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Fatigue in CML patients
physical activity remained lower in fatigued patients (mean difference 0.55 h/day, 0.67 h/day, 0.22 h/day, and 1,938 steps/day for sleeping time, light intensity physical activity, moderate to vigorous intensity physical activity, and step counts, respectively; all P<0.05).
Physical activity patterns were also analyzed for week and weekend days separately. Although there was no dif- ference between the fatigued and non-fatigued group in sit- ting time during week days (9.7 h/day [IQR 8.9-11.3] and 10.0 h/day [IQR 8.8-11.0], respectively; P=0.73), we found a trend towards longer sitting time during weekend days in fatigued patients compared to non-fatigued ones (9.6 h/day [IQR 8.6-10.9] and 9.2 h/day (IQR 8.1-10.5), respectively; P=0.06). Severely fatigued patients slept longer and per- formed less physical activity (of light as well as moderate to vigorous intensity) on both week and weekend days (all P<0.05).
Discussion
This is the first study to assess the prevalence and predic- tors of severe fatigue in CML patients receiving TKI treat- ment and to provide insight into the relationship between severe fatigue and physical activity in this population. The prevalence of fatigue in our CML population was 55%. Using multivariable logistic regression, we built a model with good discriminative ability and found five significant predictors of severe fatigue in our population: younger age, female gender, higher CCI, the use of comedication known to cause fatigue, and physical inactivity. Using physical activity monitors, we objectively confirmed that severely fatigued CML patients are less physically active during the day, with regard to both light and moderate to vigorous intensity activity, on both week and weekend days. These findings suggest that: (i) there is a subset of CML patients particularly prone to TKI-induced fatigue, and (ii) severely fatigued patients have reduced levels of physical activity.
Over half of the CML patients in the present study expe- rienced severe fatigue, which was significantly greater than that in matched controls and compared to TKI-induced fatigue rates reported in literature. In patients receiving ima- tinib, the prevalence of fatigue varied across large clinical trials from 34.5% (IRIS16) to 15.5% (CML IV17), 10% (DASI- SION18), 22% (ENESTnd19), 47% (BFORE20), and 20% (EPIC21). However, these trials were not designed to assess fatigue, which may explain the wide range of prevalence rates. We did not find a difference in fatigue prevalence between patients taking different TKI, which is in agree- ment with the findings of these large trials.18-20 Interestingly, severe fatigue was neither independently associated with treatment-related factors, such as TKI therapy dose and duration, nor with disease control. Although fatigue is a common sign of severe anemia, hemoglobin levels did not differ between fatigued and non-fatigued patients. Low hemoglobin levels were also not identified as an independ- ent predictor of fatigue in patients with other hematologic malignancies.22
We found that fatigue was more often present in younger and female patients. In line with this, Efficace et al. found that the largest differences in health-related QoL between CML patients and the general population was among younger subjects.2 Contradictory findings are reported in the literature regarding the association between age and fatigue in other populations. For example, chronic fatigue
was more often present in younger breast cancer survivors,7 while older age has been identified as a risk factor for fatigue in both hematologic23 and non-hematologic24,25 can- cer patients. Several studies showed an association between fatigue and gender in line with our results, with a more prominent risk for female cancer patients.26,27 Interestingly, compared to the general population, female CML patients are more negatively affected than male CML patients in both mental and physical health.2 Sex-related differences in disease perception and anxiety may contribute to the high- er prevalence of fatigue in women,28 although this aspect was beyond the scope of this study. Furthermore, we showed that patients with comorbidity were more often fatigued, as were patients taking comedication known to cause fatigue. This suggests the need to check patients’ medication records critically, and to stop or reduce the dose of any comedication known to cause fatigue if possible (e.g., benzodiazepines as sleep medication), especially in those CML patients who are prone to fatigue.
Both subjective and objective assessments of physical activity showed that fatigued patients were more often inactive than were non-fatigued patients. More precisely, we found that compared to the non-fatigued patients, fatigued CML patients slept approximately 0.5 h/day longer, performed 1 h less of physical activity per day and took 2,000 fewer steps per day. Although it may seem self-evident that severely fatigued patients are less physi- cally active as a result of fatigue, physically inactivity itself may contribute to the persistence of fatigue.9 Additionally, there is a significant body of evidence to support the beneficial effects of exercise interventions to reduce fatigue levels in various (post)-cancer patient pop- ulations.29 Interestingly, our study showed that the vast majority of the CML patients, both fatigued and non- fatigued, already met the recommended American College of Sports Medicine/American Heart Association guidelines for physical activity (i.e., 150-300 min of mod- erate-intensity or 75-150 min of vigorous intensity phys- ical activity per week, or an equivalent combination). However, higher activity levels were associated with lower levels of fatigue in our CML population. Furthermore, the extra amount of physical activity that non-fatigued patients performed when compared to fatigued patients (~6.3 h of light intensity and 1.4 h of moderate to vigorous intensity physical activity per week) may yield additional health benefits.30 Consequently, it is of clinical relevance to focus on pre- venting and treating TKI-induced fatigue in clinical prac- tice. This is further supported by our findings that fatigued CML patients have impaired QoL and work fewer hours when compared to non-fatigued patients.
There are several limitations to this study. First, due to the cross-sectional design of the study we cannot distin- guish between cause and effect. Although we found that a reduced level of physical activity is associated with the presence of fatigue, and thus is a predictor of fatigue, we cannot state that reduced physical activity is a risk factor for fatigue. However, regardless of whether or not there is a causal relationship between fatigue and reduced lev- els of physical activity, our results highlight the impor- tance of combating fatigue and of examining whether exercise interventions are useful to counteract fatigue. Secondly, because of the inclusion of a heterogeneous study population, we observed a considerable variation in physical activity levels. However, the representative sam-
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