Dr Nan Zhang, Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Yuzhong, Chongqing 400016, P.R. China
*Contributed equally
Phase angle (PhA), as measured by bioelectrical impedance analysis, is an important parameter in nutritional assessment and is highly predictive of clinical outcomes in various diseases; however, there is little research on its use in acute myeloid leukemia (AML). Therefore, the present study was conducted to determine the association between PhA and malnutrition and to clarify the prognostic significance of PhA for progression-free survival (PFS) and overall survival (OS) in adult patients with AML (excluding acute promyelocytic leukemia) who were undergoing chemotherapy. A total of 70 patients with newly diagnosed AML were enrolled. After chemotherapy, the nutritional risk for patients with a reduced baseline PhA increased significantly. Disease progression occurred in 28 patients, of which 23 died, with a median follow-up of 9.3 months. A reduced baseline PhA was associated with poor PFS (7.1 months vs. 11.6 months; P=0.001) and OS (8.2 months vs. 12.1 months; P=0.011). A multivariate analysis revealed that a reduced PhA was an independent risk factor for disease progression (hazard ratio, 3.13; 95% CI, 1.21-8.11; P=0.019). Overall, these results suggested that PhA is an effective and sensitive indicator that may provide important nutritional and prognostic information in patients with AML.
Acute myeloid leukemia (AML) is a group of aggressive heterogeneous malignancies. The backbone of therapy for AML is a combination of cytarabine- and anthracycline-based regimens with hematopoietic stem-cell transplantation (HSCT) for eligible candidates (
It has been confirmed that under- and overweight patients are at an increased risk of complications, non-relapse mortality and shorter overall survival (OS) after chemotherapy and HSCT (
Phase angle (PhA), which is determined by bioelectrical impedance analysis (BIA), indicates the amount and quality of soft tissue. When interpreting PhA in patient populations, a decrease in PhA is due to loss of soft tissue and could be seen as an indicator of nutritional status (
To the best of our knowledge, few studies have evaluated the use of PhA in AML. It has been reported by univariable, but not multivariable analyses, that low baseline PhA is associated with increased incidence of 60-day mortality (
The present study was conducted in the Department of Hematology at the First Affiliated Hospital of Chongqing Medical University (Yuzhong, China) in accordance with the principles of the Declaration of Helsinki (approval no. 2020-589).
A total of 100 patients were enrolled from July 2020 to February 2021. Baseline clinical data, including age and sex, are presented in
All patients with AML (excluding M3) were given the standard 3+7 induction chemotherapy comprising idarubicin (10 mg/m2d) or daunorubicin (60 mg/m2d) on days 1-3 plus cytarabine (Ara-c; 100-200 mg/m2d) on days 1-7. Consolidation chemotherapy consisted of high-dose Ara-c-based regimens (1-3 g/m2 every 12 h) for a 4-week cycle for 3~6 courses. According to disease remission, risk stratification, physical status and economic level, patients could choose whether to undergo HSCT after induction and consolidation chemotherapy.
Anthropometric variables including height (cm) and weight (kg) were measured by doctors. Nutritional Risk Screening 2002 (NRS-2002) system was implemented to screen nutritional risk (
A direct segmental multi-frequency BIA device (InBody S10; InBody Co., Ltd.) was used to determine the values of body composition indicators and PhA at 50 kHz before the initiation of fluid treatment. The participants were instructed not to eat or drink and to avoid strenuous activity for 2 h before BIA testing. The results of the parameter tests were obtained using a standard montage of outer and inner electrodes on the right hand and foot while patients were laid down with parted legs. All measurements were undertaken at the time of initial diagnosis of AML and after completion of therapy. The body composition indicators, including skeletal muscle mass (SMM), soft lean mass (SLM), percentage of body fat, fat-free mass (FFM), body cell mass (BCM), intracellular water (ICW), extracellular water (ECW), total body water (TBW) and mineral and protein contents, were measured and recorded. The parameters of resistance and reactance were determined using an electric alternating current flow of 800 mA and frequencies of 5, 50 and 250 kHz. PhA was calculated using the following equation: PhA (˚)=(arc tangent reactance/resistance) x (180˚/π). Reduced PhA was defined as PhA <5˚ for male or PhA <4.6˚ female patients (
The Kolmogorov-Smirnov test was used to analyze data normality. Normally distributed continuous variables were presented as the mean ± standard deviation, while non-normally distributed variables were presented as the median with upper and lower quartiles. A two-way mixed ANOVA followed by Bonferroni's post hoc test was used for the comparison of normally distributed body composition variables between and within groups. For non-normally distributed body composition variables, a Bonferroni correction after either Wilcoxon signed-rank test or Mann-Whitney U test was used. An unpaired Student's t-test or Mann-Whitney U test was used to analyze the rest of the comparisons. Categorical variables were presented as frequency (proportions) and compared using Chi-square test or Fisher's exact test as appropriate. The Kaplan-Meier method was used to estimate the survival probabilities and the log-rank test was utilized to compare the differences in progression-free survival (PFS) and OS between the patient subgroups. A multivariate analysis was performed by fitting the Cox proportional hazards model to assess the effects of PhA and other characteristics on PFS and OS. PFS was defined as the time from diagnosis to relapse, progression or death from any cause. OS was defined as the time from diagnosis to the date of the last follow-up examination or the date of death from any cause. All statistical analyses were performed using SPSS 21.0 software (IBM Corp.). P<0.05 was considered to indicate a statistically significant difference.
According to the established process of patient selection, 70 patients consented, underwent baseline laboratory and BIA measurements and completed the follow-up. The median age of the patients at diagnosis was 52 years and 50% were males. Of the enrolled patients, 55.7% had intermediate to adverse cytogenetic risk. Due to their financial status and treatment tolerance, only 32.9% of the patients underwent HSCT. At initial diagnosis of AML, 28.6% were at nutritional risk according to the NRS-2002 scoring system and 27.1% had decreased PhA values. The population and basic characteristics of the normal PhA and reduced PhA groups are summarized in
A decrease in body composition parameters from baseline was observed after chemotherapy or HSCT, although statistically significant differences existed only in the reduced PhA group. The post-treatment body composition parameters of the patients with AML with a reduced baseline PhA were significantly lower compared with patients with normal PhA, including TBW, ECW, ICW, protein, fat, SMM, SLM, FFM and BCM (
In total, 28 patients experienced progressive disease (PD), of which 23 deaths occurred at a median observation time of 9.3 months. Of these deaths, 13 were due to progressive AML, three deaths were related to treatment complications following HSCT and 7 patients died of severe infection or acute cerebral hemorrhage secondary to myelosuppression after chemotherapy. All the patients were subjected to survival outcome measurements based on an intention-to-treat analysis.
The 1-year PFS and OS rates of the reduced PhA group were 36.8 and 47.4%, respectively, while those of the normal PhA group were 76.5 and 76.5%, respectively. The PFS and OS rates of the reduced PhA group, estimated by Kaplan-Meier analysis, were shorter compared with those of the patients in the normal PhA group (median PFS: 7.1 months vs. 11.6 months, P=0.001; median OS: 8.2 months vs. 12.1 months, P=0.011) (
Univariate analysis suggested that both PFS (hazard ratio [HR], 3.14; 95%CI], 1.49-6.63; P=0.003) and OS (HR, 2.76; 95% CI, 1.21-6.31, P=0.016) were significantly worse in patients with reduced baseline PhA. Multivariate adjustments for age, BMI, NRS-2002 score, LDH and Cre levels confirmed the prognostic value of PhA in adult patients with AML. A reduced PhA was associated with decreased PFS (HR, 3.13; 95% CI, 1.21-8.11; P=0.019), but it was not a significant predictor of OS (HR, 2.19; 95% CI, 0.76-6.30; P=0.147) (
In the present study, the potential association of PhA, obtained using BIA, with malnutrition and prognosis was explored in adults with newly diagnosed AML who were undergoing chemotherapy. The results demonstrated that chemotherapy caused a reduction in nutrients, such as water, protein, fat and minerals, and that these changes were more pronounced in patients with a reduced baseline PhA. The results also showed that a reduction in the baseline PhA was significantly associated with an increased risk of PD and death in AML. When adjusted for age, BMI, NRS-2002 score, Cre and LDH, the present study revealed a reduced baseline PhA to be a significant predictor of PFS.
Malnutrition is a challenging clinical syndrome in onco-hematology because of its adverse effects on the patients' quality of life and survival (
At the time of the initial AML diagnosis, ~30% of the study population had reduced PhA. PhA has been suggested as an indicator of cellular health, in which higher values reflect higher cellularity, cell membrane integrity and improved cell function; therefore, the reduction in baseline PhA can be attributed to the combination of cell death and the loss of cellular integrity, as well as changes in membrane selective permeability and fluid balance (
Our previous study revealed that the incidence of sarcopenia is associated with chemotherapy of patients with AML, as reflected by body composition changes (
Previous research has confirmed that standardized PhA (sPhA) is an independent prognostic factor for the 2-year OS rate in patients with AML that undergo HSCT (
In 2012, Kyle
Tumor-specific factors, such as cytogenetics and gene mutations and other patient-specific factors, including age and Eastern Cooperative Oncology Group (ECOG) performance status, have been used to create a prognostic scoring system for OS (
The current study has certain limitations. Firstly, a follow-up study with an increased sample size is needed to clarify the impact of PhA on long-term complications and mortality. Secondly, since there were no data to assess the burden of leukemia in the bone marrow, it was not possible to determine whether PhA affects the complete remission status of patients, leading to a worse prognosis.
In summary, the findings of the present study demonstrated that PhA is a reproducible and high-precision indicator that may provide important nutritional and prognostic information in patients with newly diagnosed AML (excluding type M3). An increased risk of PD and death exists in patients with a reduced baseline PhA. Previous studies have suggested that 12 weeks of progressive resistance training may improve PhA, and nutritional support can minimize sarcopenia and increase muscle function in patients with low PhA (
Not applicable.
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
TJ designed the study, recruited patients, collected and analyzed data and drafted the manuscript. YW contributed to data collection and critically reviewed the data analysis and manuscript preparation. NZ and XT contributed to the data analysis and interpretation as well as the critical writing and revision of the manuscript. All authors have read and approved the final manuscript. TJ and XT confirm the authenticity of all the raw data.
The protocols involving patients were approved by the Ethics Committee of the First Affiliated Hospital of Chongqing Medical University (Yuzhong, China; approval no. 2020-589). The patients enrolled in this research provided written informed consent.
Not applicable.
The authors declare that they have no competing interests.
Flow chart of the study design and patient selection criteria. AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; BIA, bioelectrical impedance analysis; HSCT, hematopoietic stem-cell transplantation.
Kaplan-Meier curves for (A) PFS and (B) OS. PFS, progression-free survival; OS, overall survival; PhA, phase angle; HR, hazard ratio; CI, confidence interval.
Comparison of baseline clinical and body composition indicators according to the baseline PhA.
A, Clinical data | ||||
---|---|---|---|---|
Variable | Total (n=70) | Normal PhA group (n=51) | Reduced PhA group (n=19) | P-value |
Age, years | 51.9±14.0 | 49.7±12.8 | 58.0±15.6 | 0.025 |
Sex, male | 35 (50.0%) | 27 (52.9%) | 8 (42.1%) | 0.420 |
BMI, kg/m2 | 22.7±2.8 | 23.2±2.9 | 21.4±2.1 | 0.009 |
SBP, mmHg | 121.0±12.8 | 117.1±11.4 | 113.3±9.0 | 0.647 |
DBP, mmHg | 70.7±9.8 | 70.5±7.3 | 66.8±10.0 | 0.466 |
NRS-2002 score | 0.034 | |||
≥3 | 50 (71.4) | 40 (78.4) | 10 (52.6) | |
<3 | 20 (28.6) | 11 (21.6) | 9 (47.4) | |
B, Laboratory parameters | ||||
Variable | Total (n=70) | Normal PhA group (n=51) | Reduced PhA group (n=19) | P-value |
WBC, 109/l | 10.3 (2.7-37.8) | 13.5 (2.5-44.0) | 14.0 (8.4-286.0) | 0.219 |
Hb, g/l | 74.2±24.3 | 83.5±26.6 | 53.5±24.4 | 0.283 |
Ure, mmol/l | 315 (229-407) | 299 (233-402) | 326 (245-341) | 0.858 |
Cre, µmol/l | 66.7±16.8 | 63.1±14.4 | 75.7±31.9 | 0.085 |
Alb, g/l | 41 (38-44) | 41 (38-43) | 40 (37-56) | 0.196 |
LDH, U/l | 574 (261-1,398) | 404 (182-1,489) | 736 (478-1,646) | 0.093 |
hs-CRP, mg/l | 10.0 (2.3-20.0) | 1.5 (1.0-7.7) | 15.1 (13.5-20.0) | 0.197 |
C, Body composition indicators | ||||
Variable | Total (n=70) | Normal PhA group (n=51) | Reduced PhA group (n=19) | P-value |
TBW, kg | 33.6±5.7 | 34.0±0.9 | 32.3±4.4 | 0.280 |
ECW, kg | 13.0±2.2 | 13.0±2.3 | 13.0±1.9 | 0.992 |
ICW, kg | 19.8 (17.8~22.4) | 21.4 (18.1~23.0) | 19.6 (16.8~21.8) | 0.117 |
Protein, kg | 8.7 (7.7~9.6) | 9.2 (7.8~10.0) | 8.5 (7.3~9.4) | 0.125 |
Fat, kg | 13.1 (9.6~16.4) | 14 (9.7~16.6) | 11.5 (7.1~15.6) | 0.088 |
SMM, kg | 24.3 (21.3~27.1) | 25.9 (21.6~27.8) | 23.5 (20.3~26.3) | 0.121 |
SLM, kg | 43.0±7.3 | 43.7±7.9 | 41.2±5.5 | 0.220 |
PBF, kg | 22.5±7.1 | 23.2±7.0 | 20.6±7.2 | 0.169 |
FFM, kg | 45.6±7.7 | 46.3±8.3 | 43.9±5.8 | 0.246 |
BCM, kg | 29.5±5.1 | 30.2±5.5 | 27.8±3.6 | 0.122 |
PhA, ˚ | 5.4±0.9 | 5.9±0.7 | 4.2±0.6 | 0.001 |
D, Molecular tests | ||||
Variable | Total (n=70) | Normal PhA group (n=51) | Reduced PhA group (n=19) | P-value |
FLT3 | 10 (14.3) | 7 (13.7) | 3 (15.8) | 0.548 |
WT1 | 15 (21.4) | 12 (23.5) | 3 (15.8) | 0.365 |
E, Cytogenetic risk | ||||
Variable | Total (n=70) | Normal PhA group (n=51) | Reduced PhA group (n=19) | P-value |
Risk group | 0.413 | |||
Favorable | 31 (44.3) | 25(49) | 6 (31.6) | |
Intermediate | 14(20) | 9 (17.6) | 5 (26.3) | |
Adverse | 25 (35.7) | 17 (33.3) | 8 (42.1) | |
F, HSCT | ||||
Variable | Total (n=70) | Normal PhA group (n=51) | Reduced PhA group (n=19) | P-value |
Transplant type | 0.308 | |||
Auto-HSCT | 6 (8.6) | 5 (9.8) | 1 (5.3) | |
Allo-HSCT | 17 (24.3) | 10 (19.6) | 7 (36.8) | |
Non-HSCT | 47 (67.1) | 36 (70.6) | 11 (57.9) |
BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; NRS-2002, Nutritional Risk Screening 2002; WBC, white blood cell; Hb, hemoglobin; Ure, urea nitrogen; Cre, creatinine; Alb, albumin; LDH, lactate dehydrogenase; hs-CRP, hypersensitive C-reactive protein; TBW, total body water; ECW, extracellular water; ICW, intra cellular water; SMM, skeletal muscle mass; SLM, soft lean mass; PBF, percentage of body fat; FFM, fat free mass; BCM, body cell mass; PhA, phase angle; FLT3, FMS-like tyrosine kinase 3; WT1, Wilms' tumor antigen 1; HSCT, hematopoietic stem cell transplantation.
Comparison of body composition indicators at the end of therapy according to the baseline PhA.
Variable | Total (n=70) | Normal PhA group (n=51) | Reduced PhA group (n=19) | P-value |
---|---|---|---|---|
TBW, kg | 30.7 (27.9-35.0) | 34.8 (28.9-39.7) | 27.9 (25.4-34.6) |
0.002 |
ECW, kg | 12.1 (10.8-14.0) | 13.6 (11.2-15.1) | 11.2 (10.1-12.8) |
0.005 |
ICW, kg | 19.4±3.8 | 21.1±3.8 | 17.5±2.6 |
0.003 |
Protein, kg | 8.4±1.7 | 9.1±1.7 | 7.6±1.1 |
0.003 |
Fat, kg | 14.8±6.3 | 18.4±7.2 | 11.5±5.1 |
0.008 |
SMM, kg | 23.3±5.0 | 25.6±5.0 | 20.8±3.4 |
0.003 |
SLM, kg | 39.1 (35.7-44.9) | 44.4 (37.0-51.0) | 35.7 (32.5-41.7) |
0.002 |
PBF, kg | 24.9±7.1 | 26.1±7.7 | 22.4±5.1 | 0.062 |
FFM, kg | 41.7 (38.0-47.5) | 47.1 (39.2-54.1) | 38.0 (34.8-44.1) | 0.002 |
BCM, kg | 27.8±5.5 | 30.3±5.5 | 25.1±3.7 |
0.007 |
aP<0.05 vs. baseline levels. TBW, total body water; ECW, extracellular water; ICW, intra cellular water; SMM, skeletal muscle mass; SLM, soft lean mass; PBF, percentage of body fat; FFM, fat free mass; BCM, body cell mass.
Cox proportional hazards model for assessing the association of baseline phase angle with PFS and OS.
Model | PFS [HR (95% CI)] | OS [HR (95% CI)] |
---|---|---|
Univariate | 3.14 (1.49-6.63) |
2.76 (1.21-6.31) |
Multivariate |
3.13 (1.21-8.11) |
2.19 (0.76-6.30) |
aP<0.05;
badjusted for the confounding factors age, BMI, Nutritional Risk Screening 2002 score, creatinine and lactate dehydrogenase. PFS, progression-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval.