Impact of Exercise on the Complications of Corticosteroids in Patients with Graft-Versus-Host Disease Following Allogeneic Cell Transplantation: The Restart Trial

Background: Graft-Versus-Host Disease (GVHD) is a common but burdensome side effect of allogeneic hematopoietic cell transplant (HCT) occurring in 35-50% of recipients. Corticosteroids are standard of care for newly diagnosed GVHD; however, long-term use incurs multiple metabolic abnormalities including hypertension, atrial fibrillation, hyperglycemia, fat gain, muscle and bone loss. While exercise is a viable non-pharmacologic intervention that can mitigate common side effects associated with corticosteroids, no study to date has aimed to alleviate corticosteroid-induced side effects with exercise in the GVHD population. Therefore, the RESTART Trial will primarily examine the feasibility of a 12-week, virtually supervised, aerobic and resistance exercise intervention in allogeneic HCT recipients with GVHD receiving corticosteroids.

Study Design and Methods: This ongoing two-arm, single center, pilot randomized controlled trial is recruiting 36 patients who are randomized to an exercise or attention control group at a 2:1 ratio. Patients are eligible if they are >18 years old, newly diagnosed with acute or chronic GVHD who are prescribed systemic corticosteroids, received allogeneic HCT (any conditioning, any donor) at Dana-Farber Cancer Institute (DFCI), and currently participate in less than or equal to 60 minutes of structured exercise/week. Exclusion criteria include a plan for hospital admission within the next 13 weeks at the time of recruitment, concurrent musculoskeletal or cardiorespiratory conditions that prevent participation in moderate-vigorous intensity exercise, any uncontrolled illness including ongoing or active infection, uncontrolled diabetes, hypertension, or thyroid disease, ongoing investigational agents, or concurrent biological, chemotherapy, or radiation therapy, active malignancy, and inability to travel to DFCI for necessary data collection.

The exercise group will receive the virtually (e.g., Zoom) supervised intervention thrice weekly for 12 weeks, including aerobic-based cycling exercise performed at 50-75% heart rate maximum for 20-30 minutes and resistance exercise performed for 3 sets of 10-12 repetitions at 40-65% with 1-repetition maximum. The attention control group will receive a 12-week stretching program. The primary outcome of the study is feasibility as measured by exercise session attendance and ability to complete prescribed exercise (minutes per session). The secondary outcomes include glycemic control, body composition, physical function, and patient-reported outcomes.

We will estimate the proportion and corresponding 95% exact confidence interval (CI) of the feasibility of our program in the active intervention group. We expect that the proportion is 70% or higher. If the true proportion is 70%, the probability we observe a 70% or higher feasibility rate will be 60.8%, and the length of the exact 95% CI will be roughly 40% to 44%. If the true proportion is 75%, the probability we observe a 70% or higher feasibility rate is 78.6%. Changes in secondary endpoints will be estimated by differences, percent change, or fold-change, as is customary for the endpoint. Differences between post- and pre-intervention will be assessed using paired t-test or Wilcoxon signed-rank test. This study is approved by the institutional review board at DFCI (#21-618) and is registered at Clinical Trials.gov (NCT05236062).

Discussion: This first-of-its-kind study targets an understudied and vulnerable population of HCT patients where the effects of exercise have only been examined in pre-clinical settings. If positive, our findings will establish the pilot efficacy for the feasibility of aerobic and resistance exercises for patients with cancer diagnosed with GVHD who are receiving corticosteroids, providing the foundation for future larger phase II/III trials to confirm the findings and potentially establish exercise as a standard of care rehabilitation service.

Cutler:Incyte: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Editas: Consultancy; CareDx: Consultancy; Mallinckrodt: Consultancy; Pfizer: Consultancy; Cimeio: Current equity holder in private company; Omeros: Consultancy; Equilium: Consultancy; Jazz: Consultancy; Deciphera: Consultancy; BMS: Consultancy; CTI BioPharma: Consultancy.