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

Impact and predictors of positive response to desensitization in pediatric heart transplant candidates.

2019

1206-1213

2019 Nov

1557-3117

<p><strong>BACKGROUND: </strong>Desensitization, the process of reducing anti-human leukocyte antigen (HLA) antibodies in sensitized patients awaiting heart transplantation (HT), has unclear efficacy in pediatric HT candidates.</p>

<p><strong>METHODS: </strong>Pediatric HT candidates listed at our institution between January 1, 2013 and June 30, 2018 were retrospectively evaluated. Sensitization was defined as the calculated panel reactive antibody (cPRA) ≥ 10% with ≥ 1 a strong positive antibody. The desensitization response was defined as a ≥ 25% reduction in the mean fluorescence intensity (MFI) for ≥ 90% of the strong positive antibodies on follow-up panel reactive antibody (PRA) testing before waitlist removal, HT, or death (data available for 13 patients).</p>

<p><strong>RESULTS: </strong>The HT candidates were categorized as sensitized receiving desensitization therapy (ST, n = 14), sensitized not receiving therapy (SNT, n = 18), or non-sensitized (n = 55). A desensitization response was observed in 8 (62%) of the ST upon repeat PRA testing, with the ST responders receiving more doses of intravenous immunoglobulin (IVIG) (8 vs 2, p &lt; 0.05). The anti-HLA class I antibodies were particularly resistant for non-responders (p = 1.9 × 10). The combination of homograft and ventricular assist device was more sensitizing than either alone (p = 3.1 × 10). However, these sensitization risk factors did not impact the desensitization response. The ST was associated with a higher likelihood of remaining listed and a longer waitlist time without substantially impacting the HT rate, waitlist mortality, or early post-HT outcomes.</p>

<p><strong>CONCLUSIONS: </strong>Most ST patients had a favorable response to desensitization, with a dose-dependent response observed for IVIG. The anti-HLA class likely impacts the ST response, whereas traditional sensitization risk factors had no impact on the response.</p>

10.1016/j.healun.2019.08.018

J. Heart Lung Transplant.

31672220

Cardiac Profile of Chimeric Antigen Receptor (CAR) T-Cell Therapy in Children: a Single Institution Experience.

2018

2018 May 14

1523-6536

<p><strong>BACKGROUND: </strong>Immunotherapy with chimeric antigen receptor (CAR)-modified T-cells targeting CD19 for pediatric acute lymphoblastic leukemia (ALL) has demonstrated significant efficacy. The principle toxicity is cytokine release syndrome with resultant hypotension. However, the spectrum of cardiovascular effects associated with CAR T-cell therapy has not been systematically evaluated.</p>

<p><strong>METHODS: </strong>We reviewed all patients who received CD19-directed CAR T-cells at the Children's Hospital of Philadelphia between April 2012 and September 2016. The primary endpoint was hypotension-requiring inotropic support. Secondary endpoints included echocardiographic dysfunction at discharge and 6 month follow-up. Descriptive and univariate analyses were performed.</p>

<p><strong>RESULTS: </strong>98 encounters were included [55% male, mean age 11.8 yrs (range 1.7-27.1)]; 98% had B-ALL. Prior to infusion, 10 had cardiomyopathy and 1 had single-ventricle physiology. Primary endpoint occurred in 24 patients with mean onset 4.6 days (range 1-9) after CAR T-cell infusion, including six patients receiving milrinone. Worsened systolic function occurred in 10 patients; there were no cardiac-related deaths. Pre-treatment factors associated with primary endpoint included higher pre-treatment blast percentage on bone marrow biopsy [blast &gt; 25%: OR 15.5 (95% CI 5.1-47.1), p&lt;0.001] and baseline lower ejection fraction (p=0.019) or diastolic dysfunction (p=0.021); neither pre-existing cardiomyopathy (p=0.062), total body irradiation (p=0.629) nor anthracycline dose (p=0.444) were associated. At discharge, seven patients had worsened echocardiographic function, but persistent dysfunction by six months follow-up was rare. Pre-treatment factors were not associated with persistent dysfunction at discharge.</p>

<p><strong>CONCLUSION: </strong>This is the first study to describe the cardiovascular effects of pediatric CAR T-cell therapy. Although 10% had new systolic dysfunction after treatment, persistence was rare. Pre-treatment blast count &gt; 25% or pre-existing cardiac dysfunction increased the risk for hypotension-requiring inotropic support; these patients may warrant close observation.</p>

10.1016/j.bbmt.2018.05.014

29772353