Rationale and design of APOLLO: a personalized rehAbilitation PrOgram in aLLOgeneic bone marrow transplantation
Hematopoietic stem cell transplantation (HSCT) is a common therapy for many hematologic malignancies. While advances in transplant practice have improved cancer-specific outcomes, multiple and debilitating long term physical and psychologic effects remain . Patients undergoing allogeneic bone marrow transplantation (allo-BMT) are often critically ill at initial diagnosis and with necessary sequential treatments become increasingly frail and deconditioned . Despite modern treatment regimens and support, cardiovascular disease remains a leading cause of non-relapse mortality among allo-BMT survivors . Moreover, cardiovascular risk factors are highly prevalent in allo-BMT patients and survivors, with the prevalence of hypertension, dyslipidemia and diabetes being 58%, 63% and 9% respectively 6 years after transplant . Many patients also have poor pre-transplant cardiorespiratory fitness associated with low physical activity, reduced cardiac reserve, increased body fat or body mass index and number of chemotherapy treatments previously received . The direct myotoxic effects of HSCT chemotherapy and indirect effects of prolonged (bedrest) deconditioning and fatigue have devastating cumulative effects on health-related physical fitness, physical function and quality of life. Well-established multi-disciplinary care models such as cardiac rehabilitation offer holistic care including exercise training, nursing support, physical/occupational therapy, psychosocial support and nutritional education. HSCT patients may be excluded from conventional outpatient physical rehabilitation programs due to prolonged pancytopenia and frequent hospital admissions. In Canada, dedicated cancer-specific rehabilitation programs are available only at major tertiary academic centers. While exercise training has been reported to improve fatigue symptoms in patients undergoing allo-BMT this has inconsistently been applied . Our prior work has shown both efficacy (improvements in physical functioning with standard cardiac rehabilitation activity tolerance protocols  [ATP]) and acceptability (positive experiences) of a cardiac rehabilitation program following autologous transplant . Physical performance in HSCT may be worsened by progressive deleterious changes in muscle and fat compartments including reductions in lean body mass, gains in fat mass and accumulation of visceral and inter/intramuscular fat. Indeed, a recent review confirmed the significant role of adverse body composition changes in survival-related outcomes (non-relapse mortality, overall survival and/or relapse) regardless of the timing of assessment . Using novel magnetic resonance imaging (MRI) technology we reported that breast cancer survivors ~ 1 year after chemotherapy have significantly larger visceral fat pools (49% larger) and increased thigh intermuscular fat (41% larger) compared to age and sex-matched controls . Here, we observed that 59% of variability in cardiorespiratory fitness (VO2 peak ) was explained by the degree of intermuscular fat within the thigh muscle  (Fig. ). It is possible that early or pre-transplant rehabilitation could attenuate these effects. Closely related to body composition, nutritional status is a major and frequent issue in allo-BMT with gastrointestinal toxicities resulting in poor oral intake, malabsorption and malnutrition. Poor nutritional status before and during allo-BMT is associated with lower overall survival and higher complication rate, and can influence fat and lean body composition pools . This risk factor is potentially modifiable, but to date, robust research is lacking on the effects of nutritional intervention in this population. Historically, clinicians have assumed the acute and chronic physical and psychological symptoms associated with necessary allo-BMT are inevitable, however, of the many symptoms experienced, emotional distress may be the most modifiable. Psychologic consequences of allo-BMT are sufficiently severe to meet the diagnostic requirements for ‘post-traumatic stress disorder’ in at least 20% of allo-BMT survivors . Moreover, younger individuals have greater fears of recurrence, depression and worse quality of life, likely due to the existential impact of a cancer diagnosis at a young age with greater family, financial and employment disruptions . Careful assessment and support may positively impact a patient’s ability to engage in healthy lifestyle habits, to better cope with the peaks and valleys of recovery and better quality of life . Empowerment strategies can engage patients to have an active and informed role in managing psychological, physical and social aspects of their health. While handheld mobile technology enabled the development of social media platforms for long-term survivors, current platforms lack involvement of multidisciplinary health care professionals sharing information about – and with – the patient in real time aiming for high-quality, person-centered, coordinated care . Furthermore, currently there are no applications (i.e., mobile or web-based ‘apps’) that are evidence-based, relevant to the HSCT setting, or offer multi-disciplinary health supports inclusive of exercise, physiotherapy, nutrition and mental wellness. Given the unique, severe and long-term implications of the allo-BMT trajectory, a multidisciplinary approach is urgently required to understand and address individual needs in a ‘precision medicine’ approach. Ideally, such an intervention would address geographic disadvantages, provide real-time multidisciplinary support and be customized by and for those with firsthand experiences. Primary Aim To evaluate the feasibility and acceptability of a multimodal care navigation (nursing, exercise, nutrition) intervention with content delivery facilitated by a supportive care web-based ‘app’ extending from diagnosis to 1 year in the allogeneic bone marrow transplant population. Exploratory Aims to study the effects of a supportive care ‘app’ with care navigation on Activity Tolerance Protocol assessments, body composition, mental wellness and patient-reported outcome measures. Methods Adult patients scheduled for allo-BMT will be recruited. Eligibility criteria are the same as those for allogeneic transplantation . All standard of care interventions performed by the treatment team including multidisciplinary referrals, laboratory, and diagnostic imaging associated with allogeneic transplant processes will be maintained. After written informed consent, physical assessments will include. Baseline , Pre-Transplant (Prehabilitation) , Transplant & Recovery and Post-Transplant Rehabilitation ( Fig. Study Flow Diagram) : Multimodal care-navigation will be provided, with content delivery facilitated by a web-based app (Heal-Me) provided via continuous access to participants. This innovative web-based research application combines exercise, physiotherapy, nutrition and mental wellness content, co-designed by members of the research team . The Active Living module offers independent video sessions with exercises that can be tailored to the individual participant’s needs and the capacity for in-app videoconferencing to deliver interactive, dynamic individual or group classes for exercise. The Healthy Eating module centers on educational nutrition videos and tracking target protein intake. Nutritional intake targets can be tailored by a dietitian to meet the individual patient’s needs. Mental Wellness module incorporates mindfulness based and acceptance and commitment therapy-based content targeting chronic disease coping and symptoms of anxiety and depression. Certified Exercise Professionals (CEP) will develop and teach a personalized exercise training program derived from baseline ATP test results. Participants will take part in an individually tailored exercise training program delivered through the Active Living module of the Heal-Me application. Participants can choose from programs comprising  supervised group exercise sessions (connection via Zoom platform embedded in Heal-Me), and  independent exercise workouts within the application. Participants will be provided with the Garmin Vivofit activity tracker (Garmin Canada) to track their physical activity. Data from the Vivofit will be uploaded directly from Garmin Connect to the study’s REDCap database. Each participant’s exercise regimen will follow the general principles of overload, progression, and specificity ; and provides mild-to-moderate exercise (defined as 40–60% of maximal heart rate; 2–4 score on the 10-point Borg Rating of Perceived Exertion Scale ) and consist of full body exercise (e.g., comprising aerobic, resistance training, core stability, balance and flexibility training) a minimum of 2 times per week (one group virtual session and one independent self-directed session). The CEP will contact the participant regularly (weekly, or more often depending on patient need/preference) to provide and document coaching and support. A Registered Dietician will provide regular (weekly, or more often depending on patient need/preference) individualized counselling particularly focusing on energy (caloric) and protein intakes, healthy dietary patterns, as well as addressing any nutrition impact symptoms that may emerge during the inpatient period (mouth sores, dentition, vomiting, diarrhea, etc.). Cultural and religious preferences will be supported. The patient-specific calorie and protein intake targets will be entered into the Healthy Eating module of the Heal-Me application. A Research Nurse will contact regularly (weekly, or more often depending on patient need/preference) and perform a semi-structured interview including open-ended questions, symptom evaluation, assess physical, psychological or practical concerns (i.e., employment, family, caregiving). Mental wellness will be evaluated addressing topics such as fears, dealing with uncertainty, and self-compassion alongside the Heal-Me Wellness Module supports. Cardiac Prehabilitation and Post-Transplant Rehabilitation : ATP testing will be performed at 4 timepoints: baseline, pre-transplant, post-transplant and 1 year (Fig. ) at the rehabilitation center. Supervised or remote sessions will be encouraged at least weekly and instruction for home-based exercise provided at pre-habilitation and an 8-week session following allo-BMT. Eight weeks is the duration of standard cardiac rehabilitation at our center, moreover, the aim is to transition the participant to home-based exercise. ATP testing : timed up and go, gait speed, 30-second sit-to-stand test, right- and left-handgrip, and 6-minute walk test, will be performed. This battery of tests comprise not only of standard cardiac rehabilitation testing protocols , but have individually been shown to influence morbidity and mortality in allo-BMT . MRI : will be performed on a 3T Prisma Siemens scanner. Resting cardiac structure and function, and the tissue composition of myocardium, thigh skeletal muscle and liver will be imaged. The total volume (ml) of muscle and adipose tissues will be quantified and fat pools in the liver and skeletal muscle will also be reported as fat fraction (%, normalized to water volume from the same slices) . If MRI is contraindicated, dual energy X-ray absorptiometry (DEXA) scan will be performed. Nutritional Assessment : Food frequency questionnaire will assess usual frequency of consumption of a list of foods and food groups, focusing on protein and energy (caloric) intake and hydration The Brief Food Questionnaire is validated and utilized across many studies . Patient-reported outcome measures : Functional Assessment of Cancer Therapy–Bone Marrow Transplant (FACT-BMT) , Screening for Distress which includes both Edmonton Symptom Assessment System  and Canadian Problem Checklist  will be completed. Demographics : age; sex; diagnosis; chemotherapy dose and relative intensity; total body irradiation; distance from transplant center; comorbid conditions (cardiovascular risk, metabolic diseases); lifestyle and health habits. Analysis Primary Aim Qualitative methods aim to explore health care phenomena from first-hand experiences, and establish analytic methods to gather evidence to improve care delivery . Using the approach of interpretive description, common themes will be identified. A mixed methods approach will be applied to situate the qualitative themes alongside quantitative findings, providing an increased depth of understanding of the timing and type of experiences . Here, timing and type of HEAL-Me component participation; frequency, type and duration of exercise support, nutritional and nursing contacts; symptom frequency and severity; timing of experiences across allo-BMT trajectory; and type and timing of support provided. 

To evaluate the feasibility and acceptability of a multimodal care navigation (nursing, exercise, nutrition) intervention with content delivery facilitated by a supportive care web-based ‘app’ extending from diagnosis to 1 year in the allogeneic bone marrow transplant population. 

to study the effects of a supportive care ‘app’ with care navigation on Activity Tolerance Protocol assessments, body composition, mental wellness and patient-reported outcome measures. 

Adult patients scheduled for allo-BMT will be recruited. Eligibility criteria are the same as those for allogeneic transplantation . All standard of care interventions performed by the treatment team including multidisciplinary referrals, laboratory, and diagnostic imaging associated with allogeneic transplant processes will be maintained. After written informed consent, physical assessments will include. Baseline , Pre-Transplant (Prehabilitation) , Transplant & Recovery and Post-Transplant Rehabilitation ( Fig. Study Flow Diagram) : Multimodal care-navigation will be provided, with content delivery facilitated by a web-based app (Heal-Me) provided via continuous access to participants. This innovative web-based research application combines exercise, physiotherapy, nutrition and mental wellness content, co-designed by members of the research team . The Active Living module offers independent video sessions with exercises that can be tailored to the individual participant’s needs and the capacity for in-app videoconferencing to deliver interactive, dynamic individual or group classes for exercise. The Healthy Eating module centers on educational nutrition videos and tracking target protein intake. Nutritional intake targets can be tailored by a dietitian to meet the individual patient’s needs. Mental Wellness module incorporates mindfulness based and acceptance and commitment therapy-based content targeting chronic disease coping and symptoms of anxiety and depression. Certified Exercise Professionals (CEP) will develop and teach a personalized exercise training program derived from baseline ATP test results. Participants will take part in an individually tailored exercise training program delivered through the Active Living module of the Heal-Me application. Participants can choose from programs comprising  supervised group exercise sessions (connection via Zoom platform embedded in Heal-Me), and  independent exercise workouts within the application. Participants will be provided with the Garmin Vivofit activity tracker (Garmin Canada) to track their physical activity. Data from the Vivofit will be uploaded directly from Garmin Connect to the study’s REDCap database. Each participant’s exercise regimen will follow the general principles of overload, progression, and specificity ; and provides mild-to-moderate exercise (defined as 40–60% of maximal heart rate; 2–4 score on the 10-point Borg Rating of Perceived Exertion Scale ) and consist of full body exercise (e.g., comprising aerobic, resistance training, core stability, balance and flexibility training) a minimum of 2 times per week (one group virtual session and one independent self-directed session). The CEP will contact the participant regularly (weekly, or more often depending on patient need/preference) to provide and document coaching and support. A Registered Dietician will provide regular (weekly, or more often depending on patient need/preference) individualized counselling particularly focusing on energy (caloric) and protein intakes, healthy dietary patterns, as well as addressing any nutrition impact symptoms that may emerge during the inpatient period (mouth sores, dentition, vomiting, diarrhea, etc.). Cultural and religious preferences will be supported. The patient-specific calorie and protein intake targets will be entered into the Healthy Eating module of the Heal-Me application. A Research Nurse will contact regularly (weekly, or more often depending on patient need/preference) and perform a semi-structured interview including open-ended questions, symptom evaluation, assess physical, psychological or practical concerns (i.e., employment, family, caregiving). Mental wellness will be evaluated addressing topics such as fears, dealing with uncertainty, and self-compassion alongside the Heal-Me Wellness Module supports. Cardiac Prehabilitation and Post-Transplant Rehabilitation : ATP testing will be performed at 4 timepoints: baseline, pre-transplant, post-transplant and 1 year (Fig. ) at the rehabilitation center. Supervised or remote sessions will be encouraged at least weekly and instruction for home-based exercise provided at pre-habilitation and an 8-week session following allo-BMT. Eight weeks is the duration of standard cardiac rehabilitation at our center, moreover, the aim is to transition the participant to home-based exercise. ATP testing : timed up and go, gait speed, 30-second sit-to-stand test, right- and left-handgrip, and 6-minute walk test, will be performed. This battery of tests comprise not only of standard cardiac rehabilitation testing protocols , but have individually been shown to influence morbidity and mortality in allo-BMT . MRI : will be performed on a 3T Prisma Siemens scanner. Resting cardiac structure and function, and the tissue composition of myocardium, thigh skeletal muscle and liver will be imaged. The total volume (ml) of muscle and adipose tissues will be quantified and fat pools in the liver and skeletal muscle will also be reported as fat fraction (%, normalized to water volume from the same slices) . If MRI is contraindicated, dual energy X-ray absorptiometry (DEXA) scan will be performed. Nutritional Assessment : Food frequency questionnaire will assess usual frequency of consumption of a list of foods and food groups, focusing on protein and energy (caloric) intake and hydration The Brief Food Questionnaire is validated and utilized across many studies . Patient-reported outcome measures : Functional Assessment of Cancer Therapy–Bone Marrow Transplant (FACT-BMT) , Screening for Distress which includes both Edmonton Symptom Assessment System  and Canadian Problem Checklist  will be completed. Demographics : age; sex; diagnosis; chemotherapy dose and relative intensity; total body irradiation; distance from transplant center; comorbid conditions (cardiovascular risk, metabolic diseases); lifestyle and health habits. 

Primary Aim Qualitative methods aim to explore health care phenomena from first-hand experiences, and establish analytic methods to gather evidence to improve care delivery . Using the approach of interpretive description, common themes will be identified. A mixed methods approach will be applied to situate the qualitative themes alongside quantitative findings, providing an increased depth of understanding of the timing and type of experiences . Here, timing and type of HEAL-Me component participation; frequency, type and duration of exercise support, nutritional and nursing contacts; symptom frequency and severity; timing of experiences across allo-BMT trajectory; and type and timing of support provided. 

Qualitative methods aim to explore health care phenomena from first-hand experiences, and establish analytic methods to gather evidence to improve care delivery . Using the approach of interpretive description, common themes will be identified. A mixed methods approach will be applied to situate the qualitative themes alongside quantitative findings, providing an increased depth of understanding of the timing and type of experiences . Here, timing and type of HEAL-Me component participation; frequency, type and duration of exercise support, nutritional and nursing contacts; symptom frequency and severity; timing of experiences across allo-BMT trajectory; and type and timing of support provided. 

Participant recruitment for this study is ongoing. To our knowledge, no research team is taking such a holistic, multidisciplinary approach to address the debilitating physiologic and psychological consequences of allo-BMT. The team is exceptionally qualified in all methodological aspects. We expect the findings will inform the optimal timing and patient preferences to develop studies examining risk-specific, individualized interventions (including exercise, pharmacotherapy, combination treatments) to alleviate symptoms and dysfunction. The findings of this study are expected to power a large, multicenter randomized clinical trial. HEAL-ME is easily customizable and an HSCT version will be developed and tested, offering meaningful support whenever and wherever the patient may be. Impact will be measured by patient experience and health related outcomes (physical functioning, body composition) and quality of life. We expect this innovative pilot program to identify ways to benefit innumerable patients with hematologic and other malignancies. Ultimately, we hope to transform supportive care in hematopoietic stem cell transplantation. 

