Abstract
Chimeric antigen receptor (CAR) T-cell therapy has transformed the care of patients with relapsed/refractory B-cell-derived hematologic malignancies. To date, six CAR T-cell therapies, targeting either CD19 or B-cell maturation antigen, have received regulatory approval. Along with the promising survival benefit, CAR T-cell therapy is associated with potentially life-threatening adverse events, including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. While clinical trials evaluating CAR T-cell therapy consistently report the incidence of these adverse events, most trials do not collect health-related quality of life (HRQoL) data. As such, the impact of the CAR T-cell therapy process and related adverse events on the physical and psychological well-being of patients remains uncertain. HRQoL and other patient-reported outcome (PRO) assessments in patients with relapsed or refractory hematologic malignancies are of utmost importance, as individuals may have unmet needs and a high demand for tolerable therapy if a cure is not obtained. In addition, it is important to standardize methods of data collection to better assess the impact of CAR T-cell therapy on quality of life, optimize patients’ care and costs, and enable comparisons between different studies. We conducted a literature search up to June 2023 to identify the HRQoL tools used in clinical trials and in real-world studies investigating CAR T-cell therapy in patients with lymphomas or leukemias. In the present comprehensive review, we summarize the most commonly used CAR T-cell specific and non-specific HRQoL tools and discuss how the use of HRQoL and other PRO tools may be optimized.
Introduction
Chimeric antigen receptor (CAR) T-cell therapy has substantially transformed the care of patients with relapsed/ refractory B-cell-derived hematologic malignancies, including multiple myeloma, leukemias and lymphomas. To date, six CAR T-cell therapies have received regulatory approval: four targeting CD19, axicabtagene ciloleucel (axicel), brexucabtagene autoleucel (brexu-cel), lisocabtagene maraleucel (liso-cel), and tisagenlecleucel (tisa-cel); and two targeting B-cell maturation antigen, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel).1-3 Although CAR T-cell therapy is given with a curative intent, it is associated with potentially life-threatening adverse events, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).4 These toxicities result from the supra-physiologic activation of the immune system following CAR T-cell infusion, which leads to the overproduction of inflammatory cytokines, and subsequently to a hyper-inflammatory state.2,5,6 In addition, long-term adverse events that may arise after CAR T-cell therapy include an increased risk of infection, neurocognitive deficits, emergence of new or exacerbation of existing autoimmune toxicities, and development of recurrent or second primary malignancies.2 While clinical trials evaluating CAR T-cell therapy consistently report the frequency and grades of these unique toxicities, most trials do not collect health-related quality of life (HRQoL) data. In a review assessing the regularity of using HRQoL in ongoing clinical trials, Raymakers and colleagues7 examined 424 trials registered at the United States National Institutes of Health National Library of Medicine (http://clinicaltrials.gov) investigating CAR T-cell therapy in oncology. HRQoL was a primary or secondary objective in only 29 studies (6.8%), highlighting the current lack of adequate assessment of quality of life (QoL) in patients treated with CAR T-cell therapy.7
HRQoL tools assess the impact of treatment-specific adverse events on mental, emotional, social, and physical functions. Hence, due to the under-evaluation of HRQoL data, the impact of the CAR T-cell therapy process and related adverse events on the physical and psychological well-being of patients remains uncertain.6-8 Monitoring HRQoL following CAR T-cell therapy is important to aid patients through their recovery process. Indeed, it is anticipated that patients may regain function faster, feel more involved in their management plan, identify and control their symptoms via personalized interventions/actions, and utilize medical resources less frequently (i.e., shorter duration of hospitalization, fewer emergency room visits).6 Moreover, other patient-reported outcomes (PRO), which promote patients’ empowerment, have not been integrated into treatment guidelines.5,9 HRQoL and other PRO assessments in patients with relapsed or refractory hematologic malignancies are paramount, as individuals may have unmet needs and a high demand for tolerable therapy if cure is not obtained.8 It is also crucial to standardize data collection methods, including the choice of the questionnaire, measurement time, and statistical analysis, to better assess the impact of treatment on QoL, optimize patients’ care and costs, and enable comparisons between studies.10 In this context, we conducted a PubMed search to identify the HRQoL tools used in clinical trials and real-world studies investigating CAR T-cell therapy in patients with lymphomas or leukemias. In the present, comprehensive review, we summarize our findings regarding the existing HRQoL tools and discuss how the use of HRQoL and other PRO tools may be optimized.
Methods
We conducted a comprehensive literature search in PubMed up to July 2023 to identify the PRO tools used in clinical trials and real-world studies evaluating CAR T-cell anti-CD19 therapy in patients with B-cell lymphomas or leukemias. The following keywords were used ([CAR T-cell OR CAR-T] OR axicabtagene OR brexucabtagene OR lisocabtagene OR tisagenlecleucel) AND (haematolog* OR hematolog* OR lymphoma OR leukemia OR leukaemia) AND (“quality of life” OR “patient-reported outcomes” OR HRQoL OR PRO OR PROs OR QoL), and no filters were applied. This PubMed search was complemented with a hand search of references of relevant reviews and systematic reviews. Selected papers were restricted to those published in English and reporting studies evaluating QoL in patients with lymphomas/leukemias and receiving CAR T-cell anti-CD19 therapy. Interventional studies – single arm or randomized controlled trials – real-world studies, and qualitative studies were included. Studies evaluating CAR T-cell therapy not targeting CD19 in patients with multiple myeloma, other hematologic cancers or with solid tumors were excluded. Publications reporting only the efficacy and safety results of studies were also excluded.
The PubMed search retrieved 264 publications (Online Supplementary Figure S1). Our hand search yielded five additional relevant publications (including one paper published after the search cut-off date). Twenty-seven publications were selected, reporting data on a total of 25 studies: one validation study for a CAR T-cell specific tool, eight single-arm studies, two randomized controlled trials, ten real-world studies, and four quantitative studies.
Scales to assess health-related quality of life in chimeric antigen receptor T-cell studies: where do we stand?
CAR T-cell anti-CD19 therapy is usually administered in a single infusion. However, this treatment involves multiple phases prior to the infusion and rigorous monitoring of acute and long-term adverse events afterwards (Figure 1).2,11,12 Since CRS and ICANS develop within a few days of CAR T-cell infusion, either concomitantly or consecutively, it is suggested that HRQoL be evaluated before conditioning chemotherapy, once weekly or more frequently (twice or thrice) for the first 2 weeks after CAR T-cell infusion, and weekly for up to 1 month after the infusion.2,13 Early assessment of PRO data may aid in the identification of early toxicities related to CAR T-cell therapy such as CRS and ICANS and their impact on a patient’s QoL.9 Following this early phase, PRO collected monthly for the first year and then yearly are necessary for monitoring the long-term impact of CAR T-cell therapy and its associated adverse events and organizational burden on HRQoL.2,9
Several tools have been used in studies reporting HRQoL after CAR T-cell anti-CD19 therapy. Some of them assessed various domains in patients with cancer, regardless of cancer type, and others were disease-specific (e.g., lymphoma) or domain/symptom-specific (e.g., depression). However, the vast majority of the tools used were not specific to CAR T-cell therapy. In a systematic review, the European Quality of Life Five Dimension (EQ-5D), which is a standard scale for medico-economic evaluations, was the most commonly collected tool, measured in 65% of studies assessing HRQoL in patients with cancer treated with CAR T-cell therapy.7 It is worth mentioning that the EQ-5D is a non-cancer-specific scale that may also be used for other diseases or in healthy individuals (e.g., university students). Several forms of this questionnaire exist and are constituted of either three or five levels that allow the estimation of an EQ-5D index score and a visual analog scale (VAS) score.14 Of the cancer-specific scales, the most frequently used were the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30), the Functional Assessment of Cancer Therapy-General (FACT-G) and FACT-Lym, which is specific for lymphoma. The main shortcoming of the generic and cancer-specific PRO is that they may generate misleading results for patients receiving CAR T-cell products, due to the complexity of this therapy and the uniqueness of its toxicities.6,15 In addition, some PRO models assess the decline or improvement in HRQoL parameters using scores of general rather than specific populations, i.e., patients with the same cancer type.9 Such an approach may jeopardize the robustness of the results and their generalizability to clinical practice settings.9 To address the shortcomings of the generic and cancer-specific tools, Wang and colleagues13 recently reported the validation of the first CAR T-cell specific HRQoL assessment tool for use in hematologic malignancies, the MD Anderson Symptom Inventory (MDASI)-CAR module. The MDASI-CAR was developed according to guidance from the Food and Drug Administration. The MDASI-CAR tool consists of 29 items divided between 13 core and six interference items that constitute the general MDASI tool16 and ten module items that are specific to CAR T-cell therapy (Figure 2).13 Some limitations to the development of this CAR-T cell specific tool should be considered. Indeed, only 21 patients were included in the initial qualitative study that was used to generate the list of module items.15 Moreover, the validation study was conducted in a single institution, and included a limited number of patients (n=78). Furthermore, the majority of patients (68/78; 87.2%) were receiving one specific CAR T-cell product (axi-cel). The generalizability of the MDASI-CAR tool among patients with various hematologic malignancies and on different CAR T-cell therapies may be better assessed with larger multicenter longitudinal studies.13 This tool can be useful in assessing the impact of CAR T-cell therapy on the QoL of patients in the early phase after receiving the CAR T-cell infusion, but may be less effective in capturing disease-related QoL.
Figure 1.Treatment and monitoring of patients receiving chimeric antigen receptor T-cell therapy. T cells are collected from the patient through leukapheresis and modified in vitro by the addition of the chimeric antigen receptor (CAR) vector. The modified CAR T cells are later infused back after the patient has received conditioning chemotherapy during the week prior to infusing the CAR T cells. This conditioning therapy, also known as lymphodepletion therapy, typically includes fludarabine and/or cyclophosphamide. Patients who receive CAR T-cell therapy should be hospitalized for a minimum of 1 week after the infusion, as recommended by the CAR-T-cell Therapy Associated Toxicity (CARTOX) working group or benefit from equivalent monitoring depending on the different local organizations in the world. *Cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome usually appear within the first 2 weeks after CAR T-cell infusion.4 CAR: chimeric antigen receptor; D: day; AE: adverse events; CRS: cytokine release syndrome; ICANS: immune effector cell-associated neurotoxicity syndrome.
Table 1 presents the most frequently used non-CAR T-cell specific PRO/HRQoL tools in clinical studies assessing QoL in adults who received CAR T-cell therapy targeting CD19, and the specific MDASI-CAR tool. Of the non-specific tools, the EORTC QLQ-C30, a cancer-specific tool, and FACT-Lym evaluate many of the functions/symptoms that are assessed in the MDASI-CAR. The FACT-Lym is composed of the FACT-G and an additional lymphoma-specific subscale. Both EORTC QLQ-C30 and FACT-Lym cover cognitive, emotional, physical, and social/role functioning as well as some of the individual symptoms/items (fatigue, pain, disturbed sleep, lack of appetite, and nausea).
Figure 2.The stepwise approach used to develop the MDASI-CAR tool. The number of items for each item set is presented in parentheses. CAR: chimeric antigen receptor; MDASI-CAR: MD Anderson Symptom Inventory-chimeric antigen receptor.
Other tools used in the identified clinical studies enrolling adult patients included those that are specific to one function or one symptom, such as the Work Productivity and Activity Impairment Questionnaire: General Health (WPAI:GH); revised Edmonton Symptom Assessment Scale (ESAS17; assessing 9 symptoms); Hospital Anxiety and Depression Scale (HADS); and Post-Traumatic Stress Checklist (PCL).18-20 In addition, the PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) has been used for reporting adverse events in adult patients receiving CAR T-cell therapy.21 In the two retrieved pediatric studies, the Pediatric Quality of Life Inventory (PedsQL) (generic tool and cancer-specific tool dedicated to children), the EQ-5D and the Memorial Symptom Assessment Scale (cancer-specific) were used to assess the HRQoL of pediatric patients.22,23 Different versions of the scales were filled by different age groups, and some required a parent proxy.22,23 Of note, even though not used in the selected studies, it is important to highlight that there exists a validated pediatric version of the PRO-CTCAE tool.24
Health-related quality of life scales reported in singlearm chimeric antigen receptor T-cell studies
We retrieved a total of seven single-arm studies assessing HRQoL in patients who received CAR T-cell anti-CD19 therapy for relapsed or refractory lymphoma/leukemia through our PubMed search.22,25-30 One additional study, the PILOT study, was published after the search cut-off date and is added to Table 2.31 All retrieved studies were performed in adult patients, except one study, ELIANA,22 a multinational, multicenter, open-label, phase II trial that enrolled patients aged 3 to 23 years who received tisa-cel (Table 2). In the studies that assessed QoL in adult patients receiving CAR T-cell therapy at different timepoints, an anticipated initial decline in HRQoL was observed between 2 and 4 weeks after the CAR T-cell infusion, followed by improvements at later timepoints.25,27,29-31 Patients reported improvement in several or all domains of HRQoL scales, reaching baseline levels or better levels at a few months after the infusion. One of the studies showed that younger patients experienced worse mental problems, anxiety, and depression compared with elderly patients receiving CAR T-cell therapy.28 The JULIET study26 found that patients who responded to tisa-cel treatment reported a clinically meaningful improvement in all FACT subscales and in more than half of the Short Form-36 (SF-36) subscales (such as general QoL, physical, and social functioning) across all timepoints.26 A similar finding was made in TRANSCEND NHL 001,27 in which, at 1 month after infusion, a higher proportion of patients who responded to liso-cel had an improvement in EORTC QLQ-C30 global health status/QoL, fatigue, physical function, pain, and the EQ-5D-5L index, in comparison with those who did not respond.27 In the ELIANA study,22 reporting HRQoL data for pediatric patients, improvements in HRQoL were observed starting 28 days after the infusion, and reached a clinically meaningful phase at 3 months after the infusion. Improvements were observed for all measures at 3 months after tisa-cel with a mean change from enrollment of 13.3 (95% confidence interval: 8.9-17.6) and 16.8 (95% confidence interval: 9.4-24.3) for the PedsQL total score and EQ-5D VAS, respectively (Figure 3).22 The clinical improvement was sustained at later timepoints up to 36 months after the infusion.32
Table 1.Most frequently used non-specific health-related quality of life tools and the specific MDASI CAR tool, in chimeric antigen receptor T-cell targeting CD19 therapy clinical studies enrolling adults.
Table 2.Single-arm clinical studies evaluating health-related quality of life after chimeric antigen receptor T-cell anti-CD19 therapy.
Health-related quality of life scales reported in randomized controlled trials with autologous stem cell transplantation as the standard of care
According to our search, only two randomized controlled trials, TRANSFORM and ZUMA-7, evaluating the impact of CAR T-cell therapy on HRQoL compared to standard of care have been published.18,33,34 Both were phase III, open-label, pivotal studies conducted in adults with relapsed or refractory large B-cell lymphoma as second-line therapy (Table 3).18,33 One additional randomized phase III study (BELINDA), whose HRQoL results are not published yet, included the assessment of HRQoL via SF-36 (a generic tool), FACT-Lym, and EQ-VAS as secondary outcome measures in patients with refractory or relapsed B-cell lymphoma receiving either tisa-cel or standard therapy (Clinicaltrials.gov, NCT03570892). In TRANSFORM,33 the impact of liso-cel on HRQoL was compared to that of standard care using the EORTC QLQ-C30 and the FACT-G additional lymphoma-specific subscale (FACT-LymS) questionnaires at the timepoints specified in Table 3. Of the 184 patients constituting the intent-to-treat population, the EORTC QLQ-C30 analysis set included 90 patients (48.9%) and the FACT-LymS analysis set 85 patients (46.2%). The low percentage of patients constituting each analysis set is attributed to the low completion rates at several timepoints starting from baseline; a total of 87 patients, 44 in the liso-cel group and 43 in the standard-of-care group, failed to complete the EORTC QLQ-C30 assessment at baseline, and 46 patients in each group failed to complete the FACT-LymS assessment at baseline (Online Supplementary Figure S2). The reasons for low completion rates at baseline were related mainly to the challenges associated with telemedicine during the COVID-19 pandemic, while low rates observed later were related to other events, such as crossing over from the standard of care to the liso-cel group and initiating other antineoplastic agents. Results showed that patients who received liso-cel had clinically better scores in the EORTC QLQ-C30 global health status/QoL, cognitive function and fatigue domains than those who received standard care (Online Supplementary Figure S3). However, a greater deterioration was observed for the emotional domain of EORTC QLQ-C30 with liso-cel than with the standard of care.33 In ZUMA-7,18 EORTC QLQ-C30, EQ-5D-5L, and WPAI:GH (work and activity specific tool) version 2.0 were assessed at the timepoints specified in Table 3. Only patients who were employed at baseline were requested to answer the questions related to employment in WPAI:GH version 2.0. Of the 359 patients constituting the full analysis set, 296 (82.5%) were included in the QoL analysis set. The number of patients completing the HRQoL assessment dropped substantially over time, especially with the standard of care (Online Supplementary Figure S2). This drop was attributed to the occurrence of events (i.e., progression, death) that exclude patients from the QoL analysis set, rather than to a compliance issue. Compliance rates remained greater than 85% and 83% through 9 and 15 months after infusion, respectively. Results showed that patients reported an initial deterioration in HRQoL outcomes, at 50 days after infusion, followed by an improvement at later timepoints. At 100 days after infusion, patients who received axi-cel had statistically significantly better scores of the EQ-5D-5L VAS, EORTC QLQ-C30 global health status/QoL and physical function domain compared to those who received standard of care (Online Supplementary Figure S3).18
Figure 3.Results of the ELIANA study: change from baseline in the PedsQL total score and EQ-5D visual analog scale – mixed-model repeated measure analysis. LS: least squares; 95% CI: 95% confidence interval; PedQL: Pediatric Quality of Life Inventory; EQ-5D: European Quality of Life Five Dimension; P: P value; N: number of patients with measurements at both baseline and post-baseline visits; VAS: visual analog scale. Adapted from Laetsch et al.22
Table 3.Randomized controlled trials comparing health-related quality of life after chimeric antigen receptor T-cell anti-CD19 therapy or standard of care in adult patients.
Health-related quality of life evaluated in real-world chimeric antigen receptor T-cell studies
A total of ten real-world studies were retrieved through our PubMed search, nine of which reported PRO in adults6,19-21,35-39 and one in the pediatric population23 (Table 4). Only one of the retrieved studies compared CAR T-cell therapy to other modalities of treatment in adult patients with hematologic malignancies.21 The main objective of this study was to assess the HRQoL of patients receiving CAR T-cell therapy or stem cell transplant (SCT) (autologous or allogeneic) via the FACT-G, a cancer-specific tool (primary endpoint). Over a 6-month period, a total of 104 patients reported data on HRQoL and symptom burden during treatment. In the CAR T-cell group (n=34), PRO completion rates decreased from 100% at baseline to 44% at 6 months after infusion, mainly due to early study exit caused by disease progression, death or change in therapy (41%). Of note, 20% of patients decided not to complete the PRO at certain timepoints and 38% of patients reported QoL data for all timepoints. Results showed a deterioration in HRQoL during the first 2 weeks and an increase in the frequency and severity of adverse events, followed by improvement at later timepoints in all groups. However, the decline was less, and the improvement was faster with CAR T-cell therapy than with SCT, especially for overall QoL, and physical and functional well-being.21 Other real-world studies reported the same trends including an initial deterioration in HRQoL followed by improvement at around 3 months after the CAR T-cell infusion.6,20,36,39 Interestingly, in their longitudinal study, Johnson and colleagues20 identified worse pre-CAR T-cell therapy Eastern Cooperative Oncology Group (ECOG) performance status as a factor associated with lower pre-CAR T-cell therapy QoL, and identified worse pre-CAR T-cell therapy ECOG performance status, receipt of tocilizumab and receipt of corticosteroids for CAR T-cell toxicities as factors associated with an improved longitudinal QoL trajectory. According to the authors, it is conceivable that more aggressive management of CRS and/or ICANS leads to an improved longitudinal QoL trajectory over time.20 Ward and colleagues23 assessed HRQoL in a total of 140 pediatric patients who received treatment for hematologic malignancies (CAR T-cell or SCT). Although only 23 patients (16.4%) received CAR T-cell therapy, the value of this study in our review is that it evaluated the association between parents’ psychological well-being and their children’s HRQoL and symptoms. Results showed that parents suffer psychologically along with their children, and parental distress was associated with decreased child HRQoL and higher symptom burden. Moreover, a relatively high proportion of parents reported suicidal ideation at all collection timepoints.23
While most single-arm studies and the randomized controlled trials did not collect PRO data during the first 2 weeks, Oswald and colleagues38 incorporated PRO as early as the first day after CAR T-cell infusion and daily for the first week, followed by weekly assessments for the first month and monthly thereafter for up to 3 months after the infusion. The study included 12 patients and several PRO, each to be filled at certain timepoints. As such, the total PRO assessments amounted to 168 for the whole study population and duration, of which 143 were completed (completion rate, 85.1%). As anticipated, the most severe symptoms were reported within the first 14 days after CAR T-cell therapy, and a deterioration in several aspects of QoL was observed during the first month. In comparison to patients with progressive disease, the authors observed that patients who responded to CAR T-cell treatment suffered more toxicities.38 Of note, the main limitations of this study, as well as several other real-world studies, are their limited sample size and their conduct in single institutions.
Health-related quality of life assessed in qualitative studies
Qualitative studies based on semi-structured interviews and focus group discussions are important to gain deeper insight into the perspectives of patients receiving CAR T-cell therapy on their treatment expectations and to better characterize symptom burden.2 Patients’ perspectives obtained from qualitative studies may help to determine the main QoL aspects affected most by CAR T-cell therapy, and as such may aid in the development of CAR T-cell specific QoL tools. Based on our PubMed search, we identified four qualitative studies assessing HRQoL in patients who received CAR T-cell therapy.5,15,40,41 In the first qualitative study,15 a total of 21 patients who received CAR T-cell anti-CD19 therapy for B-cell lymphomas were interviewed up to 12 months after infusion (13 patients within the first 3 months; 3 patients between 3 and 6 months; and 5 patients between 6 and 12 months). The patients reported the following as the most common symptoms associated with treatment: fatigue, lack of appetite, headache, chills/cold, and confusion.15 This qualitative study was useful in generating a CAR T-cell specific tool, the MDASI-CAR, which was later validated by Wang and colleagues.13 The second study included a literature review and two focus groups among a total of 18 patients.5 The literature search identified several PRO that were used in studies enrolling patients with diffuse large B-cell lymphoma who received CAR T-cell therapy, and the focus groups assessed the appropriateness of the functions/ symptoms covered by these PRO. A total of eight domains were considered as the most affected by CAR T-cell therapy and comprised pain/discomfort, fatigue, sleep, and the following functions: social, emotional, physical, cognitive, and role.5 The third study recruited 40 patients with hematologic malignancies, 15 caregivers, and 15 clinicians specialized in CAR T-cell therapy to aid in the development of PRO specific to CAR T-cell therapy.40 Similar findings to those reported by the aforementioned studies5,15 were observed. Cognitive, social, and emotional functioning were considered affected by CAR T-cell therapy, with patients reporting fatigue, pain, bothersome gastrointestinal symptoms, and limited physical function.40 Likewise, the fourth qualitative study, which aimed to improve the services associated with CAR T-cell therapy, found that fatigue, pain, loss of appetite, and cognitive problems were reported by ten patients receiving CAR T-cell therapy and four of their caregivers.41
What have we learned from the current patient-reported outcome tools and their use?
To date, the most frequently used HRQoL tools are generic or cancer-specific which may not fully capture the effect of the CAR T-cell therapy process and its adverse events on the QoL of recipients. Patients who receive CAR T-cell therapy are required to reside within a 30-minute to 2-hour drive from the specialized treating center and are not allowed to drive for 8 weeks after receiving the CAR T-cell product.1 In addition, patients are sometimes in need of a caregiver for around a month after therapy.1 All these constraints would affect patients’ psychological status and subsequently their QoL. Only one CAR T-cell specific tool has been developed which still has some limitations and needs further validation in larger studies. Even though a CAR T-cell specific tool could adequately assess the impact of this therapy on the HRQoL of patients, cancer-specific PRO might be more suitable for identifying the impact of the disease on QoL. The studies identified in this review may not have used the optimal tool or at the optimal frequency. The vast majority of studies did not administer the PRO tools during the first 2 weeks after CAR T-cell infusion. This timeframe is crucial for the patient since it is a time of hospitalization and constant monitoring for CAR T-cell therapy specific short-term toxicities. Only one study, reported by Oswald and colleagues,38 incorporated PRO as early as the first day after infusion; however, this study had a limited sample size and thus no solid conclusions can be drawn. Another pitfall in the use of PRO in patients undergoing CAR T-cell therapy may be related to the design of HRQoL evaluations, leading to low completion rates. These low rates, as observed in the randomized controlled trials, have been attributed to the exclusion of patients who progressed or initiated treatment with other antineoplastic agents after CAR T-cell therapy or SCT and who were considered not eligible to complete the PRO rather than to patients’ compliance. Although it is difficult and ethically debatable, we believe that the assessment of QoL in patients who do not respond to CAR-T therapy is as equally important as that of patients who do respond, to capture the impact of the disease per se. A single-arm study, TRANSCEND NHL 001,27 showed that a higher percentage of responders to CAR T-cell therapy, at 1 month after infusion, reported an improvement in QoL parameters in comparison with those who did not respond. On the other hand, the two studies that enrolled pediatric patients administered pediatric versions of the PRO that corresponded to each patient’s age.22,23 This draws attention to the necessity of several versions of the same PRO, whether generic, cancer-specific or CAR T-cell specific, to accommodate all patients’ ages and needs. Similarly, regardless of age, the availability of the tool in different languages should be encouraged as it allows patients from different populations to complete these PRO tools, thereby fulfilling any current unmet need. Furthermore, assessment of the QoL of caregivers has not received as much attention as it should. For hematologic malignancies, especially in the pediatric population, caregivers play an important role in the patients’ treatment journey. As such, the assessment of their QoL may be informative and beneficial for themselves and subsequently their patients. When the caregiver is a parent, the associated emotional and psychological burden might be detrimental. In one of the real-word studies,23 a strikingly high percentage of parents reported having suicidal ideation when caring for their children who received treatment for a hematologic malignancy.
Perspectives
While CAR T-cell therapy is an innovative treatment with promising survival benefits in patients with advanced hematologic malignancies, its administration is associated with multiple challenges including the complex procedure of manufacturing the CAR T cells, the demanding journey that the patient must go through, and the specific side effects (e.g., CRS and ICANS).1-3 For the aforementioned reasons, the assessment of HRQoL in patients receiving CAR T-cell therapy is of major relevance.8 PRO are valuable means for patients to report HRQoL as well as symptom burden and treatment toxicities.22,37 In addition, it is important to assess the indirect effect of cancer treatment on caregivers who may be overwhelmed by the processes related to any cancer treatment, including CAR T-cell therapy.23,42 As for the time of PRO assessment, given that the majority of episodes of CRS and neurotoxicity, which may affect patients’ HRQoL, develop early after CAR T-cell infusion (median onset of CRS, 2 to 5 days; neurotoxicity, 6 to 9 days), it is paramount to incorporate frequent monitoring during the first 2 weeks after infusion, preferably several times weekly. 2,13,25,29,30,43,44 Although early frequent reporting of PRO would better capture the early deterioration in HRQoL, subsequent less frequent monitoring, up to the first year after CAR T-cell therapy, might be helpful in identifying other long-term toxic ities and adverse events.2 Nevertheless, frequent assessment of PRO, especially in the first few months after CAR T-cell therapy, might be logistically challenging. Thus, to increase patients’ compliance in completing PRO on a regular basis, electronic PRO assessments are encouraged.45 Other than the logistical challenge, patients with grade ≥2 ICANS may find it difficult to complete PRO questionnaires,13 therefore, proxy HRQoL data would be considered an option. Several HRQoL questionnaires have been used in both clinical trials and real-world studies of CAR T-cell therapy, the vast majority of which are not CAR T-cell specific. Recently, one PRO tool specific to CAR T-cell therapy, the MDASI-CAR, was developed and validated.13 Even though some of the non-specific tools, namely the EORTC QLQ-C30 and FACT-Lym, cover many elements of the MDASI-CAR tool, they fail to assess many of the module symptoms. The ability of such a specific tool to capture most functions and symptoms that are considered relevant to CAR T-cell therapy makes it a valuable tool for clinical use in the early phase after CAR T-cell infusion. At later timepoints, a disease-specific tool may be more suitable to assess the HRQoL aspects affected by the disease itself. Indeed, there is value in monitoring the QoL of non-responders to CAR T-cell therapy as well as those who respond. A cancer-specific PRO might be a better option for non-responders rather than excluding these patients from QoL assessment, and studies may conduct different analyses for each group of patients. Despite these considerations, the generalizability of MDASI-CAR to all patients with hematologic malignancies receiving this treatment and to all clinically available CAR T-cell agents still needs assessment in larger multicenter studies.13 In addition, the MDASI-CAR tool might be suitable for use in comparative studies in which only CAR T-cell agents are being compared to each other. In this respect, there is still a call to pursue the development of optimal specific tools, whether capitalizing on the MDASI-CAR or considering other tools that will address the uniqueness of CAR T-cell therapy and the limitations of MDASI-CAR. An optimal PRO scoring would balance the need to assess all functional domains, disease-specific and CAR T-cell therapy-specific symptoms, and financial burden on the one hand, and patients’ capacities and logistics on the other hand. To that end, several requirements should be fulfilled, including in-depth learning from existing findings, multidisciplinary professionals’ involvement, patients’ and caregivers’ engagement, and rigorous validation in multicenter studies enrolling an appropriate sample of patients and caregivers that should account for the decline in the eligible individuals in the long-term HRQoL evaluation.6
Table 4.Real-world studies evaluating health-related quality of life after chimeric antigen receptor T-cell anti-CD19 therapy.
Conclusions
Altogether, regular PRO assessments are crucial for patients receiving CAR T-cell therapy for hematologic malignancies. The MDASI-CAR tool opened the avenue towards the creation of optimal tools to capture the impact of CAR T-cell therapy on HRQoL in the short term, and to complement the disease-specific tools which remain valid, especially for mid- and long-term QoL evaluation. Future work should also continue to explore factors associated with QoL following CAR T-cell therapy, as these findings can guide shared decision-making between clinicians and patients as well as identify at-risk patients who may benefit from supportive care interventions aimed to decrease symptom burden during treatment. Finally, valid and reliable PRO should be integrated in clinical guidelines, as they may play a major role in improving the well-being and treatment outcomes of patients receiving CAR T-cell therapy.
Footnotes
- Received October 19, 2023
- Accepted February 29, 2024
Correspondence
Disclosures
ET has received honoraria from Gilead/Kite, Janssen, AbbVie, and AstraZeneca. AM has received honoraria from Gilead/Kite, Amgen, and Sanofi. AA has received honoraria from Gilead/ Kite, BMS, AstraZeneca, Sandoz, Ipsen, and Amgen. SB has received honoraria from Gilead/Kite, Novartis, Incyte, and BMS. FC has received honoraria from Gilead/Kite. GB has no conflicts of interest to disclose. CR has received honoraria from Astellas, Beigene, BMS, Gilead Kite, Janssen, Pfizer, and Roche. LY has received honoraria from Beigene, Gilead/Kite, Janssen, BMS, AbbVie, Roche, and AstraZeneca, and research funding from BMS, Beigene, Janssen, and Roche. EG has received honoraria from Gilead/Kite, Sanofi, Janssen, BMS, AbbVie, Astellas, Pfizer, Recordati, Jazz Pharmaceuticals, Servier, Alexion, Roche, Incyte, and AstraZeneca, and research funding from BMS, Novartis, and Sandoz.
Funding
This review article is based on a project led by Gilead Sciences SAS around quality of life & CAR T-cell therapy in which the authors participated. Gilead Sciences SAS funded this review article by supporting the coordination of the project and the manuscript writing as well as the journal publication fees.
Acknowledgments
The authors thank Julie Nassif, PharmD, and Thomas Rohban, MD, of Partner 4 Health (Paris, France) for providing medical writing support in accordance with Good Publication Practice guidelines. The authors also thank Siham Bibi, PhD, from Kephren (Boulogne-Billancourt, France) for coordination of the project.
References
- Mikhael J, Fowler J, Shah N. Chimeric antigen receptor T-cell therapies: barriers and solutions to access. JCO Oncol Pract. 2022; 18(12):800-807. Google Scholar
- Chakraborty R, Sidana S, Shah GL, Scordo M, Hamilton BK, Majhail NS. Patient-reported outcomes with chimeric antigen receptor T cell therapy: challenges and opportunities. Biol Blood Marrow Transplant. 2019; 25(5):e155-e162. Google Scholar
- Chen YJ, Abila B, Mostafa Kamel Y. CAR-T: what is next?. Cancers (Basel). 2023; 15(3):663. Google Scholar
- NCCN. Clinical Practice Guidelines in Oncology (NCCN Guidelines) - Management of Immunotherapy-Related Toxicities. 2023. Publisher Full TextGoogle Scholar
- Cheng R, Scippa K, Locke FL, Snider JT, Jim H. 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. 2022; 10(1):123-141. Google Scholar
- Wang XS, Srour SA, Whisenant M. Patient-reported symptom and functioning status during the first 12 months after chimeric antigen receptor T cell therapy for hematologic malignancies. Transplant Cell Ther. 2021; 27(11):930.e1-930.e10. Google Scholar
- Raymakers AJN, Regier DA, Peacock SJ, Freeman CL. Health-related quality of life data collected in chimeric antigen receptor T-cell (CAR-T) therapy clinical trials. J Cancer Policy. 2021; 30:100304. Google Scholar
- Paunescu AC, Copie CB, Malak S. Quality of life of survivors 1 year after the diagnosis of diffuse large B-cell lymphoma: a LYSA study. Ann Hematol. 2022; 101(2):317-332. Google Scholar
- Kamal M, Joseph J, Greenbaum U, Hicklen R, Kebriaei P, Srour SA, Wang XS. Patient-reported outcomes for cancer patients with hematological malignancies undergoing chimeric antigen receptor T cell therapy: a systematic review. Transplant Cell Ther. 2021; 27(5):390.e1-390.e7. Google Scholar
- Efficace F, Vignetti M. Quality of life and CAR-T cell therapy in children, adolescents, and young adults with haematological malignancies. Lancet Oncol. 2019; 20(12):1625-1626. Google Scholar
- Mohty M, Minnema MC. Lymphodepleting conditioning regimens. 2022;131-133. Google Scholar
- Zhao Z, Chen Y, Francisco NM, Zhang Y, Wu M. The application of CAR-T cell therapy in hematological malignancies: advantages and challenges. Acta Pharm Sin B. 2018; 8(4):539-551. Google Scholar
- Wang XS, Srour SA, Mendoza T. Development and validation of a patient-reported outcome measure to assess symptom burden after chimeric antigen receptor T-cell therapy. Br J Haematol. 2023; 201(4):738-746. Google Scholar
- Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group. Ann Med. 2001; 33(5):337-343. Google Scholar
- Whisenant MS, Srour SA, Williams LA. The unique symptom burden of patients receiving CAR T-cell therapy. Semin Oncol Nurs. 2021; 37(6):151216. Google Scholar
- Cleeland CS, Mendoza TR, Wang XS. Assessing symptom distress in cancer patients: the M.D. Anderson Symptom Inventory. Cancer. 2000; 89(7):1634-1646. Google Scholar
- Hui D, Bruera E. The Edmonton Symptom Assessment System 25 years later: past, present, and future developments. J Pain Symptom Manage. 2017; 53(3):630-643. Google Scholar
- Elsawy M, Chavez JC, Avivi I. Patient-reported outcomes in ZUMA-7, a phase 3 study of axicabtagene ciloleucel in second-line large B-cell lymphoma. Blood. 2022; 140(21):2248-2260. Google Scholar
- Dhawale TM, Johnson PC, Gaballa MR. Perception of prognosis, quality of life, and distress in patients receiving chimeric antigen receptor T-cell therapy. Cancer. 2023; 129(3):441-449. Google Scholar
- Johnson PC, Dhawale T, Newcomb RA. Longitudinal patient-reported outcomes in patients receiving chimeric antigen receptor T-cell therapy. Blood Adv. 2023; 7(14):3541-3550. Google Scholar
- Sidana S, Dueck AC, Thanarajasingam G. Longitudinal patient reported outcomes with CAR-T cell therapy versus autologous and allogeneic stem cell transplant. Transplant Cell Ther. 2022; 28(8):473-482. Google Scholar
- 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. Lancet Oncol. 2019; 20(12):1710-1718. Google Scholar
- Ward J, Smith J, Powers K, Hellsten M, Murray P. Parent psychological distress is associated with symptom burden and health-related quality of life in children and adolescents undergoing stem cell transplantation or chimeric antigen receptor T cell therapy. Transplant Cell Ther. 2023; 29(7):462.e1-e9. Google Scholar
- Reeve BB, McFatrich M, Mack JW. Validity and reliability of the pediatric patient-reported outcomes version of the Common Terminology Criteria for Adverse Events. J Natl Cancer Inst. 2020; 112(11):1143-1152. Google Scholar
- Knight JM, Szabo A, Arapi I. Patient-reported outcomes and neurotoxicity markers in patients treated with bispecific LV20.19 CAR T cell therapy. Commun Med (Lond). 2022; 2(1):49. Google Scholar
- Maziarz RT, Waller EK, Jaeger U. Patient-reported long-term quality of life after tisagenlecleucel in relapsed/refractory diffuse large B-cell lymphoma. Blood Adv. 2020; 4(4):629-637. Google Scholar
- Patrick DL, Powers A, Jun MP, Kim Y, Garcia J, Dehner C, Maloney DG. Effect of lisocabtagene maraleucel on HRQoL and symptom severity in relapsed/refractory large B-cell lymphoma. Blood Adv. 2021; 5(8):2245-2255. Google Scholar
- Ruark J, Mullane E, Cleary N. Patient-reported neuropsychiatric outcomes of long-term survivors after chimeric antigen receptor T cell therapy. Biol Blood Marrow Transplant. 2020; 26(1):34-43. Google Scholar
- Shah BD, Ghobadi A, Oluwole OO. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet. 2021; 398(10299):491-502. Google Scholar
- Wang M, Munoz J, Goy A. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020; 382(14):1331-1342. Google Scholar
- Gordon LI, Liu FF, Braverman J. Lisocabtagene maraleucel for second-line relapsed or refractory large B-cell lymphoma: patient-reported outcomes from the PILOT study. Haematologica. 2024; 109(3):857-866. Google Scholar
- Laetsch TW, Maude SL, Rives S. Three-year update of tisagenlecleucel in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia in the ELIANA trial. J Clin Oncol. 2023; 41(9):1664-1669. Google Scholar
- Abramson JS, Johnston PB, Kamdar M. Health-related quality of life with lisocabtagene maraleucel vs standard of care in relapsed or refractory LBCL. Blood Adv. 2022; 6(23):5969-5979. Google Scholar
- Westin JR, Locke FL, Dickinson M. Safety and efficacy of axicabtagene ciloleucel versus standard of care in patients 65 years of age or older with relapsed/refractory large B-cell lymphoma. Clin Cancer Res. 2023; 29(10):1894-1905. Google Scholar
- Barata A, Hoogland AI, Kommalapati A. Change in patients’ perceived cognition following chimeric antigen receptor T-cell therapy for lymphoma. Transplant Cell Ther. 2022; 28(7):401.e1-401.e7. Google Scholar
- Hoogland AI, Jayani RV, Collier A. Acute patient-reported outcomes in B-cell malignancies treated with axicabtagene ciloleucel. Cancer Med. 2021; 10(6):1936-1943. Google Scholar
- Maillet D, Belin C, Moroni C. Evaluation of mid-term (6-12 months) neurotoxicity in B-cell lymphoma patients treated with CAR T cells: a prospective cohort study. Neuro Oncol. 2021; 23(9):1569-1575. Google Scholar
- Oswald LB, Li X, Carvajal R. Longitudinal collection of patient-reported outcomes and activity data during CAR-T therapy: feasibility, acceptability, and data visualization. Cancers (Basel). 2022; 14(11):2742. Google Scholar
- Ram R, Grisariu S, Shargian-Alon L. Toxicity and efficacy of chimeric antigen receptor T-cell therapy in patients with diffuse large B-cell lymphoma above the age of 70 years compared to younger patients - a matched control multicenter cohort study. Haematologica. 2022; 107(5):1111-1118. Google Scholar
- Akinola IM, Cusatis R, Pasquini MC. Multi-stakeholder qualitative interviews to inform measurement of patient reported outcomes after CAR-T. Transplant Cell Ther. 2023; 29(4):254.e1-254.e9. Google Scholar
- Stenson CL, Vidrine J, Dewhurst F, Osborne W, Menne T, Stocker R. A qualitative service evaluation of patient and caregiver experiences of CAR-T therapy: recommendations for service development and implications for palliative care teams. Palliat Med. 2023; 37(2):215-220. Google Scholar
- Barata A, Hoogland AI, Hyland KA. Quality of life in caregivers of patients receiving chimeric antigen receptor T-cell therapy. Psychooncology. 2021; 30(8):1294-1301. Google Scholar
- Abramson JS, Palomba ML, Gordon LI. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020; 396(10254):839-852. Google Scholar
- Schuster SJ, Bishop MR, Tam CS. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019; 380(1):45-56. Google Scholar
- Efficace F, Cannella L, Sparano F. Chimeric antigen receptor T-cell therapy in hematologic malignancies and patient-reported outcomes: a scoping review. Hemasphere. 2022; 6(12):e802. Google Scholar
- EuroQol. EQ-5D-5L User Guide. 2019. Publisher Full TextGoogle Scholar
- Hays RD, Spritzer KL, Schalet BD, Cella D. PROMIS((R))-29 v2.0 profile physical and mental health summary scores. Qual Life Res. 2018; 27(7):1885-1891. Google Scholar
- Aaronson NK, Ahmedzai S, Bergman B. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993; 85(5):365-376. Google Scholar
- Cella DF, Tulsky DS, Gray G. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol. 1993; 11(3):570-579. Google Scholar
- Hlubocky FJ, Webster K, Cashy J, Beaumont J, Cella D. The development and validation of a measure of health-related quality of life for non-Hodgkin’s lymphoma: the Functional Assessment of Cancer Therapy—Lymphoma (FACT-Lym). Lymphoma. 2013; 2013:147176. Google Scholar
- Cocks K, King MT, Velikova G. Evidence-based guidelines for interpreting change scores for the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30. Eur J Cancer. 2012; 48(11):1713-1721. Google Scholar
- Shah NN, Johnson BD, Schneider D. Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial. Nat Med. 2020; 26(10):1569-1575. Google Scholar
Data Supplements
Figures & Tables
Article Information
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.