Feasibility and safety of exercise training and nutritional support prior to haematopoietic stem cell transplantation in patients with haematologic malignancies

Haematopoietic stem cell transplantation (HSCT) is a standard of care for various adverse haematologic malignancies and improves the time to disease progression and patient overall survival [1‐3]. The treatment outcome may be influenced by the underlying disease, age of the recipient, comorbidities, and allogeneic transplantation with a donor-recipient HLA mismatch [4]. The procedure can be accompanied by various complications [3]. The nutritional status [5, 6] and functional capacity [7, 8] of the patient have predictive value for the treatment outcome. In a study by Fuji et al., 14.8% of patients were underweight prior to HSCT, with a body mass index (BMI) < 18.5 kg/cm², which was associated with worse overall survival [6]. Jones et al. evaluated the functional capacity in patients undergoing HSCT using the 6-min walking test (6MWT). Compared with that for patients achieving a distance of < 400 m, the unadjusted hazard ratio for overall survival was 0.71 for patients achieving a distance of ≥400 m. Each 50-m increase in distance was associated with a 9% relative reduction in the risk of death [8]. While the proportion of patients observed to have poor physical performance was as high as 46%, Wiskemann found that on average, patients showed a relatively good level of physical fitness on admission to the hospital but that the distance in the 6MWT decreased from an initial 546 m to 445 m on discharge [9].

Most of the associated factors cannot be addressed, but the implementation of certain measures may improve both the nutritional status and functional capacity of the patient. Prehabilitation was recently introduced to patients undergoing surgery for malignant disease, with the intention of improving functional capacity and nutritional status prior to the surgical procedure [10‐13]. Preoperative exercise training and nutritional and psychological support improve the patient’s physiologic reserve prior to the surgical procedure. In patients with haematologic malignancies, exercise training in the post-HSCT period was shown to improve physical performance and muscle strength, reduce fatigue and improve health-related quality of life (HRQoL) [14, 15]. There are limited available data on the above measures prior to HSCT. In a pilot study, Bartels et al. reported on patients with lymphoma and multiple myeloma who safely performed a home-based exercise programme for an average of 11 weeks before HSCT [16]. Wiskemann et al. reported an improved survival rate at 2 years after allogeneic HSCT in a group of patients who enrolled in an exercise training programme for 21 days before, during, and 6 to 8 weeks following HSCT [17]. To prevent muscle protein depletion in cancer patients, combined nutrition and physical therapy are recommended [18]. While exercise stimulates muscle protein synthesis, protein intake can further improve training-induced muscle mass gains. Whey protein provides substantial amounts of essential amino acids and has proven to be effective in modulating postexercise muscle protein synthesis [13]. To the best of our knowledge, no data have been published on the effect of combined exercise training and nutritional support prior to HSCT. The goal of such an intervention would be for patients to increase their physiologic reserve in the anticipation of loss of muscle mass and impaired performance status during HSCT.

The purpose of our pilot study was to investigate the feasibility and safety of a multimodal intervention programme with partially supervised exercise training combined with nutritional support prior to HSCT.

Our study shows that exercise training and nutritional support protocols were feasible and safe in patients prior to HSCT. Of the eligible patients in the study, most (82.4%) accepted enrolment. Most participants successfully completed the programme, with only 17.8% leaving the programme early. Based on participation in the guided exercises, the diary data and the data recorded by sports bracelets, adherence to the protocol was above expectations. Although more than half of the patients had accompanying diseases and one-third of the patients had a poor performance status, most patients fulfilled the planned range of exercises. According to data from the diaries, almost all patients performed strength exercises regularly, three times per week. They were slightly less engaged in aerobic exercises but still performed them satisfactorily on average. Weekly controlled training at the facility, with added professional supervision and adjustment of the exercise routine, proved to be pivotal for good adherence in our patient group. The supervision of exercise techniques is also important to decrease the risk of injury and possible adverse events.

Due to chronic systemic inflammation and metabolic changes, patients with malignancies already experience an increased need for protein intake [18]. The data on the occurrence of malnutrition and underweight in haematologic patients show an association with reduced overall survival and increased rates of relapse and transplant-related mortality in some studies, while others do not show any correlation [25]. In the paediatric population, optimizing the nutritional status prior to HSCT is of great importance [26]. At least one study reported a prevalence of sarcopenia in the adult population of up to 50.6% prior to allogeneic HSCT [27]. Since an increase in muscle mass was our goal, we prescribed a protein supplement. The addition of physical exercise to protein supplementation was not performed in haematologic patients prior to HSCT. However, in surgery patients, the combination of exercise and protein supplementation is synergistic. The relative increase in muscle strength after bariatric surgery was higher in patients performing strength exercises in combination with protein supplementation than in patients only receiving protein supplementation [28]. Protein supplementation improved muscle strength and physical function more than exercise alone in ageing patients with sarcopenia [29]. There is accumulating evidence that the combination of strength exercises with nutritional support is beneficial in patients undergoing surgery or in critically ill patients with a risk of sarcopenia. In a systematic review, multimodal prehabilitation was safe with good adherence even in high-risk patients awaiting lung or heart transplantation [30]. Protein powder was well tolerated, and at the end of the study, we measured an increase in the FFM of the participants. The patients’ physical fitness at the beginning of the programme was good. The number of patients who were able to walk less than 400 m in the 6MWT, which is a risk factor for a poor HSCT outcome, was only 3 [8]. In one patient, the reason for the poor 6MWT result was peripheral neuropathy due to the underlying disease, and the other two patients performed poorly because they had just completed their last round of chemotherapy. On average, we measured better participant outcomes at the end of the programme, namely, for the 6MWT, as well as for the 30sCST and handgrip test. According to the EORTC QLQ-C30 results, patients experienced improvements in quality of life at the end of the programme. In general, they felt less ill and more emotionally balanced, and they reported less fatigue, less nausea and less insomnia. Whether this was the result of our prehabilitation programme or other factors remains to be assessed in future controlled studies.

There were no serious adverse events due to exercise or protein intake. If patients omitted aerobic exercise for a short period, they mostly reported only general malaise. Other reasons for omitting exercises were upper respiratory tract viral infections or poor weather. None of the participants terminated the programme due to limitations in blood counts or electrolyte or metabolic disturbance. No patient with multiple myeloma with bone involvement developed any musculoskeletal injuries.

Our study had some limitations. First, it was not a controlled randomized study, so we were not able to demonstrate that the positive effects were due to our intervention. Since we showed that the intervention is feasible and safe, we plan to continue and expand the study in the future. Second, patient enrolment in the study was slow, which resulted in a small patient sample. Because screening was limited to patients who could perform the programme for at least 2 weeks at home and attend the guided group exercises once per week, we were not able to screen most patients planning to undergo allogeneic HSCT, since the time to HSCT was on average very short. Recently hospitalized patients in particular could benefit from the intervention and will be included in future studies as soon as they become candidates for HSCT. Patients from remote locations were also not screened for the study. Regarding promising results from our feasibility study, we intend to increase our resources to be able to include these patients in the future. Third, body composition was measured with bioimpedance, which is an indirect method. Bioimpedance is less accurate than dual-energy X-ray absorptiometry, computed tomography or magnetic resonance imaging. However, bioimpedance is readily available, safe and commonly used in everyday clinical practice [31].

Our study shows that a multimodal intervention programme with partially supervised exercise training combined with nutritional support prior to HSCT is feasible and safe. Patients who participated in the programme showed improved body composition through increases in FFM, improved physical performance, and improved HRQoL. Further randomized trials are needed to examine the impact of multimodal interventions on quality of life, body composition, disease progression and, potentially, overall patient survival.