Remotely Monitored, Mobile Health-supported, High Intensity Interval Training Before Hematopoietic Stem Cell Transplantation (REMM-HIIT-HCT)

Each year in the U.S., approximately 8,000 patients undergo allogeneic hematopoietic stem cell transplantation (HCT) as a potentially curative therapy for leukemias, lymphomas, and other hematologic malignancies. However, treatment-related mortality (TRM) is significant, ranging from 10-30%. Moreover, survivors of HCT often face significant physical, psychological, and social challenges post-treatment, leading to a substantial decrease in quality of life (QOL). Outcomes are closely linked to pre-HCT physical activity and function. For example, patients with worse pre-HCT physical function and capacity have markedly lower one-year survival rates (50% vs. 83%). In contrast, every 50-meter increase in pre-HCT six-minute walk distance (6MWD) correlates with a 9% reduction in relative risk for mortality.

Cardiorespiratory fitness (CRF) is a crucial indicator of physical capacity, reflecting the integrated functioning of the heart, lungs, skeletal muscle, adipose tissue, pancreas, liver and adrenal tissues. While CRF naturally declines with age, this decline is notably accelerated by cancer and its treatments, with cancer patients' average CRF levels comparable to individuals 20-30 years older. Importantly, patients with low pre-HCT CRF (VO2peak <16 mL/kg/min) are at much higher risk of TRM (hazard ratio 6.70), even after accounting for other risk factors. This underscores the critical need for interventions to improve CRF prior to HCT to enhance survival and post-treatment quality of life.

It is well established that patients with better pre-HCT physical function tend to have better post-HCT outcomes. The critical question, however, is whether enhancing fitness pre-HCT can improve post-HCT outcomes. Animal studies provide optimism: exercise training in a murine model pre-HCT associated with improved survival, possibly through immune-mediated pathways. Yet, research exploring the impact of pre-HCT exercise on human post-HCT outcomes remains limited. Small studies have linked pre-HCT improvements in physical function with better survival, and preliminary results from a randomized controlled trial suggest that exercise during HCT may reduce mortality. However, a recent large (n=711) randomized Blood and Marrow Transplant Clinical Trials Network study of self-directed exercise and stress management during HCT did not show a significant benefit in outcomes. Study investigators suggested several reasons for this lack of effect, including timing of intervention (peri-HCT rather than pre-HCT), low intensity rather than high intensity exercise, and low engagement in the self-directed program.

To address prior study limitations, the investigators developed the REMM-HIIT program, focusing on pre-HCT intervention, high-intensity interval training (HIIT), and a mobile health (mHealth) platform to support participant engagement. This program, supported by the National Institute of Aging and the Duke Claude D. Pepper Older Americans Independence Center, was piloted in a successful phase 1 study of Remotely Monitored, Mobile health-supported, pre-HCT High Intensity Interval Training (REMM-HIIT). In this feasibility study, participants underwent baseline cardiopulmonary exercise testing (CPET) to ensure cardiac safety and to measure maximal cardiorespiratory fitness (VO2peak). The heart rate (HR) at VO2peak was used to personalize the high and low intensity interval goals. Participants were equipped with an iPhone and Garmin Watch for remote monitoring and exercised three times a week at home, with the first session and subsequent sessions as needed monitored remotely by the coach via videoconference. This approach ensured continuous support and maximized participant engagement while allowing the majority of sessions to occur remotely.

This program was purposely designed based on investigators' prior research and other significant studies in the field, aiming to overcome common barriers to physical activity in cancer populations. To facilitate participation, the investigators enable exercise at home utilizing the participant's preferred activity (e.g., walking, cycling, stairs) and at convenient times. The majority engaged in walking-based intervention, which despite their simplicity, provided sufficient intensity for deconditioned HCT participants. Others used cycle ergometers. This program adheres to the principles of exercise training and recommendations from Sasso and colleagues, ensuring individualization, progressive overload, appropriate recovery periods, and reasonable specificity. Exercise sessions started with a 5-minute warmup (e.g., walking or cycling at a HR corresponding to 60% VO2peak). This was followed by ten intervals, each consisting of one-minute of high intensity exercise at a HR corresponding to 95% VO2peak, alternated with one minute of low to moderate intensity interval at a HR corresponding to 60% VO2peak, totaling 20 minutes. The session concluded with a 5-minute cooldown, resulting in a comprehensive 30-minutes exercise session. For participants unable to complete all intervals, the study team began with fewer intervals and gradually increased the number as tolerated. A recovery period of 24-48 hours between HIIT sessions was recommended to prevent overtraining and ensure adequate recovery. Broad specificity was achieved by incorporating high, moderate, and low intensity aerobic exercises continuously. As such, the program is a progressive HIIT-based intervention, with flexibility given to ensure the principles of exercise training are upheld, and participants receive the best possible information and guidance to rapidly increase CRF and health outcomes pre-HCT.