Physical fitness and childhood hematopoietic stem cell transplantation: a call to action

Abstract

TO THE EDITOR: The use of hematopoietic stem cell transplantation (HSCT) to treat malignant and nonmalignant conditions has increased over the last decades, particularly among children [1]. As a result, there is a growing number of survivors but also of post-treatment complications and toxicities. Cancer survivors treated with HSCT are at greater risk of rehospitalization and mortality than their peers not receiving this treatment [2] and allogeneic HSCT (allo-HSCT) is frequently associated with a very severe condition—graft-versus-host disease (GvHD) [3]. In addition, survivors of childhood HSCT often develop some chronic conditions from early adulthood—notably, cardiometabolic disease and frailty—that are not usually prevalent in the general population until more advanced ages [4]. Another medical concern is that the side effects of cancer treatment and HSCT conditioning therapy at the multisystem level (e.g., cardiotoxicity, lung function impairment, steroid myopathy, and muscle atrophy in general) can affect the physical fitness of survivors. Cardiorespiratory fitness (CRF) is typically assessed through determination of the maximum (or ‘peak’) oxygen uptake—a concept introduced one century ago by a Nobel prize laureate in medicine, Sir A.V. Hill—achieved during dynamic aerobic exercise testing (e.g., treadmill walking or running) until volitional exhaustion. CRF is a beautiful indicator of the synergistic action (and functional reserve) of pulmonary, cardiovascular, and muscle tissue to effectively transport and deliver oxygen from the atmosphere to mitochondria in working muscles. Even more important, CRF is a strong and independent predictor of cardiometabolic risk and of all-cause and disease-specific mortality in adults [5] and children [6]. Notably, a poor CRF is prevalent among survivors of childhood cancer and is associated with all-cause mortality in this population [7]. Preservation of muscle fitness or “strength” (as simply determined with the handgrip test or the maximum resistance [weight] that can be tolerated during a single bench or leg press repetition) is also important to maintain cardiometabolic health and physical function over life [8]. For the aforementioned reasons, the systematic review and meta-analysis recently published by Fridh et al. [9] comparing the fitness status of HSCT survivors and non-HSCT controls is topical. Based on data from seven studies (N= 337 survivors), the results showed that survivors have an impaired CRF years after treatment had ended. Although the evidence was less clear, these authors reported a similar trend for muscle strength and physical performance. The question arises whether the physical deterioration associated with childhood HSCT can be prevented. The apparently bad news is that no drug or drug combination is able to counteract the numerous toxicities of cancer treatment and HSCT. Indeed, no drug therapy can simultaneously improve all the body functions (cardiopulmonary function, blood oxygen transport capacity, muscle oxidative capacity, or muscle anabolic capacity) that determine an individual’s CRF or muscle strength. The good news is physical exercise. Although it cannot be packed into a pill, physical exercise is quite feasible in virtually all settings. As opposed to drugs, it is essentially free of side effects and shows overall dose–response effects while at the same time improving not only CRF and muscle strength but also multiple body functions. The benefits of exercise on cardiometabolic health go in fact beyond “traditional” risk factors, including among others the promotion of a healthy microbiota, an improved autonomic balance or the release of muscle-derived factors, collectively known as “myokines” (or “exerkines” if released from non-muscle tissue during exertion) [8]. These molecules produced in the exercise milieu can have a muscle anabolic effect or travel through the bloodstream to reach different tissues where they induce numerous beneficial effects, including among others an antiinflammatory action, stimulation of the antitumoral properties of some immune cells, a decrease in insulin resistance, or the promotion of neutrotophism in the central nervous system. Since Winningham published her doctoral thesis in 1983 showing the benefits of cycle-ergometer exercise on the functional capacity and wellbeing of women with breast cancer strong evidence has accumulated, especially in adults, supporting the role of regular exercise as a co-adjuvant therapy to attenuate the side effects of treatment in most cancers. In a recent seminal article (“Exercise is medicine in oncology...”), world experts in the field state that “people living with and beyond cancer should be as active as is possible for them” [10]. Children undergoing HSCT are not an exception to such important recommendation. There is preliminary evidence that “exercise is medicine” also during childhood HSCT and hospitalization is not a good excuse to avoid physical activity. Chamorro-Viña studied the effect of a ~3week professionally supervised exercise intervention (aerobic and resistance exercises performed for ~60min almost daily from the beginning of the conditioning regimen until neutrophil engraftment in the patients’ isolated hospital rooms) in children undergoing allHSCT [11] (Fig. 1). The intervention was safe (with no harm to the immune system and in fact with a trend toward a faster recovery of dendritic cells after the transplant) and prevented loss of body mass compared to the control group. A more recent study applied the same type of inhospital intervention in a larger cohort (N= 65 and 53 children in the exercise and control arm, respectively) that was followed from the beginning of the conditioning phase (for either autologous or allo-HSCT) up to 6 years [12]. The exercise intervention was safe and although it did not affect major clinical outcomes (such as risk of GvHD), it did reduce the number of total and viral infections after allo-HSCT. Further research is needed but the aforementioned findings provide support to the notion that a