Factors affecting pretransplant muscle strength in allogeneic stem cell transplant candidates prior transplantation.

Introduction

Allogeneic stem cell transplantation (allo-HCT) is a curative therapy for a variety of malign hematopoietic disorders. Although remarkable therapeutic successes due to enhanced treatment techniques and supportive care lead to an improved outcome and even older or comorbid patients can be treated, there is a substantial risk of therapy-related morbidity and mortality [ 1 , 2 ]. Because of the intensive and demanding treatment, the determination of appropriate candidates for allo-HCT is crucial, as is the identification of risk factors that potentially influence the outcome [ 3 ]. It is assumed that physical performance in general is a relevant predictive factor [ 3 ]. Research in this area has primarily focused on pretransplant cardiorespiratory fitness (CRF), showing that CRF is a potentially predictive indicator for symptom burden and mortality in allo-HCT-candidates [ 4 ]. Besides CRF, it has been described that strength performance also appears to be crucial and of prognostic relevance in cancer patients [ 5 , 6 ]. In allo-HCT candidates, it has been revealed that significant muscle weakness and limitations in muscle strength exist during the course of allo-HCT [ 7 – 9 ]. Furthermore, sarcopenia, defined as a loss of muscle mass and muscle strength, has become apparent to be associated with a significantly increased risk of poor outcome in allo-HCT candidates [ 10 – 12 ]. Thus, it is reasonable that muscle strength could be a crucial influencing factor that needs to be investigated more comprehensively in the light of allo-HCT. However, in the existing literature, muscle strength performance has been primarily assessed by hand-held dynamometry and functional testing procedures, whereas gold standard procedures like stationary isokinetic dynamometry have not been applied so far. Within our RCT, aiming to investigate the effects and biological mechanisms of an 1-year exercise intervention on side effects complications and survival in allo-HCT patients during and after transplantation [ 13 ], we assessed muscle strength prior transplantation by using the gold-standard approach of stationary isokinetic dynamometry. Therefore, the aim of this manuscript is to report isokinetic and isometric muscle strength in patients prior allo-HCT and to identify potential influencing factors in a cross-sectional analysis.

Patients and methods

Setting and patients

We analyzed baseline data from 212 allo-HCT patients from the study Physical Exercise Training versus Relaxation in Allogeneic stem cell transplantation (PETRA) [ 13 ]. All patients, scheduled for an allo-HCT at the Heidelberg University Clinic, of age ≥ 18 years and able to understand and follow the study protocol, were eligible for enrollment in the PETRA trial. Exclusion criteria were inability to walk or stand, instable bone lesions, severe neurological deficiencies, severe cardiac or cardiovascular diseases, and severe overall pulmonary insufficiency. Cross-sectional data were obtained prior to admission for allo-HCT. The study has been approved by the ethic committees of the Ethic Committee II of the University of Mannheim (number 2009–349 N-MA) and the Ethic Committee of the University of Heidelberg (number S-021/2011) and is registered at ClinicalTrials.gov ( NCT01374399 ). All patients provide written informed consent.

Determination of the muscle strength

Isokinetic and isometric muscle strength was measured by using the IsoMed 2000-system B-series version (D&R Ferstl GmbH, Hemau, Germany). The reliability and validity of this measurement has been reported in serval studies [ 14 – 16 ], and isometric and isokinetic assessments are considered as gold standard method to measure muscle strength [ 5 ]. Furthermore, it was successfully applied in various cancer populations [ 17 – 20 ]. Our test protocol includes the assessment of the maximal voluntary isometric contraction (MVIC) and the maximal isokinetic peak torque (MIPT) of knee extensors and hip flexors. The measured torques are reported as Newton meter (Nm).

During test protocols, both the subject and the instructor were able to see the strength curve on the monitor. Subjects were given verbal encouragement to generate the highest possible strength. To minimize extraneous body movements, subjects were fixed by straps (thigh, pelvic, torso) and used handlebars during assessment of extensors and flexors of the knee. Each torque artifact resulting from deceleration, which often exceeds the true peak torque, was removed by using a filter; only gravity-corrected data were used for analysis.

Assessment of MVIC

Maximal voluntary isometric contraction (MVIC) was tested bilaterally for knee extensor (angle position 36°) and hip flexor (angle position 33°), which consistently were the strongest angle positions each. Patients were requested to exert maximum force against an insurmountable resistance and to hold it for 6 s.

Assessment of MIPT

Maximal isokinetic peak torque (MIPT) was assessed bilaterally for extensors and flexors of the knee and hip. Range of motion for isokinetic measurements varied from 10° to 90° flexion in the knee (straight leg is 0°) and from 10° to 100° in the hip (straight leg in dorsal position is 0°). Patients were instructed to move the machine arm for 10 repetitions as firmly and as fast as possible in the alternating direction between extension and flexion with constant angular velocity (60°/s). The highest torque value of all cycles at considered joint side was analyzed.

Descriptive and influencing variables for muscle strength

We investigated potentially influencing factors for MVIC and MIPT. Congruent with our previous analysis on cardiorespiratory fitness [ 21 ] these were age, gender, body mass index (BMI), total number of transplantations (allogeneic and autologous, n_Transplantations), number of previous cardiotoxic therapies (n_cardiotox), months between last treatment to allo-HCT (chemotherapies respectively cytostatics, radiotherapies or immunotherapies that were given for the treatment of the specific disease before admission to the allo-HCT) (T_Therapies), the hematopoietic cell transplantation-specific comorbidity index (HCT-CI), physical activity, and hemoglobin levels. Further, we gathered information on primary hematological malignancies and the proportion of myeloid and lymphatic malignancies, Karnofsky Performance Status (KPS), and months between primary diagnoses to allo-HCT (T_Diagnosis).

Potentially influencing variables and clinical data were extracted from patient’s medical records. BMI was calculated as body weight divided by square of height in meters. HCT-CI was determined according to guidelines and separated into low to intermediate risk group (< 3) and high risk group (≥ 3) [ 22 ]. We used a modified version of the SQASH [ 23 ] questionnaire to assess patients self-reported frequency (days per week), duration (hours per day), and intensity (light, moderate, partly vigorous, mainly vigorous) and type of physical activity (walking, cycling, and other exercise/sports activities) in a typical week in the year before diagnosis. The degree of physical activity was operationalized with metabolic equivalent of task (MET). MET hours per week (MET × h/week) were calculated by summing the average of self-reported hours per week spent in walking, cycling, or other physical activities. Hemoglobin (g/dl) level was measured venously on the day of muscle strength assessment. Lastly, we calculated the area under the curve values for hemoglobin levels over the last 3 months prior allo-HCT (Hemoglobin_auc).

Statistical analyses

Clinical and demographic data were reported by descriptive analysis and are reported as mean ± SD and range. Expected muscle strength values were calculated by the formula of Danneskiold-Sam (2009) [ 24 ] for healthy individuals considering age and gender distribution. Muscle strength values were presented as percentiles to illustrate the deviation to the healthy reference collective, whereas the 50th percentile represents the median of the reference sample.

Hemoglobin level over the last 3 months was calculated as area under the curve (AUC) score using the trapezoidal rule [ 25 ]. To identify determinants of muscle strength prior allo-HCT, a multivariate regression analysis was conducted. In consideration of multicollinearity, we aimed to identify the most relevant determinants. The following independent variables were entered into the regression model simultaneously: age, gender, BMI, n_Transplantations, n_Cardiotox, t_Therapies, HCT-CI, physical activity, and Hemoglobin_auc. We chose the muscle strength of the quadriceps muscle as a representative value for loads of activities of daily living. The values of MVIC and MIPT were defined as dependent variable: MVIC Knee and MIPT Knee . Significant level was set at p < 0.05. Data were analyzed using IBM SPSS v. 26 and R version 4.0.

Results

Five hundred forty-four patients were screened, and n = 99 were ineligible for the study due to exclusion criteria (18.2%). From n = 445 (81.8%), eligible patients ( n = 178, 40%) did not participate due to no interest ( n = 94, 52.8%), organizational problems (postponement, no exercise testing capacity available due to short notice admission to allo-HCT; n = 39, 21.9%) and n = 45 (25.3%) because of other reasons. Between 9/2011 and 4/2017, 267 patients were included in the study of whom n = 212 participated in the assessments of MVIC and MIPT. Major reasons for not being able to perform this strength testing can be seen in Fig. 1 . No (serious) adverse events occurred. Fig. 1 Patient flow chart showing the number of patients who were available for muscle strength assessment

Clinical data and demographics of study participants who performed MVIC and MIPT are described in Table 1 . Patients had a mean age of 54.49 ± 11.4 years, and the main diagnosis was acute leukemia (AML, 29.1%). Participants were on average 36.2 ± 48 months after main diagnosis, and 54 patients (25.6%) received one or more previous transplantations. Mean hemoglobin at the day of physical assessment was 11.6 ± 1.9 (g/dl), and hemoglobin level during the last 3 months (Hemoglobin_auc) was 11.3 ± 1.9 (g/dl) and therefore below the normal range. On average, the patients performed the measurements 2.4 ± 7.1 days prior admission to allo-HCT. Table 1 Baseline descriptive data n Mean SD Range Age (yr) at diagnosis 212 54.49 11.4 18–75 Gender, n (%) 212 (100) Males 143 (67.5) Females 69 (32.5) BMI (kg/m 2 ) 212 26.41 4.5 17–45 Diagnosis, n (%) 210 (100) AML 61 (29.1) ALL 12 (5.7) CLL 39 (18.6) MM 24 (11.4) CML/MPS 18 (8.6) MDS 19 (9.1) Other lymphomas 34 (16.2) Other 3 (1.4) Missing 2 (0.9) Time from diagnosis to alloHSCT (month) Missing 210 2 36.2 48.0 1–328 Time between exercise test to admission alloHSCT (days) 212 2.4 7.1 0–47 HCT-CI ( n ) 200 0.91 1.4 0–7 < 3 173 ≥ 3 27 Missing 12 KPS ( n ) 207 91.48 100–70 < 90 23 ≥ 90 184 Missing 5 Hemoglobin value day of testing (g/dl) 212 11.6 1.9 6.8–17.0 Remission status prior alloHSCT (%) 211 (100) CR 75 (35.5) PR 77 (36.5) No CR 55 (26.1) Unknown 4 (1.9) Missing 1 (0.5) Smokers (%) 196 (100) Current 9 (4.2) Ever 68 (32.1) Year before diagnosis 29 (13.7) Never 98 (46.2) Missing 8 (3.8) Time since last therapy (month) 212 2.9 7.5 0–88 Physical activity (MET h/week) Missing 208 4 7.9 15.5 0–99.5 Hemoglobin last 3 months (g/dl) Missing 209 3 11.3 1.9 6.5–15.7 Amount of cardiotoxic agents 210 1.5 1.4 0–9 Number of previous transplantations Received one or more transplantation Missing 211 54 1 0.32 0.6 0–3 N Newton, n number of patients, BMI body mass index, HCT-CI comorbidity index by Sorror, KPS Karnofsky Performance Status, allo-HCT allogeneic stem cell transplantation, CR complete remission, PR partial remission, AML acute myeloid leukemia, ALL acute lymphocytic leukemia, MM multiple myeloma, CML chronic myeloid leukemia, MPS myeloproliferative syndrome, MDS myelodysplastic syndrome

Description of muscle strength values for MVIC

Muscle strength assessments demonstrated mean values for MVIC Knee ( n = 212) of 159.7 ± 48.3 Nm. Men ( n = 143) reached 178.4 ± 45.6 Nm, whereas 120.9 ± 25.6 Nm were measured for the women ( n = 69). Mean values for MVIC Hip ( n = 203) were 129.72 ± 44.48 Nm. Men ( n = 140) had values of 143.82 ± 43.2 Nm, and women ( n = 63) achieved values of 92.36 ± 28.56 Nm.

Description of muscle strength values for MIPT

For MIPT Knee , we obtained mean values of 118.6 ± 40.3 Nm ( n = 211) and a coefficient of variance (CV) of 34%, with males ( n = 143) reaching 134.0 ± 40.3 Nm and females ( n = 68) achieving 86.7 ± 20.7 Nm. MIPT Hip ( n = 201) measured 100.1 ± 38.81 Nm with a CV of 38.9%. Men ( n = 139) obtained values of 110.54 ± 37.1 Nm and women ( n = 62) of 76.41 ± 22.7 Nm.

Muscle strength (MVIC and MIPT) in relation to healthy reference values

On average, assessed patients were located between the 37th and 40th reference percentile (MVIC Knee 37.5 ± 30.3, MVIC Hip 39.5 ± 31.3). The proportion of patients below the median (50th percentile) of the reference group is for both MVIC Knee and MVIC Hip at 66%. On average, the reference percentiles results for MIPT Knee were 22.9 ± 26.5, respectively, 22.6 ± 27.4 for MIPT Hip , resulting in a proportion of 84% (MIPT Knee ) and 83% (MIPT Hip ) under the 50th reference percentile.

Figure 2 demonstrates the deviation of the measured MVIC values as percentiles from the calculated healthy reference values depending on (a) male and female gender and for the different (b) age groups. In general, men showed a higher deviation than women in all investigated aspects. Concerning age, the younger patients, in particular < 20 years and 20–29, reveal the higher deviations and seem to be most affected in their physical strength performance. Fig. 2 Reference percentiles of MVIC values for gender ( a ) and age group ( b ) and reference percentiles of MIPT 60°/s values for gender ( c ) and age group ( d ). For ( b ) and ( d ) groups are displayed by age from left (< 20 years) to right (> 70 years). – , median line; ⨁, mean

Figure 2 c and d shows the deviation of the measured MIPT values from the calculated healthy reference values according to the (Fig. 2 c) female and male gender and to the different (Fig. 2 d) age groups. With regard to the muscle groups, the values of “hip” and “knee” demonstrate higher muscle performance of women. Men demonstrate a higher deviation from healthy reference values than women in the hip flexion, whereas the mean values in the knee extension are nearly congruent for both genders. Taking patients’ age into account, all age groups show a strong limitation of performance. Patients with ages < 20 reveal the highest deviation in hip values, but also the ages of 20 and 39 show substantial deviations. Focusing on the knee values, the younger patients between < 20 and the ages of 20 and 29 display the greatest difference compared to their healthy peers.

Factors affecting muscle strength (MVIC Knee and MIPT Knee )

Regression analysis for MVIC Knee with 192 patients providing a full dataset of the integrated variables shows that higher age, female gender, and lower BMI are significant determinants for low MVIC. The explaining variance is 42.3%. The analysis for MIPT Knee reveals that higher age, female gender, lower BMI, and higher HCT-CI are significant factors with an explaining variance of 46.7% (Table 2 ). Table 2 Multiple regression of the determinants of muscle strength: MVIC Knee and MIPT Knee for 60°/s MVIC Knee (Nm) R 2 = 42.3%, n = 192, p = 0.000 β p 95% CI Gender − 0.570 0.000 − 71.220; − 47.308 Age − 0.249 0.000 − 1.564; − 0.562 BMI 0.173 0.004 0.605; 3.137 T_Therapies 0.111 0.072 − 0.104; 2.382 n_cardiotox − 0.109 0.115 − 8.709; 0.954 HCT-CI − 0.091 0.118 − 7.163; 0.814 Physical activity 0.039 0.528 − 0.255; − 0.495 n_Transplantations 0.032 0.638 − 8.222; 13.389 Hemoglobin_auc 0.036 0.546 − 2.152; 4.058 MIPT Knee (Nm) R 2 = 46.7%, n = 191, p = 0.000 β p 95% CI Gender − 0.570 0.000 − 59.023; − 39.810 Age − 0.278 0.000 − 1.388; − 0.0583 BMI 0.174 0.003 − 0.550; 2.574 T_Therapies 0.080 0.177 − 0.311; − 1.677 n_cardiotox − 0.093 0.163 − 6.615; 1.121 HCT-CI − 0.114 0.043 − 6.496; − 0.111 Physical activity 0.070 0.232 − 118; 482 n_Transplantations 0.032 0.625 − 6.493; 10.784 Hemoglobin_auc 0.113 0.052 − 0.018; 4.961 MVIC , maximal voluntary isometric contraction; MIPT , maximal isokinetic peak torque; BMI , body mass index (kg/m 2 ); T_Therapie , months between last treatment to allo-HCT; n_cardiotox , number of previous cardiotoxic therapies; HCT-CI , comorbidity index by Sorror; n_Transplantations , total number of transplantations; CI , confidence interval; physical activity (MET); Hemoglobin_auc , hemoglobin levels over the last 3 months (g/dl) prior allo-HCT; Nm , Newton meter

Factors affecting muscle strength deviation in comparison to reference values (MVIC Knee and MIPT Knee )

Regression analysis for MVIC Knee with 177 patients shows that lower BMI and the HCT-CI were significant determinants for low MVIC. The explained variance ( R 2) was 13.1%. Analysis for MIPT Knee reveals also that lower BMI values and higher HCT-CI values were significantly explaining factors with an overall R 2 19.3% (Table 3 ). Table 3 Multiple regression of the determinants of muscle strength deviation from reference values: MVIC Knee and MIPT Knee for 60°/s MVIC Knee (Nm) R 2 = 13.1%, n = 177, p = 0.005 β p 95% CI Gender − 0.043 0.583 − 71.220; − 47.308 Age 0.129 0.096 − 1.564; − 0.562 BMI 0.165 0.033 0.605; 3.137 T_Therapies 0.151 0.071 − 0.104; 2.382 n_cardiotox − 0.117 0.204 − 8.709; 0.954 HCT-CI − 0.160 0.033 − 7.163; 0.814 Physical activity − 0.034 0.675 − 0.255; − 0.495 n_Transplantations 0.129 0.155 − 8.222; 13.389 Hemoglobin_auc 0.056 0.477 − 2.152; 4.058 MIPT Knee (Nm) R 2 = 19.3%, n = 184, p = 0.000 β p 95% CI Gender 0.134 0.059 − 59.023; − 39.810 Age 0.124 0.053 − 1.388; − 0.0583 BMI 0.224 0.002 0.550; 2.574 T_Therapies 0.076 0.305 − 0.311; − 1.677 n_cardiotox − 0.128 0.136 − 6.615; 1.121 HCT-CI − 0.167 0.019 − 6.496; − 0.111 Physical activity 0.107 0.151 − 118; 482 n_Transplantations 0.003 0.937 − 6.493; 10.784 Hemoglobin_auc 0.135 0.066 − 0.018; 4.961 MVIC , maximal voluntary isometric contraction; MIPT , maximal isokinetic peak torque; BMI , body mass index (kg/m 2 ); T_Therapie , months between last treatment to allo-HCT; n_cardiotox , number of previous cardiotoxic therapies; HCT-CI , comorbidity index by Sorror; n_Transplantations , total number of transplantations; CI , confidence interval; physical activity (MET); Hemoglobin_auc , hemoglobin levels over the last 3 months (g/dl) prior allo-HCT; Nm , Newton meter

Muscle strength in various subgroups

Table 4 shows descriptive muscle strength values for MVIC Knee/kg and MIPT Knee/kg MVIC Knee and MIPT Knee for 60°/s. for various clinical parameters. Overall, no distinctive subgroups could be identified, but slight tendencies can be depicted. Table 4 Muscle strength performance values for clinical subgroups Variable ( n MVIC, n MIPT) MVIC Knee/kg (Nm) Mean ± SD MIPT Knee/kg (Nm) Mean ± SD MVIC Knee (Nm) Mean ± SD MIPT Knee (Nm) Mean ± SD Diagnosis AML ( n = 61) 1.99 ± 0.49 1.49 ± 0.41 156.9 ± 47.2 118.1 ± 40.2 ALL ( n = 12) 1.91 ± 0.54 1.28 ± 0.28 136.5 ± 45.2 95.6 ± 28.4 CLL ( n = 39) 2.01 ± 0.45 1.52 ± 0.41 161.9 ± 42.1 123.4 ± 39.2 MM ( n = 24) 1.84 ± 0.64 1.35 ± 0.45 159.4 ± 60.8 117.3 ± 42.4 CML/MPS ( n = 18, n = 17) 2.22 ± 0.39 1.58 ± 0.27 172.7 ± 37.5 126.3 ± 32.5 MDS ( n = 19) 1.88 ± 0.53 1.31 ± 0.38 156.8 ± 52.8 108.4 ± 36.3 Other lymphomas ( n = 34) 2.08 ± 0.51 1.57 ± 0.57 164.2 ± 52.5 124.9 ± 47.3 Other ( n = 3) 1.66 ± 0.25 1.07 ± 0.29 137.5 ± 30.1 87.5 ± 21.1 Malignancy Myeloid ( n = 101) 2.01 ± 0.49 1.47 ± 0.38 158.8 ± 46.8 116.7 ± 38.0 Lymphatic ( n = 109) 1.98 ± 0.52 1.48 ± 0.44 160.5 ± 49.9 120.5 ± 42.2 Missing ( n = 2) Received no prior transplantation ( n = 157, n = 156) 1.98 ± 0.48 1.46 ± 0.41 158.7 ± 45.4 117.6 ± 38.6 Received one or more prior transplantations ( n = 54) 2.02 ± 0.58 1.51 ± 0.44 161.3 ± 56.3 120.7 ± 44.9 KPS 100% ( n = 73) 2.07 ± 0.57 1.56 ± 0.47 160.3 ± 52.6 120.2 ± 44.1 90% ( n = 111) 1.97 ± 0.46 1.46 ± 0.37 159.2 ± 44.7 118.8 ± 37.1 80% ( n = 22) 1.80 ± 0.45 1.23 ± 0.32 162.2 ± 52.9 110.3 ± 8.3 ≤ 70% ( n = 1) 2.12 ± 0 1.41 ± 0 141.1 ± 0 94.2 ± 0 Missing ( n = 5) HCT-CI < 3 ( n = 173, n = 172) 1.99 ± 0.51 1.49 ± 0.42 159.9 ± 49.6 120.3 ± 41.2 ≥ 3 ( n = 27, n = 27) 1.98 ± 0.42 1.42 ± 0.37 158.5 ± 44.9 112.5 ± 35.5 Missing ( n = 12, n = 13) T_Therapy < 3 months ( n = 163, n = 162) 2.00 ± 0.48 1.46 ± 0.39 160.5 ± 45.8 118.3 ± 38.4 3–6 months ( n = 38) 1.93 ± 0.55 1.49 ± 0.46 157.6 ± 58.1 121.6 ± 47.3 > 6 months ( n = 14) 2.00 ± 0.63 1.45 ± 0.54 164.5 ± 58.7 122.6 ± 48.2 Missing ( n = 1, n = 2) T_Diagnosis ≤ 6 months ( n = 73, n = 72) 1.96 ± 0.53 1.42 ± 0.42 154.4 ± 46.7 113.6 ± 40.4 ≥ 7 months ( n = 137) 2.01 ± 0.49 1.50 ± 0.41 161.9 ± 49.2 120.8 ± 40.2 Missing ( n = 2, n = 3) Physical activity (MET h/week) < 7.0 ( n = 143) 1.96 ± 0.48 1.44 ± 0.40 156.9 ± 47.7 116.1 ± 39.8 ≥ 7.0 ( n = 65) 2.01 ± 0.54 1.56 ± 0.44 166.3 ± 49.1 125.6 ± 40.6 Missing ( n = 4) Hemoglobin last 3 months ≤ 10 (g/dl) ( n = 67, n = 66) 1.91 ± 0.50 1.39 ± 0.41 147.9 ± 47.5 108.8 ± 37.9 > 10 (g/dl) ( n = 142) 2.03 ± 0.49 1.51 ± 0.46 165.6 ± 47.7 123.3 ± 40.3 Missing ( n = 3, n = 4) Nm , Newton meter; n , number of patients; BMI , body mass index; HCT-CI , comorbidity index by Sorror; KPS , Karnofsky Performance Status; allo-HCT , allogeneic stem cell transplantation; AML , acute myeloid leukemia; ALL , acute lymphocytic leukemia; MM , multiple myeloma; CML , chronic myeloid leukemia; MPS , myeloproliferative syndrome; MDS , myelodysplastic syndrome; MVIC , maximal voluntary isometric contraction; MIPT , maximal isokinetic peak torque; MET , metabolic equivalent of task; T_Therapie , months between last therapy to allo-HCT; T_Diagnosis , months between last therapy to allo-HCT

Discussion

Muscle function and performance in patients prior allo-HCT is considerably low. Our analysis in patients prior allo-HCT shows that two-third (66%) of the population have MVIC-values below the 50th percentile of the healthy reference group. Further, a considerable proportion of 84% for MIPT Knee and 83% for MIPT Hip are below the 50th percentile of the healthy reference group. Identified determinates for lower muscle strength were older age, lower BMI, being a women, and having a higher comorbidity-index (HCT-CI). Compared to the healthy reference values, sub-group analyses showed that patients with younger age and male gender possess highest deviations when comparing to other gender/age subgroups.

A few studies in the past have examined muscle strength in hematologic patients, including allo-HCT candidates demonstrated impaired muscle strength and function [ 8 , 11 ]. Studies have shown significant respiratory and skeletal muscle weakness in patients after [ 7 , 9 ] and prior allo-HCT treatment [ 8 ]. In comparison with reference values, significantly reduced muscle strength of the knee extensors assessed by handheld dynamometry were observed prior allo-HCT [ 26 ]. In addition to the muscle strength-based findings, it has been well described that cardiorespiratory fitness in allo-HCT candidates [ 4 , 21 , 27 ] is also significantly impaired prior transplantation showing the general physical deconditioning of allo-HCT candidates.

Compared to other cancer populations where stationary dynamometry has been applied, MVIC values in knee extensors, as a representative indicator muscle group for the locomotor function and for daily functional tasks [ 28 ], were higher than those of pancreatic cancer patients [ 29 ] (mean MVIC Knee 159.7 Nm vs. 141.3 Nm respective 125.7 Nm). Similar results were reported for the MVIC for the hip flexors. With regard to the MIPT values, the results of our allo-HCT patients were also slightly higher [ 30 ]. When compared to breast cancer patients, our female subsample showed lower MVIC values of knee extensors, whereas the MIPT values are comparable or slightly higher depending on the treatment [ 17 ].

Presumably, there are multicausal reasons associated with reduced muscle strength in cancer patients and particular in allo-HCT transplant candidates. To explore the relevance of different potential reasons associated with muscle strength performance, we conducted a regression analysis for MIPT/MVIC of knee muscles. In general, the variance explaining characters of the different variables were comparable between models, showing same trends with small differences.

It is conceivable that various anti-cancer treatments (e.g., doxorubicin) and their adverse side effects negatively impact muscle mass and function [ 31 ]. Although we were not able to significantly detect this association within our regression analysis, some variables (time since last chemotherapy treatment and number of cardiotoxic treatment) showed borderline results, biologically plausible pathways have been reported, and findings from preclinical studies do exist [ 31 ]. Findings could be amplified by the fact that physical inactivity and inactivity increasing side effects are prevalent in cancer populations, further increasing the risk of degeneration of the locomotor muscles [ 32 , 33 ]. As an example associations between impairments in contractile strength, muscle function, muscle power, and cancer-related fatigue with physical inactivity have been largely demonstrated [ 33 ]. The result is a vicious circle [ 34 ] in which it becomes increasingly difficult to perform activities of daily living.

With regard to gender differences, not surprisingly, our regression model showed that the values of the female gender are significantly lower. However, the deviation from the reference values indicates that men have considerably lower muscle strength than women. This finding is supported by observations that sarcopenia was more prevalent in men before allo-HCT [ 35 ].

A further possible reason for lower MVIC and MIPT could be related to hemodynamics respectively reduced hemoglobin levels. Kirkham and colleagues were able to show that muscle blood flow and O 2 extraction adapt to compensate for chemotherapy-induced hemoglobin reduction during exercise with small muscle mass, but are not sufficient with large muscle mass [ 36 ]. In our analyses, hemoglobin was a marginally non-significant explaining factor of muscle strength for MIPT. Our descriptive report furthermore reveals a remarkable deviation in muscle strength, in the group with lower hemoglobin values (hemoglobin value MVIC − 11.9% and hemoglobin value MIPT − 13.3%) compared to those with higher hemoglobin values.

Our regression model did not show a significant influence of cardiotoxic treatment, as we could demonstrate for CRF [ 21 ]. Presumably, the reason for that is the nature of maximum strength testing procedure, only requiring short term local metabolic resources in comparison to CRF testing protocol [ 21 , 27 ]. However, there is also evidence for a negative impact on the skeletal muscle due to cardiotoxic therapies [ 37 ] as well as glucocorticoid-induced myopathy [ 38 , 39 ] and the general negative impact on muscle function of prior chemotherapies [ 40 ].

Significant influence was shown for higher age on lower muscle strength values. This is in line with observations, that muscle strength levels decrease with age. However, our results showed that the deviation from the healthy reference values was associated with patient age in that way and that younger patients were more affected by muscle strength loss than older patients. This is in line with the findings that an increasing proportion of older patients are eligible for allo-HCT and not only the age but possibly also the muscle strength status is crucial [ 10 ]. With increasing age, the higher prevalence comorbidities could also impact physical functioning of HCT patients [ 41 ]. This can be also seen in our regression models with the comorbidity index HCT-CI becoming a significant variance explaining character for MVIC knee .

It has been shown that sarcopenia and the loss of muscle mass as well as low muscle strength, with special emphasis on low knee extensor muscle strength values to predict overall survival and non-relapse mortality after transplantation [ 11 ], is associated with risk for treatment-related complications and poor prognosis in patients undergoing allo-HCT treatment [ 10 , 11 , 42 , 43 ]. Furthermore, we are able to show that lower BMI values are predictive of lower muscle strength. This relationship is obvious on the one hand, but on the other hand, there is an association between low pretransplant BMI and poor clinical outcome after allo-HCT [ 44 ].

Based on the clinically relevant associations of muscle mass/function and prognosis after allo-HCT as well as our finding that muscle function seems to be generally impaired prior transplant, the revealed parameters in the regression analysis can be used for early identification and detection of patients with the goal to modify this risk parameter via interventions aiming to increase muscle mass.

First studies investigating so-called prehabilitative exercise interventions before allo-HCT already exist, demonstrating the feasibility of such approaches; however, larger RCTs are warranted to build robust knowledge on the effectivity of such approaches [ 45 , 46 ].

A central strength of our study is the large sample of allo-HCT patients being investigated using gold standard muscle strength assessment procedures, limited by the factor of retrospective data collection obtained from available patient medical records. Furthermore, subgroup analyses of primary diagnosis were not adequately powered, and further studies are needed to provide specific estimation for high-risk patients of allo-HCT.

In conclusion, by applying gold standard assessment procedures, we were able to quantify in a rather large sample that muscle strength values are remarkably reduced directly prior allo-HCT. We can contribute to the existing knowledge that younger patients with male gender, lower hemoglobin-levels, and comorbidity burden are particularly affected by muscle impairments. Our data supports the approach of integration of early exercise programs (prehabilitation) to prepare for allo-HCT. However, more research is needed on further (clinical) factors playing a role in risk stratification prior allo-HCT and that may be influenced by physical exercise.

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Acknowledgements

This work was supported by the Deutsche José Carreras Leukämie Stiftung e.V. (project no. R10/42pf and R13/27).

Author contribution

M.L.: collected data, statistical analysis, drafting the main manuscript text

R.K.: collected data, critical review of the manuscript,

M.K.: critical review of the manuscript, statistical analysis.

P.D.: provision of study materials or patients, critical review of the manuscript.

T.L.: provision of study materials or patients, critical review of the manuscript.

M.B. conception and design of the study, critical review of the manuscript.

J.W.: conception and design of the study, provision of study materials or patients, statistical analysis, critical review of the manuscript.

All authors reviewed the manuscript and approved the submitted version.

Funding

Open Access funding enabled and organized by Projekt DEAL. This work was supported by the Deutsche José Carreras Leukämie Stiftung e.V. (project no. R10/42pf and R13/27). Date of registration: June 16, 2011.

Data availability

No datasets were generated or analyzed during the current study.

Code availability

Not applicable.

Declarations

Ethics approval

This study was performed in line with the principles of Declaration of Helsinki. The study has been approved by the ethic committees of the Ethic Committee II of the University of Mannheim (number 2009–349 N-MA) and the Ethic Committee of the University of Heidelberg (number S-021/2011) and is registered at ClinicalTrials.gov ( NCT01374399 ).

Consent to participate

All patients provide written informed consent for study participation.

Consent for publication

All patients provide written informed consent for publication.

Competing interests

The authors declare no competing interests.

References

1. Henig I Zuckerman T Hematopoietic stem cell transplantation-50 years of evolution and future perspectives Rambam Maimonides Med J 2014 5 4 e0028 10.5041/rmmj.10162 25386344 PMC4222417 Henig I, Zuckerman T (2014) Hematopoietic stem cell transplantation-50 years of evolution and future perspectives. Rambam Maimonides Med J 5(4):e0028. 10.5041/rmmj.10162 25386344 10.5041/RMMJ.10162 PMC4222417

2. Styczyński J Tridello G Koster L Iacobelli S van Biezen A van der Werf S Mikulska M Gil L Cordonnier C Ljungman P Averbuch D Cesaro S de la Camara R Baldomero H Bader P Basak G Bonini C Duarte R Dufour C Kuball J Lankester A Montoto S Nagler A Snowden JA Kröger N Mohty M Gratwohl A Death after hematopoietic stem cell transplantation: changes over calendar year time, infections and associated factors Bone Marrow Transplant 2020 55 1 126 136 10.1038/s41409-019-0624-z 31455899 PMC6957465 Styczyński J, Tridello G, Koster L, Iacobelli S, van Biezen A, van der Werf S, Mikulska M, Gil L, Cordonnier C, Ljungman P, Averbuch D, Cesaro S, de la Camara R, Baldomero H, Bader P, Basak G, Bonini C, Duarte R, Dufour C, Kuball J, Lankester A, Montoto S, Nagler A, Snowden JA, Kröger N, Mohty M, Gratwohl A (2020) Death after hematopoietic stem cell transplantation: changes over calendar year time, infections and associated factors. Bone Marrow Transplant 55(1):126–136. 10.1038/s41409-019-0624-z 31455899 10.1038/s41409-019-0624-z PMC6957465

3. Deeg HJ Sandmaier BM Who is fit for allogeneic transplantation? Blood 2010 116 23 4762 4770 10.1182/blood-2010-07-259358 20702782 PMC3253743 Deeg HJ, Sandmaier BM (2010) Who is fit for allogeneic transplantation? Blood 116(23):4762–4770. 10.1182/blood-2010-07-259358 20702782 10.1182/blood-2010-07-259358 PMC3253743

4. Wood WA Deal AM Reeve BB Abernethy AP Basch E Mitchell SA Shatten C Hie Kim Y Whitley J Serody JS Shea T Battaglini C Cardiopulmonary fitness in patients undergoing hematopoietic SCT: a pilot study Bone Marrow Transplant 2013 48 10 1342 1349 10.1038/bmt.2013.58 23584437 Wood WA, Deal AM, Reeve BB, Abernethy AP, Basch E, Mitchell SA, Shatten C, Hie Kim Y, Whitley J, Serody JS, Shea T, Battaglini C (2013) Cardiopulmonary fitness in patients undergoing hematopoietic SCT: a pilot study. Bone Marrow Transplant 48(10):1342–1349. 10.1038/bmt.2013.58 23584437 10.1038/bmt.2013.58

5. Christensen JF Jones LW Andersen JL Daugaard G Rorth M Hojman P Muscle dysfunction in cancer patients Ann Oncol : Off J Eur Soc Med Oncol / ESMO 2014 25 5 947 958 10.1093/annonc/mdt551 24401927 Christensen JF, Jones LW, Andersen JL, Daugaard G, Rorth M, Hojman P (2014) Muscle dysfunction in cancer patients. Ann Oncol : Off J Eur Soc Med Oncol / ESMO 25(5):947–958. 10.1093/annonc/mdt551 10.1093/annonc/mdt551 24401927

6. Fairman CM Lønbro S Cardaci TD VanderVeen BN Nilsen TS Murphy AE Muscle wasting in cancer: opportunities and challenges for exercise in clinical cancer trials JCSM rapid Commun 2022 5 1 52 67 10.1002/rco2.56 36118249 PMC9481195 Fairman CM, Lønbro S, Cardaci TD, VanderVeen BN, Nilsen TS, Murphy AE (2022) Muscle wasting in cancer: opportunities and challenges for exercise in clinical cancer trials. JCSM rapid Commun 5(1):52–67. 10.1002/rco2.56 36118249 10.1002/rco2.56 PMC9481195

7. Kovalszki A Schumaker GL Klein A Terrin N White AC Reduced respiratory and skeletal muscle strength in survivors of sibling or unrelated donor hematopoietic stem cell transplantation Bone Marrow Transplant 2008 41 11 965 969 10.1038/bmt.2008.15 18264142 Kovalszki A, Schumaker GL, Klein A, Terrin N, White AC (2008) Reduced respiratory and skeletal muscle strength in survivors of sibling or unrelated donor hematopoietic stem cell transplantation. Bone Marrow Transplant 41(11):965–969. 10.1038/bmt.2008.15 18264142 10.1038/bmt.2008.15

8. White AC Terrin N Miller KB Ryan HF Impaired respiratory and skeletal muscle strength in patients prior to hematopoietic stem-cell transplantation Chest 2005 128 1 145 152 10.1378/chest.128.1.145 16002928 White AC, Terrin N, Miller KB, Ryan HF (2005) Impaired respiratory and skeletal muscle strength in patients prior to hematopoietic stem-cell transplantation. Chest 128(1):145–152. 10.1378/chest.128.1.145 16002928 10.1378/chest.128.1.145

9. Schulz SVW Bizjak DA Moebes E John L Wais V Bunjes D Sala E Steinacker JM Kirsten J Monitoring of strength, inflammation and muscle function in allogenic stem-cell transplantation patients - a pilot study for novel biomarker and risk stratification determination Front Immunol 2023 14 1129687 10.3389/fimmu.2023.1129687 37256146 PMC10225503 Schulz SVW, Bizjak DA, Moebes E, John L, Wais V, Bunjes D, Sala E, Steinacker JM, Kirsten J (2023) Monitoring of strength, inflammation and muscle function in allogenic stem-cell transplantation patients - a pilot study for novel biomarker and risk stratification determination. Front Immunol 14:1129687. 10.3389/fimmu.2023.1129687 37256146 10.3389/fimmu.2023.1129687 PMC10225503

10. Kirsten J Wais V Schulz SVW Sala E Treff G Bunjes D Steinacker JM Sarcopenia screening allows identifying high-risk patients for allogenic stem cell transplantation Cancers 2021 13 8 1771 10.3390/cancers13081771 33917738 PMC8068111 Kirsten J, Wais V, Schulz SVW, Sala E, Treff G, Bunjes D, Steinacker JM (2021) Sarcopenia screening allows identifying high-risk patients for allogenic stem cell transplantation. Cancers 13(8):1771. 10.3390/cancers13081771 33917738 10.3390/cancers13081771 PMC8068111

11. Kondo S Kagawa K Saito T Oura M Sogabe K Harada T Fujii S Nakamura S Miki H Sato N Ono R Abe M Katoh S Allogeneic haematopoietic stem cell transplantation-clinical outcomes: impact of leg muscle strength BMJ Support Palliat Care 2021 10.1136/bmjspcare-2021-003256 34949601 Kondo S, Kagawa K, Saito T, Oura M, Sogabe K, Harada T, Fujii S, Nakamura S, Miki H, Sato N, Ono R, Abe M, Katoh S (2021) Allogeneic haematopoietic stem cell transplantation-clinical outcomes: impact of leg muscle strength. BMJ Support Palliat Care. 10.1136/bmjspcare-2021-003256 34949601 10.1136/bmjspcare-2021-003256

12. Nagayama T Fujiwara SI Kikuchi T Onda K Murahashi R Nakashima H Ikeda T Matsuoka S Kawaguchi SI Toda Y Ito S Ban T Umino K Minakata D Nakano H Yamasaki R Morita K Ashizawa M Yamamoto C Hatano K Sato K Oh I Ohmine K Kanda Y Impact of muscle mass loss assessed by computed tomography on the outcome of allogeneic stem cell transplantation Leuk Lymphoma 2022 63 7 1694 1700 10.1080/10428194.2022.2034159 35156892 Nagayama T, Fujiwara SI, Kikuchi T, Onda K, Murahashi R, Nakashima H, Ikeda T, Matsuoka S, Kawaguchi SI, Toda Y, Ito S, Ban T, Umino K, Minakata D, Nakano H, Yamasaki R, Morita K, Ashizawa M, Yamamoto C, Hatano K, Sato K, Oh I, Ohmine K, Kanda Y (2022) Impact of muscle mass loss assessed by computed tomography on the outcome of allogeneic stem cell transplantation. Leuk Lymphoma 63(7):1694–1700. 10.1080/10428194.2022.2034159 35156892 10.1080/10428194.2022.2034159

13. Wiskemann J Kuehl R Dreger P Huber G Kleindienst N Ulrich CM Bohus M Physical exercise training versus relaxation in allogeneic stem cell transplantation (PETRA Study) - rationale and design of a randomized trial to evaluate a yearlong exercise intervention on overall survival and side-effects after allogeneic stem cell transplantation BMC Cancer 2015 15 1 619 10.1186/s12885-015-1631-0 26345187 PMC4562345 Wiskemann J, Kuehl R, Dreger P, Huber G, Kleindienst N, Ulrich CM, Bohus M (2015) Physical exercise training versus relaxation in allogeneic stem cell transplantation (PETRA Study) - rationale and design of a randomized trial to evaluate a yearlong exercise intervention on overall survival and side-effects after allogeneic stem cell transplantation. BMC Cancer 15(1):619. 10.1186/s12885-015-1631-0 26345187 10.1186/s12885-015-1631-0 PMC4562345

14. Drouin JM Valovich-mcLeod TC Shultz SJ Gansneder BM Perrin DH Reliability and validity of the Biodex system 3 pro isokinetic dynamometer velocity, torque and position measurements Eur J Appl Physiol 2004 91 1 22 29 10.1007/s00421-003-0933-0 14508689 Drouin JM, Valovich-mcLeod TC, Shultz SJ, Gansneder BM, Perrin DH (2004) Reliability and validity of the Biodex system 3 pro isokinetic dynamometer velocity, torque and position measurements. Eur J Appl Physiol 91(1):22–29. 10.1007/s00421-003-0933-0 14508689 10.1007/s00421-003-0933-0

15. Eitzen I Hakestad KA Risberg MA Inter- and intrarater reliability of isokinetic thigh muscle strength tests in postmenopausal women with osteopenia Arch Phys Med Rehabil 2012 93 3 420 427 10.1016/j.apmr.2011.10.001 22265342 Eitzen I, Hakestad KA, Risberg MA (2012) Inter- and intrarater reliability of isokinetic thigh muscle strength tests in postmenopausal women with osteopenia. Arch Phys Med Rehabil 93(3):420–427. 10.1016/j.apmr.2011.10.001 22265342 10.1016/j.apmr.2011.10.001

16. Webber SC Porter MM Reliability of ankle isometric, isotonic, and isokinetic strength and power testing in older women Phys Ther 2010 90 8 1165 1175 10.2522/ptj.20090394 20488976 Webber SC, Porter MM (2010) Reliability of ankle isometric, isotonic, and isokinetic strength and power testing in older women. Phys Ther 90(8):1165–1175. 10.2522/ptj.20090394 20488976 10.2522/ptj.20090394

17. Klassen O, Schmidt ME, Ulrich CM, Schneeweiss A, Potthoff K, Steindorf K, Wiskemann J (2017) Muscle strength in breast cancer patients receiving different treatment regimes. J Cachexia Sarcopenia Muscle 8(2):305–316. 10.1002/jcsm.12165 10.1002/jcsm.12165 PMC5377413 27896952

18. Jones LW Mourtzakis M Peters KB Friedman AH West MJ Mabe SK Kraus WE Friedman HS Reardon DA Changes in functional performance measures in adults undergoing chemoradiation for primary malignant glioma: a feasibility study Oncologist 2010 15 6 636 647 10.1634/theoncologist.2009-0265 20484122 PMC3227991 Jones LW, Mourtzakis M, Peters KB, Friedman AH, West MJ, Mabe SK, Kraus WE, Friedman HS, Reardon DA (2010) Changes in functional performance measures in adults undergoing chemoradiation for primary malignant glioma: a feasibility study. Oncologist 15(6):636–647. 10.1634/theoncologist.2009-0265 20484122 10.1634/theoncologist.2009-0265 PMC3227991

19. Kilgour RD Vigano A Trutschnigg B Hornby L Lucar E Bacon SL Morais JA Cancer-related fatigue: the impact of skeletal muscle mass and strength in patients with advanced cancer J Cachexia Sarcopenia Muscle 2010 1 2 177 185 10.1007/s13539-010-0016-0 21475694 PMC3060645 Kilgour RD, Vigano A, Trutschnigg B, Hornby L, Lucar E, Bacon SL, Morais JA (2010) Cancer-related fatigue: the impact of skeletal muscle mass and strength in patients with advanced cancer. J Cachexia Sarcopenia Muscle 1(2):177–185. 10.1007/s13539-010-0016-0 21475694 10.1007/s13539-010-0016-0 PMC3060645

20. Weber MA Krakowski-Roosen H Schröder L Kinscherf R Krix M Kopp-Schneider A Essig M Bachert P Kauczor HU Hildebrandt W Morphology, metabolism, microcirculation, and strength of skeletal muscles in cancer-related cachexia Acta Oncol (Stockholm, Sweden) 2009 48 1 116 124 10.1080/02841860802130001 18607877 Weber MA, Krakowski-Roosen H, Schröder L, Kinscherf R, Krix M, Kopp-Schneider A, Essig M, Bachert P, Kauczor HU, Hildebrandt W (2009) Morphology, metabolism, microcirculation, and strength of skeletal muscles in cancer-related cachexia. Acta Oncol (Stockholm, Sweden) 48(1):116–124. 10.1080/02841860802130001 10.1080/02841860802130001 18607877

21. Limbach M Kuehl R Dreger P Luft T Rosenberger F Kleindienst N Friedmann-Bette B Bondong A Bohus M Wiskemann J Influencing factors of cardiorespiratory fitness in allogeneic stem cell transplant candidates prior to transplantation Support Care Cancer : Off J Multinatl Assoc Support Care Cancer 2021 29 1 359 367 10.1007/s00520-020-05485-y PMC7686174 32367227 Limbach M, Kuehl R, Dreger P, Luft T, Rosenberger F, Kleindienst N, Friedmann-Bette B, Bondong A, Bohus M, Wiskemann J (2021) Influencing factors of cardiorespiratory fitness in allogeneic stem cell transplant candidates prior to transplantation. Support Care Cancer : Off J Multinatl Assoc Support Care Cancer 29(1):359–367. 10.1007/s00520-020-05485-y 10.1007/s00520-020-05485-y PMC7686174 32367227

22. Sorror ML How I assess comorbidities before hematopoietic cell transplantation Blood 2013 121 15 2854 2863 10.1182/blood-2012-09-455063 23355537 PMC3624933 Sorror ML (2013) How I assess comorbidities before hematopoietic cell transplantation. Blood 121(15):2854–2863. 10.1182/blood-2012-09-455063 23355537 10.1182/blood-2012-09-455063 PMC3624933

23. Wendel-Vos GC Schuit AJ Saris WH Kromhout D Reproducibility and relative validity of the short questionnaire to assess health-enhancing physical activity J Clin Epidemiol 2003 56 12 1163 1169 10.1016/s0895-4356(03)00220-8 14680666 Wendel-Vos GC, Schuit AJ, Saris WH, Kromhout D (2003) Reproducibility and relative validity of the short questionnaire to assess health-enhancing physical activity. J Clin Epidemiol 56(12):1163–1169. 10.1016/s0895-4356(03)00220-8 14680666 10.1016/s0895-4356(03)00220-8

24. Danneskiold-Samsoe B Bartels EM Bulow PM Lund H Stockmarr A Holm CC Watjen I Appleyard M Bliddal H Isokinetic and isometric muscle strength in a healthy population with special reference to age and gender Acta Physiol (Oxf) 2009 197 Suppl 673 1 68 10.1111/j.1748-1716.2009.02022.x 19744082 Danneskiold-Samsoe B, Bartels EM, Bulow PM, Lund H, Stockmarr A, Holm CC, Watjen I, Appleyard M, Bliddal H (2009) Isokinetic and isometric muscle strength in a healthy population with special reference to age and gender. Acta Physiol (Oxf) 197(Suppl 673):1–68. 10.1111/j.1748-1716.2009.02022.x 19744082 10.1111/j.1748-1716.2009.02022.x

25. Duh MS Lefebvre P Fastenau J Piech CT Waltzman RJ Assessing the clinical benefits of erythropoietic agents using area under the hemoglobin change curve Oncologist 2005 10 6 438 448 10.1634/theoncologist.10-6-438 15967837 Duh MS, Lefebvre P, Fastenau J, Piech CT, Waltzman RJ (2005) Assessing the clinical benefits of erythropoietic agents using area under the hemoglobin change curve. Oncologist 10(6):438–448. 10.1634/theoncologist.10-6-438 15967837 10.1634/theoncologist.10-6-438

26. Morishita S Kaida K Ikegame K Yoshihara S Taniguchi K Okada M Kodama N Ogawa H Domen K Impaired physiological function and health-related QOL in patients before hematopoietic stem-cell transplantation Support Care Cancer : Off J Multinatl Assoc Support Care Cancer 2012 20 4 821 829 10.1007/s00520-011-1156-2 21479522 Morishita S, Kaida K, Ikegame K, Yoshihara S, Taniguchi K, Okada M, Kodama N, Ogawa H, Domen K (2012) Impaired physiological function and health-related QOL in patients before hematopoietic stem-cell transplantation. Support Care Cancer : Off J Multinatl Assoc Support Care Cancer 20(4):821–829. 10.1007/s00520-011-1156-2 10.1007/s00520-011-1156-2 21479522

27. Kelsey CR Scott JM Lane A Schwitzer E West MJ Thomas S Herndon JE 2nd Michalski MG Horwitz ME Hennig T Jones LW Cardiopulmonary exercise testing prior to myeloablative allo-SCT: a feasibility study Bone Marrow Transplant 2014 49 10 1330 1336 10.1038/bmt.2014.159 25068429 PMC4516174 Kelsey CR, Scott JM, Lane A, Schwitzer E, West MJ, Thomas S, Herndon JE 2nd, Michalski MG, Horwitz ME, Hennig T, Jones LW (2014) Cardiopulmonary exercise testing prior to myeloablative allo-SCT: a feasibility study. Bone Marrow Transplant 49(10):1330–1336. 10.1038/bmt.2014.159 25068429 10.1038/bmt.2014.159 PMC4516174

28. Ploutz-Snyder LL Manini T Ploutz-Snyder RJ Wolf DA Functionally relevant thresholds of quadriceps femoris strength J Gerontol A Biol Sci Med Sci 2002 57 4 B144 152 10.1093/gerona/57.4.b144 11909879 Ploutz-Snyder LL, Manini T, Ploutz-Snyder RJ, Wolf DA (2002) Functionally relevant thresholds of quadriceps femoris strength. J Gerontol A Biol Sci Med Sci 57(4):B144–152. 10.1093/gerona/57.4.b144 11909879 10.1093/gerona/57.4.b144

29. Clauss D Tjaden C Hackert T Schneider L Ulrich CM Wiskemann J Steindorf K Cardiorespiratory fitness and muscle strength in pancreatic cancer patients Support Care Cancer : Off J Multinatl Assoc Support Care Cancer 2017 25 9 2797 2807 10.1007/s00520-017-3694-8 28417202 Clauss D, Tjaden C, Hackert T, Schneider L, Ulrich CM, Wiskemann J, Steindorf K (2017) Cardiorespiratory fitness and muscle strength in pancreatic cancer patients. Support Care Cancer : Off J Multinatl Assoc Support Care Cancer 25(9):2797–2807. 10.1007/s00520-017-3694-8 10.1007/s00520-017-3694-8 28417202

30. Wiskemann J Clauss D Tjaden C Hackert T Schneider L Ulrich CM Steindorf K Progressive resistance training to impact physical fitness and body weight in pancreatic cancer patients: a randomized controlled trial Pancreas 2019 48 2 257 266 10.1097/MPA.0000000000001221 30589829 Wiskemann J, Clauss D, Tjaden C, Hackert T, Schneider L, Ulrich CM, Steindorf K (2019) Progressive resistance training to impact physical fitness and body weight in pancreatic cancer patients: a randomized controlled trial. Pancreas 48(2):257–266. 10.1097/MPA.0000000000001221 30589829 10.1097/MPA.0000000000001221

31. Pedrosa MB Barbosa S Vitorino R Ferreira R Moreira-Gonçalves D Santos LL Chemotherapy-induced molecular changes in skeletal muscle Biomedicines 2023 11 3 905 10.3390/biomedicines11030905 36979884 PMC10045751 Pedrosa MB, Barbosa S, Vitorino R, Ferreira R, Moreira-Gonçalves D, Santos LL (2023) Chemotherapy-induced molecular changes in skeletal muscle. Biomedicines 11(3):905. 10.3390/biomedicines11030905 36979884 10.3390/biomedicines11030905 PMC10045751

32. LeBlanc AD Schneider VS Evans HJ Pientok C Rowe R Spector E Regional changes in muscle mass following 17 weeks of bed rest J Appl Physiol 1992 73 5 2172 2178 10.1152/jappl.1992.73.5.2172 1474100 LeBlanc AD, Schneider VS, Evans HJ, Pientok C, Rowe R, Spector E (1992) Regional changes in muscle mass following 17 weeks of bed rest. J Appl Physiol 73(5):2172–2178. 10.1152/jappl.1992.73.5.2172 1474100 10.1152/jappl.1992.73.5.2172

33. Lakoski SG Eves ND Douglas PS Jones LW Exercise rehabilitation in patients with cancer Nat Rev Clin Oncol 2012 9 5 288 296 10.1038/nrclinonc.2012.27 22392097 PMC3640332 Lakoski SG, Eves ND, Douglas PS, Jones LW (2012) Exercise rehabilitation in patients with cancer. Nat Rev Clin Oncol 9(5):288–296. 10.1038/nrclinonc.2012.27 22392097 10.1038/nrclinonc.2012.27 PMC3640332

34. Aversa Z Costelli P Muscaritoli M Cancer-induced muscle wasting: latest findings in prevention and treatment Ther Adv Med Oncol 2017 9 5 369 382 10.1177/1758834017698643 28529552 PMC5424865 Aversa Z, Costelli P, Muscaritoli M (2017) Cancer-induced muscle wasting: latest findings in prevention and treatment. Ther Adv Med Oncol 9(5):369–382. 10.1177/1758834017698643 28529552 10.1177/1758834017698643 PMC5424865

35. Morishita S Kaida K Tanaka T Itani Y Ikegame K Okada M Ishii S Kodama N Ogawa H Domen K Prevalence of sarcopenia and relevance of body composition, physiological function, fatigue, and health-related quality of life in patients before allogeneic hematopoietic stem cell transplantation Support Care Cancer : Off J Multinatl Assoc Support Care Cancer 2012 20 12 3161 3168 10.1007/s00520-012-1460-5 22526152 Morishita S, Kaida K, Tanaka T, Itani Y, Ikegame K, Okada M, Ishii S, Kodama N, Ogawa H, Domen K (2012) Prevalence of sarcopenia and relevance of body composition, physiological function, fatigue, and health-related quality of life in patients before allogeneic hematopoietic stem cell transplantation. Support Care Cancer : Off J Multinatl Assoc Support Care Cancer 20(12):3161–3168. 10.1007/s00520-012-1460-5 10.1007/s00520-012-1460-5 22526152

36. Kirkham AA Pituskin E Mackey JR Grenier JG Ian Paterson D Haykowsky MJ Thompson RB Longitudinal changes in skeletal muscle metabolism, oxygen uptake, and myosteatosis during cardiotoxic treatment for early-stage breast cancer Oncologist 2022 27 9 e748 e754 10.1093/oncolo/oyac092 35579489 PMC9438914 Kirkham AA, Pituskin E, Mackey JR, Grenier JG, Ian Paterson D, Haykowsky MJ, Thompson RB (2022) Longitudinal changes in skeletal muscle metabolism, oxygen uptake, and myosteatosis during cardiotoxic treatment for early-stage breast cancer. Oncologist 27(9):e748–e754. 10.1093/oncolo/oyac092 35579489 10.1093/oncolo/oyac092 PMC9438914

37. Gouspillou G Scheede-Bergdahl C Spendiff S Vuda M Meehan B Mlynarski H Archer-Lahlou E Sgarioto N Purves-Smith FM Konokhova Y Rak J Chevalier S Taivassalo T Hepple RT Jagoe RT Anthracycline-containing chemotherapy causes long-term impairment of mitochondrial respiration and increased reactive oxygen species release in skeletal muscle Sci Rep 2015 5 8717 10.1038/srep08717 25732599 PMC4346812 Gouspillou G, Scheede-Bergdahl C, Spendiff S, Vuda M, Meehan B, Mlynarski H, Archer-Lahlou E, Sgarioto N, Purves-Smith FM, Konokhova Y, Rak J, Chevalier S, Taivassalo T, Hepple RT, Jagoe RT (2015) Anthracycline-containing chemotherapy causes long-term impairment of mitochondrial respiration and increased reactive oxygen species release in skeletal muscle. Sci Rep 5:8717. 10.1038/srep08717 25732599 10.1038/srep08717 PMC4346812

38 LaPier TK Glucocorticoid-induced muscle atrophy. The role of exercise in treatment and prevention J Cardiopulm Rehabil 1997 17 2 76 84 10.1097/00008483-199703000-00002 9101384 LaPier TK (1997) Glucocorticoid-induced muscle atrophy. The role of exercise in treatment and prevention. J Cardiopulm Rehabil 17(2):76–84. 10.1097/00008483-199703000-00002 9101384 10.1097/00008483-199703000-00002

39. Morishita S Kaida K Yamauchi S Sota K Ishii S Ikegame K Kodama N Ogawa H Domen K Relationship between corticosteroid dose and declines in physical function among allogeneic hematopoietic stem cell transplantation patients Support Care Cancer : Off J Multinatl Assoc Support Care Cancer 2013 21 8 2161 2169 10.1007/s00520-013-1778-7 23475197 Morishita S, Kaida K, Yamauchi S, Sota K, Ishii S, Ikegame K, Kodama N, Ogawa H, Domen K (2013) Relationship between corticosteroid dose and declines in physical function among allogeneic hematopoietic stem cell transplantation patients. Support Care Cancer : Off J Multinatl Assoc Support Care Cancer 21(8):2161–2169. 10.1007/s00520-013-1778-7 10.1007/s00520-013-1778-7 23475197

40. Pin F Couch ME Bonetto A Preservation of muscle mass as a strategy to reduce the toxic effects of cancer chemotherapy on body composition Curr Opin Support Palliat Care 2018 12 4 420 426 10.1097/spc.0000000000000382 30124526 PMC6221433 Pin F, Couch ME, Bonetto A (2018) Preservation of muscle mass as a strategy to reduce the toxic effects of cancer chemotherapy on body composition. Curr Opin Support Palliat Care 12(4):420–426. 10.1097/spc.0000000000000382 30124526 10.1097/SPC.0000000000000382 PMC6221433

41. Extermann M Measurement and impact of comorbidity in older cancer patients Crit Rev Oncol Hematol 2000 35 3 181 200 10.1016/s1040-8428(00)00090-1 10960800 Extermann M (2000) Measurement and impact of comorbidity in older cancer patients. Crit Rev Oncol Hematol 35(3):181–200. 10.1016/s1040-8428(00)00090-1 10960800 10.1016/s1040-8428(00)00090-1

42. Sakatoku K Ito A Tajima K Yamaguchi K Kuno M Aoki N Tanaka T Kurosawa S Inamoto Y Kim SW Fukuda T Prognostic significance of low pre-transplant skeletal muscle mass on survival outcomes in patients undergoing hematopoietic stem cell transplantation Int J Hematol 2020 111 2 267 277 10.1007/s12185-019-02773-0 31713713 Sakatoku K, Ito A, Tajima K, Yamaguchi K, Kuno M, Aoki N, Tanaka T, Kurosawa S, Inamoto Y, Kim SW, Fukuda T (2020) Prognostic significance of low pre-transplant skeletal muscle mass on survival outcomes in patients undergoing hematopoietic stem cell transplantation. Int J Hematol 111(2):267–277. 10.1007/s12185-019-02773-0 31713713 10.1007/s12185-019-02773-0

43. Armenian SH Xiao M Berano Teh J Lee B Chang HA Mascarenhas K Lee S Iukuridze A Xie JJ Scott JM Jones LW Lennie Wong F Forman SJ Nakamura R Impact of sarcopenia on adverse outcomes after allogeneic hematopoietic cell transplantation J Natl Cancer Inst 2019 111 8 837 844 10.1093/jnci/djy231 30951603 PMC6695315 Armenian SH, Xiao M, Berano Teh J, Lee B, Chang HA, Mascarenhas K, Lee S, Iukuridze A, Xie JJ, Scott JM, Jones LW, Lennie Wong F, Forman SJ, Nakamura R (2019) Impact of sarcopenia on adverse outcomes after allogeneic hematopoietic cell transplantation. J Natl Cancer Inst 111(8):837–844. 10.1093/jnci/djy231 30951603 10.1093/jnci/djy231 PMC6695315

44. Fuji S Takano K Mori T Eto T Taniguchi S Ohashi K Sakamaki H Morishima Y Kato K Miyamura K Suzuki R Fukuda T Impact of pretransplant body mass index on the clinical outcome after allogeneic hematopoietic SCT Bone Marrow Transplant 2014 49 12 1505 1512 10.1038/bmt.2014.178 25111511 Fuji S, Takano K, Mori T, Eto T, Taniguchi S, Ohashi K, Sakamaki H, Morishima Y, Kato K, Miyamura K, Suzuki R, Fukuda T (2014) Impact of pretransplant body mass index on the clinical outcome after allogeneic hematopoietic SCT. Bone Marrow Transplant 49(12):1505–1512. 10.1038/bmt.2014.178 25111511 10.1038/bmt.2014.178

45. Kuehl R Feyer J Limbach M Pahl A Stoelzel F Beck H Wegner A Rosenberger F Dreger P Luft T Wiskemann J Prehabilitative high-intensity interval training and resistance exercise in patients prior allogeneic stem cell transplantation Sci Rep 2023 13 1 22069 10.1038/s41598-023-49420-7 38086868 PMC10716116 Kuehl R, Feyer J, Limbach M, Pahl A, Stoelzel F, Beck H, Wegner A, Rosenberger F, Dreger P, Luft T, Wiskemann J (2023) Prehabilitative high-intensity interval training and resistance exercise in patients prior allogeneic stem cell transplantation. Sci Rep 13(1):22069. 10.1038/s41598-023-49420-7 38086868 10.1038/s41598-023-49420-7 PMC10716116

46. Wood WA Weaver M Smith-Ryan AE Hanson ED Shea TC Battaglini CL Lessons learned from a pilot randomized clinical trial of home-based exercise prescription before allogeneic hematopoietic cell transplantation Support Care Cancer : Off J Multinatl Assoc Support Care Cancer 2020 28 11 5291 5298 10.1007/s00520-020-05369-1 PMC7483208 32112353 Wood WA, Weaver M, Smith-Ryan AE, Hanson ED, Shea TC, Battaglini CL (2020) Lessons learned from a pilot randomized clinical trial of home-based exercise prescription before allogeneic hematopoietic cell transplantation. Support Care Cancer : Off J Multinatl Assoc Support Care Cancer 28(11):5291–5298. 10.1007/s00520-020-05369-1 10.1007/s00520-020-05369-1 PMC7483208 32112353