SEN-ENERGY: A Multisite Randomized Controlled Trial to Improve Functional Recovery and Mitigate Frailty after Hematopoietic Cell Transplantation in Older Adults
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PROJECT SUMMARY Hematopoietic cell transplantation (HCT) is a curative therapy for hematologic malignancies that is increasingly being used in older (>60y) adults. It is estimated that >45% of HCT recipients are over >60y, and this proportion is projected to increase with ongoing advances in therapy and survival. Despite this demographic shift, older HCT survivors remain vastly understudied, leaving clinicians with little evidence on how best to optimize their care after completion of HCT. This is important because HCT is extremely taxing and recovery can be difficult, particularly for older adults whose physiologic reserve has typically been strained by the effects of malignancy as well as pre-existing comorbidities; as a result, even mild toxicities or complications can push them into frailty— a state of low physiologic reserve. Our group previously evaluated physiologic reserve pre- and post-HCT and found that, within just 6 months, 1 in 3 survivors experienced an accelerated, substantial decline in physiologic reserve that is equivalent to what we see in over 40y of normal aging. Not surprisingly, we found that older HCT survivors invariably exhibit marked signs of accelerated aging; in particular, older HCT survivors were 5x more likely to develop frailty when compared to age- and sex-matched siblings. Yet, to date, there are currently no evidence-based strategies to mitigate frailty in this growing, understudied, and high-risk population. To address this gap, we assembled a transdisciplinary team with complementary expertise in geriatric oncology, HCT survivorship, exercise physiology, aging, and biostatistics, with extensive experience: (1) characterizing long- term outcomes, including functional impairment and frailty, in HCT survivors; (2) investigating mechanisms of cancer treatment-related accelerated aging; and (3) leading clinical trials of mechanism-based, risk-reduction strategies in survivors. Guided by our preliminary data, we propose to test the hypothesis that, in older HCT survivors, adding a safe and well-tolerated senolytic therapy to exercise will produce greater improvements in physical function than exercise alone, senolytics alone, or control. We will recruit older HCT survivors (≥60y at the time of transplant) and ≥6-months to 2-years post-HCT and randomize them to one of four arms: exercise plus senolytics; exercise alone; senolytics alone; or control, for 16 weeks. Our primary endpoint will be change in physical function from baseline to 16 weeks (Aim 1); secondary endpoints include change in frailty (Aim 2) and senescence biomarkers (exploratory aim). To evaluate for sustainability, we will examine the change in outcomes of interest at 6 months after completion of the intervention. Successful completion of this study will set the stage for a larger-scale, multi-center confirmatory trial. If successful, our intervention would fill a critical gap, as these older patients currently have no evidence-based strategy to improve their functional recovery or mitigate frailty post-HCT. Moreover, in the era of unprecedented population aging, an intervention that successfully restores function and mitigates frailty could have a major positive impact that extends well beyond HCT survivors.
