Abstract
Hematopoietic stem cell transplantation (HSCT) or Bone Marrow Transplantation (BMT) has significantly improved the survival rates of patients suffering from hematological malignancies. However, the cure can only be achieved at the price of morbidity and long-term complications. Thus, this study aimed to evaluate the short-term effect of HSCT on depressive behavior, cognition, and quality of life (QoL) in leukemia patients. Sixty patients were included in this prospective observational study. The current study assessed depression using Patient Health Questionnaire (PHQ-9) scale, cognition using Montreal Cognitive Assessment (MOCA) scale and QoL using European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ C30) before 7 days of the therapy i.e., preconditioning/baseline (TP1) and after 30 days of the treatment (TP2) in leukemia patients undergoing HSCT. At TP2, there was a significant improvement in PHQ-9 (p = 0.001), MOCA (p < 0.0001), functional scale (p < 0.0001) and global health & QoL scale (p = 0.001) of EORTC QLQ C30 scores whereas there was a significant decrease in symptom scale of EORTC QLQ C30 score (p = 0.005). Furthermore, at TP2 a statistically significant (p < 0.05) negative correlation was observed between MOCA and symptom scale of EORTC QLQ C30 after Pearson correlation analysis. In conclusion, post-30 days of HSCT there was alleviation in depressive behavior, cognition, and QoL in leukemia patients compared to before therapy.
Graphical abstract
Keywords: Bone metabolism, Hematopoietic stem cell transplantation, Quality of life, Cognition
Introduction
Hematopoietic stem cell transplantation (HSCT) or Bone Marrow Transplantation (BMT) has been observed to improve the survival rates of patients with hematological malignancies significantly. After the infusion, the host’s hematopoietic cells are replaced by transplanted cells. The disease is cured or prevented through the substitution of donor cells and the anti-tumor activity of the transplanted cells [1]. Allogenic BMT has become the choice of treatment for various congenital, hematologic, and neoplastic disorders. Moreover, allogeneic BMT has been shown to provide disease-free survival in approximately 20–90% of patients with various neoplastic diseases [2, 3]. However, this can only be achieved at the cost of morbidity and long-term complications.
Hematopoietic stem cell transplantation is a complex medical procedure involving invasive medical interventions associated with long periods of isolation, extended hospitalizations, adverse effects, long recovery time and risk of mortality or relapse (Rueda-Lara and Lopez-Patton, 2014). Patients often experience substantial changes in their physical functioning due to symptoms such as dry mouth, fatigue, loss of appetite, mucositis and nausea (Rueda-Lara and Lopez-Patton, 2014). Even if the transplantation is successful, patients are at risk of short- and long-term medical consequences such as chronic Graft-vs.-Host Disease (GvHD), secondary malignancies, infections and endocrine dysfunction (Lowe et al., 2007).
Furthermore, QoL assessment is essential as relapse, morbidity and mortality are remarkable during the first year following HSCT in cancer patients [4, 5]. It is estimated that by 2030, approximately 500,000 HSCT recipients will have disease-free survival for a longer duration. These survivors have an increased risk of morbidity and thus their QoL may be reduced [6]. Previous researchers have shown that approximately 20% of patients develop clinically significant depression, anxiety or adjustment disorder during hospitalization for HSCT [7]. Further, degradation in psychomotor speed, executive functioning, learning, visuospatial skill, attention and memory were observed in patients post HSCT [8, 9]. However, the clinical studies demonstrating the short-term impact of HSCT on depression, cognition and QoL are scarce.
Thus, the present study was designed to evaluate the effect of HSCT on depression, cognition and QoL of leukemia patients receiving HSCT.
Methodology
Hospital Setting and Study Population
This prospective observational study was conducted at Rajiv Gandhi Cancer Institute and Research Centre (RGCIRC), Delhi, India from 01-01-2021 (starting of patient recruitment) to 30-10-2021 (end of patient recruitment). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study enrolled 60 leukemia patients (M + F), who were hospitalized for 1 month to undergo HSCT. No patient had relapsed leukemia. Most patients who underwent BMT were independent and lively. Before transplant, none of the woman in the study were taking birth control or hormonal pills. Informed consent was obtained from each participant prior to inclusion in the study. The research protocol was approved by the Scientific Ethical Committee of the Rajiv Gandhi Cancer Institute and Research Center, Rohini, Delhi.
Inclusion criteria- 1. The patient must have a confirmed diagnosis of one of the following 1. Acute Myeloid Leukemia (AML), 2. Acute lymphocytic leukemia (ALL) 3. Chronic myeloid Leukemia (CML) 2. Patients undergoing allogeneic HSCT 3. Both male and female patients 4. Patient capable of giving informed consent 5. Patients willing to participate in study 6. No major organ dysfunction precluding transplantation.
Exclusion criteria-1. Patients having a history of cognitive impairment and Alzheimer disease 2. Patients having a history of head injury, organ failure, and organ transplant 3. Patients having secondary cancer 4. Patients with relapsed leukemia 5. Patients having neuropsychiatric disorders or neurobehavioral diseases 6. Patients on psychotropic medications 7. Patients using concurrent medication like antidepressants drugs 8. Patients unable to give informed consent 9. Lactating or pregnant patients 10. Patients who have a history of undergoing allogeneic or autologous transplant.
Assessment of Cognition
The cognition of the patients was assessed using Montreal Cognitive Assessment (MOCA) scale before 7 days of the therapy i.e., preconditioning/baseline (TP1) and after 30 days of the transplant (TP2). The MoCA assesses several cognitive domains such as the short-term and delayed (after 5 min) memory recall. Visuospatial abilities were assessed using a clock-drawing task and a line drawing three-dimensional cube copy. Executive functions are assessed through a short version of the trail-making B, a phonemic fluency task and a two-item verbal abstraction task. Attention, concentration and working memory are evaluated, using a sustained attention task, a serial subtraction task and a digit forward and backward task. Language is assessed using a naming task with relatively low-familiarity animals, repetition of two syntactically complex sentences. Finally, orientation to time and place is also evaluated [10]. The maximum score is 30. A score of ≥ 26 is considered to be normal.
Assessment of Depression
Patient Health Questionnaire (PHQ-9) scale was used to estimate the minimal to moderately severe depression in patients at TP1 and TP2. The PHQ-9 consists of 9 questions that are based on the 9 Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (DSM-IV), a criteria for a major depressive disorder. The questionnaire explores the symptoms experienced by patients during the 2 immediately preceding weeks. For a score ≤ 4 minimal depression is indicated, for range 5–14, mild-moderate depression is depicted and for > 14 moderate-severe depression is reported.
Assessment of Quality of Life
The QoL of the patients was checked using European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ C30) at TP1 and TP2. This questionnaire incorporates nine multi-item scales: five functional scales (physical, role, cognitive, emotional, and social); three symptom scales (fatigue, pain, and nausea and vomiting); and global health and QoL scale [11].
Ethics Information
This observational study was approved by the 37th Scientific Committee, Rajiv Gandhi Cancer Institute and Research Centre (RGCIRC). All the documents- Protocol, Informed consent form (ICF), Case report form (CRF) had been approved by the Institutional Review Board (IRB) (REF/2019/12/030223).
Statistical Analysis
Paired Student t-test was used to compare the significant difference in the score of PHQ-9, MOCA and EORTC QLQ C30 between TP1 and TP2. Pearson correlation was used to assess the association of MOCA, PHQ-9 and EORTC QLQ C30 at TP2. All these statistics were accompanied by 95% confidence intervals (CI). All the reported p-values are two-sided and p-values < 0.05 are considered to indicate statistical significance. All data entries and statistical analyses are performed by using SPSS® Version 23.0 software.
Data Handling and Record-Keeping
All the data are recorded manually in both hard and soft copy and are archived at Rajiv Gandhi Cancer Institute and Research Centre for inspection purposes. Confidentiality will be maintained and the data will be protected with a secure password and only authorized persons will have the access to the data. Data will be used for research, scientific presentation, and publication without disclosing the subject’s identity.
Results
Demographic Details of the Patients
At the baseline, demographic data were collected from patient interviews and files. A total of 60 patients (male and female) with different types of leukemia or hematological disorder i.e., 28 AML, 13 CML, 19 acute lymphocytic leukemia (ALL) were enrolled. The mean age of the included patients was 38.92 ± 12.86. A specific transplantation regimen was prepared for each patient, i.e., 50% of the population received fludarabine/busulfan/antithymocyte globulin-cyclosorin/methotrexate (FLU/BU/r ATG-CSA/Mtx) regimen and the remaining patients received total body irradiation (TBI) or treosulfan (TREO) in substitutions of BU. 38.33% of patients received matched sibling donor (MSD) type of transplant, 10% patients got matched family donor (MFD), 31.67% received matched unrelated donor (MUD) and 20% of the total patients received Haploidentical transplant. The mean duration of the disease was 6.6 months. As per the comorbidity index, 12% patients were at low risk, 20% were at intermediate risk and 28% were at high risk. Additionally, about 66.67% of patients were found suffering from comorbidities (Table 1).
Table 1.
Demographic and baseline table
| Item (Measure) | Patient N (%) |
|---|---|
| Sample Size | 60 |
| Gender | |
| Male | 24 (40) |
| Female | 36 (60) |
| Avg. Age | 38.92 ± 12.86 |
| Avg. BMI | 24.85 ± 4.05 |
| Avg. BSA | 1.68 ± 0.19 |
| Comorbidity | |
| Hypertension | 6 (10) |
| diabetes | 4 (6.67) |
| Obesity | 3 (5) |
| Thyroid | 5 (8.33) |
| Others | 22 (36.67) |
| Habits | |
| Alcohol | 18 (30) |
| Smoking | 12 (20) |
| No addiction | 41 (68.33) |
| Type of hematological malignancy | |
| AML | 28 (46.67) |
| CML | 13 (21.66) |
| ALL | 19 (31.67) |
| Donor type | |
| MSD | 23 (38.33) |
| MFD | 6 (10) |
| MUD | 19 (31.67) |
| Haplo | 12 (20) |
| Mean duration of disease | 6.6 months |
| HCT-CI | |
| 1(low) | 12 (20) |
| 2(intermediate) | 20 (33.33) |
| 3(high) | 18 (30) |
| 4(high) | 8 (13.33) |
| 5 (high) | 1 (1.67) |
| 6 (high) | 1 (1.67) |
BMI: Body mass index; BSA: Body surface area; AML: Acute myeloid leukemia; CML: Chronic myelogenous leukemia; ALL: Acute lymphocytic leukemia; MSD: matched sibling donor; MFD: matched family donor; MUD: Matched unrelated donor; Haplo: haploidentical transplant; HCT-CI: Hematopoietic cell transplantation-comorbidity index
Effect of HSCT on Cognition
A significant increase in the score of MOCA (p = 0.001) was found at TP2 as compared to TP1 indicating improvement in cognition (Table 2).
Table 2.
Depression, cognition, and QoL parameters of leukemia patients at TP1 & TP2
| PHQ-9 | MOCA | EORTC QLQ C30 | |||
|---|---|---|---|---|---|
| Functional Scale | Symptom scale | Global health and QoL | |||
| TP 1 | 7.5 ± 1.88 | 22.57 ± 3.4 | 0.68 ± 0.17 | 0.15 ± 0.06 | 0.66 ± 0.13 |
| TP 2 | 6.41 ± 1.55 | 25.48 ± 2.87 | 0.71 ± 0.15 | 0.13 ± 0.05 | 0.72 ± 0.14 |
| % Change | − 14.5333 | 12.89322 | 4.411765 | − 13.3333 | 9.090909 |
| Significance (P) | 0.001 | 0.000 | 0.000 | 0.005 | 0.001 |
TP1: Time-point 1; TP2: Time-point 2; PHQ-9: Patient Health Questionnaire; MOCA: Montreal Cognitive Assessment; EORTC QLQ C30: European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire
Effect of HSCT on Depression
At TP2, a significant decrease in the PHQ-9 score (p < 0.001) was observed as compared to TP1 which shows that BMT helps in significant alleviation of depression in HSCT patients.
Effect of HSCT on QoL
Post 30 days of BMT, there was a significant increase in the score of functional scale (p < 0.001) and global health and QoL (p = 0.001), whereas there was a significant decrease in the score of symptom scale (p = 0.005) as compared to baseline (Table 2).
Correlation of PHQ-9, MOCA and EORTC QLQ C30
At TP2, a statistically significant (p < 0.05) negative correlation was observed between MOCA and symptom scale of EORTC QLQ C30 (Table 3).
Table 3.
Correlations between PHQ-9, MOCA, and EORTC QLQ C30 score at TP 2
| Correlations (TP 2) | |||||||
|---|---|---|---|---|---|---|---|
| PHQ-9 | MOCA | EORTC QLQ C30 | |||||
| Functional | Symptom | Global health and QoL | |||||
| PHQ-9 | Pearson Correlation | 1 | − 0.083 | 0.109 | 0.205 | − 0.144 | |
| Sig. (2-tailed) | ns | ns | ns | ns | |||
| N | 60 | 60 | 60 | 60 | 60 | ||
| MOCA | Pearson Correlation | − 0.083 | 1 | 0.153 | − .328* | − 0.018 | |
| Sig. (2-tailed) | ns | ns | 0.034 | ns | |||
| N | 60 | 60 | 60 | 60 | 60 | ||
| EORTC QLQ C30 | Functional scale | Pearson Correlation | 0.109 | 0.153 | 1 | − 0.130 | 0.171 |
| Sig. (2-tailed) | ns | ns | ns | ns | |||
| N | 60 | 60 | 60 | 60 | 60 | ||
| Symptom scale | Pearson Correlation | 0.205 | − .328* | − 0.130 | 1 | − 0.212 | |
| Sig. (2-tailed) | ns | 0.034 | ns | ns | |||
| N | 60 | 60 | 60 | 60 | 60 | ||
| Global health and QoL | Pearson Correlation | − 0.144 | − 0.018 | 0.171 | − 0.212 | 1 | |
| Sig. (2-tailed) | ns | ns | ns | ns | |||
| N | 60 | 60 | 60 | 60 | 60 | ||
**Correlation is significant at the 0.01 level (2-tailed)
TP2: Time-point 2; PHQ-9: Patient Health Questionnaire; MOCA: Montreal Cognitive Assessment; EORTC QLQ C30: European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire
Discussion
The number of long-term survivors of hematological malignancies is continuously increasing after the HSCT. Thus, HSCT has become the most acclaimed treatment of choice for remission in patients suffering from leukemia. However, despite increase in number of survivors, clinicians have reported that patients suffer from short term and long term complications in psychological functioning and QoL [12]. Therefore, various studies have attempted to evaluate the effect of HSCT on psychological symptoms and QoL, however, this led to heterogenous study design, population, assessment tools, assessment time frames and outcome. In general, evidence have suggested recovery in patients in years following HSCT [13, 14].
It is a well-known fact that there is a negative psychological effect of acute leukemia on survivors at the time of diagnosis and even throughout their life. A study reported high distress score in long-term survivors post HSCT as per the Brief symptom inventory scale. It has also observed that anxiety and depression is experienced by the patients during the treatment and some exhibit post-traumatic stress disorder after HSCT. Thus, such neurobehavioral diseases during leukemia or post-HSCT could adversely affect the QoL of the patients. Chemotherapy could also hamper the day-to-day life of the patients, leading to fatigue and pain [15]. A clinical trial investigated the QoL of the patients following allogeneic stem cell transplant for myelofibrosis through the functional assessment of cancer therapy-bone marrow transplantation (FACT-BMT) scale. Their results showed a decrease in QoL on day 30, followed by improvement in QoL post 1 year of BMT [16].
In the current study, we observed high PHQ-9 whereas low MOCA score in leukemia patients before HSCT indicating depressive symptoms and impaired cognition. This could be due to the adverse effect of the disease on the neurological behavior of the patients. Moreover, chemotherapy has also been reported to adversely affect the neurological behavior of the patients. In our recent systematic review also, we reported that chemotherapy lead to adverse cognitive impact in leukemia patients [17]. Likewise, studies have indicated that leukemia has led to development of depression like symptoms in the patients. A study reported that around 18% of the acute leukemia patients had clinically significant depressive symptoms [18]. A similar study reported that around 24% of included CLL patients had clinically significant depressive symptoms [19]. An observational study reported the neurological and cognitive problems in children who received chemotherapy or radiotherapy during the leukemia treatment [20]. A cross-sectional study reported that higher-risk CLL patients had impaired memory and executive function, suggesting that disease biology contributes to cognitive impairment independent of treatment [21]. Few studies have reported cognitive deficits in ALL survivors [22, 23]. Furthermore, in the current study we observed low EORTC QLQ C30 scores indication poor QoL of leukemia patients. A systematic review concluded that survivors of acute leukemia have low QoL because they interfere with survivors’ activities of daily living and ability to carry out social roles [24]. Moreover, depressive behavior and cognitive impairment may add on to the low QoL of the patients.
Further in the current study we observed a significant improvement in PHQ-9 and MOCA scores. In EORTC QLQ C30 scores, there was improvement in functional scale and global health & QoL scale whereas there was decrease in symptom scale after 30 days of HSCT. This indicates that in short-term HSCT helps to alleviate depressive symptoms, cognition, and few parameters of QoL of the leukemia patients. In literature there are contradictory results regarding the impact of HSCT on the depressive symptoms, cognition and QoL of the cancer patients [25, 26]. Studies have shown that depressive symptoms may even be observed in survivors post 5-years of transplant [26]. However, short-term impact of HSCT on psychological behavior and QoL is not clear from current available literature. It has been reported that preventive measures in HSCT receiving patients addressing depressive symptoms, sleep difficulties and fatigue may help to improve cognitive functioning [27]. Another cohort study of CML patients who received HSCT reported decline in depressive symptoms over post-HSCT [28]. A cross-sectional study aimed to determine the depressive symptoms and QoL of HSCT survivors and their spouses [29]. They reported no clinically significant difference between the depressive symptoms and QoL among HSCT survivors and their spouses [29]. A study reported significant systematic decrease in physical symptoms in time, moderated by the type of disease, transplant, and preparatory treatment (conditioning) [30]. This is in accordance to the current study where we observed decease in symptom scale score after HSCT.
The main limitation of the study is the small sample size and short follow-up. Another limitation is that a heterogeneous population included in the current study may also affect the outcome. Thus, future studies assessing the discussed parameters on different time points in homogeneous population are required.
Conclusion
In conclusion, the present study suggests that post 30 days of HSCT, there is improvement in cognition, depression, and QoL. Allogenic BMT has the potential to cure a significant proportion of patients with otherwise fatal diseases. Improved short-term survival exposes patients to long-term complications and side effects. All these late complications present with a great diversity in respect of frequency, time of onset, risk factors, prevention and treatment approaches and outcome. The long-term goal is the maintenance of health and to ensure the best possible QOL. Thus, further studies are required to check the impact on psychological behavior and QoL post HSCT for a longer duration.
Acknowledgements
The authors would like to thank the staff of Rajiv Gandhi Cancer Institute and Research Centre, New Delhi for permitting us to carry out this research
Author’s Contribution
RJ: Design, Conducted study, manuscript writing AG: Data analysis and manuscript writing ZK: Design, Conducted study, manuscript writing DB: Design, Data analysis, Editing Nidhi: Manuscript writing and editing M. AK: Design, Conceptualization of idea, data analysis, final manuscript writing and editing.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declarations
Conflict of interest
None.
Informed consent
Informed consent was obtained from each participant prior to inclusion in the study.
Statement Regarding the Welfare of Animals
Not Applicable.
Ethical approval
The study had been approved by the Institutional Review Board (IRB) (REF/2019/12/030223).
Footnotes
Rhythm Joshi and Aakriti Garg share equal authorship in this paper.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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