Chimeric Antigen Receptor T-cell Therapy in Hematologic Malignancies and Patient-reported Outcomes: A Scoping Review.

INTRODUCTION

Chimeric antigen receptor (CAR) T-cell therapy is an innovative therapy that has the potential to change the clinical outcomes of many patients with hematological malignancies. Adoptive T-cell therapies, which have been genetically engineered for a new antigen-specificity 1 , showed impressive response rates and response durability even in patients with advanced relapsed/refractory (R/R) hematologic malignancies such as acute B-lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). 2 – 15 More recently, treatment with B-cell maturation antigen (BCMA)–directed CAR T cells also resulted in frequent and deep responses in heavily pretreated patients with R/R multiple myeloma (MM). 16 , 17

The first 2 CAR T-cell therapies approved in the United States and Europe for relapsed/refractory B aggressive NHLs in the third line and beyond were axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel). These approvals were based on the results of the ZUMA-1 and JULIET studies, respectively, demonstrating a 30% to 50% complete response (CR) rate and a 30% to 40% long-term disease-free survival after a single infusion. 3 , 4 , 9 , 10 To date, the following 6 CAR T-cell therapies have been approved: tisa-cel, axi-cel, lisocabtagene maraleucel (liso-cel), brexucabtagene autoleucel (brexu-cel), idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) for the treatment of R/R ALL, R/R NHL and R/R MM, respectively. 18 , 19

However, during clinical testing, all CAR T-cell therapies demonstrated severe and different toxicities compared to those observed in other cellular therapies (such as autologous or allogeneic hematopoietic stem cell transplantation (SCT) or donor lymphocyte infusion) or traditional chemotherapies, suggesting profound, and generalized immune system activation. 20 – 22 The 2 most commonly observed toxicities are cytokine-release syndrome (CRS), characterized by high fever, hypotension, hypoxia, and/or multiorgan toxicity; and immune effector cell-associated neurotoxicity syndrome (ICANS), typically characterized by delirium, encephalopathy, aphasia, lethargy, difficult concentrating, agitation, tremor, confusion, and occasional seizures and cerebral edema. 23 , 24 While CRS toxicity typically occurs within the first 2 weeks after CAR T-cell therapy, 23 the manifestation of ICANS can occur concurrently with high fever and other CRS symptoms, 25 – 28 or shortly after CRS subsides, or as a delayed form in the third or fourth week after CAR T-cell therapy. 21 , 23 , 27 Furthermore, the observation that 3%–10% of neurologic events in the majority of early trials remain unresolved at the time of study reporting (median follow-up of 3 to 28 months or even less, up to about 12 months in the case of myeloma) 2 , 9 , 16 , 29 , 30 and anecdotal reports of long-term sequelae of neurotoxicity, 31 mild memory impairment, 32 or confusion, and disorientation followed by expressive aphasia, 33 point to the importance of monitoring for the occurrence of late neurologic events. 34 There is also evidence indicating that patients who receive CAR T-cell therapy may experience long-term adverse events (AEs) such as prolonged B-cell aplasia, hypogammaglobinemia, prolonged cytopenia, infections, and autoimmune reactions. 2 , 10 , 34 , 35

While evidence of the clinical efficacy and safety of CAR T-cell therapy continues to accumulate, it is also important to better understand the impact of this therapy from the unique patient’s standpoint. Inclusion of patient-reported outcome (PRO) measures in cancer clinical trials, for example, may be critical to more thoroughly evaluate benefit/risk profile of a treatment by complementing physicians’ understanding of toxicity and informing tolerability. 36 , 37 Some examples of the added value of PROs in clinical research in hematology are available. 38

A recent review of the available PRO evidence for patients with hematologic malignancies receiving CAR T-cell therapy was published by Kamal et al, 39 and only 3 published studies were identified up to April 2020. Given the increasing interest in this area of research, we performed a scoping review to map available literature on the use of PRO measures in CAR T-cell therapy studies, to summarize the main findings and gain insights for future research directions.

METHODS

Identification of relevant studies

We performed a scoping review 40 based on the Preferred Reporting Items for Systematic Reviews and Meta-analysis extension for Scoping Reviews (PRISMA-ScR). 41 No protocol was published for this review. We conducted a systematic literature search in PubMed, Cochrane and Web of Science databases to identify CAR T-cell therapy studies in patients with hematologic malignancies which have assessed PROs and were published from January 2015 to July 2022. The starting point of the time window was selected considering that the first CAR T-cell therapy was only approved by the US FDA in 2017. 42 The following searching strategy was used: “quality of life” OR “health related quality of life” OR “health status” OR “health outcomes” OR “patient outcomes” OR “depression” OR “anxiety” OR “emotional” OR “social” OR “psychosocial” OR “psychological” OR “distress” OR “social functioning” OR “social wellbeing” OR “patient reported symptom” OR “patient reported outcomes” OR pain OR fatigue OR “patient reported outcome” OR “PRO” OR “PROs” OR “HRQL” OR “QOL” OR “HRQOL” OR “symptom distress” OR “symptom burden” OR “symptom assessment” OR “functional status” OR sexual OR functioning) and (“chimeric antigen receptor” OR “ CAR”) AND (gammopathy OR myelodysplastic OR myelodysplasia OR leukemia OR leukaemia OR lymphoma OR myeloma OR myelofibrosis OR myeloproliferative OR polycythemia OR polycythaemia OR thrombocythemia OR thrombocythaemia). Additional publications were identified by hand searching the reference lists of these articles or consulting relevant study publication lists at http://clinicaltrials.gov .

An independent search was also performed on PubMed using the DistillerSR software 43 for abstract and full-text screening (see the search terms used in Suppl. Appendix 1 ). Only English language articles were considered, and no restrictions were included in the search field description. Case reports, reviews, and articles on laboratory or in vitro researches were excluded by title and abstract screening. If a selected study had multiple publications, information from all related papers was extracted to maximize the quality of the information in our review.

Selection criteria

Types of participants

Participants were patients diagnosed with any hematologic malignancy, regardless of the stage of the disease and patients’ age. Studies including mixed hematologic malignancies were still considered as long as did not include patients with solid tumors.

Types of intervention

Interventions included any kind of CAR T-cell therapy either used alone or in combination with other drugs. Any CAR T-cell product was considered, regardless of its approval from regulatory agencies.

Types of outcome measures examined

Studies incorporating PRO measures were considered. Publications of study protocols were excluded as they do not report original PRO results. Studies reporting cost-utility analyses only were excluded as beyond the scope of this review.

Types of studies

All types of studies were considered regardless of their research design, providing they reported quantitative analyses. Conference abstracts, studies reporting results from qualitative analyses or reporting results from online surveys were excluded. No restriction in the number of patients enrolled was applied.

Data extraction and evaluation

A predefined data extraction form was used to collect the following information from each eligible study for this review: (1) basic study characteristics (ie, study acronyms if available, multicenter study [y/n], study design); (2) clinical details (ie, type of hematologic disease, type of CAR T-cell product, patient’s age, number of patients); (3) PRO assessment characteristics (ie, PRO measure/s used, type of PRO analysis [longitudinal/cross-sectional] and PRO assessment schedule). For descriptive purposes, this latter aspect was classified as occurring during the following: acute phase, subacute phase and long-term follow-up. 44 More specifically, we also assessed whether a PRO assessment occurred within the first 2 weeks after the procedure, as CRS toxicity typically occurs in this period 23 ; (4) summary of PRO findings. With regard to the latter aspect, information on the statistical significance of PRO results (ie, based on P values or confidence intervals) was also extracted if available in the manuscript. Improvements and/or deterioration of PROs from baseline assessment were reported for each timepoint, in the case of a longitudinal PRO analysis. When no information on statistical significance was provided in the article or none of the PROs significantly differed from the baseline assessment, we summarized descriptive PRO findings based on what the authors reported in the article. Data extraction was performed independently by 2 reviewers (LC, FS, or JMR). If discrepancies in the evaluation of any item occurred, the reviewers revisited the papers to reconcile any differences. A third senior reviewer (FE) was consulted if no consensus was achieved.

RESULTS

The literature search identified 2473 records published from January 1, 2015, until July 1, 2022, that were screened for eligibility. Of these, we retrieved a total of 14 eligible studies reporting PRO results. 14 , 15 , 45 – 56 Details of the search strategy and selection process of the articles included in this review were documented according to the PRISMA guidelines 57 and are reported in Figure 1 .

Overview of study characteristics

All eligible studies enrolled patients with advanced hematologic diseases: twelve studies examined patients with B-cell lymphoproliferative malignancies treated with CD19-directed CAR T cells, one study examined patients with multiple myeloma treated with BCMA-directed CAR T cells and one study examined patients with either B-cell lymphoproliferative malignancy or multiple myeloma treated with any type of CAR T-cell therapy.

Overall, 1162 (range 12–269) patients treated with CAR T-cell therapy were included in the selected studies. Most of the studies (n = 9, 64.3%) enrolled fewer than 100 patients. In 7 studies (50%) the median or mean age of treated patients was 60 years or older. Seven studies (50%) were investigational early-phase trials (5 phase 2 trials, one phase 1 trial, 1 seamless design trial), one (7.1%) was a pilot study and 6 (42.9%) were observational studies.

Twelve studies (85.7%) examined longitudinal PRO assessments including PRO collection at baseline (prior and/or on the same day of CAR T-cell infusion); 2 studies (14.3%) had a cross-sectional design for PRO evaluation.

In most studies (n = 11, 78.6%), PROs were assessed with more than 1 measure. The EQ-5D was the most frequently used one (n = 6, 42.9%), followed by the Patient-Reported Outcomes Measurement Information System 29 (PROMIS-29) being used in 5 studies (35.7%) (Table 1 ).

Overview of PRO findings from early-phase clinical trials

Of the 7 clinical trials describing PROs in hematologic patients treated with CAR T-cell therapy, none were randomized clinical trials (RCT) and all trials had a longitudinal design of PRO evaluation (Table 2 ).

The ELIANA 45 and JULIET 47 studies assessed the health-related quality of life (HRQoL) impact of tisa-cel, administered to pediatric and young adult patients with R/R B-ALL and adult patients with R/R diffuse large B-cell lymphoma (DLBCL), respectively. Laetsch et al described a rapid and sustained improvement in broad aspects of HRQoL, measured with PedsQL and EQ-5D VAS, in pediatric and young adult R/R B-ALL patients who were in second or greater bone marrow relapse, chemorefractory, relapsed after allogeneic stem cell transplant, or were otherwise ineligible for allogeneic stem cell transplant. 45 PRO improvements from baseline were observed from day 28 after infusion as measured with PedsQL total score and EQ-5D VAS, albeit lower mean score changes were reported in patients who had severe CRS or neurotoxicity. Clinically meaningful improvements from baseline in all HRQoL subscales/dimensions (eg, physical functioning, emotional functioning, school functioning and social functioning) were achieved by month 3 and were confirmed at later timepoints (months 6, 9, and 12), irrespective of severe toxicity occurrence. Maziarz et al reported that adult patients with R/R DLBCL, who responded to tisa-cel and have had at least 2 or more lines of prior therapy including rituximab and anthracycline, and either had relapsed after, were ineligible for, or did not consent to autologous hematopoietic stem cell transplant, had clinically meaningful and long-term improvement in HRQoL, measured with FACT-Lym and SF-36. 47 The lack of PRO assessments in patients who did not respond to tisa-cel therapy (as they discontinued the study due to death, disease progression or loss to follow-up) and the low completion rates of PRO assessments at months 12 and 18, impaired the ability of this study to explore the relationship between treatment effect and HRQoL 47 .

The ZUMA-2 14 and ZUMA-3 15 studies reported the HRQoL impact of brexu-cel in adult patients with R/R mantle cell lymphoma (MCL) and R/R ALL, respectively. Wang et al 14 observed that adult R/R MCL patients, who had received up to 5 previous therapies including anthracycline or bendamustine-containing chemotherapy, anti-CD20 monoclonal antibody therapy, and ibrutinib or acalabrutinib, reported a transient decline in HRQoL at week 4 after brexu-cel infusion, followed by return or improvement of HRQoL status at 3 and 6 months, as measured with descriptive statistics of EQ-5D scores (both the VAS score and the dimension of mobility, self-care, and usual activity). Shah et al 15 indicated that the majority of evaluable adult patients with R/R ALL (ie, with first CR of 12 months or less, or after at least 2 previous lines of systemic disease or after allogeneic hematopoietic stem cell transplant and with an ECOG of 0-1) experienced improved or stable HRQoL over time after brexu-cel infusion, as measured with EQ-5D-5L (both the VAS score and EQ-5D dimensions). In this brief descriptive analysis, the proportion of patients reporting no problem in 3 dimensions of EQ-5D (ie, mobility, usual activity and self-care) decreased at one month after infusion, but starting from month 3, this proportion of patients reporting no problem reached stably higher levels than those at baseline across all 5 EQ-5D dimensions. 15

In the TRANSCEND NHL001 study, 49 R/R LBCL adult patients, who had previously received 2 or more previous lines of systemic treatment including chemoimmunotherapy containing anti-CD20 and anthracycline, reported a significant initial deterioration of physical functioning at 1 month after liso-cel treatment followed by significant improvement at 2, 9, and 12 months. 49 Patrick et al described clinically meaningful improvements in global health status/QoL and fatigue, as measured with the EORTC QLQ-C30, as early as 2 months after liso-cel infusion and maintained thereafter through 18 months. 49 The EORTC QLQ-C30 pain score profile over time after liso-cel infusion showed significant improvement at 2 months, deterioration to near-baseline value at 3 to 9 months, and then improvements at 12 months. 49 The mean EQ-5D-5L index score was significantly increased at 2, 12, and 18 months. 49 Despite a small number of treatment nonresponders completed PRO assessments at later timepoints, PRO improvements at any timepoint after liso-cel infusion were described as more frequent in treatment responders than in treatment nonresponders. 49 The median time to first clinically meaningful improvement was shorter in treatment responders than in nonresponders in global health status/QoL, fatigue, and pain. Individual-level PRO analysis revealed that more patients reported clinically meaningful improvements in HRQoL and symptom burden than clinically meaningful deterioration at each timepoint. 49

In the KarMMa study, 52 triple-class exposed R/R MM patients who received ide-cel infusion as the fourth line or later treatment reported statistically and clinically meaningful improvements in most PROs, including pain and disease symptoms by month 1, and, later on, including fatigue, pain, physical functioning, cognitive functioning, global health status/QoL, disease symptoms, and side effects from month 2 through month 9, as measured with the EORTC QLQ-C30 and QLQ-MY20. Improvements in fatigue and physical functioning generally persisted through 18 months. Patients’ baseline HRQoL scores (fatigue, pain, global health status/QoL, physical and cognitive functioning) were worse than those of the re-weighted general population at baseline and became comparable to those of the general population at 1 to 3 months and throughout month 18. 52

Recently, the trajectory of self-reported depression, sleep quality, fatigue, anxiety, and pain in 15 R/R NHL or CLL patients, who received bispecific anti-CD19 anti-CD20 CAR T cells (LV20.19) in a phase 1 trial and survived at day 28 after infusion, revealed a significant reduction only in depression between day 14 and day 90 after CAR T-cell infusion and, a correlation between changes in depression scores and in blood kynurenine concentration, as a possible biomarker of depression, during study timepoints. 54

Overview of PRO findings in pilot or observational studies

Among the 6 eligible observational studies and one pilot study, 2 had a cross-sectional design for PRO assessment, and 5 analyzed PRO changes over time (Table 3 ). These studies mainly described symptom experience of patients over time after CAR T-cell infusion and contributed to defining the unique toxicity profile of CAR T-cell therapy.

Ruark et al 46 observed that, at the median follow-up of 3 years after CAR T-cell infusion, 40 long-term hematologic cancer survivors enrolled at Fred Hutchinson Cancer Center (Seattle, USA) reported an overall good self-neuropsychiatric status (ie, PROMIS-Global Health and PROMIS-29) that was similar to that of the general US population. 46 However, nearly 50% of patients reported at least one cognitive difficulty and/or clinically meaningful depression and/or anxiety. Younger age, longer time since treatment, depression pre-CAR T-cell, and acute neurotoxicity were suggested as potential risk factors for adverse neuropsychiatric outcomes after CAR T-cell infusion to be validated for planning of interventional strategies. 46

The longitudinal assessment of HRQoL and symptom burden in 103 adult NHL patients over a period of 3 months after axi-cel infusion 48 at the Moffitt Cancer Center (Tampa, USA) suggested that improvement in physical functioning, reduction of pain and fatigue and worsening of anxiety (measured with PROMIS-29) from baseline were not associated with disease response, CRS or neurotoxicity. Patient-reported toxicity monitoring (measured with PRO-CTCAE) revealed peaks of symptoms such as cough, decreased appetite, dry mouth, fatigue, hair loss, hand-foot syndrome, headache, nausea, problems with concentration, problems with memory at 14 days after CAR T-cell infusion followed by decline over time. 48

A prospective cohort study of 27 NHL patients followed after axi-cel or tisa-cel infusion at Hopital Saint Louise (Paris, France), documented an improvement in self-reported prospective memory without any mid-term cognitive deterioration (measured by HADS and QMRD) between months 6 and 12 after CAR T-cell infusion. 50 However, anxiety and memory complaints (48% and 30% of patients, respectively) were more frequently reported at baseline CAR T-cell infusion than at the time of follow-up, and the frequency of anxiety (but not depression) was higher than in the general population. 50

Profiles of self-reported symptom burden and functional impairments reported during the first 12 months after CAR T-cell therapy in a cohort of 60 patients who received axi-cel or tisa-cel at the University of Texas MD Anderson Cancer Center suggested that the period up to 90 days after CAR T-cell infusion was the most symptomatic period (internal group comparison of symptom burden according to the time from CAR T-cell infusion). 51 Fatigue-related symptoms (eg, fatigue, lack of energy, weakness in the arm and legs, and malaise) were the most severe symptoms reported at any time of PRO assessment. 51 Symptoms like fatigue, lack of appetite, weakness, inability to eat, and mood interference (as assessed with MDASI instruments) were less severe in patients who completed PRO assessment later than month 3 after infusion compared to those who completed PROs in the period between months 1 and 3. 51 Physical functioning impairment was worse in the first month after infusion compared to that reported from month 3 to 1 year after infusion (as measured with MDASI instruments and PROMIS-29) 51 . Patients who developed grade 2–4 CRS or neurotoxicity consistently reported more severe multiple symptom profiles compared with those who experienced grade 0–1 CRS or neurotoxicity after 1 month following CAR T-cell infusion (as measured with MDASI instruments and PROMIS-29). 51

Ram et al 53 observed a transient increase in disability, worsening of symptoms, and emotional distress at 30 days after CAR T-cell infusion compared to baseline (before CAR T-cell infusion) in a matched control cohort study of 23 DLBC patients treated with axi-cel or tisa-cel. Improvement of overall health perception was found at 3 months after treatment infusion, as measured with the EORTC QLQ-C30. However, the paucity of PRO information (missing details on EORTC QLQ-C30 scale scoring and comparison) reported in the publication and the very small size of PRO sample hamper a critical appraisal of study findings.

Descriptive analysis of HRQoL patterns in 12 patients with various hematologic malignancies during the early timepoints after CAR T-cell infusion (up to month 3 after infusion) revealed clinically low physical well-being on day 7, and clinically low functional well-being from the day of CAR T-cell infusion up to month 1 (as measured with FACT-G). 55 Oswald et al reported mild fatigue perception from the day of CAR T-cell infusion up to month 1, mild interference pain interference only on day 14 after infusion, and impaired ability to participate in social role and activities between day 7 and month 1 after infusion (as measured with PROMIS-29). 55 The impairment level of physical function (as measured with PROMIS-29) was mild prior to CAR T-cell infusion, then changed to moderate from day 7 to month 1 after infusion and then returned to mildly impaired on month 2 after CAR T-cell therapy. FACT-G7 total scores revealed low HRQoL in the first week after CAR T-cell infusion. 55

Among 118 NHL patients who received CAR T-cell at Moffitt Cancer Center (USA), longitudinal PRO assessment focused on patients’ perception of cognition changes in the first year after CAR T-cell infusion revealed that only from month 3 to 1 year after CAR T-cell treatment patients reported worsening in global cognition and in the domains of memory, language, organization, and divided attention (as measured with Everyday Cognition Questionnaire). 56 Greater baseline fatigue, anxiety, and depression (as measured with the PROMIS-29) were associated with worse global cognition at month 3 after CAR T-cell infusion. In addition, patients with higher severity of neurotoxicity (ie, grade 2 or above) reported significantly worse cognition at 1-year timepoint compared to those with low grade neurotoxicity (ie, grade 0 or 1). 56

DISCUSSION

We identified 14 CAR T-cell therapy studies on hematologic malignancies which have also evaluated PROs over the last 7 years. Despite substantial differences in study designs and patient populations, there seems to be evidence of improvements over time since CAR T-cell infusion in important aspects, such as physical functioning and fatigue. Notably, such improvements were observed using different PRO measures thereby lending further credit to the beneficial effects of CAR T-cell therapy. However, it should be noted that evidence of such improvements was mainly available from patients who responded to therapy. The most accurate information found in our review on this aspect was provided by Patrick et al 49 who reported PRO results of patients achieving a complete or partial response and those who did not achieve a complete or partial response or whose treatment response was not evaluable. More research is required to better understand HRQoL and symptoms trajectories by response to therapy.

While no comparative studies were identified in our review, we note that 2 works were published in recent weeks (hence just beyond the timeframe of our search) which provided novel insights on the relative value of CAR T-cell therapy compared to more traditional approaches. 59 , 60 Elsawy et al 59 compared axi-cel versus standard of care in patients with R/R LBCL in an RCT setting, and showed statistically and clinically meaningful improvements at days 100 and 150 for prespecified PRO endpoints which favored patients treated with axi-cel. However, these differences were substantially attenuated at later timepoints, resulting in similar HRQoL outcomes between treatment groups. 59 While it is possible that the lack of long-term HRQoL differences between treatment groups may simply depend on study-specific design issues, more evidence is needed from other comparative RCTs to better contextualize PRO improvements after CAR T-cell infusion in relation to standard treatments. Sidana et al 60 , in a prospective observational study over a 6-month period, compared HRQoL and symptom burden of patients with mixed hematologic malignancies receiving CAR T-cell therapy to contemporary cohorts of patients receiving autologous SCT (auto-SCT) and allogeneic SCT (allo-SCT). Some key strengths of this study were that of having measured PROs already at 2 weeks after CAR T-cell infusion and showing that longitudinal collection of patient-reported symptoms with selected items from the PRO-CTCAE library is feasible in this setting. The authors found a short-term decline in HRQoL (nadired at week 2) in all 3 groups which then returned to baseline levels over time (ie, at 6 months). However, the decline in some key domains, such as physical well-being was significantly less with CAR-T versus auto-SCT or allo-SCT and returned to baseline faster. Furthermore, patients receiving CAR-T had fewer overall patient-reported AEs compared to patients who received auto-SCT and allo-SCT. 60

Although we found 14 studies that provided PRO data, this may be a negligible number if put into the larger context of ongoing research in this area. Using clinical trial registry data ( http://clinicaltrials.gov ), Raymakers et al 61 examined 424 trials investigating CAR-T for the treatment of cancer (of which 76% were on patients with hematologic malignancies), and observed that only 29 (6.8%) included HRQoL as a primary or secondary outcome measure, suggesting that inclusion of PROs is still uncommon in CAR T-cell therapy research. As expected, considering the novelty of this therapy, many trials considered in their work (88.4%) were phase I or II trials, 61 and this may partly explain the lack of a more consistent use of PRO measures in ongoing trials. In our review half of the studies identified were indeed phase I or II trials.

The inclusion of PROs in early-phase trials of advanced cancer populations (as is typically the case for patients eligible for CAR T-cell therapy) may pose some challenges. However, evidence from other research settings including vulnerable hematologic populations, indicates that PRO assessment is feasible and can provide high-quality clinically relevant information. 62 – 65 Furthermore, it is known that in early-phase clinical trials, clinicians may underreport important symptomatic AEs of their patients, 66 thereby making the use of patients’ self-reported symptoms a critical aspect to consider. For example, recent data support the use of the PRO-CTCAE already in phase I cancer trials to measure patient symptoms. 67 The PRO-CTCAE item library, 68 or other libraries such as the ones by the EORTC 69 and the FACIT, 70 are examples of valuable options to consider as they offer the opportunity to select specific validated items most relevant for a given research context. Of course, the selection of the most appropriate PRO assessment strategy should be guided by a specific research question and a combination of existing PRO validated questionnaires and ad-hoc items is also a valid option. A trend of improvement over time regarding the inclusion of PROs in early-phase cancer trials was recently observed, 71 and it is hoped this trend will continue considering the importance of the unique patient’s perspective in the drug development process. 72 An advantage of including PRO measures in early-phase trials could also be that of using preliminary results to better inform the PRO design of later phase trials. Examples of the use of PRO measures in early-phase trials in vulnerable hematologic populations, and their implications, are available. 73 , 74

Our review identified very limited evidence regarding patient experience during important phases of the disease trajectory. We found that only 4 and 5 studies provided information on PROs during the first 2 weeks from CAR T-cell infusion and during the long-term phase (ie, after the first year), respectively. Despite previous studies pointing to the importance of collecting long-term PRO data to identify symptoms or functional problems, which may only become evident several months or years after therapy, 75 our review indicates that major efforts are yet to be made in this direction. The integration of routine monitoring of PROs may be particularly relevant for patients who have received CAR T-cell therapy, for example, for collecting data on late toxicities. Given the logistics of CAR T-cell infusion, which typically requires patients to be treated and hospitalized in highly specialized centers and then return to their home local hospital, electronic (e)-PRO monitoring may be a valuable option. 44 For example, e-PROs monitoring via digital health tools may offer several advantages for these patients throughout the disease trajectory (including short-and long-term phases) as these may enhance physicians’ ability to identify problems that require special attention. These tools may allow the triggering of alerts to clinicians based on predefined algorithms, thereby facilitating early identification of potentially clinically relevant problems. 76 , 77 Of course, the setting of these algorithms will have to consider several aspects, such as, the specific hematologic population, the timing of assessment during the disease trajectory, the type of PRO measure/s as well as other important features of the data collection infrastructure and available resources.

Remote monitoring systems in the CAR-T setting could also consider the collection of biometric parameters and vital signs in the acute care setting immediately after infusion, as preliminary data support the value of this approach, for example, to identify patients requiring expedited hospitalization. 78 The study by Oswald et al 55 identified in our review, also supported the feasibility of collecting biometric information via wearable devices (in addition to PROs) among patients with hematologic malignancies receiving CAR-T. Kenzik et al, reported that re-hospitalizations and emergency department visits after CAR-T are not uncommon during the first year, and this is particularly relevant within the first month after infusion. 79 Therefore, remote monitoring systems that include a combination of wearable technology and systematic e-PRO assessment may play a valuable role in improving healthcare delivery across all phases of the disease trajectory (see Figure 2 , which also lists some potential advantages of this approach). In any case, we emphasize that future developments in this area should consider important digital health equity issues. 80 The recently published ESMO clinical practice guidelines on the use of PRO measures in cancer care, provide several high-quality recommendations, including the use of digital symptom monitoring via PROs. 81

Previous studies have noted the importance of considering the implication of financial burden in patients receiving CAR-T 75 ; however, we did not identify studies addressing this aspect. Indeed, in addition to the high costs associated with this therapy for healthcare systems, patients themselves may also report financial difficulties related, for example, to costs associated with follow-up visits or the management of toxicities. Cusatis et al 82 recently reported a qualitative and quantitative analysis suggesting that the financial impact of CAR T-cell therapy may increase over time, thereby emphasizing the importance of ensuring durable support to help patients face financial problems. There are now validated PRO measures that can be used to assess financial toxicity, for example, for the US cancer population, 83 and other PRO measures have been recently developed for patients living in countries with other types of healthcare systems. 84 Financial problems may differently affect patients depending on the specific country and type of healthcare system 85 and have been found to be associated with both HRQoL and survival outcomes. 86 – 88 Therefore, further research is needed to elucidate the implications of the financial burden on patients receiving CAR T-cell therapy.

Our review has limitations. Given the search strategy used, we may have provided limited evidence on specific areas of patient experience, for example, on neurocognitive problems. We did not include studies using performance-based measures (PBMs) to assess this aspect, while recent evidence indicates that PBMs may provide accurate information on cognitive problems (on top of the one generated via PRO measures) experienced by patients treated with CAR T-cell therapy, 89 and future work is needed to better understand the impact of CAR-T on potential neurocognitive deficits. Also, we did not evaluate the quality of PRO assessment methodology and outcome reporting and future research should focus on this important aspect. Although beyond the scope of our review, the HRQoL of caregivers of patients treated with CAR T-cell therapy may also be affected and this is a valuable area for further investigation. 90

CONCLUSIONS

Current evidence seems to indicate that CAR T-cell therapy is associated with improved PROs (in selected domains) compared to baseline, at least in responding patients. This may suggest that AEs, while potentially severe, are also generally manageable and do not seem to substantially impact HRQoL after the acute phase. Some initial comparative data also indicate that, during the early phases after infusion, CAR T-cell therapy may be associated with a lower impact on HRQoL and symptom burden in relation to standard treatments.

These are reassuring results which have shown the added value of PRO assessment in CAR T-cell therapy research, but more evidence is needed from patients who did not respond to therapy and major efforts are also needed to address several unanswered questions. For example, future research will need to identify subgroups of patients for whom the effects of CAR-T on HRQoL may be more profound and long lasting. These may include patients with comorbidities, lower performance status at baseline, and more severe physical and psychosocial distress at baseline. These patients are frequently excluded from investigational trials. Real-world studies in which PRO measures are routinely assessed at baseline and at regular follow-up of all patients who receive CAR-T (regardless of response to therapy) will be able to better characterize these effects in more vulnerable populations. Also, HRQoL trajectories may vary depending on the hematologic population and there may be disease-specific issues. Patients with ALL may achieve complete or partial remission following CAR T-cell therapy but the risk of relapse is still high. 91 Hence, PRO measures could also be implemented in a more standardized way in the context of the model of integration of early palliative care with standard hematologic care as recently implemented for hematologic malignancies, 92 – 94 to more accurately engage patients in goals-of-care discussion, earlier in the disease course based on effective communication. 92

The relationship between the financial burden experienced by these patients and HRQoL outcomes over the long-term period is also an important aspect that deserves special consideration. Remote monitoring systems including collection of e-PROs and other types of biometric data could potentially play a key role, and future research will have to elucidate the best practices to maximize their use across all phases of the disease trajectory.

AUTHOR CONTRIBUTIONS

FE and LC contributed to the study conception and design. FE, LC, FS, and JMG collected and assembled the data. All authors contributed in data interpretation, writing – original draft, and critically reviewed and approved the final version of the manuscript.

DISCLOSURES

FE has a consulting or advisory role: Amgen, AbbVie, Janssen, and Novartis. Research support (Institution) from AbbVie and Novartis outside the submitted work. FB has received travel grants and/or speaker honoraria from Pfizer, Celgene, Abbvie, Novartis, and Sanofi outside the submitted work. ML has been on the Advisory Boards for Novartis, Jazz Pharma, Sanofi, MSD, Abbvie, Daiichi-Sankyo, Gilead Sci, outside of the submitted work and has received a travel grant from Gilead Sci. MV reports honoraria from Amgen, Incyte, Novartis, Dephaforum Srl, Abbvie, and Astrazeneca and is on the advisory board for Amgen outside of the submitted work. UP reports honoraria from Gilead, BMS, and Novartis. All the other authors have no conflicts of interest to disclose.

Supplementary Material

Footnotes

Supplemental digital content is available for this article.

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