Exercise Training and NR Supplementation Trial to Improve Fitness in AYA HCT Survivors

Adolescents and young adults (AYAs) who undergo hematopoietic cell transplantation (HCT) are at an especially high risk of developing sarcopenia (loss of skeletal muscle mass), which occurs earlier than would be expected from advancing age alone. This is important as not only it doubles their risk for non-relapse mortality, but it also leads to premature cardiovascular disease. The investigators propose a mechanistic randomized controlled trial of home-based remotely supervised exercise (aerobic and resistance) training and supplementation with nicotinamide riboside, a precursor of NAD+, a metabolite that is critical for muscle metabolism, in AYA survivors of HCT. The findings will lay the critical groundwork for future trials to prevent or mitigate the myriad downstream adverse effects of low muscle mass in AYA HCT survivors.

Inclusion criteria

• Males and females, ages 10-30 years at enrollment
• Able to understand and speak English
• Diagnosis of leukemia (myeloid, lymphoid), aplastic anemia, bone marrow failure syndrome, or myelodysplastic syndrome requiring allogeneic HCT
• 6-48 months from allogeneic HCT
• Females must have a negative urine/serum pregnancy test and must use an acceptable method of contraception, including abstinence, a barrier method (diaphragm or condom), Depo-Provera, or an oral contraceptive, for the duration of the study.
• Subject's informed consent or parental/guardian permission (informed consent) and if appropriate, child assent
• Minimum weight of 24 kg

Exclusion criteria

• Known sensitivity to NR
• Concurrent use of any medications, including statins, likely to increase risk of NR toxicity
• Active malignancy, investigational agent(s) within 4 wks, or supraphysiological glucocorticoids at the baseline visit
• Currently meeting public health exercise guidelines
• Use of NAD+ precursors (supra-physiologic) within 4 weeks
• Hemoglobin < 10 g/dL
• Platelets < 50K
• Diabetes Mellitus requiring insulin or insulin secretagogue
• HbA1C ≥ 8% or fasting glucose > 125 mg/dL; However if the participant is diabetic, both fasting glucose level and HbA1C must meet the criteria to be deemed eligible.
• Kidney disease (eGFR < 60 ml/min/1.73 m2)
• Liver disease Alanine aminotransferase (ALT)/Aspartate aminotransferase (AST) (ALT/AST > 3 x ULN)
• Limitations in physical function preventing exercise testing/training
• Unstable angina or history of acute myocardial infarction (<5 days of planned study procedures)
• Recurrent syncope
• Symptomatic severe aortic stenosis
• Uncontrolled arrhythmia causing symptoms
• Pulmonary embolus <3 months of study procedures
• Thrombosis of lower extremities
• Symptomatic moderate or severe persistent asthma based on Forced Expiratory Volume (FEV) from pre-HCT pulmonary function testing
• Room air desaturation at rest ≤85%
• Females: Pregnant or planning pregnancy
• Non-cardiopulmonary disorders that may affect exercise performance or be aggravated by exercise (e.g. infection, renal failure, thyrotoxicosis, >moderate Graft versus host disease (GVHD) resulting in physical or functional impairment)
• Parents/guardians or subjects who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures.
• For MRI procedure: Contraindications to MRI. Individuals will be screened to ensure they can safely complete the MRI. *participants who cannot complete the MRI will not be excluded from participation in the remainder of the study procedures if they meet those inclusion and exclusion criteria.
• Current weight precludes safe completion of study procedures