Body composition after allogeneic haematopoietic cell transplantation/total body irradiation in children and young people: a restricted systematic review

Purpose To collate evidence of changes in body composition following treatment of leukaemia in children, teenagers and young adults (CTYA, 0–24 years) with allogeneic haematopoietic stem cell transplant and total body irradiation (HSCT+TBI). Methods Papers were identified by searching Medline and Google Scholar, reference lists/citations and contacting key authors, with no date or language restrictions. Inclusion criteria were as follows: leukaemia, HSCT+TBI, aged ≤ 24 years at HSCT and changes in body composition (total fat, central adiposity, adipose tissue function, muscle mass, muscle function). Quality was assessed using a brief Newcastle–Ottawa scale. Results Of 900 papers, 20 were included: seven controlled, five uncontrolled studies and eight case reports. Study quality appeared good. There was little evidence of differences in total fat/weight for HSCT + TBI groups (compared to healthy controls/population norms/short stature controls). There was some evidence of significantly higher central adiposity and differences in adipose tissue function (compared to leukaemic/non-leukaemic controls). Muscle mass was significantly lower (compared to healthy/obese controls). Muscle function results were inconclusive but suggested impairment. Case reports confirmed a lipodystrophic phenotype. Conclusions Early remodelling of adipose tissue and loss of skeletal muscle are evident following HSCT + TBI for CTYA leukaemia, with extreme phenotype of overt lipodystrophy. There is some evidence for reduced muscle effectiveness. Implications for Cancer Survivors Body composition changes in patients after HSCT + TBI are apparent by early adult life and link with the risk of excess cardiometabolic morbidity seen in adult survivors. Interventions to improve muscle and/or adipose function, perhaps utilizing nutritional manipulation and/or targeted activity, should be investigated. Electronic supplementary material The online version of this article (10.1007/s11764-020-00871-1) contains supplementary material, which is available to authorized users.


Introduction
Leukaemia is the commonest type of cancer in children (0 to < 16 years) and one of the most common diagnoses affecting teenagers and young adults (16 to < 25 years). Patients who fail primary treatment, or those with very high risk factors at diagnosis, may be treated with allogeneic haematopoietic stem cell transplantation (HSCT) after conditioning with high dose chemotherapy and total body irradiation (TBI) [1]. Adult survivors of HSCT with TBI conditioning experience long-term morbidity, impaired quality of life and reduced life expectancy. Endocrine disorders including growth hormone deficiency, hypothyroidism and gonadal failure are well-described, but there is now good evidence of a phenotype emerging in early adult life that resembles accelerated ageing [2] with early post-transplant telomere shortening [3], long-term metabolic dysfunction [4], abnormal body composition [5], frailty [6] and fatigue [7]. Investigation has identified specific findings which incorporate features of the metabolic syndrome including hypertension, dyslipidaemia, insulin resistance, visceral adiposity and a pro-inflammatory state [8,9].
Screening for adverse adiposity that increases cardiometabolic risk in the general population is relatively easy using standard measures of obesity (raised BMI and/or waist circumference) but is less straightforward in HSCT/TBI survivors who may not be overtly obese by these criteria. In contrast, the phenotype is characterized by the presence of increased visceral but reduced subcutaneous fat and reduced lean mass, i.e. they also demonstrate, at extremes, overt sarcopenic and lipodystrophic phenotypes [10]. These changes seem causally linked to the increased risk of metabolic syndrome in this patient population [1]. Metabolic syndrome has six components that relate to cardiovascular disease risk (based on the ATPIII definition): abdominal obesity, atherogenic dyslipidaemia, raised blood pressure, insulin resistance ± glucose intolerance, proinflammatory and prothrombotic states [11].
Survivors of all forms of cancer diagnosed as children or as teenagers and young adults (CTYA), including leukaemia treated without HSCT/TBI, may also face long-term morbidity in adult life depending on the nature of the treatment received; cardiovascular disease is the most common cause of early mortality in CTYA cancer survivors after the risk of death from second cancer [12]. Metabolic syndrome is also reported in other survivors of childhood cancer, but HSCT, TBI and cranial or abdominal irradiation all appear to incur greater risk [13]. Recent studies also confirm an increased risk of type 2 diabetes in adult survivors of childhood leukaemia [14].
The incidence, severity, progression and outcome of changes in body composition/BMI in survivors of HSCT/TBI undertaken in the CTYA age range are unclear. Nor is it known how their risk compares with survivors of CTYA leukaemia treated without HSCT/TBI or with individuals without a history of cancer treatment with or without evidence of obesity. Clarifying the phenotype of HSCT/TBI survivors may assist in developing future studies to investigate the critical pathophysiological changes that drive the associated cardiometabolic consequences likely to occur in adult life and in designing potential interventions.

Aims
This restricted systematic review aimed to: & collate evidence of changes in body composition/BMI in survivors of leukaemia treated in the CTYA age range (age 0-< 25 years) with HSCT with TBI & identify evidence that body composition is associated with change in metabolic status in survivors & describe dietary and exercise interventions used to ameliorate these changes in body composition & compare findings, with studies of leukaemia survivors treated without HSCT with TBI and with the general population

Methods
This review was registered on PROSPERO International prospective register of systematic reviews, reference number CRD42019138493. We followed Plüddemann's framework for rapid reviews [15].

Study selection
Titles and abstracts were assessed for eligibility by AL, with RP independently assessing a random sample of 10% of records. Articles meeting inclusion criteria were retrieved in full and independently considered by two reviewers (MS, JHS). The reviewers resolved disagreements through discussion; reasons for excluding studies were recorded in a For studies which used interventions, we ensured adverse event data was extracted. The template was piloted before starting the review and modified as required to ensure consistency. Disagreements in opinion of data extracted were resolved through discussion.

Quality assessment
To assess the quality of included studies, AL used a modified, brief Newcastle-Ottawa quality assessment scale [17]. Quality scores are reported in a table. Figure 1 details the search process. A total of 900 papers were identified, of which 880 were excluded. The most common reasons for exclusion were that studies were not about cancer or had no body composition outcomes (full reasons are given in Fig. 1). Of 24 emails to key authors, we received nine responses.
Our exclusion criteria aimed to create a homogeneous set of papers relevant to a future study of interventions for body composition and frailty in childhood leukaemia HSCT with TBI. However, we are aware that some of the excluded papers may include relevant information so have provided these references in Online Resource 2. Table 1 gives details of the twelve controlled and uncontrolled studies and outcome data are summarized in Table 2. ALL was the most common diagnostic group. Four studies included a range of diagnoses. Four of the seven controlled studies had two control groups and three studies only one. Controls included leukaemia patients without HSCT (5 studies), healthy people (3 studies) and other clinical groups (short stature or obese; 3 studies). Studies were conducted between 6 and 16.7 years after HSCT. Of our chosen body composition outcomes, eleven of the twelve studies measured total body fat, seven measured central adiposity and six measured adipose tissue function. Only four measured muscle mass and muscle function.

Study designs
The eight case reports/series are presented in Table 3, representing a total of eleven cases.

Study quality
The assessment of study quality was brief (using a modified Newcastle-Ottawa scale with 8 very simple criteria). As shown in Table 4, apart from a lack of blinding of outcome assessors (not present in any study), most studies fulfilled most criteria. Table 2 provides the outcome data for the controlled and uncontrolled studies. Outcomes for the case reports are included in Table 3. Due to heterogeneity within included studies (especially in terms of outcomes), we did not synthesize the data or perform any metaanalysis.

Changes in body composition
The body composition results of the studies are reported in Table 2 and briefly summarized below.      [23] NS not significant, NR not reported *Values for Adachi et al. [26] were calculated for this review from datasets sent by the author  Dyslipidaemia and hyperinsulinism.
Fatty changes in the liver.

Total body fat
There was little evidence of differences in total fat/weight between HSCT + TBI groups and healthy controls, population norms or short stature controls. Nysom et al. found significantly lower BMI compared to healthy controls [20]. Wei et al. also found significantly lower BMI and fat mass index, but this was compared to obese controls [10,22]. Three studies found significantly higher body fat: body fat % compared to short stature controls [19] and healthy controls [20] and whole body fat mass z score compared to reference controls [1]. Data from Adachi et al. [26] suggests BMI may be lower than leukaemic controls with no TBI, and, although significance could not be tested, within the normal range for age.

Central adiposity
Most of the studies which measured central adiposity found significantly higher central adiposity for HSCT + TBI groups compared to leukaemic controls and non-leukaemic (obese/ short stature/healthy) controls. Evidence from four studies found significant differences for lower waist-to-hip ratios and higher android-gynoid fat ratios compared to leukaemic controls and for higher waist circumference/waist-height ratio, greater trunk fat % and visceral fat %, compared to nonobese non-leukaemic controls [1,19,22,118]. One study found evidence of significant differences for lower waist circumference/waist-height ratio, higher visceral fat % and higher visceral fat to total/subcutaneous fat ratios compared to obese non-leukaemic controls [10].
High waist-to-hip ratio was associated with features of metabolic syndrome in one study [22], and visceral fat % was associated with insulin resistance in another [1].

Adipose tissue function
All three studies which measured adipose tissue function found significant differences for HSCT + TBI groups compared to leukaemic controls and some to non-leukaemic controls. Compared to leukaemic controls, adiponectin was lower, leptin higher, triglycerides higher and high-density lipoprotein (HDL) lower [10,18,22]. The only difference compared to non-leukaemic controls (obese) was for raised triglycerides [22]. Lower adiponectin and HDL levels were more common in those with insulin resistance [1,18].

Muscle mass
Four studies measured muscle mass (fat free/lean mass, muscle density), and all found significantly lower muscle mass for HSCT + TBI groups compared to healthy/obese controls and in HSCT + TBI patients compared with findings before HSCT + TBI [1,10,19,27]. Wei et al. [10] found limited evidence NR not reported *No studies reported muscle mass outcomes for lower fat-free mass index compared to leukaemic controls. Lean mass/height 2 was lower in females [27].

Muscle function
For HSCT + TBI groups compared to leukaemic controls, Taskinen et al. [21] found significant differences in some physical performance tests but not others, and Chow et al. found lower physical activity scores [18]. Davis et al. found some increase in strength following an exercise intervention [23].

Association of body composition changes with metabolic status
Some studies commented on associations of body composition outcomes with the presence of features of metabolic syndrome. Associations with metabolic syndrome/insulin resistance were found with: & Whole body fat mass [1] & Waist-to-hip ratio and waist-to-height ratio [22] & Subcutaneous adipose tissue, visceral adipose tissue [1] & Lower adiponectin levels [25] & Lower HDL [25] Potential factors modifying impact of HSCT on body composition Although not an aim of this review, most studies reported on certain factors which may impact the relationship between HSCT and body composition, in particular graft versus host disease (GVHD), growth hormone deficiency and cranial radiation. This section briefly reports these results.

GVHD and treatment
Most studies reported the number of participants with GVHD, which varied from 0 to 61.5%. However, there was wide variability in reporting this and the details, i.e. whether acute or chronic. This is not a primary focus for this review. One study found that GVHD was predictive of underweight post-HSCT, and extensive chronic GVHD was predictive of lower BMI, but this was an uncontrolled study [27]. Three studies reported that GVHD or glucocorticoid treatment was not associated with body composition (cytokine levels [18]; marrow adipose tissue, any measures of adiposity or lean mass [1]; or wholebody % fat z score [20]).

Cranial radiation
Some studies explored the association of cranial radiation with body composition and found differences in BMI and whole body fat [20] but not in cytokine levels [18] or cardiometabolic traits [18].

Age at/time since HSCT
The studies showed mixed results regarding the relationship between time since HSCT and body composition. Age at HSCT was not associated with body composition in two studies (adiposity or lean mass [1] or whole-body % fat z score

Interventions to ameliorate changes in body composition
Only one study included an intervention [23]. The intervention (a 6-month programme of supervised, combined resistance and aerobic exercise) significantly improved aerobic fitness, insulin resistance and quality of life, although there were no changes in body composition. The authors concluded that the intervention had a metabolic training effect on muscle. Table 3 presents characteristics and body composition data from the eleven cases reported in the eight case reports/ series [28][29][30][31][32][33][34][35]. Seven had ALL and four AML; ten were female and one male. The cases were followed up an average of 11 years after HSCT. Nine of the eleven cases had GVHD and most had multiple complications/other diagnoses. The data reported in the case reports/series presents a phenotype of lipodystrophy in leukaemic HSCT TBI patients which appears well described. All the cases were under-or normal weight based on their BMI (range 12.2 to 23.1) but showed clinical evidence of lipodystrophy with reduced fat in the limbs and gluteal region and increased fat centrally and in the face, with abdominal distension. Dyslipidaemia was noted in many cases, with elevated fasting triglycerides of between 332 and 927 mg/dL (3.75-10.5 mmol/L) (normal range < 150 mg/dL or < 1.7 mmol/L) but seemingly normal leptin levels of 3.5-7.4 ng/mL (normal range for females 8.8 + SEM 2.10 ng/mL [36]). Only one case report mentioned muscle function (limited range of motion and poor muscle tone); none of the reports mentioned muscle mass changes.

Discussion
This review has found evidence that following HSCT with TBI as treatment for leukaemia in CTYA before the age of 25 years, there is remodelling of adipose tissue earlier than would be expected for age and an extreme phenotype of overt lipodystrophy. There is also some evidence for frailty and a reduction in muscle effectiveness/bulk/strength. These changes are associated with evidence for metabolic disadvantage which contributes to the risk of cardiovascular disease, particularly as abdominal obesity has been shown to be a risk factor for insulin resistance and impaired glucose tolerance following HSCT [37]. Although the literature is heterogeneous, limiting the conclusions we can draw, other studies of wider populations (not just leukaemia or not all TBI; excluded from our review) confirm this phenotype-for example reduced lean mass/increased fat mass for height in HSCT patients [5], increased abdominal adiposity and hypertriglyceridemia [38] and increased sarcopenia [39].
Although the mechanisms for how HSCT with TBI affects body composition was a not a focus for this review, some studies mentioned factors which may additionally impact on body composition, including GVHD, growth hormone deficiency and cranial radiation. There is a need to understand why the changes in muscle and fat occur following HSCT.

Clinical implications
The 2012 guidelines on screening and preventive practices for long-term survivors of HSCT [40] include recommendations for early treatment of cardiovascular risk factors such as diabetes, hypertension and dyslipidaemia and education and counselling on healthy lifestyle (regular exercise, maintaining healthy weight, no smoking, dietary counselling). Griffith et al. [41] also provide detailed recommendations on the evaluation and management of dyslipidaemia in HSCT patients. Nevertheless, the key issue is whether any interventions can be shown to help mitigate or even reverse the adverse changes to body composition and the apparent link to the cardiometabolic risk.
We only identified one study which tested an intervention [23]; whilst this showed effects on fitness, insulin resistance and quality of life, it did not demonstrate any effects on body composition. Studies on wider populations have found some positive effects for exercise and nutritional supplementation during or after TBI: increased body mass and BMI, partly mediated by an increase in fat-free mass [42]; improved muscular strength and endurance performance [43]; increased fat free mass and decreased body fat [44]; and improved muscle mass [45].
Many conventional weight loss techniques would not be appropriate in this population as patients after HSCT with TBI are not overweight and nonspecific weight loss could exacerbate their situation due to further loss of muscle mass. Although one study demonstrated the feasibility and acceptability of a strength-training intervention for patients undergoing HSCT [46], it is possible that exercise benefits may be limited, due to reduced muscle mass. There is therefore a need to develop innovative interventions to improve the muscle function and metabolic effectiveness of long-term survivors of HSCT with TBI in the CTYA years, perhaps utilizing dietary supplements and targeted forms of physical activity.

Limitations
There are limitations to this review. As a restricted systematic review, the screening of articles was less comprehensive than for a systematic review and there is a chance that eligible papers were excluded. We have included in Online Resource 2 lists of excluded papers. Responses from key authors in the field confirmed that we had identified most relevant studies. Searching only one database may have meant we missed relevant papers. However, this methodology is acceptable for a restricted systematic review, and we also attempted to identify grey literature and did not limit by date or language [15].
This review did not aim to identify potential mechanisms leading to body composition changes, so did not systematically collect data on associations with factors such as GVHD, additional/prior radiotherapy, e.g. to the central nervous system or abdomen, or endocrine status.
Most of the included studies were not designed with body composition as their primary outcome, meaning our final sample covered a very diverse range of study designs and outcomes, making data synthesis difficult. The variation in demographics of the study populations makes it difficult to compare outcome data to population norms.
The studies included also have their own limitations. Studies all used convenience samples, with very little information reported on those who did not volunteer to participate. We are therefore unable to comment on how representative our results are to the general leukaemia HSCT with TBI population. Few studies reported participants' ethnicity or were mostly composed of those with white ethnicities, which is a potential deficiency given that ethnicity can affect body composition and the risk of metabolic disruption when abnormal [47].

Conclusion
This review has found evidence that allogeneic HSCT with TBI for CTYA leukaemia results in remodelling of adipose tissue earlier than is expected for age, with the extreme phenotype of overt lipodystrophy. There is also some evidence for a reduction in muscle effectiveness/bulk/strength. These changes mirror those seen with normal ageing and appear to associate with measures of early cardiovascular morbidity. Innovative interventions are needed to determine if changes in muscle and adipose function and metabolic effectiveness can be reversed/mitigated at any age after HSCT, perhaps utilizing dietary manipulation and/or targeted exercise and activity interventions.