The utility of a portable muscle ultrasound in the assessment of muscle alterations in children with acute lymphoblastic leukaemia

Background:During treatment for acute lymphoblastic leukaemia (ALL), children are prone to musculoskeletal deterioration. However, non-invasive tools to measure muscle mass and intramuscular alterations are limited. In this study we explored the feasibility of muscle ultrasound in children with ALL. Additionally, we analysed whether automated ultrasound outcomes of muscle size and intramuscular fat infiltration (IMAT) were associated with appendicular skeletal muscle mass (ASMM), muscle strength and physical performance. Methods: Children with ALL, aged 3–18 years were included during maintenance therapy. Bilateral images of the rectus femoris muscle were captured using a portable linear array transducer connected to a tablet. Subsequently, an automated image annotation software (MuscleSound) was used to estimate cross-sectional area, muscle thickness and IMAT. Feasibility was assessed using acceptance (percentage of children approached who were enrolled), practicality (percentage of children that completed the ultrasound measurement after enrolment) and implementation (percentage of children that had sufficient imaging to be processed and analysed by the software). Assessments of ASMM by bioimpedance analysis, muscle strength using handheld dynamometry and timed physical performance tests were administered at the same visit. Multivariable linear models were estimated to study the associations between muscle ultrasound outcomes and ASMM, strength and physical performance, adjusted for sex, age, body mass index and ALL treatment week. Results: Muscle ultrasound was performed in 60 out of 73 invited patients (76.9%), of which 37 were boys (61.7%), and median age was 6.1 years (range: 3–18.8 years). The acceptance was 98.7%, practicality 77.9% and implementation was 100%. Patients who refused the examination (n = 13) were younger (median: 3.6, range: 3–11.2 years) compared with the 60 examined children (P = 0.0009). In multivariable models, cross-sectional area was associated with ASMM (β = 0.49 Z-score, 95% confidence interval [CI]:0.3,2.4), knee-extension strength (β = 16.9 Newton [N], 95% CI: 4.8, 28.9), walking performance (β = −0.46 s, 95% CI: −0.75, −0.18) and rising from the floor (β = −1.07 s, 95% CI: −1.71, −0.42). Muscle thickness was associated with ASMM (β = 0.14 Z-score, 95% CI: 0.04, 0.24), knee-extension strength (β = 4.73 N, 95% CI: 0.99, 8.47), walking performance (β = −0.13 s, 95% CI: −0.22, −0.04) and rising from the floor (β = −0.28 s, 95% CI: −0.48, −0.08). IMAT was associated with knee-extension strength (β = −6.84 N, 95% CI: −12.26, −1.41), walking performance (β = 0.2 s, 95% CI: 0.08, 0.32) and rising from the floor (β = 0.54 s, 95% CI: 0.27, 0.8). None of the muscle ultrasound outcomes was associated with handgrip strength. Conclusions: Portable muscle ultrasound appears a feasible and useful tool to measure muscle size and intramuscular alterations in children with ALL. Validation studies using magnetic resonance imaging (gold standard) are necessary to confirm accuracy in paediatric populations.</p

Physical frailty deteriorates after a 5-day dexamethasone course in children with acute lymphoblastic leukemia, results of a national prospective study

Background: Dexamethasone is important in the treatment for pediatric acute lymphoblastic leukemia (ALL) but induces muscle atrophy with negative consequences for muscle mass, muscle strength, and functional abilities. The aim of this study was to establish the effect of a dexamethasone course on sarcopenia and physical frailty in children with ALL, and to explore prognostic factors. Methods: Patients with ALL aged 3–18 years were included during maintenance therapy. Patients had a sarcopenia/frailty assessment on the first day of (T1) and on the day after (T2) a 5-day dexamethasone course. Sarcopenia was defined as low muscle strength in combination with low muscle mass. Prefrailty and frailty were defined as having two or ≥three of the following components, respectively: low muscle mass, low muscle strength, fatigue, slow walking speed, and low physical activity. Chi-squared and paired t-tests were used to assess differences between T1 and T2. Logistic regression models were estimated to explore patient- and therapy-related prognostic factors for frailty on T2. Results: We included 105 patients, 61% were boys. Median age was 5.3 years (range: 3–18.8). At T1, sarcopenia, prefrailty, and frailty were observed in respectively 2.8%, 23.5%, and 4.2% of patients. At T2, the amount of patients with frailty had increased to 17.7% (p = 0.002), whereas the number of patients with sarcopenia and prefrailty remained similar. Higher ASMM (odds ratio [OR]: 0.49, 95% CI: 0.28–0.83), stronger handgrip strength (OR: 0.41, 95% CI: 0.22–0.77) and more physical activity minutes per day (OR: 0.98, 95% CI: 0.96–0.99) decreased the risk of frailty at T2. Slower walking performance (OR: 2, 95% CI: 1.2–3.39) increased the risk. Fatigue levels at T1 were not associated with frailty at T2. Conclusion: Physical frailty increased strikingly after a 5-days dexamethasone course in children with ALL. Children with poor physical state at start of the dexamethasone course were more likely to be frail after the course.</p

Dexamethasone-Induced Sarcopenia and Physical Frailty in Children With Acute Lymphoblastic Leukemia: Protocol for a Prospective Cohort Study

Background: During treatment for pediatric acute lymphoblastic leukemia (ALL), children receive high doses of dexamethasone for its apoptotic effect on leukemia cells; however, muscle atrophy is a well-known serious side effect. Muscle atrophy (loss of muscle mass) accompanied by a decreased muscle strength may lead to a generalized impaired skeletal muscle state called sarcopenia. Loss of muscle mass is also an indicator of physical frailty, which is defined as a state of increased vulnerability that is characterized by co-occurrence of low muscle mass, muscle weakness, fatigue, slow walking speed, and low physical activity. Both sarcopenia and physical frailty are related to an increased risk of infections, hospitalizations, and decreased survival in children with chronic diseases. Objective: This study aims to (1) estimate the occurrence of sarcopenia and physical frailty in children during ALL maintenance therapy, (2) evaluate the effect of administering dexamethasone, and (3) explore determinants associated with these outcomes. Methods: This prospective study is being pursued within the framework of the DexaDays-2 study: a randomized controlled trial on neurobehavioral side effects in pediatric patients with ALL. A total of 105 children (3-18 years) undergoing ALL maintenance treatment at the Princess Máxima Center for Pediatric Oncology are included in this study. Sarcopenia/frailty assessments are performed before and just after a 5-day dexamethasone course. A subset of 50 children participating in the DexaDays-2 trial because of severe dexamethasone-induced neurobehavioral problems were assessed at 3 additional timepoints. The sarcopenia/frailty assessment consists of bioimpedance analysis (skeletal muscle mass [SMM]), handheld dynamometry (handgrip strength), Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (fatigue), Timed Up and Go Test (TUG; walking speed), and physical activity questionnaires. To evaluate potential change in sarcopenia/frailty components after a 5-day dexamethasone administration, a paired Student t test or Mann-Whitney U test will be used. Because of the presence of repeated measurements, generalized linear mixed models will be used to estimate the effect of dexamethasone on sarcopenia and frailty outcomes. Multivariable regression models will be estimated to investigate associations between the assessment scores and patient and treatment-related factors. Results: Patient accrual started in 2018 and was finalized in spring 2021. From autumn 2021 onward final data analyses will be performed. Conclusions: This first study combining parameters of sarcopenia and physical frailty is of importance because these conditions can seriously complicate continuation of ALL therapy, independence in physical functioning, reaching motor milestones, and participating in daily life activities

Dexamethasone-Induced Sarcopenia and Physical Frailty in Children With Acute Lymphoblastic Leukemia: Protocol for a Prospective Cohort Study

Background: During treatment for pediatric acute lymphoblastic leukemia (ALL), children receive high doses of dexamethasone for its apoptotic effect on leukemia cells; however, muscle atrophy is a well-known serious side effect. Muscle atrophy (loss of muscle mass) accompanied by a decreased muscle strength may lead to a generalized impaired skeletal muscle state called sarcopenia. Loss of muscle mass is also an indicator of physical frailty, which is defined as a state of increased vulnerability that is characterized by co-occurrence of low muscle mass, muscle weakness, fatigue, slow walking speed, and low physical activity. Both sarcopenia and physical frailty are related to an increased risk of infections, hospitalizations, and decreased survival in children with chronic diseases. Objective: This study aims to (1) estimate the occurrence of sarcopenia and physical frailty in children during ALL maintenance therapy, (2) evaluate the effect of administering dexamethasone, and (3) explore determinants associated with these outcomes. Methods: This prospective study is being pursued within the framework of the DexaDays-2 study: a randomized controlled trial on neurobehavioral side effects in pediatric patients with ALL. A total of 105 children (3-18 years) undergoing ALL maintenance treatment at the Princess Máxima Center for Pediatric Oncology are included in this study. Sarcopenia/frailty assessments are performed before and just after a 5-day dexamethasone course. A subset of 50 children participating in the DexaDays-2 trial because of severe dexamethasone-induced neurobehavioral problems were assessed at 3 additional timepoints. The sarcopenia/frailty assessment consists of bioimpedance analysis (skeletal muscle mass [SMM]), handheld dynamometry (handgrip strength), Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (fatigue), Timed Up and Go Test (TUG; walking speed), and physical activity questionnaires. To evaluate potential change in sarcopenia/frailty components after a 5-day dexamethasone administration, a paired Student t test or Mann-Whitney U test will be used. Because of the presence of repeated measurements, generalized linear mixed models will be used to estimate the effect of dexamethasone on sarcopenia and frailty outcomes. Multivariable regression models will be estimated to investigate associations between the assessment scores and patient and treatment-related factors. Results: Patient accrual started in 2018 and was finalized in spring 2021. From autumn 2021 onward final data analyses will be performed. Conclusions: This first study combining parameters of sarcopenia and physical frailty is of importance because these conditions can seriously complicate continuation of ALL therapy, independence in physical functioning, reaching motor milestones, and participating in daily life activities

Hydrocortisone to reduce dexamethasone-induced neurobehavioral side-effects in children with acute lymphoblastic leukaemia—results of a double-blind, randomised controlled trial with cross-over design

Background: Dexamethasone is a cornerstone of paediatric acute lymphoblastic leukaemia (ALL) treatment, although it can induce serious side-effects. Our previous study suggests that children who suffer most from neurobehavioural side-effects might benefit from physiological hydrocortisone in addition to dexamethasone treatment. This study aimed to validate this finding. Methods: Our phase three, double-blind, randomised controlled trial with cross-over design included ALL patients (3–18 years) during medium-risk maintenance therapy in a national tertiary hospital between 17th May 2018 and 5th August 2020. A baseline measurement before and after a 5-day dexamethasone course was performed, whereafter 52 patients with clinically relevant neurobehavioural problems were randomised to receive an intervention during four subsequent dexamethasone courses. The intervention consisted of two courses hydrocortisone (physiological dose 10 mg/m2/d in circadian rhythm), followed by two courses placebo, or vice versa. Neurobehavioural problems were assessed before and after each course using the parent-reported Strengths and Difficulties Questionnaire (SDQ) as primary end-point. Secondary end-points were sleep problems, health-related quality of life (HRQoL), hunger feeling, and parental stress, measured with questionnaires and actigraphy. A generalised mixed model was estimated to study the intervention effect. Results: The median age was 5.5 years (range 3.0–18.8) and 61.5% were boys. The SDQ filled in by 51 primary caregivers showed no difference between hydrocortisone and placebo in reducing dexamethasone-induced neurobehavioral problems (estimated effect -2.05 (95% confidence interval (CI) -6.00–1.90). Also, no benefit from hydrocortisone compared to placebo was found for reducing sleep problems, hunger, parental stress or improving HRQoL. Conclusions: Hydrocortisone, when compared to placebo, had no additional effect in reducing clinically relevant dexamethasone-induced neurobehavioural problems. Therefore, hydrocortisone is not advised as standard of care for children with ALL who experience dexamethasone-induced neurobehavioural problems. Trial registration: Netherlands Trial Register NTR6695/NL6507 (https://trialsearch.who.int/) and EudraCT 2017–002738–22 (https://eudract.ema.europa.eu/)