Health-related quality of life in patients with steroid-refractory acute graft-versus-host disease
Abstract
Background
Evidence regarding health-related quality of life (HRQoL) in patients with steroid-refractory acute graft-versus-host disease (SR-aGvHD) is lacking. Evaluating HRQoL was a secondary objective of the HOVON 113 MSC trial. Here we describe the outcomes of the EQ-5D-5L, EORTC QLQ-C30, and FACT-BMT for all adult patients who completed these questionnaires at baseline (i.e., before the start of treatment; n = 26).
Methods
Descriptive statistics were used to describe baseline patient and disease characteristics, EQ-5D dimension scores and values, EQ VAS scores, EORTC QLQ-C30 scale/item and summary scores, and FACT-BMT subscale and total scores.
Results
The mean EQ-5D value was 0.36. In total, 96% of the patients reported problems with usual activities, 92% with pain/discomfort, 84% with mobility, 80% with self-care, and 72% with anxiety/depression. The mean EORTC QLQ-C30 summary score was 43.50. Mean scale/item scores ranged from 21.79 to 60.00 for functioning scales, from 39.74 to 75.21 for symptom scales, and from 5.33 to 91.67 for single items. The mean FACT-BMT total score was 75.31. Mean subscale scores ranged from 10.09 for physical well-being to 23.94 for social/family well-being.
Conclusion
Our study showed that HRQoL in patients with SR-aGvHD is poor. Improving HRQoL and symptom management in these patients should be a top priority.
Novelty statements
What is the new aspect of your work?
To the best of our knowledge, this is the first study describing health-related quality of life (HRQoL) in patients with steroid-refractory acute graft-versus-host disease (SR-aGvHD).
What is the central finding of your work?
HRQoL in patients with SR-aGvHD is poor. Patients predominantly reported problems with physical functioning/well-being, role functioning/functional well-being, and pain/discomfort. The most distressing symptoms were diarrhea, fatigue, appetite loss, and insomnia.
What is (or could be) the specific clinical relevance of your work?
Our study underlines the debilitating nature of SR-aGvHD and highlights the importance of improving care of patients with the disease. To improve care of these patients, improving HRQoL and symptom management should be a top priority.
1 INTRODUCTION
Acute graft-versus-host disease (aGvHD) is a debilitating and life-threatening complication of hematopoietic stem cell transplantation (HSCT), occurring in 30%–50% of the patients.1 Systemic corticosteroids are the mainstay of first-line treatment for aGvHD. If there is disease progression after 3–5 days of treatment or there is no response to treatment after 1 week, aGvHD is considered steroid-refractory.2 About 35%–50% of the patients will develop steroid-refractory aGvHD (SR-aGvHD), which is associated with a very poor prognosis.3, 4 The 6-month survival rate is only 50%.5
Patients with SR-aGvHD are generally treated with immunosuppressive drugs, but no optimal treatment has been identified.5, 6 Consequently, the choice of treatment is often based on the discretion of the physicians, which is, among other factors, guided by the risk of (severe) toxicities and the potential exacerbation of preexisting comorbidities.7 Although these factors may interfere with a patient's health-related quality of life (HRQoL), patient-reported outcomes (PROs) are not routinely included in the treatment decision-making process.8, 9 Incorporating PROs in daily clinical practice may, however, improve the understanding of symptom burden, patient–physician communication, and patient satisfaction.9, 10 This is particularly important given the already poor prognosis of these patients. Besides improving treatment decision-making, insight into PROs (such as HRQoL) may also facilitate clinical and economic evaluations of treatments, since PROs contribute to a better understanding of the impact of the disease and its treatment.8
To date, evidence regarding HRQoL in patients with SR-aGvHD, either measured by generic or disease-specific questionnaires, is lacking. To obtain insight into HRQoL in these patients, three HRQoL questionnaires were included as a secondary outcome measure in the Haemato Oncology Foundation for Adults in the Netherlands (HOVON) 113 MSC trial,11, 12 which was conducted by the REgeneration THRough IMmunomodulation (RETHRIM) consortium. RETHRIM was funded through the European Union's Horizon 2020 research and innovation program.13 Here we describe the outcomes of the three questionnaires for all adult patients who completed these questionnaires at baseline.
2 METHODS
2.1 Data source and patients
The HOVON 113 MSC trial11, 12 was a European, multi-national, placebo-controlled, randomized phase III trial in patients who underwent HSCT for hematological diseases and subsequently developed SR-aGvHD. In the trial, SR was defined as progressive disease, mixed response, or grade IV disease after at least 5 days, or stable grade II/III disease after at least 7 days of treatment with prednisolone (or equivalent) and a calcineurin-inhibitor at therapeutic trough levels. The trial was approved by the national independent ethics committees of all participating centers, and was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization Good Clinical Practice guideline, and the European Union Clinical Trial Directive 2001/20/EC. All patients provided written informed consent.
The primary objective of the trial was to assess whether early addition of mesenchymal stromal cells (MSC) to standardized second-line treatment improved response to treatment. Evaluating HRQoL was a secondary objective. The following HRQoL questionnaires were used in the trial: the five-level version of the EuroQol-5D (EQ-5D-5L), the third version of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), and the fourth version of the Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT). These questionnaires were considered most relevant from both a clinical and economic perspective. All patients were asked to complete the questionnaires at baseline (i.e., before the start of treatment), at day 29, and at 3, 6, 12, and 24 months.
Between October 2014 and November 2019, a total of 41 patients were randomly assigned to receive MSC (n = 20) or placebo (n = 21) in addition to standardized second-line treatment. In total, 7 patients were children, and 34 patients were adults. For this analysis, we selected all adult patients who completed at least one of the questionnaires at baseline.
2.2 HRQoL questionnaires
The EQ-5D-5L is a generic, preference-based questionnaire consisting of a short descriptive system and a visual analogue scale (EQ VAS). The descriptive system comprises five dimensions, each describing a different aspect of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has five levels of severity, ranging from no problems (1) to extreme problems/unable to (5). The responses to the five dimensions can be combined to describe a patient's EQ-5D profile (or health state). The value attached to an EQ-5D profile (i.e., an EQ-5D value) can be generated by using a country-specific value. This value represents the utility that a patient would derive from being in a specific health state. EQ-5D values generally range from <0 to 1, where negative values represent health states worse than death, 0 is the value of a health state equivalent to death, and 1 is the value of perfect health. The EQ VAS records a patient's self-rated health on a scale from 0 to 100, with 0 indicating the worst imaginable health and 100 the best imaginable health.14
The EORTC QLQ-C30 is a cancer-specific questionnaire consisting of a global health status/QoL scale, five functional scales (i.e., physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), three symptom scales (i.e., fatigue, nausea/vomiting, and pain), and six single items (i.e., dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The functional scales, symptom scales, and single items are scored on a four-point scale (i.e., not at all, a little, quite a bit, and very much); the global health status/QoL scale is scored on a seven-point scale (ranging from very poor to excellent). A higher score represents a better HRQoL (for the global health status/QoL scale), a higher level of functioning (for the functioning scales), or a higher level of symptoms (for the symptom scales and single items).15
The FACT-BMT is a disease-specific questionnaire consisting of the FACT-General (FACT-G) and the BMT subscale. The FACT-G comprises 27 items and is designed to measure four dimensions of HRQoL in cancer patients: physical well-being, social/family well-being, emotional well-being, and functional well-being. The BMT subscale includes 23 items and assesses the effect of specific BMT-related concerns. All items are scored on a five-point scale (i.e., not at all, a little bit, somewhat, quite a bit, and very much). The higher the score, the better the HRQoL.16
2.3 Data analysis
Data were analyzed using descriptive statistics. Continuous variables were presented as mean with standard deviation (SD), median with interquartile range (IQR), and range. Categorial variables were described as frequency (n) with proportion (%). To generate EQ-5D values, we used the country-specific value sets of the investigator site where the patient was treated, that is, the value sets of Belgium,17 Germany,18 Spain,19 and the Netherlands.20 EORTC QLQ-C30 scale and item scores were computed according to the EORTC QLQ-C30 scoring manual.15 A summary score was calculated from the scores of 13 of the 15 scales/items (the global health status/QoL scale and the financial difficulties item were not included).21, 22 FACT-BMT subscale (or dimension) and total scores were computed using the FACT-BMT scoring document.16 The FACT-G total score was calculated from the scores of the FACT-G subscales; the FACT-BMT total score was derived from the scores of the FACT-G subscales and the BMT subscale. All analyses were conducted using STATA statistical analysis software, version 16.23
3 RESULTS
3.1 Patients
At baseline, 26 of the 34 adult patients completed at least one of the questionnaires. Eight patients did not complete any questionnaire, of which seven patients died shortly after inclusion in the trial (i.e., within 17 days on average). Twenty-three patients completed all three questionnaires.
Baseline patient and disease characteristics are presented in Table 1. The patients' age ranged from 31 to 70 years, with a mean age of 55 years (SD: 11). Thirteen patients (50%) were female. The mean Karnofsky score was 49 (SD: 24). About two-thirds of the patients (65%) were transplanted for leukemia and 17 patients (65%) received unrelated donor grafts. Most patients (85%) were diagnosed with severe aGvHD (i.e., grade III or IV) and almost all patients had gut involvement (96%).
| n = 26 | |
|---|---|
| Age, years | |
| Mean (SD) | 55 (11) |
| Median (IQR) | 58 (51–64) |
| Range | 31–70 |
| Gender, n (%) | |
| Male | 13 (50%) |
| Female | 13 (50%) |
| Country of investigator site, n (%) | |
| Belgium | 2 (8%) |
| Germany | 7 (27%) |
| Spain | 5 (19%) |
| The Netherlands | 12 (46%) |
| Karnofsky performance status | |
| Mean (SD) | 49 (24) |
| Median (IQR) | 40 (30–70) |
| Range | 20–90 |
| Hematologic malignancy, n (%) | |
| Myelodysplasia | 4 (15%) |
| Leukemia | 17 (65%) |
| Lymphoma | 2 (8%) |
| Other | 3 (12%) |
| Type of donor, n (%) | |
| Mismatched unrelated | 5 (19%) |
| Matched unrelated | 12 (46%) |
| Mismatched related | 1 (4%) |
| Matched related | 8 (31%) |
| Grade of aGvHD, n (%) | |
| II | 4 (15%) |
| III | 18 (69%) |
| IV | 4 (15%) |
| Organ involvement, n (%) | |
| Gut | 18 (69%) |
| Liver | 1 (4%) |
| Both | 7 (27%) |
- Abbreviations: aGvHD, acute graft-versus-host disease; IQR, interquartile range; n, number; SD, standard deviation.
3.2 HRQoL according to the EQ-5D-5L
Of the 26 patients, 23 patients completed the entire EQ-5D-5L questionnaire, two patients provided incomplete profile data (i.e., data on anxiety/depression were missing), and one patient did not complete the questionnaire at all. Table 2 presents a summary of the results. Almost all patients reported problems (i.e., levels 2–5) with respect to usual activities (96%) and pain/discomfort (92%). Also, for the other dimensions, problems were reported by the majority of patients; 84% reported problems with mobility, 80% with self-care, and 72% with anxiety/depression. None of the patients reported perfect health (i.e., EQ-5D profile 11 111), and one patient reported the worst possible health state (i.e., EQ-5D profile 55 555). EQ-5D values (generated by using the pertinent value sets) ranged from −0.66 to 0.92, with a mean value of 0.36 (SD: 0.39). Four patients (16%) had a negative EQ-5D value (i.e., a health state perceived as worse than death). The mean EQ VAS score was 41 (SD: 15).
| n = 25a | |
|---|---|
| Dimensions, n (%) | |
| Mobility | |
| No problems walking (1) | 4 (16%) |
| Slight problems walking (2) | 4 (16%) |
| Moderate problems walking (3) | 6 (24%) |
| Severe problems walking (4) | 5 (20%) |
| Unable to walk (5) | 6 (24%) |
| Self-care | |
| No problems washing or dressing myself (1) | 5 (20%) |
| Slight problems washing or dressing myself (2) | 5 (20%) |
| Moderate problems washing or dressing myself (3) | 4 (16%) |
| Severe problems washing or dressing myself (4) | 3 (12%) |
| Unable to wash or dress myself (5) | 8 (32%) |
| Usual activities | |
| No problems doing my usual activities (1) | 1 (4%) |
| Slight problems doing my usual activities (2) | 3 (12%) |
| Moderate problems doing my usual activities (3) | 3 (12%) |
| Severe problems doing my usual activities (4) | 4 (16%) |
| Unable to do my usual activities (5) | 14 (56%) |
| Pain/discomfort | |
| No pain/discomfort (1) | 2 (8%) |
| Slight pain/discomfort (2) | 7 (28%) |
| Moderate pain/discomfort (3) | 10 (40%) |
| Severe pain/discomfort (4) | 3 (12%) |
| Extreme pain/discomfort (5) | 3 (12%) |
| Anxiety/depression | |
| Not anxious/depressed (1) | 5 (20%) |
| Slightly anxious/depressed (2) | 9 (36%) |
| Moderately anxious/depressed (3) | 6 (24%) |
| Severely anxious/depressed (4) | 1 (4%) |
| Extremely anxious/depressed (5) | 2 (8%) |
| Missing | 2 (8%) |
| Patients reporting perfect health (i.e., 11 111), n (%) | 0 (0%) |
| Patients reporting the worst possible health state (i.e., 55 555), n (%) | 1 (4%) |
| Patients reporting a health state worse than death, n (%) | 4 (16%) |
| EQ-5D value | |
| Mean (SD) | 0.36 (0.39)b |
| Median (IQR) | 0.40 (0.22–0.68)b |
| Range | −0.66-0.92b |
| EQ VAS score | |
| Mean (SD) | 41 (15) |
| Median (IQR) | 40 (30–50) |
| Range | 0–75 |
- Abbreviations: EQ, EuroQol; HRQoL, health-related quality of life; IQR, interquartile range; n, number; SD, standard deviation; VAS, visual analogue scale.
- a One patient did not complete the questionnaire at all.
- b Missing for two of the 25 patients.
3.3 HRQoL according to the EORTC QLQ-C30
All patients completed the EORTC QLQ-C30 questionnaire, of which 24 patients completed the entire questionnaire. Data were incomplete for two patients. A summary of the results is presented in Table 3. The mean global health status/QoL scale score was 24.00 (SD: 16.72). Mean scale/item scores ranged from 21.79 (for role functioning) to 60.00 (for cognitive functioning) for the functioning scales, from 39.74 (for nausea/vomiting) to 75.21 (for fatigue) for the symptom scales, and from 5.33 (for constipation) to 91.67 (for diarrhea) for the single items. The mean summary score was 43.50 (SD: 12.74).
| n | Mean (SD) | Median (IQR) | Range | |
|---|---|---|---|---|
| Global health status/QoL scale (score range: 0–100a) | 25 | 24.00 (16.72) | 16.67 (16.67–33.33) | 0.00–58.33 |
| Functioning scales (score range: 0–100a) | ||||
| Physical functioning | 26 | 33.33 (29.09) | 30.00 (6.67–60.00) | 0.00–86.67 |
| Role functioning | 26 | 21.79 (30.83) | 0.00 (0.00–33.33) | 0.00–83.33 |
| Emotional functioning | 24 | 46.18 (25.06) | 50.00 (25.00–62.50) | 0.00–100.00 |
| Cognitive functioning | 25 | 60.00 (27.64) | 66.67 (50.00–83.33) | 0.00–100.00 |
| Social functioning | 25 | 29.33 (32.02) | 16.67 (0.00–50.00) | 0.00–100.00 |
| Symptom scales (score range: 0–100a) | ||||
| Fatigue | 26 | 75.21 (25.01) | 83.33 (55.56–100.00) | 22.22–100.00 |
| Nausea/vomiting | 26 | 39.74 (32.69) | 33.33 (16.67–50.00) | 0.00–100.00 |
| Pain | 26 | 60.90 (35.26) | 66.67 (33.33–83.33) | 0.00–100.00 |
| Single items (score range: 0–100a) | ||||
| Dyspnea | 26 | 26.92 (34.02) | 16.67 (0.00–33.33) | 0.00–100.00 |
| Insomnia | 25 | 61.33 (32.89) | 66.67 (33.33–100.00) | 0.00–100.00 |
| Appetite loss | 25 | 70.67 (30.91) | 66.67 (33.33–100.00) | 0.00–100.00 |
| Constipation | 25 | 5.33 (15.75) | 0.00 (0.00–0.00) | 0.00–66.67 |
| Diarrhea | 24 | 91.67 (22.52) | 100.00 (100.00–100.00) | 0.00–100.00 |
| Financial difficulties | 25 | 28.00 (36.87) | 0.00 (0.00–33.33) | 0.00–100.00 |
| Summary (score range: 0–100a) | 24 | 43.50 (12.74) | 42.31 (37.84–50.11) | 20.51–72.05 |
- Abbreviations: EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; (HR)QoL, (health-related) quality of life; IQR, interquartile range; n, number; SD, standard deviation.
- a A higher score represents a better HRQoL (for the global health status/QoL scale), a higher level of functioning (for the functioning scales), or a higher level of symptoms (for the symptom scales and single items).
3.4 HRQoL according to the FACT-BMT
In total, 24 of the 26 patients completed the entire FACT-BMT questionnaire. Two patients provided incomplete data. Table 4 presents a summary of the results. The mean subscale score was 10.09 (SD: 5.63) for physical well-being, 23.94 (SD: 3.27) for social/family well-being, 13.67 (SD: 5.94) for emotional well-being, 9.79 (SD: 4.62) for functional well-being, and 18.55 (SD: 5.68) for BMT. Mean FACT-G and FACT-BMT total scores were 57.34 (SD: 11.39) and 75.31 (SD: 13.56), respectively.
| n | Mean (SD) | Median (IQR) | Range | |
|---|---|---|---|---|
| Subscales | ||||
| Physical well-being (score range: 0–28a) | 26 | 10.09 (5.63) | 10.25 (6.00–13.00) | 0.00–22.00 |
| Social/family well-being (score range: 0–28a) | 26 | 23.94 (3.27) | 24.25 (21.00–26.83) | 18.00–28.00 |
| Emotional well-being (score range: 0–24a) | 24 | 13.67 (5.94) | 15.00 (9.50–18.00) | 2.00–22.00 |
| Functional well-being (score range: 0–28a) | 25 | 9.79 (4.62) | 10.50 (6.00–12.83) | 0.00–18.00 |
| Bone marrow transplant (score range: 0–40a) | 25 | 18.55 (5.68) | 19.00 (15.56–21.11) | 7.00–32.50 |
| FACT-G (score range: 0–108a) | 24 | 57.34 (11.39) | 58.50 (49.00–65.42) | 33.00–74.87 |
| FACT-BMT (score range: 0–148a) | 24 | 75.31 (13.56) | 76.58 (66.67–85.92) | 48.00–97.50 |
- Abbreviations: FACT-BMT, Functional Assessment of Cancer Therapy-Bone Marrow Transplantation; FACT-G, Functional Assessment of Cancer Therapy-General; HRQoL, health-related quality of life; IQR, interquartile range; n, number; SD, standard deviation.
- a A higher score represents a better HRQoL.
4 DISCUSSION
This is the first study describing HRQoL in patients with SR-aGvHD. Twenty-six of the 34 adult patients who were included in the HOVON 113 MSC trial completed at least one of the HRQoL questionnaires at baseline. Across all questionnaires, most patients reported a poor HRQoL. They predominantly reported problems with physical functioning/well-being, role functioning/functional well-being, and pain/discomfort. The most distressing symptoms were diarrhea, fatigue, appetite loss, and insomnia. According to the EQ-5D-5L results, four patients (16%) considered their health state to be worse than death. One patient even reported the worst possible health state. These results underline the debilitating nature of SR-aGvHD and highlight the importance of improving care of patients with the disease.
Remarkably, we found a much lower mean score for the EORTC QLQ-C30 global health status/QoL scale (24.00; score range: 0–100) than for the EORTC QLQ-C30 summary score (43.50; score range 0–100). Since both scores can be used as summary measures, it would have been reasonable to expect that they were comparable. However, Giesinger et al.22 previously demonstrated that the summary score was psychometrically more robust than the global health status/QoL scale score. Our results may provide further support for this, considering that the mean EORTC QLQ-C30 summary score was comparable to the mean EQ VAS score (41; score range: 0–100).
Another notable finding of our study is the substantial difference between the social (sub)scales scores of the EORTC QLQ-C30 and the FACT-BMT. Taking into account the possible score range of both questionnaires, the mean scale score for social functioning (29.33; score range: 0–100) was much lower than the mean subscale score for social/family well-being (23.94; score range: 0–28). This may be due to the fact that both (sub)scales measure different aspects, despite the similarity of their names. The EORTC QLQ-C30 social functioning scale measures whether the disease interferes with a patient's social activities and family life, whereas the FACT-BMT social/family well-being subscale focuses on relationships and support from friends/family.24 As our patients were hospitalized at the time of completing the questionnaires, it is very likely that they experienced more problems with social activities and family life than with relationships and support from friends/family. It is worth noting that previous studies24, 25 already showed low correlations between the social (sub)scales scores of the EORTC QLQ-C30 and the FACT-BMT in other patient populations.
To facilitate the interpretation of our results, normative data can be used to compare HRQoL in our patient population with HRQoL in the general population of a country or region. For countries represented in our study, EQ-5D-5L population norms ranged from 0.84 for Belgium to 0.90 for Spain.17-20 The mean utility score assigned to the EQ-5D scores of patients in our study was only 0.36. European normative data for the EORTC QLQ-C30 also showed that HRQoL was better in the general population. Across 13 European countries, mean scale/items scores (a higher score represents a higher level of functioning/symptoms) ranged from 74.2 to 86.2 for the functioning scales, from 5.9 to 29.5 for the symptom scales, and from 9.5 to 26.6 for the single items.26 In our study, mean scale/items scores ranged from 21.79 to 60.00 for the functioning scales, from 39.74 to 75.21 for the symptom scales, and from 5.33 to 91.67 for the single items (see Table 3). National or regional normative data are, to the best of our knowledge, not (yet) available for the FACT-G/BMT.24
More importantly, HRQoL in our patients was not only lower than that of the general population, but also lower than HRQoL in patients with hematologic malignancies without SR-aGvHD.25, 27 For example, Kurosawa et al.28 found that patients with acute (myeloid and lymphoblastic) leukemia who underwent HSCT and did not develop aGvHD had a mean EQ-5D value of 0.80, which was 0.36 in our patients. Furthermore, for bone marrow transplant recipients, Kopp et al.25 reported mean scores of 68.16 for the EORTC QLQ-C30 global health status/QoL scale (score range: 0–100), 84.46 for the FACT-G (score range: 0–108), and 118.23 for the FACT-BMT (score range: 0–148). By comparison, in our study, these scores were considerably lower: 24.00, 57.34, and 75.31, respectively. It should, however, be noted that comparing HRQoL across studies can be challenging, partly due to differences in study designs and patient populations. Therefore, a future study evaluating HRQoL in patients with hematologic malignancies undergoing HSCT throughout the entire disease course may provide valuable insights into how different disease stages, such as no aGvHD, aGvHD, and SR-aGvHD, impact HRQoL in these patients.
A few limitations should be considered while interpreting the results of our study. First, as in all questionnaire-based studies, results could only be derived from patients who completed the questionnaire(s). Eight of our patients did not complete any questionnaire, of which seven died shortly after inclusion in the trial. Therefore, our results seem to represent results of patients who felt fit enough to complete the questionnaire(s) or patients who were motivated by concerns or symptoms. Second, the low number of patients hampered analyzing the impact of specific baseline characteristics, such as hematologic malignancy and organ involvement. Finally, our results were derived from only one measurement (at baseline). Although some patients completed the questionnaires at multiple time points, an adequate description of the impact of the disease (and its treatment) on HRQoL over time was not feasible (due to the low number of patients). Nevertheless, our results provide important insight into HRQoL and symptom burden at baseline, that is, before start of treatment, which may facilitate future (clinical and economic) evaluations of treatments for SR-aGvHD.
In conclusion, our study showed that HRQoL in patients with SR-aGvHD is poor, especially in comparison with HRQoL in general populations but also in comparison with patients with hematologic malignancies without SR-aGvHD. To improve care of patients with SR-aGvHD, improving HRQoL and symptom management should be a top priority. Consequently, monitoring HRQoL and symptoms in daily clinical practice is essential.
AUTHOR CONTRIBUTIONS
Hedwig M. Blommestein, Mattia Algeri, Willem E. Fibbe, Liesbeth Oosten, Carin A. Uyl-de Groot contributed to the protocol of the HOVON 113 MSC trial. Brenda Leeneman, Hedwig M. Blommestein, Annemieke van Dongen-Leunis, and Frederick W. Thielen designed the current study and interpreted the data. Brenda Leeneman analyzed the data and wrote the manuscript. All authors provided feedback and approved the final manuscript.
ACKNOWLEDGMENTS
The authors thank all RETHRIM members and participating centers for their manifold ways of supporting this manuscript.
FUNDING INFORMATION
The HOVON 113 MSC trial was funded through the European Union's Horizon 2020 research and innovation program (grant agreement number: 643580) and the Dutch Cancer Society.
CONFLICT OF INTEREST STATEMENT
The authors declare that there is no conflict of interest.
Open Research
DATA AVAILABILITY STATEMENT
The dataset used in this manuscript can be obtained from the corresponding author on reasonable request.
