-based technique, and iii) circulating correlates of NAD metabolism via metabolomics. Eighty AYAs (ages 15-30y) will be recruited 6-24 months post-HCT and randomized to 1 of 4 arms: exercise + NR, exercise alone, NR alone, or control. Outcomes will be collected at baseline and after the 16-week intervention.

DISCUSSION: We expect that exercise with NR will produce larger changes than exercise alone in key outcomes, and that changes will be mediated by increases in muscle OXPHOS. We will apply the insights gained from this trial to develop individualized, evidence-supported precision initiatives that will reduce chronic disease burden in high-risk cancer survivors.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT05194397. Registered January 18, 2022, https://clinicaltrials.gov/ct2/show/NCT05194397 {2a}.

10.1186/s12885-022-09845-1

BMC Cancer

35854224

Persistent Musculoskeletal Deficits in Pediatric, Adolescent and Young Adult Survivors of Allogeneic Hematopoietic Stem-Cell Transplantation.

2022

2022 Jan 25

1523-4681

<p>Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a common therapy for pediatric hematologic malignancies. With improved supportive care, addressing treatment-related late effects is at the forefront of survivor long-term health and quality of life. We previously demonstrated that alloHSCT survivors had increased adiposity, decreased lean mass, and lower bone density and strength, 7 years (median) from alloHSCT compared to their healthy peers. Yet it is unknown whether these deficits persist. Our longitudinal study characterized changes in muscle and bone over a period of 3.4 (range 2.0 to 4.9) years in 47 childhood alloHSCT survivors, age 5-26 years at baseline (34% female). Tibia cortical bone geometry and volumetric density and lower leg muscle cross-sectional area (MCSA) were assessed via peripheral quantitative computed tomography (pQCT). Anthropometric and pQCT measurements were converted to age, sex, and ancestry-specific standard deviation scores, adjusted for leg length. Muscle-specific force was assessed as strength relative to MCSA adjusted for leg length (strength Z-score). Measurements were compared to a healthy reference cohort (n=921), ages 5 to 30 years (52% female). At baseline and follow up, alloHSCT survivors demonstrated lower height-, weight-, and leg length Z-scores compared to the healthy reference cohort. Deficits in MCSA, trabecular volumetric bone density, and cortical bone size and estimated strength (section modulus) were evident in survivors (all p&lt;0.05). Between the two study time points, anthropometric, muscle, and bone Z-scores did not change significantly in alloHSCT survivors. Approximately 15% and 17% of alloHSCT survivors had MCSA and section modulus Z-score less than -2.0, respectively, at baseline and follow up. Furthermore, those with a history of total body irradiation compared to those without demonstrated lower MCSA at follow up. The persistent muscle and bone deficits in pediatric alloHSCT survivors support the need for strategies to improve bone and muscle health in this at-risk population. This article is protected by copyright. All rights reserved.</p>

10.1002/jbmr.4513

J Bone Miner Res

35080067

Abnormal body composition is a predictor of adverse outcomes after autologous haematopoietic cell transplantation.

2020

2020 Mar 25

2190-6009

<p><strong>BACKGROUND: </strong>The number of patients undergoing autologous haematopoietic cell transplant (HCT) is growing, but little is known about the factors that predict adverse outcomes. Low muscle mass and obesity are associated with disability and premature mortality in individuals with non-malignant diseases and may predict outcomes after autologous HCT.</p>

<p><strong>METHODS: </strong>This was a retrospective cohort study of 320 patients who underwent autologous HCT for Hodgkin or non-Hodgkin lymphoma between 2009 and 2014. Sarcopenia {skeletal muscle index male: &lt;43 cm/m [body mass index (BMI) &lt; 25 kg/m ] or &lt; 53 cm/m [BMI ≥ 25 kg/m ] and female: &lt;41 cm/m [regardless of BMI]) and obesity [total abdominal adiposity ≥450.0 cm (male), ≥396.4 cm (female)] were assessed from single-slice abdominal pre-HCT computed tomography images. Length of hospital stay, first unplanned intensive care unit admission, and 30-day unplanned readmission were evaluated based on body composition using multivariable regression analysis, and mortality was evaluated with Kaplan-Meier analysis and Gray's test.</p>

<p><strong>RESULTS: </strong>Median age at HCT was 53.3 years (range, 18.5 to 78.1 years); 26.3% were sarcopenic and an additional 7.8% were sarcopenic obese pre-HCT. Sarcopenic obesity was associated with increased risk of prolonged hospitalization [odds ratio (OR) = 3.6, 95% confidence interval (CI) 1.3-9.8], intensive care unit admission (OR = 4.7, 95% CI 1.5-16.1), and unplanned readmission after HCT (OR = 13.6, 95% CI 2.5-62.8). Patients who were sarcopenic obese also had the highest mortality risk at 1 year [hazard ratio (HR): 3.9, 95% CI 1.1-11.0] and 5 years (HR: 2.5, 95% CI 1.1-5.5), compared with patients with normal body composition. Sarcopenia alone, but not obesity alone, was associated with an increased risk of these outcomes, albeit with a lower magnitude of risk than in patients who were sarcopenic obese.</p>

<p><strong>CONCLUSIONS: </strong>Sarcopenic obesity was an important predictor of outcomes in patients undergoing autologous HCT. These findings could inform targeted prevention strategies in patients at highest risk of complications after HCT.</p>

10.1002/jcsm.12570

J Cachexia Sarcopenia Muscle

32212263