Remotely Monitored, Mobile Health-supported, High Intensity Interval Training Before Hematopoietic Stem Cell Transplant

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.

The investigators' prior phase 1 study was successful. Out of 24 participants approached, 14 enrolled (10 males, 4 females), achieving a recruitment rate of 58%. Of the 14 enrolled, 13 (age 59±12, range 34-76 yrs; 10 White, 3 Black) were medically cleared to proceed with HIIT following a CPET. One participant did not proceed to HIIT and was withdrawn due to cardiac concerns detected on baseline CPET. Importantly, there were no adverse events associated with exercise among the remaining participants. Participants were able to engage in HIIT, even with a baseline CRF as low as 10.6 mL/kg/min; for reference, independent living in healthy adults is generally associated with a CRF >18 in men and >15 in women. Some participants who were habitually exercising were able to complete ten intervals immediately and to maintain intensity over time, while other participants who were less fit required more coaching but were able to rapidly improve fitness to reach program goals. Remarkably, even with low baseline CRF and concomitant chemotherapy (some requiring hospitalization), nine of the 13 participants engaged in the exercise program (69%), and average adherence to the prescribed 3 sessions/week in those nine was excellent at 104 +/- 28%. Mean intervention length was 13.8 +/- 7.5 weeks, with participants staying engaged in the exercise program for approximately three months prior to HCT; this compares very favorably to the 50-70% adherence rates commonly reported in other home-based exercise studies. All 7 participants who had repeat CPET showed improvements in CRF, with average change in VO2peak from 14.6 ± 3.1 mL/kg/min at enrollment to 17.9 ± 3.3 by the start of transplant, or 23% increase (p<0.001). For the other 6, 3 were not evaluated due to the onset of the COVID-19 pandemic, which suspended research operations. Because CRF declines at about 10% per decade, this substantial improvement in CRF equates to a fitness level increase that typically would take over 20 years to achieve, aligning participants' fitness more closely with that of healthy adults34. As highlighted by Wood et al.,16 a pre-HCT VO2peak <16 mL/kg/min is associated with higher post-HCT mortality rate (HR 6.70 (1.29-34.75), p=0.02) and longer hospital stay (median number of hospitalized days before Day 100: 33 vs. 21, p=0.004). Thus, increasing CRF pre-HCT has the potential to improve post-HCT outcomes, suggesting this program could substantially impact participant health and recovery.

The investigators believe this program's success is from a combination of participant motivation and mHealth platform and coaching. Because participants know that they were to undergo HCT within a few months, with a 10-30% chance of death related to the treatment itself, they were highly motived to do anything they could to improve their chances of survival. Furthermore, knowing that an oncology-experienced exercise professional is monitoring their exercise sessions, coupled with personalized and frequent feedback (at least once a week), likely helped improve adherence, with resultant improvements in CRF.

Allogeneic HCT has curative potential for hematologic malignancies but is associated with significant morbidity and TRM, especially in patients with low pre-HCT CRF. Improving CRF through a time-efficient, high-intensity interval training (HIIT) approach, facilitated remotely via mHealth, could improve physical function and clinical outcomes for HCT patients. The investigators hypothesize that patients undergoing REMM-HIIT program will experience improved CRF, physical function, and QOL pre-HCT, leading to better post-HCT outcomes, including improved physical function, reduced TRM, and increased overall survival.