Quality of life and symptom burden among hematologic malignancy patients undergoing CAR-T therapy: a cross-sectional study.

Introduction

The advancement of treatment modalities has contributed to the improvement of both survival rates and quality of life in individuals with hematological malignancies 1 , 2 . However, hematological malignancies, including leukemia, lymphoma, and myeloma, continue to pose significant challenges due to their resistant nature and propensity for frequent relapse 3 , 4 . A comprehensive analysis, along with two cross-sectional investigations conducted in Europe, has revealed that patients afflicted with hematological malignancies experience a lower quality of life in comparison to the general population 5 – 7 . The physiological, psychological, and social dimensions significantly impact the quality of life for individuals diagnosed with hematological cancer. Specifically, these patients are prone to experience a higher prevalence of adverse symptoms 8 , including pain 9 , fatigue 10 , and loss of appetite 7 , which subsequently contribute to a deterioration in their functional capabilities 5 . Currently, there is a dearth of knowledge regarding the experiences of hospitalized patients with hematologic cancers, all we know is that symptom burden is amplified during hospitalization and that individuals participating in clinical trials may encounter a further decline in their quality of life 8 .

Chimeric antigen receptor T-cell (CAR-T) therapy, a form of cellular immunotherapy, utilizes genetic engineering techniques to activate T cells and equip them with chimeric antigen receptors (CARS) capable of precisely recognizing and killing tumor cells within the body. Consequently, these modified T cells exhibit heightened efficacy in eliminating malignant tumor cells, thereby offering a promising treatment option for individuals afflicted with relapsed and refractory hematological malignancies 11 . To date, a number of CAR-T therapies have demonstrated remarkable efficacy in managing relapsed/refractory acute lymphoblastic leukemia (ALL), diffuse large B lymphoma (DLBCL), and multiple myeloma (MM). Currently, the primary focus of clinical investigations involving CAR-T patients revolves around assessing efficacy, long-term safety, and the management of toxic and adverse effects 12 .

Clinical trials have demonstrated that a majority of patients encounter significant and potentially life-threatening adverse effects, namely cytokine release syndrome (CRS) and neurotoxicity, subsequent to the administration of CAR-T cell infusion 13 , 14 . These reports suggest that the incidence rates of CRS and neurotoxicity are approximately 92–95% and 11–60%, respectively 15 – 17 . Such complications can substantially compromise the therapeutic effects of CAR T-treatment during hospitalization and exert a profound influence on their overall quality of life (QOL). A qualitative investigation conducted on patients undergoing CAR-T therapy revealed significant impairments in eight domains following treatment, namely social function, emotional function, fatigue, physical function, cognitive function, role function, sleep, and pain/discomfort 18 . Our prior research demonstrated that CAR-T patients experienced compromised mental well-being during their hospitalization post-treatment, with depressive symptoms being particularly severe 19 . Furthermore, the current clinical trials have demonstrated the remarkable efficacy of CAR-T therapy, however, the durability of its effect remains suboptimal 16 , 20 .

The utilization of quality of life as a metric for assessing the effectiveness of anticancer medications is provided by the US Food and Drug Administration 21 . Quality of life encompasses health outcomes in a more comprehensive manner than morbidity or mortality, as it is evaluated from the patient’s standpoint. This metric enables the evaluation of the condition’s impact on the patient’s health and daily activities, and additionally offers valuable prognostic information that cannot be obtained through routine clinical observation 22 . A research investigation conducted on breast cancer patients revealed a significant association between higher quality of life scores and reduced mortality rates as well as a decreased risk of recurrence 23 . Additionally, a separate study focusing on patients with MM identified Psychosocial QOL as an independent prognostic factor for overall survival 24 . Existing literature has extensively examined the detrimental effects of patients’ diminished quality of life on various treatment outcomes, including treatment adherence and their ability to cope with the diagnosis and prognosis 25 . As a result of the limited duration of clinical implementation of CAR-T therapy technology, healthcare professionals have limited experience in providing care for patients undergoing such treatment. Jennifer M. Knight et al. 26 utilized validated tools to assess anxiety, depressive symptoms, fatigue, sleep, and pain in CAR-T patients following infusion. Additionally, they investigated data on neurotoxicity, tryptophan and its metabolites, and serum cytokines. Their research focused on the relationship between kynurenine, a metabolite of CAR-T cell receptors, and patients’ depressive symptoms and neurotoxicity. In a longitudinal study of adult patients with r/r DLBCL, Richard T. Maziarz et al. 27 demonstrated sustained improvements in health-related quality of life (HRQoL) among those achieving complete or partial remission. The study included a detailed analysis of minimal clinically important differences (MCID) across various HRQoL dimensions. However, the authors did not measure or analyze potential contributing factors. Consequently, certain scholars advocate for an accurate assessment of the post-treatment quality of life and its associated factors 28 . Simultaneously, a comprehensive evaluation of post-treatment symptom burden is essential, as it holds significant implications for the management and care of patients during their hospitalization following CAR-T cell infusion 29 .

In summary, this study examined the patient-reported outcomes of individuals diagnosed with hematological malignancies who underwent CAR-T cell therapy during hospitalization. The primary objective was to investigate the self-reported symptom burden and quality of life, and to explore the factors associated with quality of life.

Materials and methods

Participants

Data were collected in the affiliated hospital of Xuzhou Medical University (Xuzhou, China) over a period between October 2019 and April 2021. Patients who have been receiving CAR-T therapy and age 16 years or older were included in the study. Exclusion criteria included patients who received other treatment after CAR-T cells infusion, unable to communicate, physicians rejected and death. A total of 97 patients participated in our voluntary convenience-sampled survey. The flow model diagram of the recruitment process is shown in Fig. 1 .

Fig. 1 The flow model diagram of the recruitment process.

We obtained the informed consents signed by the patients and cooperation of their families. Approval for the study was obtained from the Ethics Committee of the Affiliated Hospital of Xuzhou Medical University (XYFY2019-KL201-01). All methods were performed in accordance with the relevant guidelines and regulations. Patients baseline characteristics were extracted from electronic medical records and obtained by patients’ self-report. Face-to-face questionnaire was administered in week 4 after CAR-T cell infusion.

Patient-reported measures

The Functional Assessment of Cancer Therapy generic scale (FACT-G) 30 was used to assess QOL. The FACT-G contains 27 items that comprise 4 subscales assessing physical, functional, emotional and social well-being. The scale used a 5-point Likert scale, ranging from 0 (not at all) to 4 (very much). High total and subscales scores represented better QOL. The Chinese version of the FACT-G has good reliability and validity and has been applied in a wide range in clinical 31 , 32 .

The Common Terminology Criteria Adverse Events (CTCAE) 33 was used to evaluate the symptom burden of patients after treatment. The latest iteration of this tool, Version 5.0, encompasses a comprehensive checklist of diverse adverse reactions and events. The severity of these adverse effects is assessed through a 5-point scoring system, wherein each adverse effect is assigned a grade ranging from 1 to 5, accompanied by a specific clinical description. Grade 1 signifies a mild adverse effect that is typically asymptomatic and does not necessitate intervention. Grade 2 denotes moderate adverse effects accompanied by clinical symptoms, for which appropriate intervention can be undertaken. Grade 3 indicates more severe adverse reactions that necessitate active intervention. Grade 4 signifies adverse reactions that may potentially endanger life and cause significant harm to the body. A grade 5 adverse effect is defined as resulting in death. It is important to note that not all adverse effects adhere to the grading criteria ranging from 1 to 5. In general, reactions classified as grade 1–2 were deemed to be of low severity, while grade 3–4 reactions were considered severe. The utilization of patient-reported measurements of adverse symptoms in the CTCAE facilitates a more precise evaluation and intervention of diverse adverse symptoms by researchers. This tool and data collection method, as reported by patients, have gained widespread adoption in clinical trial reports 34 . The ASTCT Consensus Grading criteria for CRS and neurotoxicity associated with chimeric antigen receptor T-cell (CAR-T) therapy were employed 35 .

Statistical analysis

Demographic and clinical characteristics were summarized using descriptive statistics, with continuous variables reported as mean ± standard deviation (SD) and categorical variables as frequencies (percentages). Quality of life outcomes were assessed by comparing FACT-G scores between CAR-T patients and general population normative means 36 using one-sample t-tests. For between-group comparisons, we applied appropriate parametric tests (independent Student’s t-tests for two groups, one-way ANOVA for multiple groups) when data met normality and homogeneity of variance assumptions, and non-parametric alternatives (Mann-Whitney U tests) when these assumptions were violated.

For multivariate analysis, multiple linear regressions analysis was performed with the scores of FACT-G and its sub-scales as the dependent variable. Independent variables that had significance on univariate analysis were eligible for inclusion in multivariate analysis.

Two-sided P -value were calculated, and P < 0.05 was considered to indicated a statistically significant difference. Participants with missing data will be excluded from further analysis. Data was analyzed with the SPSS software (version 25.0; SPSS).

Results

Patients characteristics and demographics

In total, 97 patients completed questionnaire, and 20 patients qualified for the study refused to participate. The average age of the patients was 50.5 years old (SD = 14.7), with a percentage of 35.1% women. The average duration of illness was 3.7 years (SD = 2.7). Of 54 (55.7%) patient with multiple myeloma, 1 (1.8%) patients had stage I cancer, 19 (35.2%) had stage II cancer, 34 (63.0%) had stage III cancer. Of 31 (32.0%) patients with lymphoma, 2 (6.5%) had stage II cancer, 10 (32.3%) had stage III cancer, 19 (61.3%) had stage IV cancer. Myeloma and lymphoma staging was reported using the Revised International Staging System 37 and the modified Ann Arbor staging system 38 , respectively. Additionally, 4 and 6 patients were missing data on medical expenditure and monthly household income per capital, respectively. Detailed clinical and demographic characteristics data are presented in Table 1 .

Table 1 CAR-T patients demographic and clinical characteristics. Characteristics No. of patients(%), N = 97 Gender Male 63(64.9) Female 34(35.1) Age, year ≤ 44 27(27.8) 45–59 40(41.3) ≥ 60 30(30.9) Household registration Urban 60(61.9) Rural 37(38.1) Religion No 81(83.5) Yes 16(16.5) Education Junior high school and below 48(49.5) High school and above 49(50.5) Occupation Manual 42(43.3) Non-manual 55(56.7) Marital status Unmarried 19(19.6) Married 78(80.4) Monthly household income per capita, dollors < 450 55(56.7) ≥ 450 36(37.1) Missing 6(6.2) Diagnosis Leukemia 12(12.4) Multiple myeloma 54(55.6) Lymphoma 31(32.0) Duration of illness, year < 2 27(27.8) 2–4 41(42.3) > 4 29(29.9) Medical expenditure, dollors < 45 thousand 35(36.1) ≥ 45 thousand 58(59.8) Missing 4(4.1) Comorbidity No 63(64.9) Yes 34(35.1) History of bone marrow transplant No 80(82.5) Yes 17(17.5)

Symptoms burden

During the period of hospitalization subsequent to CAR-T treatment, the prevalence of self-reported symptoms among CAR-T patients was highest for fatigue (89.7%), followed by sleep disorders (79.4%) and decreased appetite (66.0%). Additional symptoms with an incidence exceeding 20% included pain, cough, dyspepsia, nausea, dyspnea, expectoration, chills, vomiting, constipation, and diarrhea. The occurrence rates of CRS and neurotoxicity associated with CAR-T therapy were 82.4% and 15.4%, respectively. The classification of symptoms and adverse effects can be found in Table 2 .

Table 2 Most symptoms and adverse reactions related to CAR-T therapy (n (%), N = 97). Symptom Any grade Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Fatigue 87(89.7) 35(36.1) 38(39.2) 14(14.4) – – Sleep disturbances 77(79.4) 43(44.3) 24(24.7) 10(10.4) – – Decreased appetite 64(66.0) 29(29.9) 32(33.0) 3(3.1) 0 0 Pain 50(51.5) 22(22.7) 27(27.8) 1(1.0) – – Cough 39(40.2) 28(28.9) 11(11.3) 0 – – Indigestion 32(33.0) 15(15.5) 17(17.5) 0 – – Nausea 27(27.9) 22(22.7) 5(5.2) 0 – – Dyspnea 26(26.8) 11(11.3) 11(11.3) 4(4.2) 0 0 Expectoration 26(26.8) 18(18.6) 8(8.2) 0 – – Chills 22(22.7) 22(22.7) 0 0 – – Constipation 21(21.7) 5(5.2) 15(15.5) 1(1.0) 0 0 Vomiting 21(21.6) 20(20.6) 1(1.0) 0 0 0 Diarrhea 20(20.6) 14(14.4) 5(5.2) 1(1.0) 0 0 Adverse reactions Cytokine release syndrome 80(82.4) 50(51.5) 24(24.7) 4(4.1) 2(2.1) 0 Neurotoxicity 15(15.4) 7(7.2) 4(4.1) 4(4.1) 0 0 -No such grade

Patients-reported quality of life

When week 4 after CAR-T cells infusion, the mean score of FACT-G was 69.06 (SD = 13.88), and the mean scores of physical, functional, emotional and social well-being dimensions of FACT-G were 17.07 (SD = 5.58), 14.18 (SD = 5.57), 18.46 (SD = 4.61), 19.35 (SD = 3.51), respectively. Except social well-being dimension, the total mean scores of FACT-G and each dimension were significantly below the normative means. The comparison of QOL between the means of CAR-T patients scores and normative means are listed in Table 3 .

Table 3 Comparisons of Patients-reported quality of life with population normative means. Scale CAR-T patients score, mean (SD) Normative mean (SD) # P FACT-G total 69.06 (13.88) 80.1 (18.1) < 0.001 Physical well-being 17.07 (5.58) 22.7 (5.4) < 0.001 Functional well-being 14.18 (5.57) 18.5 (6.8) < 0.001 Emotional well-being 18.46 (4.61) 19.9 (4.8) 0.003 Social well-being 19.35 (3.51) 19.1 (6.8) 0.484 FACT-G, The Functional Assessment of Cancer Therapy generic scale (Quality of life). #From literature point estimates.

Univariate analysis of quality of life

Preliminary univariate analysis revealed significant associations between higher medical expenditure, a history of hematopoietic stem cell transplantation (HSCT), fatigue, sleep disorders, decreased appetite, nausea, vomiting, and diarrhea with lower FACT-G total scores. Additionally, higher medical expenditure, a history of HSCT, fatigue, sleep disorders, decreased appetite, pain, nausea, and diarrhea were found to be associated with poorer physical well-being. Higher medical expenditure and experienced cytokine release syndrome, fatigue, sleep disorders, decreased appetite were associated with poorer functional well-being score. Having comorbidity, fatigue, sleep disorders, decreased appetite, nausea and vomiting were associated with poorer emotional well-being score. Expectoration was associated with social well-being score. The results of univariate analysis are listed as F value or t value in Table 4 .

Table 4 Univariate and multivariate analysis of QOL (n (%), N = 97). Independant variable Univariate analysis ¶ Multivariate analysis § PWB FWB EWB SWB FACT-G PWB FWB EWB SWB FACT-G Age NS NS NS NS NS Diagnosis NS NS NS NS NS Duration of illness NS NS NS NS NS Gender NS NS NS NS NS Household registration NS NS NS NS NS Religion NS NS NS NS NS Education NS NS NS NS NS Occupation NS NS NS NS NS Marital status NS NS NS NS NS Monthly household income per capita NS NS NS NS NS Medical expenditure 2.40* 2.04* NS NS 2.62* NS NS NS Comorbidity NS NS -2.13* NS NS NS History of bone marrow transplant 2.57* NS NS NS 2.34* -0.20* -0.21* Cytokine release syndrome NS 2.15* NS NS NS NS Neurotoxicity NS NS NS NS NS Fatigue 6.89 # 4.29* 3.51* NS 6.95 # -0.26* NS -0.26* -0.28 Sleep disturbances 5.16* 10.21 # 4.53* NS 9.69 # NS -0.25* NS NS Decreased appetite 6.71 # 9.25 # 3.98* NS 9.82 # -0.20* -0.31* NS -0.30* Pain 3.73* NS 5.28* NS NS -0.23* Cough NS NS NS NS NS Indigestion NS NS NS NS NS Nausea 7.21* NS 7.27* NS 8.21* -0.23* -0.28* -0.26 Dyspnea NS NS NS NS NS Expectoration NS NS NS 3.11* NS -0.24* Chills NS NS NS NS NS Constipation NS NS NS NS NS Vomiting NS NS 5.37* NS 3.99* NS NS Diarrhea 5.57* NS NS NS 3.59* -0.20* NS ¶ F value or t value. §Standardized β coefficients. * P < 0.05. # P < 0.001.

Associated factors of quality of life

Multiple linear regression analysis demonstrated that decreased appetite ( β = -0.20, 95%CI = -2.38 to -0.05, P = 0.042), diarrhea ( β = -0.20, 95%CI = -3.49 to -0.23, P = 0.026), fatigue ( β = -0.26, 95%CI = -2.81 to -0.54, P = 0.004), nausea ( β = -0.23, 95%CI = -3.90 to -0.50, P = 0.012) and a history of HSCT ( β = -0.20, 95%CI = -5.27 to -0.41, P = 0.023) were associated with poorer physical well-being. Decreased appetite ( β = -0.31, 95%CI = -3.29 to -0.53, P = 0.007) and sleep disorders ( β = -0.25, 95%CI = -2.94 to -0.20, P = 0.025) was associated with poorer functional well-being. Nausea ( β = -0.28, 95%CI = -3.71 to -0.71, P = 0.004), fatigue ( β = -0.26, 95%CI = -2.33 to -0.41, P = 0.005) and pain ( β = -0.23, 95%CI = -2.16 to -0.21, P = 0.018) was associated with poorer emotional well-being, and expectoration ( β = 0.24, 95%CI = -2.47 to -0.26, P = 0.016) was associated with better emotional well-being. Decreased appetite ( β = -0.30, 95%CI = -7.48 to -1.83, P = 0.002), fatigue ( β = -0.28, 95%CI = -7.23– -1.69, P = 0.002), nausea ( β = -0.26, 95%CI = -10.50 to -2.16, P = 0.003) and a history of HSCT ( β = -0.21, 95%CI = -13.38– -1.56, P = 0.014) was associated with poorer quality of life. The results of the multivariate linear regression analysis, with the FACT-G and its sub-scales as dependent variables, are reported as standardized β coefficients in Table 4 .

Discussion

To our knowledge, this investigation constitutes the earliest systematic characterization of quality-of-life (QOL) and symptom burden profiles in CAR-T patients during the first-month post-infusion.

Following the administration of CAR-T cell therapy, a majority of patients encountered treatment-associated adverse reactions, specifically cytokine release syndrome (82.4%) and neurotoxicity (15.4%), aligning with the documented incidence in various CAR-T clinical trials 15 – 17 . The magnitude of symptomatology experienced by cancer patients surpasses that of individuals in good health. Within this investigation, the foremost three self-reported symptoms among CAR-T patients were fatigue, sleep disturbance, and decreased appetite. These primary adverse symptoms were consistent with the findings of Rebecca Cheng et al.‘s qualitative research on CAR-T patients 18 .

Fatigue is widely acknowledged as a prevalent and distressing adverse symptom experienced by patients with hematological cancers, particularly during the administration of diverse treatments 5 , 39 . The reported prevalence rates of fatigue and other associated symptoms differ across studies due to variations in patient cohorts, treatment modalities, and assessment methodologies. In this study, after receiving CAR-T therapy, various biochemical indicators of patients will be greatly deranged, such as hypoalbuminemia, thrombocytopenia, anemia, etc 40 . , and fatigue is closely associated with these hematological indicators 41 . During this time frame, patients commonly experience decreased appetite and reduced food intake, which further exacerbates fatigue due to poor nutritional status 42 . As previously stated, the majority of patients undergoing CAR-T therapy will develop cytokine release syndrome, a significant treatment-related adverse reaction that profoundly affects patients. When patients experience cytokine release syndrome, the primary manifestation is the presence of fever, which tends to be intermittent. In addition, the patient’s sleep quality is also significantly compromised, which exacerbates the symptoms of fatigue. Several studies have indicated that fatigue may serve as a susceptibility, precipitating, and enduring factor for sleep disorders, while sleep disorders themselves can contribute to heightened fatigue levels 43 , 44 . These findings imply the potential existence of a detrimental cycle involving the aforementioned symptoms.

According to a scholarly review 45 , symptoms frequently manifest in groups, a phenomenon that is particularly noticeable among CAR-T patients. The present investigation revealed that all participants experienced two or more symptoms. Several studies 46 , 47 have indicated a potential association between certain inflammatory markers and the severity of symptom burden. Notably, heightened levels of Interleukin-6 (IL-6) have been linked to fatigue, impaired cognitive function, and sleep disorders. Furthermore, a separate investigation conducted on breast cancer patients 48 has demonstrated that the manifestation of numerous symptoms among individuals with cancer can be ascribed to the liberation of proinflammatory factors. Notably, the cytokine release syndrome that arises subsequent to CAR-T cell therapy exhibits a strong correlation with the elevation of IL-6 concentration 49 . Consequently, this association may serve as a key explanation for the heightened symptom burden experienced by CAR-T patients.

However, prior investigations 41 , 50 have suggested that the monitoring of nonspecific patient-reported symptoms is frequently insufficient compared to toxic effects, primarily due to underreporting by patients or underestimation of the symptoms’ significance by healthcare providers. Consequently, it is imperative for clinical medical personnel to actively prioritize and provide suitable symptom management for patients undergoing CAR-T therapy.

In the present study, it was observed that the overall quality of life (QOL) score among CAR-T patients during their hospitalization post-treatment was significantly lower than the standard mean. This is consistent with findings from the prior research conducted on patients with hematological malignancies 9 , and has also been found in the same time point from longitudinal studies involving CAR-T patients 28 , 51 . However, it is important to acknowledge that certain investigations on long-term survivors of hematologic cancers have reported no discernible disparity in the overall QOL when compared to the general population 6 . This discrepancy may be attributed to the fact that the patients included in our study were hospitalized and undergoing treatment. Research findings indicate that patients who undergo hospitalization, receive medical intervention, and experience relapse exhibit a diminished quality of life 5 , 8 . The receipt of medical intervention is correlated with a deterioration in functional capacity, and the prolonged clinical treatment of individuals with hematological malignancies entails enduring lasting impairments 6 .

This study found that CAR-T patients experienced significant impairments in their quality of life in terms of physical well-being, functional well-being, and emotional well-being, aligning with previous research on the quality of life of individuals with hematological cancer 5 , 7 . In contrast to previous studies 6 , the social well-being dimension score of CAR-T patients did not differ significantly from the standard mean, and in fact, was slightly higher, representing a noteworthy finding in this study. Prior to undergoing CAR-T therapy, patients will typically undergo conventional treatments such as chemotherapy and bone marrow transplantation. The prolonged duration of the disease necessitates substantial medical expenses. Furthermore, as previously mentioned, the long-term effectiveness and safety of CAR-T therapy are not highly promising, thereby presenting economic and treatment outcome challenges for patients and their families. In this particular scenario, patients who maintain their intention to undergo CAR-T treatment must adequately equip themselves, a process that is intricately intertwined with the compassionate assistance and financial backing from family members, alongside the nurturing support and motivation from friends.

The findings from the linear regression analysis indicated a significant association between severe symptom burden, encompassing fatigue, sleep disorders, decreased appetite, nausea, and other related symptoms, and the overall quality of life as well as its various dimensions of CAR-T patients. These results align with previous research conducted on individuals with hematological malignancies 52 . Additionally, a qualitative study 53 demonstrated that treatment-related side effects have the potential to adversely impact the quality of life among patients receiving hospital care. In general, patients experience a significant burden of symptoms, resulting in severe impairment of their physical and functional well-beings, ultimately leading to a diminished quality of life. The limitation of mobility can hinder normal social activities, further exacerbating the impact on patients’ quality of life. Additionally, the abrupt escalation in symptom burden may contribute to the development of psychological disorders and adversely affect patients’ mental well-being 54 . Fatigue and sleep disorders can contribute to inadequate rest and physical strength, while symptoms such as decreased appetite, nausea, and vomiting fall within the gastrointestinal symptom cluster. Hence, it is imperative for clinical nursing practice to enhance the provision of sleep care and gastrointestinal care for patients undergoing CAR-T therapy.

The examination revealed a perplexing association between lower QOL scores in the social well-being and expectoration, a phenomenon lacking substantial empirical support. Consequently, further research endeavors are warranted to delve into the intricacies of expectoration and elucidate its underlying nature.

In this study, CAR-T patients who had undergone hematopoietic stem cell transplantation had poor global quality of life and physical well-being. A review of multiple myeloma patients reveals that HSCT negatively affects quality of life and exacerbates symptom burden 55 . This may be attributed to the adverse effects of transplantation therapy, such as immune rejection. Furthermore, the already frail physiological state of patients’ post-transplantation is further compromised when they undergo CAR-T therapy. Consequently, it is imperative for clinical medical staff, to prioritize the care and monitoring of CAR-T patients following HSCT.

Previous studies have confirmed the correlation between acute adverse reactions following treatment and a diminished quality of life 56 . However, the present study did not observe a significant link between treatment-related adverse reactions and quality of life, thereby deviating from the anticipated findings of the study. It has been observed that despite the lack of definitive evidence establishing a causal relationship between the occurrence of adverse reactions and the efficacy of CAR-T treatment 17 , 57 , patients undergoing CAR-T therapy tend to perceive adverse reactions as indicative of the treatment’s effectiveness. This phenomenon necessitates a dialectical examination. On one hand, adverse reactions have the potential to diminish patients’ physical and functional well-being, while on the other hand, they may align with patients’ expectations of effectiveness, thereby bolstering their confidence and instilling hope. In the future, the intricate association between adverse reactions and the quality of life of CAR-T patients will be further explored.

Our study has several limitations. First, the cross-sectional survey of a convenience sample also limits firm conclusions. Second, the analysis did not incorporate alterations in the disease progression among these patients due to limitations in the study design. It is important to note that the disease remission following CAR-T therapy is a dynamic process. Typically, patients enter a “Stable disease” phase approximately one month post-surgery, after which there may be diverse changes, including either further improvement or deterioration leading to mortality 57 . In our study, the measurement point coincided with the fourth week of treatment, rendering accurate determination of response to CAR-T therapy unfeasible. Consequently, we intend to longitudinally monitor the correlation between disease remission and quality of life. Third, it should be noted that the measurement of symptom burden in our study was conducted using the ATCAE rather than a validated scale. While the use of a validated scale, such as the Edmonton Symptom Assessment Scale, may seem more conventional, it could potentially restrict the comprehensive understanding of the symptom burden experienced by CAR-T patients. This is due to the limited number of symptom items included in such scales, which may not encompass the full range of symptoms experienced by CAR-T patients. In contrast, the ATCAE has the capability to measure nearly all symptoms. In future studies, we intend to delve deeper into the investigation of symptom burden among patients. Finally, the heterogeneity of diseases among the patients in this study may impose limitations on the generalizability of the findings. Nonetheless, the data analysis revealed no statistically significant disparity in the quality of life among CAR-T patients with varying diseases.

In conclusion, the symptom burden experienced by patients undergoing CAR-T cell infusion during hospitalization is severe and significantly compromises their quality of life. The prior history of HSCT has a notable impact on the global QOL and physical well-being of CAR-T patients, thus warranting attention from clinical medical staff. It is imperative for nursing professionals to prioritize the management of symptom burden in CAR-T patients and implement effective interventions, particularly in enhancing sleep quality and mitigating gastrointestinal reactions.

FUNDING SUPPORT.

This study was funded by the National Science and Technology Innovation 2030, Noncommunicable Chronic Diseases-National Science and Technology Major Project (Grant No. 2024ZD0524300 and 2024ZD0524305), the Key Projects of the Medical Research Program of Jiangsu Provincial Health Commission. the “3456” Cultivation Program For Junior Talents of Nanjing Stomatological Hospital, Medical School of Nanjing University (0222N404), the National Institute of Hospital Administration (YLZLXZ23G019), the China Association for Mental Health (22-23-72), the Chinese Postdoctoral Science Foundation (2018T110553), the Postdoctoral Science Foundation of Jiangsu Province, Postdoctoral Start-up Funding (2017107002), the Open Project of Jiangsu Province Key Laboratory of Anesthesiology (KJS1801), the Graduate Research and Innovation Projects of Jiangsu Province (KYCX18_2184). These funders had no role in the study design, data collection and analysis, interpretation of data and writing the manuscript.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Hongyuan Dai and Shuya Xu contributed equally to this work.

Author contributions

H.D.: Conception and design of work, data collection and analysis, writing draft. S.X.: Data collection and analysis, writing draft. Z.W.: editing draft. Z.L.: data collection, editing draft, supervision. J.C.: editing draft, supervision. T.H.: data collection, editing draft, supervision. F.Z.: Conception and design of work, writing draft, supervision.

Data availability

The patient data supporting this study cannot be publicly disclosed to protect patient privacy. However, anonymized portions of the data may be made available upon reasonable request from qualified researchers, subject to ethical approval. For inquiries regarding this work or data requests, please contact the first author, Hongyuan Dai, at Dai.hongyuan@outlook.com.

Declarations

Competing interests

The authors declare no competing interests.

References

1. Morabito F Martino EA Nizzoli ME Comparative analysis of bispecific antibodies and CAR T-Cell therapy in follicular Lymphoma[J] Eur. J. Haematol. 2025 114 1 4 16 10.1111/ejh.14335 39462177 PMC11613673 Morabito, F., Martino, E. A. & Nizzoli, M. E. Comparative analysis of bispecific antibodies and CAR T-Cell therapy in follicular lymphoma. Eur. J. Haematol. 114 (1), 4–16. 10.1111/ejh.14335 (2025). 39462177 10.1111/ejh.14335 PMC11613673

2. Shu J Xie W Chen Z The enchanting canvas of CAR technology: unveiling its wonders in non-neoplastic diseases[J] Med. (New York NY) 2024 5 6 495 529 10.1016/j.medj.2024.03.016 38608709 Shu, J., Xie, W. & Chen, Z. The enchanting canvas of CAR technology: Unveiling its wonders in non-neoplastic diseases. Med 5 (6), 495–529. 10.1016/j.medj.2024.03.016 (2024). 10.1016/j.medj.2024.03.016 38608709

3. Vanhooren J Dobbelaere R Derpoorter C CAR-T in the treatment of acute myeloid leukemia: barriers and how to overcome Them[J] HemaSphere 2023 7 9 e937 10.1097/hs9.0000000000000937 37674860 PMC10479376 Vanhooren, J., Dobbelaere, R. & Derpoorter, C. CAR-T in the treatment of acute myeloid leukemia: Barriers and how to overcome them. HemaSphere 7 (9), e937. 10.1097/hs9.0000000000000937 (2023). 37674860 10.1097/HS9.0000000000000937 PMC10479376

4. O'Shea PJ Johnson PC El-Jawahri A Unmet needs and lived experience of patients receiving CAR T-cell therapy[J] Leuk. Lymphoma 2025 10.1080/10428194.2025.2455488 39838695 O’Shea, P. J., Johnson, P. C. & El-Jawahri, A. Unmet needs and lived experience of patients receiving CAR T-cell therapy. Leuk. Lymphoma . 10.1080/10428194.2025.2455488 (2025). 39838695 10.1080/10428194.2025.2455488

5. Allart-Vorelli P Porro B Baguet F Haematological cancer and quality of life: a systematic literature review[J] Blood cancer J. 2015 5 e305 10.1038/bcj.2015.29 25909835 PMC4450328 Allart-Vorelli, P., Porro, B. & Baguet, F. Haematological cancer and quality of life: A systematic literature review. Blood Cancer J. 5 , e305. 10.1038/bcj.2015.29 (2015). 25909835 10.1038/bcj.2015.29 PMC4450328

6. Esser P Kuba K Mehnert A Quality of life in survivors of hematological malignancies stratified by cancer type, time since diagnosis and stem cell transplantation[J] Eur. J. Haematol. 2018 101 3 340 348 10.1111/ejh.13104 29858505 Esser, P., Kuba, K. & Mehnert, A. Quality of life in survivors of hematological malignancies stratified by cancer type, time since diagnosis and stem cell transplantation. Eur. J. Haematol. 101 (3), 340–348. 10.1111/ejh.13104 (2018). 29858505 10.1111/ejh.13104

7. Gulbrandsen N Hjermstad MJ Wisloff F Interpretation of quality of life scores in multiple myeloma by comparison with a reference population and assessment of the clinical importance of score differences[J] Eur. J. Haematol. 2004 72 3 172 180 10.1046/j.0902-4441.2003.00195.x 14962235 Gulbrandsen, N., Hjermstad, M. J. & Wisloff, F. Interpretation of quality of life scores in multiple myeloma by comparison with a reference population and assessment of the clinical importance of score differences. Eur. J. Haematol. 72 (3), 172–180. 10.1046/j.0902-4441.2003.00195.x (2004). 14962235 10.1046/j.0902-4441.2003.00195.x

8. Johnsen AT Tholstrup D Petersen MA Health related quality of life in a nationally representative sample of haematological patients[J] Eur. J. Haematol. 2009 83 2 139 148 10.1111/j.1600-0609.2009.01250.x 19284418 PMC2730555 Johnsen, A. T., Tholstrup, D. & Petersen, M. A. Health related quality of life in a nationally representative sample of haematological patients. Eur. J. Haematol. 83 (2), 139–148. 10.1111/j.1600-0609.2009.01250.x (2009). 19284418 10.1111/j.1600-0609.2009.01250.x PMC2730555

9. Kang HY Choi EY Factors influencing quality of life in patients with multiple myeloma[J] Contemp. Nurse 2019 55 2–3 109 121 10.1080/10376178.2019.1623699 31124394 Kang, H. Y. & Choi, E. Y. Factors influencing quality of life in patients with multiple myeloma. Contemp. Nurse 55 (2–3), 109–121. 10.1080/10376178.2019.1623699 (2019). 31124394 10.1080/10376178.2019.1623699

10. Cheng MJ Smith BD Hourigan CS A single center survey of Health-Related quality of life among acute myeloid leukemia survivors in first complete Remission[J] J. Palliat. Med. 2017 20 11 1267 1273 10.1089/jpm.2017.0069 28537498 PMC5672616 Cheng, M. J., Smith, B. D. & Hourigan, C. S. A single center survey of health-related quality of life among acute myeloid leukemia survivors in first complete remission. J. Palliat. Med. 20 (11), 1267–1273. 10.1089/jpm.2017.0069 (2017). 28537498 10.1089/jpm.2017.0069 PMC5672616

11. Shimabukuro-Vornhagen A Böll B Schellongowski P Critical care management of chimeric antigen receptor T-cell therapy recipients[J] Cancer J. Clin. 2022 72 1 78 93 10.3322/caac.21702 34613616 Shimabukuro-Vornhagen, A., Böll, B. & Schellongowski, P. Critical care management of chimeric antigen receptor T-cell therapy recipients. Cancer J. Clin. 72 (1), 78–93. 10.3322/caac.21702 (2022). 10.3322/caac.21702 34613616

12. Parikh RH Lonial S Chimeric antigen receptor T-cell therapy in multiple myeloma: A comprehensive review of current data and implications for clinical practice[J] Cancer J. Clin. 2023 73 3 275 285 10.3322/caac.21771 36627265 Parikh, R. H. & Lonial, S. Chimeric antigen receptor T-cell therapy in multiple myeloma: A comprehensive review of current data and implications for clinical practice. Cancer J. Clin. 73 (3), 275–285. 10.3322/caac.21771 (2023). 10.3322/caac.21771 36627265

13. Quintás-Cardama A GPRC5D-Targeted CAR T cells for Myeloma[J] N. Engl. J. Med. 2022 387 24 2295 2296 10.1056/NEJMc2213985 36516097 Quintás-Cardama, A. GPRC5D-targeted CAR T cells for Myeloma. N. Engl. J. Med. 387 (24), 2295–2296. 10.1056/NEJMc2213985 (2022). 36516097 10.1056/NEJMc2213985

14. Baker DJ Levine BL June CH Assessing the oncogenic risk: the long-term safety of autologous chimeric antigen receptor T cells[J] Lancet (London England) 2025 405 10480 751 754 10.1016/s0140-6736(25)00039-x 40023653 Baker, D. J., Levine, B. L. & June, C. H. Assessing the oncogenic risk: The long-term safety of autologous chimeric antigen receptor T cells. Lancet 405 (10480), 751–754. 10.1016/s0140-6736(25)00039-x (2025). 40023653 10.1016/S0140-6736(25)00039-X

15. Locke FL Miklos DB Jacobson CA Axicabtagene Ciloleucel as Second-Line therapy for large B-Cell Lymphoma[J] N. Engl. J. Med. 2022 386 7 640 654 10.1056/NEJMoa2116133 34891224 Locke, F. L., Miklos, D. B. & Jacobson, C. A. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N. Engl. J. Med. 386 (7), 640–654. 10.1056/NEJMoa2116133 (2022). 34891224 10.1056/NEJMoa2116133

16. Wang Y Cao J Gu W Long-Term Follow-Up of combination of B-Cell maturation antigen and CD19 chimeric antigen receptor T cells in multiple Myeloma[J] J. Clin. Oncology: Official J. Am. Soc. Clin. Oncol. 2022 40 20 2246 2256 10.1200/jco.21.01676 35333600 Wang, Y., Cao, J. & Gu, W. Long-term follow-up of combination of B-Cell maturation antigen and CD19 chimeric antigen receptor T cells in multiple Myeloma. J. Clin. Oncol. 40 (20), 2246–2256. 10.1200/jco.21.01676 (2022). 10.1200/JCO.21.01676 35333600

17. Park JH Rivière I Gonen M Long-Term Follow-up of CD19 CAR therapy in acute lymphoblastic Leukemia[J] N. Engl. J. Med. 2018 378 5 449 459 10.1056/NEJMoa1709919 29385376 PMC6637939 Park, J. H., Rivière, I. & Gonen, M. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N. Engl. J. Med. 378 (5), 449–459. 10.1056/NEJMoa1709919 (2018). 29385376 10.1056/NEJMoa1709919 PMC6637939

18. Cheng R Scippa K Locke FL Patient Perspectives on Health-Related Quality of Life in Diffuse Large B-Cell Lymphoma Treated with Car T-Cell Therapy: A Qualitative Study[J] Oncol. therapy 2021 10.1007/s40487-021-00174-0 PMC8590924 34778941 Cheng, R., Scippa, K. & Locke, F. L. Patient perspectives on health-related quality of life in diffuse large B-cell lymphoma treated with car T-Cell therapy: A qualitative study. Oncol. Ther. 10.1007/s40487-021-00174-0 (2021). 10.1007/s40487-021-00174-0 PMC8590924 34778941

19. Dai H Xu S Han J Prevalence and factors associated with anxiety and depressive symptoms among patients hospitalized with hematological malignancies after chimeric antigen receptor T-cell (CAR-T) therapy: A cross-sectional study[J] J. Affect. Disord. 2021 286 33 39 10.1016/j.jad.2021.02.041 33676261 Dai, H., Xu, S. & Han, J. Prevalence and factors associated with anxiety and depressive symptoms among patients hospitalized with hematological malignancies after chimeric antigen receptor T-cell (CAR-T) therapy: A cross-sectional study. J. Affect. Disord. 286 , 33–39. 10.1016/j.jad.2021.02.041 (2021). 33676261 10.1016/j.jad.2021.02.041

20. Shah N Chari A Scott E B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches[J] Leukemia 2020 34 4 985 1005 10.1038/s41375-020-0734-z 32055000 PMC7214244 Shah, N., Chari, A. & Scott, E. B-cell maturation antigen (BCMA) in multiple myeloma: Rationale for targeting and current therapeutic approaches. Leukemia 34 (4), 985–1005. 10.1038/s41375-020-0734-z (2020). 32055000 10.1038/s41375-020-0734-z PMC7214244

21. Johnson JR Temple R Food and drug administration requirements for approval of new anticancer drugs[J] Cancer Treat. Rep. 1985 69 10 1155 1159 4042094 Johnson, J. R. & Temple, R. Food and drug administration requirements for approval of new anticancer drugs. Cancer Treat. Rep. 69 (10), 1155–1159 (1985). 4042094

22. Wu X Li Z Cao J The association between major complications of immobility during hospitalization and quality of life among bedridden patients: A 3 month prospective multi-center study[J] PloS One 2018 13 10 e0205729 10.1371/journal.pone.0205729 30312330 PMC6185860 Wu, X., Li, Z. & Cao, J. The association between major complications of immobility during hospitalization and quality of life among bedridden patients: A 3 month prospective multi-center study. PloS One 13 (10), e0205729. 10.1371/journal.pone.0205729 (2018). 30312330 10.1371/journal.pone.0205729 PMC6185860

23. Sitlinger A Zafar SY Health-Related quality of life: the impact on morbidity and Mortality[J] Surg. Oncol. Clin. N. Am. 2018 27 4 675 684 10.1016/j.soc.2018.05.008 30213412 PMC6428416 Sitlinger, A. & Zafar, S. Y. Health-Related quality of life: The impact on morbidity and Mortality. Surg. Oncol. Clin. N. Am. 27 (4), 675–684. 10.1016/j.soc.2018.05.008 (2018). 30213412 10.1016/j.soc.2018.05.008 PMC6428416

24. Strasser-Weippl K Ludwig H Psychosocial QOL is an independent predictor of overall survival in newly diagnosed patients with multiple myeloma[J] Eur. J. Haematol. 2008 81 5 374 379 10.1111/j.1600-0609.2008.01126.x 18637124 Strasser-Weippl, K. & Ludwig, H. Psychosocial QOL is an independent predictor of overall survival in newly diagnosed patients with multiple myeloma. Eur. J. Haematol. 81 (5), 374–379. 10.1111/j.1600-0609.2008.01126.x (2008). 18637124 10.1111/j.1600-0609.2008.01126.x

25. Hemingway H Marmot M Evidence based cardiology: psychosocial factors in the aetiology and prognosis of coronary heart disease. Systematic review of prospective cohort studies[J] BMJ (Clinical Res. ed) 1999 318 7196 1460 1467 10.1136/bmj.318.7196.1460 PMC1115843 10346775 Hemingway, H. & Marmot, M. Evidence based cardiology: Psychosocial factors in the aetiology and prognosis of coronary heart disease. Systematic review of prospective cohort studies. BMJ 318 (7196), 1460–1467. 10.1136/bmj.318.7196.1460 (1999). 10.1136/bmj.318.7196.1460 PMC1115843 10346775

26. Knight JM Szabo A Arapi I Patient-reported outcomes and neurotoxicity markers in patients treated with bispecific LV20.19 CAR T cell therapy[J] Commun. Med. 2022 2 1 49 10.1038/s43856-022-00116-5 35603278 PMC9098435 Knight, J. M., Szabo, A. & Arapi, I. Patient-reported outcomes and neurotoxicity markers in patients treated with bispecific LV20.19 CAR T cell therapy. Commun. Med. 2 (1), 49. 10.1038/s43856-022-00116-5 (2022). 35603278 10.1038/s43856-022-00116-5 PMC9098435

27. Maziarz RT Waller EK Jaeger U Patient-reported long-term quality of life after tisagenlecleucel in relapsed/refractory diffuse large B-cell lymphoma[J] Blood Adv. 2020 4 4 629 637 10.1182/bloodadvances.2019001026 32074277 PMC7042998 Maziarz, R. T., Waller, E. K. & Jaeger, U. Patient-reported long-term quality of life after tisagenlecleucel in relapsed/refractory diffuse large B-cell lymphoma. Blood Adv. 4 (4), 629–637. 10.1182/bloodadvances.2019001026 (2020). 32074277 10.1182/bloodadvances.2019001026 PMC7042998

28. Laetsch TW Myers GD Baruchel A Patient-reported quality of life after tisagenlecleucel infusion in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukaemia: a global, single-arm, phase 2 trial[J] Lancet Oncol. 2019 10.1016/s1470-2045(19)30493-0 31606419 PMC7480957 Laetsch, T. W., Myers, G. D. & Baruchel, A. Patient-reported quality of life after tisagenlecleucel infusion in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukaemia: A global, single-arm, phase 2 trial. Lancet Oncol. 10.1016/s1470-2045(19)30493-0 (2019). 31606419 10.1016/S1470-2045(19)30493-0 PMC7480957

29. Efficace F Vignetti M Quality of life and CAR-T cell therapy in children, adolescents, and young adults with haematological malignancies[J] Lancet Oncol. 2019 10.1016/s1470-2045(19)30641-2 31606418 Efficace, F. & Vignetti, M. Quality of life and CAR-T cell therapy in children, adolescents, and young adults with haematological malignancies. Lancet Oncol. 10.1016/s1470-2045(19)30641-2 (2019). 31606418 10.1016/S1470-2045(19)30641-2

30. Cella DF Tulsky DS Gray G The functional assessment of Cancer therapy scale: development and validation of the general measure[J] J. Clin. Oncology: Official J. Am. Soc. Clin. Oncol. 1993 11 3 570 579 10.1200/jco.1993.11.3.570 8445433 Cella, D. F., Tulsky, D. S. & Gray, G. The functional assessment of Cancer therapy scale: Development and validation of the general measure. J. Clin. Oncol. 11 (3), 570–579. 10.1200/jco.1993.11.3.570 (1993). 10.1200/JCO.1993.11.3.570 8445433

31. Zhang K Gong K Zhou LQ [Quality of life among patients with advanced prostate cancer: a survey using functional assessment of cancer therapy-prostate in China][J] Zhonghua Yi Xue Za Zhi 2008 88 10 665 668 18642765 Zhang, K., Gong, K. & Zhou, L. Q. Quality of life among patients with advanced prostate cancer: A survey using functional assessment of cancer therapy-prostate in China. Zhonghua Yi Xue Za Zhi 88 (10), 665–668 (2008). 18642765

32. Wan CH Meng Q Yang Z [Development of the general module of the system of quality of life instruments for cancer patients: reliability and validity analysis][J] Ai zheng = Aizheng = Chin. J. cancer 2007 26 3 225 229 17355781 Wan, C. H., Meng, Q. & Yang, Z. Development of the general module of the system of quality of life instruments for cancer patients: Reliability and validity analysis. Ai Zheng = Aizheng = Chinese Journal of Cancer 26 (3), 225–229 (2007). 17355781

33. Basch E Reeve BB Mitchell SA Development of the National Cancer Institute’s patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE)[J] J. Natl Cancer Inst. 2014 10.1093/jnci/dju244 25265940 PMC4200059 Basch, E., Reeve, B. B. & Mitchell, S. A. Development of the National Cancer Institute’s patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE). J. Natl. Cancer Inst. 10.1093/jnci/dju244 (2014). 25265940 10.1093/jnci/dju244 PMC4200059

34. Yan Z Cao J Cheng H A combination of humanised anti-CD19 and anti-BCMA CAR T cells in patients with relapsed or refractory multiple myeloma: a single-arm, phase 2 trial[J] Lancet Haematol. 2019 6 10 e521 e529 10.1016/s2352-3026(19)30115-2 31378662 Yan, Z., Cao, J. & Cheng, H. A combination of humanised anti-CD19 and anti-BCMA CAR T cells in patients with relapsed or refractory multiple myeloma: a single-arm, phase 2 trial. Lancet Haematol. 6 (10), e521–e529. 10.1016/s2352-3026(19)30115-2 (2019). 31378662 10.1016/S2352-3026(19)30115-2

35. Lee, D. W., Santomasso, B. D. & Locke, F. L. et.al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol. Blood Marrow Transpl. 25 (4), 625–638. 10.1016/j.bbmt.2018.12.758 (2019). 10.1016/j.bbmt.2018.12.758 PMC12180426 30592986

36. Brucker PS Yost K Cashy J General population and cancer patient norms for the functional assessment of Cancer Therapy-General (FACT-G)[J] Eval. Health Prof. 2005 28 2 192 211 10.1177/0163278705275341 15851773 Brucker, P. S., Yost, K. & Cashy, J. General population and cancer patient norms for the functional assessment of Cancer Therapy-General (FACT-G). Eval. Health Prof. 28 (2), 192–211. 10.1177/0163278705275341 (2005). 15851773 10.1177/0163278705275341

37. Rajkumar SV Dimopoulos MA Palumbo A International myeloma working group updated criteria for the diagnosis of multiple myeloma[J] Lancet Oncol. 2014 15 12 e538 548 10.1016/s1470-2045(14)70442-5 25439696 Rajkumar, S. V., Dimopoulos, M. A. & Palumbo, A. International myeloma working group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 15 (12), e538–548. 10.1016/s1470-2045(14)70442-5 (2014). 25439696 10.1016/S1470-2045(14)70442-5

38. Lister TA Crowther D Sutcliffe SB Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds meeting[J] J. Clin. Oncology: Official J. Am. Soc. Clin. Oncol. 1989 7 11 1630 1636 10.1200/jco.1989.7.11.1630 2809679 Lister, T. A., Crowther, D. & Sutcliffe, S. B. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds meeting. J. Clin. Oncol. 7 (11), 1630–1636. 10.1200/jco.1989.7.11.1630 (1989). 10.1200/JCO.1989.7.11.1630 2809679

39. Bower JE Cancer-related fatigue–mechanisms, risk factors, and treatments[J] Nat. Reviews Clin. Oncol. 2014 11 10 597 609 10.1038/nrclinonc.2014.127 PMC4664449 25113839 Bower, J. E. Cancer-related fatigue–mechanisms, risk factors, and treatments. Nat. Rev. Clin. Oncol. 11 (10), 597–609. 10.1038/nrclinonc.2014.127 (2014). 10.1038/nrclinonc.2014.127 PMC4664449 25113839

40. Heffernan AE Wu Y Benz LS Quality of life after surgery for lower grade gliomas[J] Cancer 2023 10.1002/cncr.34980 37599093 PMC10872908 Heffernan, A. E., Wu, Y. & Benz, L. S. Quality of life after surgery for lower grade gliomas. Cancer . 10.1002/cncr.34980 (2023). 37599093 10.1002/cncr.34980 PMC10872908

41. Berger AM Gerber LH Mayer DK Cancer-related fatigue: implications for breast cancer survivors[J] Cancer 2012 118 8 Suppl 2261 2269 10.1002/cncr.27475 22488700 Berger, A. M., Gerber, L. H. & Mayer, D. K. Cancer-related fatigue: Implications for breast cancer survivors. Cancer 118 (8 Suppl), 2261–2269. 10.1002/cncr.27475 (2012). 22488700 10.1002/cncr.27475

42. Carnio S Di Stefano RF Novello S Fatigue in lung cancer patients: symptom burden and management of challenges[J] Lung Cancer (Auckland NZ) 2016 7 73 82 10.2147/lctt.S85334 PMC5310693 28210163 Carnio, S., Di Stefano, R. F. & Novello, S. Fatigue in lung cancer patients: Symptom burden and management of challenges. Lung Cancer 7 , 73–82. 10.2147/lctt.S85334 (2016). 10.2147/LCTT.S85334 PMC5310693 28210163

43. Berger AM Abernethy AP Atkinson A NCCN clinical practice guidelines Cancer-related fatigue[J] J. Natl. Compr. Cancer Network: JNCCN 2010 8 8 904 931 10.6004/jnccn.2010.0067 20870636 Berger, A. M., Abernethy, A. P. & Atkinson, A. NCCN clinical practice guidelines Cancer-related fatigue. J. Natl. Compr. Cancer Netw. JNCCN 8 (8), 904–931. 10.6004/jnccn.2010.0067 (2010). 10.6004/jnccn.2010.0067 20870636

44. Mustian KM Sprod LK Janelsins M Exercise recommendations for Cancer-Related fatigue, cognitive impairment, sleep problems, depression, pain, anxiety, and physical dysfunction: A Review[J] Oncol. Hematol. Rev. 2012 8 2 81 88 10.17925/ohr.2012.08.2.81 23667857 PMC3647480 Mustian, K. M., Sprod, L. K. & Janelsins, M. Exercise recommendations for cancer-related fatigue, cognitive impairment, sleep problems, depression, pain, anxiety, and physical dysfunction: A review. Oncol. Hematol. Rev. 8 (2), 81–88. 10.17925/ohr.2012.08.2.81 (2012). 23667857 10.17925/ohr.2012.08.2.81 PMC3647480

45. Cleeland CS Symptom burden: multiple symptoms and their impact as patient-reported outcomes[J] J. Natl. Cancer Inst. Monogr. 2007 10.1093/jncimonographs/lgm005 17951226 Cleeland, C. S. Symptom burden: Multiple symptoms and their impact as patient-reported outcomes. J. Natl. Cancer Inst. Monogr. . 10.1093/jncimonographs/lgm005 (2007). 17951226 10.1093/jncimonographs/lgm005

46. Pang QP Ji YB Xu CP Correlation among symptom clusters, inflammatory cytokine and quality of life among cancer patients based on cluster analysis[J] Chin. Nurs. Res. 2019 33 24 4205 4210 Pang, Q. P., Ji, Y. B. & Xu, C. P. Correlation among symptom clusters, inflammatory cytokine and quality of life among cancer patients based on cluster analysis. Chin. Nurs. Res. 33 (24), 4205–4210 (2019).

47. Späth-Schwalbe E Hansen K Schmidt F Acute effects of Recombinant human interleukin-6 on endocrine and central nervous sleep functions in healthy men[J] J. Clin. Endocrinol. Metab. 1998 83 5 1573 1579 10.1210/jcem.83.5.4795 9589658 Späth-Schwalbe, E., Hansen, K. & Schmidt, F. Acute effects of Recombinant human interleukin-6 on endocrine and central nervous sleep functions in healthy men. J. Clin. Endocrinol. Metab. 83 (5), 1573–1579. 10.1210/jcem.83.5.4795 (1998). 9589658 10.1210/jcem.83.5.4795

48. Doong SH Dhruva A Dunn LB Associations between cytokine genes and a symptom cluster of pain, fatigue, sleep disturbance, and depression in patients prior to breast cancer surgery[J] Biol. Res. Nurs. 2015 17 3 237 247 10.1177/1099800414550394 25304131 PMC5486211 Doong, S. H., Dhruva, A. & Dunn, L. B. Associations between cytokine genes and a symptom cluster of pain, fatigue, sleep disturbance, and depression in patients prior to breast cancer surgery. Biol. Res. Nurs. 17 (3), 237–247. 10.1177/1099800414550394 (2015). 25304131 10.1177/1099800414550394 PMC5486211

49. Davila ML Riviere I Wang X Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia[J] Sci. Transl. Med. 2014 6 224 224ra225 10.1126/scitranslmed.3008226 PMC4684949 24553386 Davila, M. L., Riviere, I. & Wang, X. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci. Transl. Med. 6 (224), 224ra225. 10.1126/scitranslmed.3008226 (2014). 10.1126/scitranslmed.3008226 PMC4684949 24553386

50. Loh KP Zittel J Kadambi S Elucidating the associations between sleep disturbance and depression, fatigue, and pain in older adults with cancer[J] J. Geriatric Oncol. 2018 9 5 464 468 10.1016/j.jgo.2018.02.006 PMC12491937 29506921 Loh, K. P., Zittel, J. & Kadambi, S. Elucidating the associations between sleep disturbance and depression, fatigue, and pain in older adults with cancer. J. Geriatric Oncol. 9 (5), 464–468. 10.1016/j.jgo.2018.02.006 (2018). 10.1016/j.jgo.2018.02.006 PMC12491937 29506921

51. Patrick DL Powers A Jun MP Effect of lisocabtagene Maraleucel on HRQoL and symptom severity in relapsed/refractory large B-cell lymphoma[J] Blood Adv. 2021 5 8 2245 2255 10.1182/bloodadvances.2020003503 33904895 PMC8095132 Patrick, D. L., Powers, A. & Jun, M. P. Effect of lisocabtagene Maraleucel on HRQoL and symptom severity in relapsed/refractory large B-cell lymphoma. Blood Adv. 5 (8), 2245–2255. 10.1182/bloodadvances.2020003503 (2021). 33904895 10.1182/bloodadvances.2020003503 PMC8095132

52. Zaleta AK Miller MF Olson JS Symptom burden, perceived control, and quality of life among patients living with multiple Myeloma[J] J. Natl. Compr. Cancer Network: JNCCN 2020 18 8 1087 1095 10.6004/jnccn.2020.7561 32755984 Zaleta, A. K., Miller, M. F. & Olson, J. S. Symptom burden, perceived control, and quality of life among patients living with multiple Myeloma. J. Natl. Compr. Cancer Netw. JNCCN 18 (8), 1087–1095. 10.6004/jnccn.2020.7561 (2020). 10.6004/jnccn.2020.7561 32755984

53. Sibeoni J Picard C Orri M Patients’ quality of life during active cancer treatment: a qualitative study[J] BMC cancer 2018 18 1 951 10.1186/s12885-018-4868-6 30286733 PMC6172766 Sibeoni, J., Picard, C. & Orri, M. Patients’ quality of life during active cancer treatment: A qualitative study. BMC Cancer 18 (1), 951. 10.1186/s12885-018-4868-6 (2018). 30286733 10.1186/s12885-018-4868-6 PMC6172766

54. Lord K Ibrahim K Kumar S Are depressive symptoms more common among British South Asian patients compared with British White patients with cancer? A cross-sectional survey[J] BMJ open. 2013 10.1136/bmjopen-2013-002650 23794580 PMC3686160 Lord, K., Ibrahim, K. & Kumar, S. Are depressive symptoms more common among British South Asian patients compared with British white patients with cancer? A cross-sectional survey. BMJ Open . 10.1136/bmjopen-2013-002650 (2013). 23794580 10.1136/bmjopen-2013-002650 PMC3686160

55. Chakraborty R Health-Related Quality of Life after Autologous Stem Cell Transplantation for Multiple Myeloma Biology of Blood and Marrow Transplantation 2018 24 8 1546 1553 10.1016/j.bbmt.2018.03.027 29626515 PMC6108907 Chakraborty, R. et.al. Health-related quality of life after autologous stem cell transplantation for multiple Myeloma. Biol. Blood Marrow Transpl. 24 (8), 1546–1553. 10.1016/j.bbmt.2018.03.027 (2018). 29626515 10.1016/j.bbmt.2018.03.027 PMC6108907

56. Seo HJ Baek YG Cho BS Anxiety and depression of the patients with hematological malignancies during hospitalization for hematopoietic stem cell Transplantation[J] Psychiatry Invest. 2019 16 10 751 758 10.30773/pi.2019.07.12 PMC6801322 31558690 Seo, H. J., Baek, Y. G. & Cho, B. S. Anxiety and depression of the patients with hematological malignancies during hospitalization for hematopoietic stem cell Transplantation. Psychiatry Invest. 16 (10), 751–758. 10.30773/pi.2019.07.12 (2019). 10.30773/pi.2019.07.12 PMC6801322 31558690

57. Raje N Berdeja J Lin Y Anti-BCMA CAR T-Cell therapy bb2121 in relapsed or refractory multiple Myeloma[J] N Engl. J. Med. 2019 380 18 1726 1737 10.1056/NEJMoa1817226 31042825 PMC8202968 Raje, N., Berdeja, J. & Lin, Y. Anti-BCMA CAR T-Cell therapy bb2121 in relapsed or refractory multiple Myeloma. N. Engl. J. Med. 380 (18), 1726–1737. 10.1056/NEJMoa1817226 (2019). 31042825 10.1056/NEJMoa1817226 PMC8202968