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Systematic Review

The Impact of Outpatient versus Inpatient Administration of CAR-T Therapies on Clinical, Economic, and Humanistic Outcomes in Patients with Hematological Cancer: A Systematic Literature Review

1
H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
2
Janssen Scientific Affairs, Horsham, PA 19044, USA
3
Putnam Associates, Gurgaon 122002, India
4
Putnam Associates, New York, NY 10282, USA
5
Legend Biotech USA, Inc., Piscataway, NJ 08854, USA
6
Janssen Biotech, Horsham, PA 19044, USA
*
Authors to whom correspondence should be addressed.
Cancers 2023, 15(24), 5746; https://doi.org/10.3390/cancers15245746
Submission received: 9 November 2023 / Revised: 1 December 2023 / Accepted: 3 December 2023 / Published: 7 December 2023
(This article belongs to the Section Systematic Review or Meta-Analysis in Cancer Research)

Abstract

:

Simple Summary

The administration of chimeric antigen receptor (CAR)-T cell therapies in an outpatient setting is expanding; however, there is limited evidence comparing outcomes from outpatient and inpatient administration. This research aims to compare the clinical and economic outcomes associated with the administration of CAR-T therapies in either setting for patients with hematological cancer, by summarizing existing evidence, and also to test the hypothesis that outpatient administration of CAR-T therapies yields comparable clinical effectiveness as inpatient treatment while offering significant cost reduction and lower humanistic burden.

Abstract

Although chimeric antigen receptor (CAR)-T cell therapies are typically administered in the inpatient setting, outpatient administration is rapidly expanding. However, there is limited summarized evidence comparing outcomes between outpatient and inpatient administration. This systematic literature review aims to compare the safety, efficacy, quality of life (QoL), costs, and healthcare resource utilization (HCRU) outcomes in patients with hematological cancer who are administered CAR-T therapy in an outpatient versus an inpatient setting. Publications (2016 or later) that reported the outcomes of interest in patients treated with a CAR-T therapy in both outpatient and inpatient settings, or only the outpatient setting, were reviewed. In total, 38 publications based on 21 studies were included. Safety findings suggested the comparable frequency of adverse events in the two settings. Eleven studies that reported data in both settings showed comparable response rates (80–82% in outpatient and 72–80% in inpatient). Improvements in the QoL were observed in both settings while costs associated with CAR-T therapy were lower in the outpatient setting. Although unplanned hospitalizations were higher in the outpatient cohort, overall HCRU was lower. Outpatient administration of CAR-T therapy appears to have comparable outcomes in safety, efficacy, and QoL to inpatient administration while reducing the economic burden.

1. Introduction

Hematological cancers are a significant global health issue characterized by high mortality rates [1,2]. They negatively affect patients’ life expectancy and quality of life (QoL) and impose a substantial economic burden [3,4,5,6]. The clinical outcomes for hematological cancers have improved with the development of targeted therapies, such as small molecule inhibitors, monoclonal antibodies, and recombinant immunotoxins and, more recently, chimeric antigen receptor (CAR)-T cell therapies, antibody–drug conjugates, and bispecific T-cell engagers [7]. CAR-T therapies have emerged as a revolutionary treatment option, demonstrating remarkably effective and durable clinical responses for hematological cancers [8,9]. This therapy involves reprogramming the patient’s own T-cells to target the tumor cells wherein host T-cells are collected and are genetically modified ex vivo to express a CAR targeting a tumor-specific antigen [10]. To date, a total of six CAR-T therapies (tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel, idecabtagene vicleucel, and ciltacabtagene autoleucel) have been approved by the United States Food and Drug Administration (FDA) for multiple hematological cancers [11,12,13] based on pivotal clinical trials demonstrating promising results of efficacy outcomes [14,15,16,17,18,19]. Notably, clinical trials focusing on CAR-T therapies have exhibited complete remission rates of 70–90% in relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) [14,15,16] and 40–58% in non-Hodgkin lymphoma (NHL) [17]. Additionally, an overall response rate of 97% was shown in relapsed or refractory multiple myeloma [19,20]. Furthermore, the complete response rate of 73.1% was shown in lenalidomide-refractory multiple myeloma in a phase 3 randomized open-label trial, CARTITUDE-4 [21].
CAR-T therapies have typically been administered in an inpatient setting followed by monitoring of patients closely for several weeks for serious side effects, such as cytokine release syndrome (CRS) and neurotoxicity [22]. However, the outpatient delivery of CAR-Ts is rapidly expanding for patients with a suitable benefit–risk clinical profile and based on overall greater predictability of the clinical course and patient preference. This has the potential to significantly reduce the treatment burden for patients and caregivers and the overall cost burden to the healthcare system associated with inpatient care [22]. Previous trials have demonstrated the feasibility of outpatient CAR-T administration and indicated that such outpatient infusion may be more convenient and preferred by patients and health systems [22,23,24,25]. Challenges in outpatient CAR-T administration, however, include the availability of trained multidisciplinary teams and the infrastructure required to identify and manage complications that need early intervention, suitable reimbursement policies, and caregiver education. Furthermore, patient-specific factors including disease characteristics, clinical status, predictability of adverse events (AEs), medical center proximity, and caregiver support impact the decision on the setting of CAR-T administration [22,26]. Although there are some standalone studies that have presented a case for outpatient delivery of CAR-T therapies, there is currently no published systematic literature review (SLR) comparing the clinical safety, efficacy, QoL, economic implication, and healthcare resource utilization (HCRU) of CAR-T administration in the two settings. This SLR aims to fill this gap by identifying and summarizing the existing clinical and economic evidence on CAR-T therapies and comparing the outcomes for inpatient versus outpatient CAR-T administration in patients with hematological cancer.

2. Methods

2.1. Study Design and Search Process

This SLR was carried out in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) checklist [27] and the Cochrane handbook for systematic reviews of interventions, version 6.3 [28]. The protocol has not been registered. Records were retrieved from MEDLINE, Embase, and Cochrane electronic databases. Additionally, manual searching of conference proceedings, bibliographic sources, and other grey literature sources, such as Google, Google Scholar, and disease-specific websites/conferences [American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), American Society of Hematology (ASH), European Hematology Association (EHA), International Society for Pharmacoeconomics and Outcomes Research (ISPOR), and Academy of Managed Care Pharmacy (AMCP)] was carried out. The bibliographies of relevant SLRs on the research topic were also searched to identify any additional studies. The search strategies for each database are provided in Tables S1–S3. The literature search was limited to articles published from 1 January 2016 to 4 January 2023. The starting year was chosen as 2016 to ensure the coverage of all relevant studies that may have influenced the approvals of CAR-T therapy, the first of which occurred in 2017.

2.2. Eligibility Criteria

This SLR included studies reporting relevant outcomes of CAR-T therapy administration in both outpatient and inpatient settings or only the outpatient setting among patients with lymphoma, ALL, or multiple myeloma. Relevant outcomes included safety, efficacy, QoL, costs, and HCRU measures. Studies that did not report the setting of CAR-T administration were excluded. Clinical trials and observational (prospective and retrospective) studies were included whereas non-human studies were excluded. The screening of articles to evaluate conformance to eligibility criteria was performed independently by two reviewers and any disagreements were resolved in discussion with a third reviewer.

2.3. Data Extraction

Two reviewers independently extracted the following data from the included studies: study characteristics, patient characteristics, treatment-related information, and outcomes of interest. Any inconsistencies were resolved through discussion between the two reviewers. If necessary, a third reviewer was consulted to mediate and reach a consensus.

2.4. Quality Assessment and Risk of Bias

The Cochrane risk-of-bias tool version 2 (RoB 2) for randomized controlled trials (RCTs) [29], the Downs and Black (Downs 1998) checklist for non-RCTs [30], and the Newcastle and Ottawa scale (NOS) for observational studies [31] were utilized for quality assessment.

2.5. Data Analysis

Evidence identified from the systematic literature search was analyzed qualitatively. The compiled evidence was tabulated, summarized, and presented graphically for the following elements of the research: study details (trial design, tumor type, treatment setting, sample size, and follow-up duration) and outcomes presented (safety, efficacy, QoL, HCRU, and costs incurred). Safety outcomes included the cytokine release syndrome (CRS), neurologic toxicities, and other toxicities reported in individual publications while the collated efficacy outcomes included the complete response (CR), partial response (PR), overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). HCRU measures reported included the rate of, time to, and reasons for hospitalization, length of hospital stay, rate of ICU admissions and length of stay, and outpatient visits. Costs incurred in different follow-up periods post-infusion were compiled and categorized as available.
The data were reported separately for outpatient and inpatient cohorts and included evidence from comparative as well as single cohort studies.

3. Results

3.1. Literature Search Results

Database searches identified 7701 initial records. After deduplication, 5648 records remained for screening against inclusion and exclusion criteria. A total of 1125 records met the relevant criteria and an additional 83 records were obtained from supplementary sources including Google Scholar, conference proceedings, and a bibliography of identified studies and SLRs, resulting in a total of 1208 records. Ultimately, 38 records that reported outcomes for patients who underwent infusion/management in the outpatient setting or in both outpatient and inpatient settings were considered for qualitative synthesis (Figure 1).

3.2. Study Characteristics

The 38 included records were based on 21 unique studies, most of which were published in 2022 and 2023. The patient populations of these studies included individuals diagnosed with ALL, various types of lymphoma, such as B-cell lymphoma (BCL) and follicular lymphoma (FL), and multiple myeloma.
In total, 18 of these 21 studies were conducted in the United States [26,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63]. The TRANSFORM phase 3 clinical trial was conducted in the United States, Japan, and various European countries including Belgium, France, Germany, Italy, the Netherlands, Spain, Sweden, Switzerland, and the United Kingdom [64,65]. Additionally, the ELARA phase 2 clinical trial encompassed multinational locations, including centers in the United States and Australia [66,67]. Only one retrospective study did not report the specific location where it was conducted [68]. Eleven studies reported data on CAR-T administration in both outpatient and inpatient settings [26,32,33,34,35,36,37,38,39,40,41,42,43,44,52,53,54,58,61,62,64,65,66,67,68]. These publications were based on 5 clinical trials, namely OUTREACH [32,33,34,35,36,37,38], ELARA [66,67], PILOT [39,40,41], TRANSCEND NHL 001 [42,43,44], and TRANSFORM [64,65], where the choice of site of care for patients treated with CAR-T therapies was determined at the investigator’s discretion, taking into consideration the perspectives of multiple stakeholders including healthcare providers, patients, and caregivers.
Nine of the shortlisted studies reported efficacy outcomes including response rates and survival outcomes [36,37,39,42,47,55,57,60,63,67]. Only one clinical trial reported QoL in the patient groups of interest [38]. Five studies reported data on AEs, including CRS and neurologic toxicity [37,39,42,53,67]. Seven studies reported costs/reimbursement amounts associated with the administration of CAR-T in both settings [26,41,52,53,62,65,67]. Ten studies reported data on HCRU [26,37,39,41,52,53,54,62,67,68] in both settings while a further seven studies reported HCRU among patients who received CAR-T only in the outpatient setting [26,37,39,41,46,52,53,54,55,57,59,60,62,63,64,67,68]. The distribution of age, sex, performance status, number of prior treatment lines, and other patient characteristics varied across the studies. Details of the included studies and patient characteristics are shown in Table 1 and Table 2.

3.3. Quality Assessment

All of the 21 studies included in the analysis underwent a quality assessment using relevant checklists based on their study design. The assessment aimed to evaluate the risk of bias and the overall quality of the studies. The ROB 2 checklist was used to assess the RCTs conducted by Kamdar in 2022 [64]. The findings from this assessment revealed a high risk of bias in the trial (Table S4). The modified Downs and Black checklist with 27 items assessed eight non-randomized single-arm trials. Table S5 highlights one study of good quality (score, 15–17), five of fair quality (score, 12–14), and two of poor quality (score < 11) [38,39,42,46,49,51,67]. The NOS criteria were used to assess the quality of double-arm and single-arm observational studies. Of the six double-arm studies, five were considered of good quality (score > 6) and one of fair quality (score 5) (Table S6). Among the six single-arm studies, five were rated as good quality (score > 4) and one as fair quality (score 4) [26,41,45,53,54,55,57,59,60,62,63,68].

3.4. Clinical Outcomes

3.4.1. Safety

The safety of CAR-T therapy was evaluated in several studies, with data available for both outpatient and inpatient settings [37,39,42,53,67]. In total, 5 publications provided safety data for both settings while 10 publications reported data solely on patients treated in the outpatient setting. In the publications reporting data for both settings, the frequency of AEs was generally comparable or higher for patients who received CAR-T in the inpatient setting. Two publications by Denlinger (2022) [53] and Sehgal (2022) [39] reported a higher frequency of CRS in patients who received CAR-T in the inpatient setting whereas the other three publications found similar rates of CRS between the two cohorts. The OUTREACH and ELARA trials reported other AEs, including infections, leukopenia, anemia, and thrombocytopenia. In the OUTREACH trial, the incidence of infections was comparable between the outpatient and inpatient settings, with 33% and 32% of patients experiencing infections, respectively. Additionally, prolonged cytopenia at the Day 29 visit was also consistent between outpatient and inpatient settings, with 33% and 32% of patients affected, respectively. In the ELARA trial, the incidence of infections was lower in the outpatient setting compared with the inpatient setting, with any grade infections reported in 17.6% of outpatient versus 21.3% of inpatient cohorts. Although none of the patients in the outpatient group experienced a Grade 3–4 infection, 7.5% of those in the inpatient group experienced such severe infections. Furthermore, the ELARA trial indicated a higher occurrence of hematological disorders in the inpatient setting, with any grade cytopenia reported in 77.5% of inpatient compared with 64.7% of outpatient administration groups. Similarly, the occurrence of Grade 3–4 cytopenia was lower in the outpatient group (47.1%) versus the inpatient group (73.8%). Three publications reported a higher frequency of neurologic toxicities among patients who received CAR-T in the inpatient setting [39,53,67]. Conversely, one publication by Abramson (2020) [42] reported a substantially higher frequency of neurologic toxicities among patients who received CAR-T in the outpatient setting (Table 3). Most of the publications pertaining to only the outpatient cohort reported high frequencies of CRS-related (40–92%) and neurologic (6–57%) toxicities [45,47,48,49,51,55,57,59,60,63]. Detailed safety outcomes are presented in Table 4. For studies involving CAR-T treatment in both inpatient and outpatient settings, three publications reported no deaths from CRS and neurological toxicities [37,39,42]. For studies based on treatment in only the outpatient setting, Turtle et al. reported a 5% mortality rate, with most deaths occurring during the dose-finding phase, primarily due to CRS and neurological events [51].

3.4.2. Efficacy: Response and Survival Outcomes

In the studies reporting response outcomes from both settings, the overall response rate (ORR) was found to be comparable between patients managed in the outpatient setting (ORR, 80–82%) and those managed in the inpatient setting (ORR, 72–80%) [36,37,39,42]. In the OUTREACH trial, the ORR was 82% in the outpatient cohort and 76% in the inpatient cohort [36,37]. In the PILOT trial, the ORR was 80% in both outpatient and inpatient groups [39]. In the TRANSCEND NHL 001 trial, the ORR was 80% in the outpatient cohort and 72% in the inpatient cohort [42]. The response rates observed in real-world studies (43–88%) were lower than those observed in clinical trials (80–100%) for patients managed in the outpatient setting. The median duration of response was found to range from 8.2 to 15.1 months among the CAR-T–treated patients managed in the outpatient setting and were comparable to the duration of response in those managed in the inpatient setting (12.1 to 14.8 months) (Table 5) [36,37,39]. Progression-free survival (PFS) data for patients managed in the outpatient setting were reported in a limited number of studies. In the OUTREACH trial, patients receiving treatment in the outpatient setting had a 12-month PFS rate of 41% which was similar to the rate observed in an inpatient setting (39%). In the ELARA trial, the 12-month PFS rate was 60% for patients in the outpatient group compared with 70% for patients receiving treatment in an inpatient setting (Table 6) [37,39,42,63,67]. Similarly, the overall survival (OS) data for patients managed in the outpatient setting were limited. The Kaplan–Meier estimates for 12-month OS ranged from 60% to 75% among patients with lymphoma managed in the outpatient setting and were reported to be 60% among those managed in the inpatient setting [37,39,47,60,63]. Notably, a real-world study reported a median OS of 26.5 months in patients with lymphoma managed in the outpatient setting (Table 7) [60].

3.4.3. Quality of Life

Linhares et al. (2022) reported QoL assessments in patients treated with CAR-T therapy at multiple time points, including pre-treatment (baseline), on day of infusion, on several dates after infusion (days 29, 50, 90, 180, 270, 365, 545, and 730/end of study), and at disease progression and assessed the least squares (LS) mean change from the baseline for visits with ≥10 patients. Both the outpatient and inpatient groups exhibited comparable meaningful improvements in various aspects of QoL, including global health status/QoL, fatigue, pain, assessed by EORTC-QLQ-C30, and the EuroQol 5-Level 5-Dimension questionnaire (EQ-5D-5L) visual analog scale (VAS) scores (Table 8) [38].

3.5. Economic Outcomes

3.5.1. Direct Costs

Seven studies reported costs/reimbursement amounts associated with CAR-T administration in both outpatient and inpatient settings in the United States (Table 9) [26,41,52,53,62,65,67]. Of these, six reported that the post-infusion costs were lower for patients who received CAR-T in an outpatient setting compared with those who received it in an inpatient setting [41,52,53,62,65,67]. Costs in the 6-month post-infusion period reported from TRANSCEND NHL 001, OUTREACH, TRANSFORM, and PILOT trials revealed to be two to four times greater costs in the inpatient setting—these ranged from USD 61,772 to USD 96,297. Pooled analysis of TRANSCEND NHL 001 and OUTREACH trials similarly showed a lower 6-month post-infusion cost in the outpatient setting (USD 36,702) compared with the inpatient setting (USD 89,535) [52]. The main driver for the higher costs in the inpatient setting was identified to be hospitalization costs [41,52,65]. Yang et al. (2022), the only study that assessed the Medicare reimbursement amount, including CAR-T product costs, reported that costs in the first month were nominally higher in the outpatient cohort compared with the inpatient cohort and were comparable in subsequent months [26].

3.5.2. Healthcare Resource Utilization

The analysis of HCRU among patients who received CAR-T in the outpatient setting was reported in 17 publications [26,37,39,41,46,52,53,54,55,57,59,60,62,63,64,67,68]. Of these, 10 also reported data for patients who received CAR-T in the inpatient setting (Table 10) [26,37,39,41,52,53,54,62,67,68]. Most of the HCRU data were related to inpatient admissions, length of stay (LOS), and intensive care unit (ICU) admissions. Some publications also reported a median time to hospitalization for the outpatient cohort, ranging from 4 to 9 days [37,39,52,55,57,64,67]. Chihara et al. (2022) and Wright et al. (2020) reported lower rates of unplanned hospitalization (defined as post-CAR-T infusion in the outpatient cohort and re-hospitalizations in the inpatient cohort) in the inpatient cohort [54,68]. Despite such higher unplanned hospitalization observed in the outpatient cohort, the overall HCRU was lower for the outpatient cohort in publications that reported data for both cohorts. Most studies reported higher overall mean LOS for the inpatient cohort, with two to three times longer durations compared with the outpatient cohort across studies [26,37,39,41,52,53,62,67]. Additionally, ICU utilization was found to be higher for the inpatient vs. outpatient cohort, as shown by Fowler et al. (2022) (9% vs. 0%), Palomba et al. (2020) (7% vs. 6%), and Sehgal et al. (2022) (20% vs. 5%) [26,41,52,53,62,65,67]. Similarly, the mean ICU LOS was two to three times higher for the inpatient cohort across studies, except the study by Sehgal et al. (2022) which reported a lower ratio (0.8) of ICU LOS for the inpatient cohort [39]. Additional HCRU data available in the identified studies are presented in Table S7.

4. Discussion

This comprehensive SLR on CAR-T therapies in patients with hematological cancer highlights the potential benefits of outpatient compared with inpatient administration. Safety outcomes, a key consideration in CAR-T treatments and a principal driver for traditionally treating patients in the inpatient setting, were comparable between those treated in the outpatient setting and those treated in the inpatient setting. Moreover, the analysis revealed comparable effectiveness outcomes between the two settings, including the response rates, duration of response, and survival outcomes where reported. Furthermore, both outpatient and inpatient cohorts experienced meaningful improvements in QoL measures. These findings collectively provide compelling evidence to clinicians and other decision-makers to actively consider administering CAR-T therapies in the outpatient setting for patients whose disease and clinical characteristics permit this. Treating institutions may upgrade their processes and protocols to encourage treatment in the outpatient setting, including preparing for and managing early complications.
In the reviewed studies, the choice of outpatient administration was at the investigator’s discretion, taking into account patient disease characteristics, clinical status, and logistical considerations, such as the availability of caregiver support and the ability to remain within a short distance from the treatment site for 30 days after infusion [32,34,35,36,37,38,39,42,43,44,64,65,66,67]. Typically, patients receiving CAR-T therapy in the outpatient setting are closely monitored by a multidisciplinary CAR-T therapy team and adhere to standard operating procedures for outpatient AE monitoring and management [32,34,35,36,37,38,66,67].
To further bolster the case for outpatient administration of CAR-T therapies, assessment of such administration in the real world with longer-term follow-up to allow for the evaluation of survival outcomes such as PFS and OS is warranted. These endpoints are crucial in evaluating the long-term benefits and potential risks associated with the two treatment settings [69].
The observed enhancement in QoL reported by Linhares et al. (2022) likely represents the comprehensive impact of CAR-T therapy on hematological cancer patients, regardless of the treatment setting [38]. Further research is needed to explore the underlying factors contributing to the improvement in QoL, paying particular attention to factors related to reduced hospitalization as this could enhance the overall patient experience and improve their QoL during treatment. It is also important to evaluate QoL at multiple time points after CAR-T therapy use and examine if the resolution of AEs reflects improved QoL outcomes. Furthermore, the utilization of other measures, such as the hospital anxiety and depression scale depression subscale (HADS-D), in patients with hematological cancer is important in understanding and addressing their mental health needs more specifically [70]. Additionally, a previous SLR emphasized the importance of identifying patients’ preferences for involvement in cancer treatment decisions. Establishing these preferences will encourage the healthcare system to become more responsive to individual patient needs and expectations and ultimately, contribute to improving their QoL [71].
The economic outcomes indicate that outpatient treatment may offer cost advantages over inpatient treatment, with patients treated in the latter incurring two to four times higher costs (USD 62,000–96,000) than by outpatient-treated patients (USD 16,000–38,000) [41,52,65]. The lower costs observed in the outpatient cohort were primarily driven by reduced hospitalization costs [41,62,65,67]. These findings align with an economic evaluation of CAR-T therapy based on the site of care, wherein outpatient CAR-T administration resulted in a substantial decrease in total costs (by 40.4%), with notable reductions observed in hospitalization, office visits, and procedural expenses [72]. However, a study by Yang (2022) found that the Medicare reimbursement in the outpatient cohort was slightly higher than that in the inpatient cohort during the first month post-infusion and comparable in subsequent months. The authors, however, attributed this to the inadequate reimbursement for CAR-T infusion in the inpatient setting whereas the outpatient setting reimbursement, which is covered under Medicare Part B, covers not only the CAR-T product cost more completely but also the handling, storage, and a portion of the physician’s service fees. Additional efforts are recommended to improve the reimbursement structure and care policies for CAR-T therapy in either infusion setting to suitably incentivize providers [26].
The outpatient cohort experienced more unplanned hospitalizations, with CRS being the main reason for hospitalization. However, the overall HCRU was lower in cases where data were available for both settings as the inpatient cohort exhibited longer stays and a higher HCRU [26,37,39,41,46,52,53,54,55,56,57,59,60,62,63,64,67,68]. An improved understanding of the predictive risk factors for CRS and neurotoxicity development, including patient disease characteristics and clinical status, can influence personalized decisions regarding outpatient administration as it may offer potential benefits in terms of overall resource utilization.
Outpatient CAR-T administration can potentially expand treatment access by freeing up inpatient capacity and addressing geographic obstacles. A prior economic model concluded that lower costs through outpatient administration could enable more patients to receive treatment with limited resources. [72].
This review provides a comprehensive analysis of both clinical and economic outcomes derived from clinical trials and observational studies concerning CAR-T therapies in a broad patient population with hematological cancer. The review was conducted in accordance with a predefined protocol, with clear inclusion and exclusion criteria, and adhered to the Cochrane guidelines for systematic review reporting. A comprehensive search strategy was employed to minimize reporting bias in the review process.
While this SLR adhered to rigorous selection criteria, it had some limitations. The included studies exhibited heterogeneity in terms of methodology and populations, which prevented direct comparisons. Additionally, in studies that reported outcomes related to the two settings, patients were not randomized between the settings, introducing the potential for bias and raising concerns about the comparability of reported outcomes. In line with the objective of this study, outcomes data were presented here only if reported by setting. The molecular aspect of the therapy has not been discussed as none of the identified publications referred to it as either the driver for the decision of inpatient vs. outpatient administration or as the cause of any difference in the outcomes. Furthermore, patient characteristics were not available for all the studies as the majority of the identified publications were conference abstracts with minimal information on patient characteristics.

5. Conclusions

Findings from our study showed comparable overall outcomes in safety, efficacy, and QoL between outpatient and inpatient CAR-T administration. While CAR-Ts are typically administered in an inpatient setting, outpatient administration of CAR-T can provide a reduced economic burden without negatively impacting clinical outcomes and should be actively considered where patient disease characteristics and logistical considerations permit this. Future research is needed to explore the impact of administration settings of new CAR-T therapies on patients with multiple myeloma and other hematological cancers.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/cancers15245746/s1. Table S1. MEDLINE search strategy; Table S2. Embase search strategy; Table S3. Cochrane search strategy; Table S4. Quality assessment of randomized controlled trial using the Risk-of-Bias version 2 checklist; Table S5. Quality assessment of non-randomized clinical trials (single-arm) using Downs and Black checklist; Table S6. Quality assessment of observational studies (single-arm and double-arm) using the NOS checklist; Table S7. Additional healthcare resource utilization data available in identified studies.

Author Contributions

Conceptualization, D.K.H., Y.-H.L., K.C.D.B. and S.H.; methodology, D.K.H., Y.-H.L., S.R., H.B., R.P., L.M., K.C.D.B. and S.H.; software, S.R., H.B. and R.P.; validation, Y.-H.L., S.R., H.B. and R.P.; formal analysis, Y.-H.L., S.R., H.B. and R.P.; investigation, D.K.H., Y.-H.L., S.R., H.B., R.P., L.M., K.C.D.B. and S.H.; resources, S.H.; data curation, S.R., H.B. and R.P.; writing—original draft preparation, D.K.H., Y.-H.L., S.R., H.B., R.P., L.M., K.C.D.B. and S.H.; writing—review and editing, D.K.H., Y.-H.L., S.R., H.B., R.P., L.M., K.C.D.B. and S.H.; visualization, S.R., H.B. and R.P.; supervision, D.K.H., K.C.D.B. and S.H.; project administration, Y.-H.L., R.P. and S.H.; funding acquisition, S.H. All authors have read and agreed to the published version of the manuscript.

Funding

This study was funded by Janssen Scientific Affairs, LLC. and Legend Biotech USA, Inc.

Data Availability Statement

All data generated or analyzed during this study are included in this published article (and its Supplementary Information Files).

Acknowledgments

The writing support was provided by Mohammed Alshaikheid from Putnam Associates, UK.

Conflicts of Interest

D.K.H. is a member of the Bristol-Myers Squibb IMW Ide-Cel Academic Advisory Board, Bristol-Myers Squibb Multiple Myeloma ASH Steering Committee, and Multiple Myeloma Pfizer Advisory Board; received honoraria for Onc Live and Survivorship; received research funding from Bristol-Myers Squibb, Karyopharm, International Myeloma Society Young Investigator Award, and the Pentecost Family Myeloma Research Center; and has consulted with Bristol-Myers Squibb, Karyopharm, Janssen, and Pfizer. Y.L. is an employee of Janssen Scientific Affairs, LLC. S.R., H.B., and R.P. are employees of Putnam Associates. L.M. is an employee of Legend Biotech and holds stock in the company. K.D.B. is an employee of Janssen Biotech, a subsidiary of Johnson & Johnson, holds Johnson & Johnson stock, and has a patent planned, issued, or pending. S.H. is an employee of Janssen Scientific Affairs, LLC, and holds Johnson & Johnson stock.

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Figure 1. The preferred reporting items for systematic reviews and meta-analysis (PRISMA) flow diagram.
Figure 1. The preferred reporting items for systematic reviews and meta-analysis (PRISMA) flow diagram.
Cancers 15 05746 g001
Table 1. Characteristics of included studies.
Table 1. Characteristics of included studies.
StudyCountryTrial Name/IDStudy DesignTreatmentPatient PopulationSetting (IP/OP/Both)Sample Size, nReason for Different Sample SizesList of Outcomes
Kamdar (2022) [64]US, Europe, and JapanTRANSFORM/NCT03575351Ph 3 trialLiso-celR/R LBCL (2L+)Both91 Response, LOS
McGarvey (2022) [65]90Total post-infusion monitoring costs, hospitalizations cost
Godwin (2021) [32]USOUTREACH/NCT03744676Ph 2 trialLiso-celR/R LBCL (3L+)Both34Preliminary results 1Response, AEs, hospitalizations, LOS
Godwin (2020) [33]34Response, AEs, hospitalizations, time to hospitalization, LOS
Godwin (2021) [34]46Preliminary results 2Response, AEs
Godwin (2021) [35]46Response, AEs, hospitalizations, time to hospitalization, LOS
Godwin (2021) [36]71Preliminary results 3Response, AEs, time to hospitalization, LOS
Linhares (2022) [37]82Updated resultsResponse, AEs, hospitalizations, time to hospitalization
Linhares (2022) [38]82Response, AEs, hospitalizations, time to hospitalization, QoL
Sehgal (2022) [39]USPILOT/NCT03483103Ph 2 trialLiso-celR/R LBCL (2L+ not intended for HSCT)Both61 Response, time to response, DOR, PFS, OS, EFS, AEs, hospitalization, ICU admission
Sehgal (2019) [40]R/R aggressive NHL (2L+)10SubgroupResponse, AEs, HCRU
McGarvey (2022) [41]R/R LBCL (2L+ not intended for HSCT)61 Hospitalizations, LOS, monitoring costs
Abramson (2020) [42]USTRANSCEND NHL 001/NCT02631044Ph 1 trialLiso-celR/R LBCL (2L+)Both25Preliminary results 1Response, PFS, AEs
Maloney (2017) [43]R/R B-cell NHL (2L+)69Preliminary results 2AEs
Palomba (2018) [44]R/R DLBCL (2L+)94Updated resultsResponse, AEs, hospitalizations, time to hospitalization, ICU admission, LOS, OP visits
Gofshteyn (2018) [45]USPedi CART19/NCT01626495Ph 1/2a trialTisa-celPediatric and young adults with R/R ALLOP51NAAEs
Fowler (2021) [66], Fowler (2023) [67]MultinationalELARA/NCT03568461Ph 2 trialTisa-celR/R FL (3L+)Both97NAHospitalizations, LOS, ICU admission,
hospitalization costs
Myers (2020) [46]USNCT01626495/NCT02906371/NCT02374333Pooled analysis (3
Ph 1/2 trials)
Tisa-celPediatric ALL93% patients treated as OPs213NAHospitalizations, LOS, ICU admission, mortality rate, other HCRU
Shadman (2021) [47]USNCT03277729Ph 1/2 trialMB-106R/R B-NHL (FL, MCL, DLBCL) and CLLOP25Updated resultsResponse, AEs
Shadman (2020) [48]12Preliminary results
Shadman (2021) [49]12
Shadman (2022) [50]R/R FL16Updated results for a subgroup
Turtle (2017) [51]USNCT01865617Ph 1/2 trialCD19 CAR-T cellsB-ALL, NHL or CLLOP161NAAEs
Palomba (2020) [52]US-Cost analysis (pooled trial data)Liso-celR/R LBCL (3L+)Both303NAStandard IP and ICU LOS, costs (diagnostics and procedures, medications, hospitalization/ICU)
Denlinger (2022) [53]US-Retrospective studyTisa-cel, axi-celBCLBoth63NAAEs, LOS, costs and charges, out-of-pocket charges
Chihara (2022) [54]US-RWEAny CAR-TR/R DLBCLBoth551NAPFS, OS, hospitalization, ER visits, OP visits (initial and follow-up), costs
Borogovac (2022) [55], Borogovac (2021) [56]US-Retrospective studyAny CAR-TDLBCL, FL and ALL, MCL91% patients treated as OPs23NAResponse, AEs
Shao (2021) [57]US-Retrospective studyTisa-celDLBCL (3L+)OP12NAResponse, AEs, hospitalization, LOS
Yang (2022) [26], Zhao (2021) [58]US-RWE (Medicare claims database)Tisa-cel, axi-celR/R DLBCLBoth430NAICU admission, LOS, costs
Farooqui (2022) [59]US-Retrospective studyAxi-celNHLOP83NAAEs, ICU admission
Nasta (2022) [60]US-Retrospective studyTisa-celLymphoma (3L+)OP72NAResponse, OS, PFS, AEs
Maziarz (2021) [61]
Maziarz (2022) [62]
US-Retrospective studyTisa-cel, axi-celR/R DLBCLBoth119NAHospitalizations, ICU admissions, LOS, OP visits, costs
Hospitalizations, ICU, LOS, OP visits (initial and follow-up), costs
Wright (2020) [68]NR-Retrospective studyAxi-cel/tisa-celR/R NHLBoth31NAHospitalizations, LOS
Kirby (2022) [63]US-Retrospective studyAxi-cel, tisa-cel, brexu-cel, liso-celR/R BCLOP20NAPFS, OS, AEs, hospitalizations
Abbreviations: 2L+, second line and greater; 3L+, third line and greater; AE, adverse event; ALL, acute lymphoblastic leukemia; axi-cel, axicabtagene ciloleucel; brexu-cel, brexucabtagene autoleucel; BCL, B-cell lymphoma; CAR-T, chimeric antigen receptor T-cell; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; DOR, duration of response; EFS, event-free survival; ER, emergency room; FL, follicular lymphoma; HCRU, healthcare resource utilization; HSCT, hematopoietic stem cell transplant; ICU, intensive care unit; IP, inpatient; LBCL, large B-cell lymphoma; liso-cel, lisocabtagene maraleucel; LOS, length of stay; MCL, mantle cell lymphoma; NA, not available; NHL, non-Hodgkin lymphoma; NR, not reported; OP, outpatient; OS, overall survival; Ph, phase; PFS, progression-free survival; PR, partial response; QoL, quality of life; R/R, relapsed/refractory; RWE, real-world evidence; tisa-cel, tisagenlecleucel; US, United States.
Table 2. Patient characteristics.
Table 2. Patient characteristics.
StudyStudy/Trial Name/Trial IDTreatmentSetting (IP/OP)nAge, Median (Years)Age ≥ 65, (%)Male (%)ECOG PS (%)Number of Prior LinesPrior Transplant Therapy, (%)Refractory Patients, (%)
Godwin (2021) [36]OUTREACH/NCT03744676Liso-celOP5464.550.070.00: 33.0
1: 67.0
2.0 (2.0–4.0) *20.089.0
IP2368.061.061.00: 26.0
1: 74.0
2.0 (1.0–6.0) *9.096.0
Fowler (2021) [66], Fowler (2023) [67]ELARA/NCT03568461Tisa-celOP17NR23.576.5≥1: 23.5≥5: 41.2%NR41.2
IP80NR25.063.8≥1: 47.5≥5: 25.0%NR26.3
Gofshteyn (2018) [45]Pedi CART19—NCT01626495Liso-cel OP5111.5NR49.0NRNRNRNR
Shadman (2022) [50]NCT03277729MB-106 (CD20 CART-T)OP1661.5NRNRNRNRNRNR
Myers (2020) [46]NCT01626495/NCT02906371/NCT02374333Tisa-celOP21312.4NR60.0NRNRNRNR
Shao (2021) [57]NRTisa-celOP1269.583.066.7NR2: 75.0%
3: 25.0%
16.7NR
Zhao (2021) [58], Yang (2022) [26]NRTisa-cel, axi-celOP50Mean: 68.4NR70.0NRNRNRNR
IP380Mean: 70.8NR62.4NRNRNRNR
Farooqui (2022) [59]NRAxi-celOP83Mean: 55.2NR65.1NRNRNRNR
Nasta (2022) [60]NRTisa-celOP7265.7NR58.30: 31.9
1: 62.5
2: 4.2
NR: 1.4
NR18.1NR
Kirby (2022) [63]NRTisa-cel, axi-cel,
liso-cel, brexu-cel
OP2069.5NR60.0≥2: 25.0NRNRNR
* Median (range); Abbreviations: axi-cel, axicabtagene ciloleucel; brexu-cel, brexucabtagene autoleucel; CAR-T, chimeric antigen receptor T-cell; ECOG PS, Eastern Cooperative Oncology Group performance status; IP, inpatient; liso-cel, lisocabtagene maraleucel; NR, not reported; OP, outpatient; tisa-cel, tisagenlecleucel.
Table 3. Safety data in inpatient and outpatient settings reported in the included studies.
Table 3. Safety data in inpatient and outpatient settings reported in the included studies.
First Author, YearTrial Name/IDStudy DesignPatient PopulationTreatmentSite of CareFollow-UpnCRS-Related Toxicity
(%)
Neurologic Toxicity
(%)
Other AEs (%)
Linhares (2022) [37]OUTREACH/NCT03744676Ph 2 trialR/R LBCL (3L+)Liso-cel Outpatient vs. inpatientNA54 vs. 25Any grade: 37.0 vs. 44.0Any grade: 30.0 vs. 32.0
Grade 3–4: 13.0 vs. 4.0
Infection: Any grade, 33 vs. 32; Grade 3–4, 13.0 vs. 4.0.
Prolonged cytopenia at Day 29 visit: Any grade, 33.0 vs. 32.0.
Hypogammaglobulinemia: Any grade, 11.0 vs. 4.0
Fowler (2023) [67]ELARA/NCT03568461Ph 2 trialR/R FL (3L+)Tisa-celOutpatient vs. inpatientMedian: 20 months17 vs. 80Any grade: 52.9 vs. 47.5Any grade: 5.9 vs. 11.3
Grade 3–4: 0.0 vs. 1.3
At least 1 AE: Any grade, 82.4 vs. 92.5; Grade 3–4, 47.1 vs. 75.
Hematological disorders, including cytopenias: Any grade, 64.7 vs. 77.5; Grade 3–4, 47.1 vs. 73.8.
Infections: Any grade, 17.6 vs. 21.3; Grade 3–4, 0.0 vs. 7.5.
Prolonged depletion of normal B cells or agammaglobulinemia: Any grade, 11.8 vs. 10.0.
Tumor lysis syndrome: Any grade: 0.0 vs. 1.3; Grade 3–4, 0.0 vs. 1.3
Sehgal (2022) [39]PILOT/NCT03483103Ph 2 trialR/R LBCL (2L+ not intended for HSCT)Liso-celOutpatient vs. inpatientMedian: 12.3 months20 vs. 41Any grade: 15.0 vs. 48.0Any grade: 10.0 vs. 41.0NA
Abramson (2020) [42]TRANSCEND NHL 001/NCT02631044Ph 3 trialR/R LBCL (2L+)Liso-cel Outpatient vs. inpatientMedian: 18.8 months25 vs. 244Any grade: 40.0 vs. 42.0
Grade 3–4: 4.0 vs. 2.0
Any grade: 44.0 vs. 28.0
Grade 3–4: 8.0 vs. 10.0
NA
Denlinger (2022) [53] *NARetrospective studyBCLTisa-cel vs. axi-celOutpatient vs. inpatientNA18 vs. 45Any grade: 44.0 vs. 96.0Any grade: 22.0 vs. 73.0NA
* Denlinger et al. did not specify the settings; however, it seems that tisa-cel was administered in the outpatient setting and axi-cel in the inpatient setting; Abbreviations: 2L+, second line and greater; 3L+, third line and greater; AE, adverse event; axi-cel, axicabtagene ciloleucel; BCL, B-cell lymphoma; CRS, cytokine release syndrome; FL, follicular lymphoma; HSCT, hematopoietic stem cell transplant; LBCL, large B-cell lymphoma; liso-cel, lisocabtagene maraleucel; NA, not available; Ph., phase; R/R, relapsed/refractory; tisa-cel, tisagenlecleucel.
Table 4. Safety data in outpatient settings reported in the included studies.
Table 4. Safety data in outpatient settings reported in the included studies.
First Author, YearTrial Name/IDStudy DesignPatient PopulationTreatmentFollow-UpSample Size, nCRS-Related Toxicity (%)Neurologic Toxicity
(%)
Other AE (%)
Gofshteyn (2018) [45]Pedi CART19/NCT01626495Ph 1/2a trialPediatric and young adult patients with R/R ALLTisa-celNA51Any grade: 92.0Any neurotoxicity: 45.0
Common neurotoxicity: 41.0
NA
Turtle (2017) [51]NCT01865617Ph 1/2 trialB-ALL, NHL or CLLAnti-CD19 CAR-T cell therapyNA133Any grade: 71.0
Grade 1–2: 60.0
Grade 3: 4.0
Grade ≥ 4: 8.0
Any grade: 40.0
Grade 1–2: 19.0
Grade 3: 16.0
Grade ≥ 4: 5.0
NA
Shadman (2021) [49]NCT03277729Ph 1/2 trialR/R B-NHL and CLL (FL, MCL, CLL, DLBCL) Entire cohortCD20 CAR-T cellsNA12Grade 1: 16.0
Grade 2: 8.0
NANA
Shadman (2021) [47]NCT03277729Ph 1/2 trialFLCD20 Targeted CAR T-cell therapy (MB-106)Maximum 13.0 months post-infusion18Grade 1: 22.0
Grade 2: 5.5
Grade 3: 0.0
Grade 4: 0.0
Grade 1: 0.0
Grade 2: 0.0
Grade 3: 0.0
Grade 4: 0.0
NA
CLL, MCL, DLBCL, WM7Grade 1: 28.0
Grade 2: 28.0
Grade 3: 0.0
Grade 4: 0.0
Grade 1: 14.0
Grade 2: 14.0
Grade 3: 0.0
Grade 4: 0.0
NA
FL, CLL, MCL, DLBCL, WM25Grade 1: 24.0
Grade 2: 12.0
Grade 3: 0.0
Grade 4: 0.0
Grade 1: 4.0
Grade 2: 4.0
Grade 3: 0.0
Grade 4: 0.0
NA
Shadman (2020) [48]NCT03277729Ph 1/2 trialR/R B-cell NHLCD20 CAR-TNA11NANAGrade ≥ 3 AEs
Anemia: 36.0
Lymphopenia: 27.0
Neutropenia: 18.0
Hypertension: 9.0
Hypotension: 9.0
Thromboembolic event: 9.0
Neutropenia: 9.0
Elevated alkaline phosphatase: 9.0
Pneumonia: 9.0
Bacteremia: 9.0
Hyperglycemia: 9.0
Pleural effusion: 9.0
Generalized pain: 9.0
Shao (2021) [57]NARetrospective studyDLBCLTisa-celMedian: 29.1 weeks, (range: 2.6–60.0)12Any grade: 50.0
Grade 3–4: 8.3
Any grade: 8.3
Grade 3–4: 0.0
Any grade AEs
Anemia: 75.0
Thrombocytopenia: 66.7
Neutropenia: 66.7
Grade 3–4 AEs
Anemia: 33.3
Thrombocytopenia: 37.5
Neutropenia: 66.7
Borogovac (2022) [55]NARetrospective studyDLBCL, ALL, MCLAxi-celNA13Any grade: 69.0
Grade 3–4: 8.0
Any grade: 31.0
Grade 3–4: 0.0
NA
Tisa-celNA6Any grade: 50.0
Grade 3–4: 17.0
Any grade: 17.0
Grade 3–4: 17.0
NA
Brexu-celNA1Any grade: 0.0
Grade 3–4: 0.0
Any grade: 100
Grade 3–4: 0.0
NA
Liso-celNA1Any grade: 0.0
Grade 3–4: 0.0
Any grade: 0.0
Grade 3–4: 0.0
NA
Farooqui (2022) [59]NARetrospective studyRefractory NHL, patients without acute kidney injury Axi-cel NA69Incidence: 85.5
Grade None: 14.5
Grade 1: 49.3
Grade 2: 34.8
Grade 3: 0.0
Grade 4: 1.4
Incidence: 52.2
Grade
None: 47.8
Grade 1: 21.7
Grade 2: 18.8
Grade 3: 7.2
Grade 4: 4.3
NA
Refractory NHL, patients with acute kidney injury Axi-celNA14Incidence: 85.7
Grade None: 14.3
Grade 1: 35.7
Grade 2: 42.9
Grade 3: 0.0
Grade 4: 7.1
Incidence: 57.1
Grade
None: 42.9
Grade 1: 7.1
Grade 2: 21.4
Grade 3: 21.4
Grade 4: 7.1
NA
Nasta (2022) [60]NARetrospective studyLymphoma (3L+)Tisa-celMedian: 39.5 weeks (range: 3.0–127.3)72None: 59.7
Grade 1: 22.2
Grade 2: 18.1
None: 94.4
Grade 1: 2.8
Grade 3–4: 2.8
NA
Kirby (2022) [63]NARetrospective studyR/R BCLTisa-cel, axi-cel, liso-cel, and brexu-celNA20Any grade: 55.0
Grade ≥ 3: 5.0
All grades: 45.0
Grade ≥ 3: 25.0
Late infection events: 29.0,
Hypogammaglobulinemia (IgG < 400 mg/dL or IVIg)
Pre-lymphodepletion: 31.0
Late hypogammaglobulinemia: 83.0
Axi-celNA3Grade ≥ 3: 33.0Grade ≥ 3: 67.0NA
Liso-celNA14NAGrade ≥ 3: 7.0NA
Brexu-celNA1NAGrade ≥ 3: 100NA
Abbreviations: 3L+, third line and greater; AE, adverse event; ALL, acute lymphoblastic leukemia; axi-cel, axicabtagene ciloleucel; BCL, B-cell lymphoma; brexu-cel, brexucabtagene autoleucel; CAR-T, chimeric antigen receptor T-cell; CLL, chronic lymphocytic leukemia; CRS, cytokine release syndrome; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; Ig, immunoglobulin; IV, intravenous; liso-cel, lisocabtagene maraleucel; MCL, mantle cell lymphoma; NA, not available; NHL, non-Hodgkin lymphoma; Ph., phase; R/R, relapsed/refractory; tisa-cel, tisagenlecleucel; WM, Waldenstrom macroglobulinemia.
Table 5. Detailed response results from the studies identified.
Table 5. Detailed response results from the studies identified.
StudyTrial Name/IDStudy DesignPatient PopulationTreatmentFollow-UpOutpatientsInpatients
nORR
% (95% CI)
CR
% (95% CI)
PR
% (95% CI)
Other DetailsnORR
% (95% CI)
CR
% (95% CI)
PR
% (95% CI)
Other Details
Linhares (2022) [37], Godwin (2021) [36]OUTREACHPh 2 trialR/R LBCL (3L+)Liso-celNR5782.4 (70.0–91.0)58.025.0SD: 5.0%
Median DOR: 15.1 (3.9–NR)
2576.0 (55.0–91.0)44.032.0SD: 12.0; median DOR: 14.8 (2.0–NR)
Sehgal (2022) [39]PILOTPh 2 trialR/R LBCL (2L+)Liso-celMedian: 104.3 weeks2080.0 (56.3–94.3)50.0 (27.2–72.8)30.0Median DOR: 8.2 (2.1–NR)4180.056.024.0IP/OP (n = 61); SD: 5.0%; median DOR: 12.1 (6.2–NR)
Abramson (2020) [42]TRANSCEND NHL 001Ph 2 trialR/R LBCL (2L+)Liso-celNR2580.0 (59.3–93.2)56.0 (34.9–75.6)24.0Median DOR: NR (2.4–NR)23172.053.019.0IP/OP (n = 256): ORR: 73.0%, CR: 53.0%
Shadman (2021) [47]NCT03277729Ph 1/2 trialR/R FLCAR-T cells13.0 months post-infusion1894.078.017.0NRNANANANANA
R/R MCL, CLL, DLBCL, WM/LPL7100.057.043.0NRNANANANANA
Borogovac (2022) [57]-Obs. studyDLBCL and ALLAxi-cel1.0 month1377.069.08.0PR or SD: 8.0%NRNRNRNRNR
Tisa-cel, brexu-cel,
liso-cel
887.575.012.5PR or SD: 13.0%NRNRNRNRNR
Nasta (2022) [60]-Obs. StudyLymphomaTisa-cel39.5 weeks7243.034.78.3SD: 5.6%NRNRNRNRNR
Shao (2021) [57]-Obs. studyDLBCLTisa-cel29.1 weeks1258.025.033.0SD: 8.3%NRNRNRNRNR
Shadman (2021) [47]NCT03277729Ph 1/2, CTFLCAR-T cells13.0 months post-infusion1894.078.017.0NRNRNRNRNRNR
DLBCL210050.050.0NRNRNRNRNRNR
WM/LPL21001000NRNRNRNRNRNR
CLL11001000NRNRNRNRNRNR
MCL2100NR100NRNRNRNRNRNR
Borogovac (2022) [57]-Obs. StudyDLBCL and ALLAxi-cel1.0 month1377.069.08.0PR or SD: 8.0%NRNRNRNRNR
Tisa-cel610083.017.0PR or SD: 17.0%NRNRNRNRNR
Brexu-cel11001000PR or SD: 0.0%NRNRNRNRNR
Liso-cel1000PR or SD: 0.0%NRNRNRNRNR
Nasta (2022) [60]-Obs. StudyLymphoma Tisa-cel
No Bridging
39.5 weeks1753.029.423.5SD: 5.9%NRNRNRNRNR
Tisa-cel Bridging5540.036.43.6SD: 5.5%NRNRNRNRNR
Abbreviations: 2L+, second line and greater; 3L+, third line and greater; axi-cel, axicabtagene ciloleucel; brexu-cel, brexucabtagene autoleucel; CAR-T, chimeric antigen receptor T-cell; CI, confidence interval; CLL, chronic lymphocytic leukemia; CR, complete response; CT, clinical trial; DLBCL, diffuse large B-cell lymphoma; DOR, duration of response; FL, follicular lymphoma; IP, inpatient; LBCL, large B-cell lymphoma; liso-cel, lisocabtagene maraleucel; LPL, lymphoplasmacytic lymphoma; MCL, mantle cell lymphoma; NA, not applicable; NHL, non-Hodgkin lymphoma; NR, not reported; Obs., observational; OP, outpatient; ORR, overall response rate; ph, phase; PR, partial response; R/R, relapsed/refractory; RWE, real-world evidence; SD, stable disease; tisa-cel, tisagenlecleucel; WM, Waldenstrom macroglobulinemia.
Table 6. Progression-free survival data reported in the included studies.
Table 6. Progression-free survival data reported in the included studies.
StudyTrial Name/IDStudy DesignPatient PopulationTreatmentFollow-Up OutpatientInpatient
nMedian PFS in Months (95% CI)PFS Rate (95% CI)Other DatanMedian PFS in Months (95% CI)PFS Rate (95% CI)Other Data
Linhares (2022) [37]OUTREACHPh 2 trialR/R LBCL (3L+)Liso-cel 576.1 (2.9-NR)12-mo: 41.0%-254.3 (2.8-NR)12-mo: 39.0%
Fowler (2023) [67]ELARA Ph 2 trialR/R FL (3L+)Tisa-cel20.0 months17NA12-mo: 60%
18-mo:
57.0%
-80NA12-mo: 70.0%
18-mo:
62.5 (34.9–81.1)
-
Sehgal (2022) [39]PILOTPh 2 trialR/R LBCL (2L+)Liso-cel12.3 (IQR, 6.1–18.0)207.2 (2.4- 13.0)NRMedian EFS: 7.1 months (2.4–13.0)NANANAOverall patients (n = 61)
Median PFS: 9.0 months (4.2–NR)
Abramson (2020) [42]TRANSCEND NHL 001Ph 1 trialR/R LBCL (2L+)Liso-cel18.8 months25NR (3.0–NR)NR-NANANAOverall patients (n = 256)
Median PFS: 6.8 months (3.3–14.1)
6-mo PFS: 51.4% (45.0–58.0)
12-mo PFS: 44.1% (37.3–50.7)
Kirby (2022) [63]Kirby 2022Retr. studyR/R BCLLiso-cel, axi-cel, tisa-cel, brexu-cel>3.3 months20NR6-mo: 65.0%
12-mo: 60.0%
-----
Abbreviations: 2L+, second line and greater; 3L+, third line and greater; axi-cel, axicabtagene ciloleucel; BCL, B-cell lymphoma; brexu-cel, brexucabtagene autoleucel; CI, confidence interval; EFS, event-free survival; FL, follicular lymphoma; IQR, interquartile range; LBCL, large B-cell lymphoma; liso-cel, lisocabtagene maraleucel; mo, month; n, total population; NA, not applicable; NR, not reached; ph, phase; PFS, progression-free survival; R/R, relapsed/refractory; Retr., retrospective; tisa-cel, tisagenlecleucel.
Table 7. Overall survival data reported in the included studies.
Table 7. Overall survival data reported in the included studies.
StudyTrial Name/IDStudy DesignPatient PopulationTreatmentFollow-UpOutpatientInpatient
nMedian OS in Months (95% CI)OS Rate (95% CI)Other DatanMedian OS in Months (95% CI)OS Rate (95% CI)Other Data
Linhares (2022) [37]OUTREACHPh 2 trialR/R LBCL (3L+)Liso-cel-57NR
(NR-NR)
12-mo: 60.0%-2522.2
(8.0-NR)
12-mo: 60.0%-
Sehgal (2022) [39]PILOTPh 2 trialR/R LBCL (2L+)Liso-cel12.3 (IQR, 6.1–18.0)20NR (10.5–NR)NA-NANANAOverall patients (n = 61): 17.6 months
Median (months) (95% CI): Not reached (19.3-not reached)
Nasta (2022) [60]Nasta 2022Retr. studyLymphoma tisa-cel9.17226.5 (19.0–NR)NA-----
Kirby (2022) [63]Kirby 2022Retr. studyR/R BCLLiso-cel, axi-cel, tisa-cel, brexu-cel>3.3 months20NA6-mo: 85.0%
12-mo: 75.0%
-----
Shadman (2021) [47]NCT03277729Ph 1/2 trialR/R B-NHL and CLLMB-106 (CD20 CAR-T)8.925NA1.01 death over FU----
R/R FLMB-106 (CD20 CAR-T)9.318NA0.91 death over FU----
Abbreviations: 2L+, second line and greater; 3L+, third line and greater; axi-cel, axicabtagene ciloleucel; BCL, B-cell lymphoma; B-NHL, B-cell non-Hodgkin lymphoma; brexu-cel, brexucabtagene autoleucel; CAR-T, chimeric antigen receptor T-cell; CI, confidence interval; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; FU, follow-up; IQR, interquartile range; LBCL, large B-cell lymphoma; liso-cel, lisocabtagene maraleucel; mo, month; n, total population; NA, not available; NR, not reported; OS, overall survival; Ph, phase; PR, partial response; Retr., retrospective; R/R, relapsed/refractory; tisa-cel, tisagenlecleucel.
Table 8. Quality of life in the OUTREACH trial.
Table 8. Quality of life in the OUTREACH trial.
StudyInstrumentsDomainsOutpatient (n = 54),
LS Mean Change from Baseline (95% CI)
Inpatient (n = 28),
LS Mean Change from Baseline (95% CI)
p Value
Linhares (2022) [38] (OUTREACH)EORTC QLQ-C30GH/QoL7.80 (3.99–11.61)10.39 (5.37–15.42)0.415
Physical functioning0.38 (−1.11 to 4.08)3.50 (−1.33 to 8.34)0.312
Role functioning5.17 (0.27–10.01)4.8 (−1.63 to 11.21)0.927
Cognitive functioning0.71 (−1.08 to 4.51)1.83 (−3.19 to 6.84)0.716
Fatigue−6.28 (−10.73 to −1.82)−11.18 (−16.99 to −5.36)0.188
Pain−13.46 (−17.50 to −9.41)−13.25 (−18.51 to −8.00)0.951
EQ-5D-5LHUI0.02 (−0.02 to 0.06)0.04 (−0.01 to 0.10)0.51
VAS7.48 (4.10–10.86)10.34 (5.76–14.91)0.31
Higher scores on GH/QoL and EQ-5D VAS reflect better QoL. Higher scores on the functioning scales (physical, role, and cognitive) indicate better QoL. Higher scores on the symptom scales (fatigue and pain) indicate worse QoL. Abbreviations: CI, confidence interval; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; EQ-5D-5L, EuroQol 5-level 5-Dimension Questionnaire; GH, Global Health; HUI, Health Utility Index; LS, least-squares; QoL, quality of life; VAS, visual analog scale.
Table 9. Costs associated with patients receiving chimeric antigen receptor T-cell therapy in outpatient and inpatient settings.
Table 9. Costs associated with patients receiving chimeric antigen receptor T-cell therapy in outpatient and inpatient settings.
First Author, YearTrial Name/IDCountry for Cost Analysis Study Design Patient PopulationTreatmentCost ComponentsFollow-UpSite of Care: OutpatientSite of care: Inpatient
nTotal CostsHosp. CostsOther CostsnTotal CostsHosp. CostsOther Costs
Palomba (2020) [52]TRANSCEND NHL 001 and OUTREACHUSPooled analysisR/R LBCL (3L+)Liso-celIP and ICU LOS, diagnostics, procedures, medications6.0 months476-month post-infusion cost: USD 36,702
First month: USD 19,837
NANA2566-month post-infusion cost: USD 89,535
First month: USD 50,369
NANA
Denlinger (2022) [53] *NAUSRetrospective studyBCLTisa-cel; axi-celNAMedian: Axi-cel: 31.4 months
Tisa-cel: 23.8 months
18Tisa-cel (outpatient *):
Median (range): USD 64,834 (USD 4007–USD 429,380)
NANA45Axi-cel (inpatient *):
Median (range): USD 176,535 (USD 30,977–USD 1187,965)
NANA
McGarvey (2022) [41]PILOT/NCT03483103USPh 2 trialR/R LBCL (2L+) not intended for HSCTLiso-celIP and ICU LOS, diagnostics, procedures, medicationsNA206-month post-infusion monitoring cost: USD 16,172
First month: USD 13,261
USD 9455NA416-month post-infusion monitoring cost: USD 61,772
First month: USD 46,947
USD 49,495NA
McGarvey (2022) [65]TRANSFORM/NCT03575351USPh 3 trialR/R LBCL (2L+)Liso-celIP and ICU LOS, diagnostics, procedures, medicationsNA196-month post-infusion monitoring cost: USD 38,314
First month: USD 18,774
USD 20,867NA716-month post-infusion monitoring cost: USD 96,297
First month: USD 49,111
USD 69,153NA
Fowler (2023) [67]ELARA/NCT03568461USPh 2 trial R/R FL (3L+)Tisa-celIP and ICU LOSMedian: 20.0 months17NAUSD 7477NA80NAUSD 40,054NA
Maziarz (2022) [62]NAUSRetrospective studyR/R DLBCLTisa-cel, axi-celIP and OPMean: 5.0 monthsTisa-cel: 8For FU period:
Tisa-cel: USD 13,389
For infusion encounter:
Tisa-cel: USD 4741
Tisa-cel: USD 4753OP costs:
Tisa-cel: USD 8636
Tisa-cel: 25
Axi-cel: 86
For FU period:
Axi-cel: USD 46,575
Tisa-cel: USD 33,701
Infusion encounter:
Axi-cel: USD 51,378
Tisa-cel: USD 34,908
For FU period:
Axi-cel: USD 44,561
Tisa-cel: USD 29,953
For FU period:
OP costs: Axi-cel: USD 2014 Tisa-cel: USD 3748
Yang (2022) [26] **NAUSRWER/R DLBCLTisa-cel, axi-celIP, ER, OP, other medical
services, medications
CAR-T IP: 6.6 months,
CAR-T OP: 6.0 months
50Total Medicare reimbursement amounts for months 1, 2, 3, 4, 5, 6, and 7: USD 371,839, USD 9120, USD 4927, USD 8300, USD 8102, USD 6724, and USD 10,883, respectivelyNANA380Total Medicare reimbursement amounts for months 1, 2, 3, 4, 5, 6, and 7: USD 348,364, USD 9756, USD 7318, USD 8259, USD 7052, USD 5748, and USD 6741, respectivelyNANA
* Denlinger et al. did not specify the settings; however, it seems that tisa-cel was administered in the outpatient setting and axi-cel in the inpatient setting. ** Reimbursement amounts were assessed only among patients who received CAR-T in non-prospective payment system-exempt hospitals. Abbreviations: 2L+, second line and greater; 3L+, third line and greater; axi-cel, axicabtagene ciloleucel; BCL, B-cell lymphoma; CAR-T, chimeric antigen receptor T-cell; DLBCL, diffuse large B-cell lymphoma; ER, emergency room; FL, follicular lymphoma; FU, follow-up; hosp., hospitalization; ICU, intensive care unit; IP, inpatient; LBCL, large B-cell lymphoma; LOS, length of stay; NA, not available; OP, outpatient; Ph, phase; RWE, real-world evidence; R/R, relapsed/refractory; tisa-cel, tisagenlecleucel; US, United States.
Table 10. Healthcare resource utilization associated with patients receiving chimeric antigen receptor T-cell therapy in the outpatient and inpatient settings.
Table 10. Healthcare resource utilization associated with patients receiving chimeric antigen receptor T-cell therapy in the outpatient and inpatient settings.
Study DetailsTreatmentOutpatient CohortInpatient Cohort
nOP VisitsHospitalization RateTime to HospitalizationReasons for HospitalizationLOSICU AdmissionsnOP VisitsHospitalization RateTime to HospitalizationLOSICU Admissions
Chihara (2022) [54]Any CAR-T therapy95NAFollow-up hospitalization: 41.8%NANANANA456NAWithin 90 days: rehospitalization: 28.7%NA21.4 daysNA
Wright (2020) [68]Tisa-cel, axi-cel12NAUnplanned hospitalization: 33.0%NANANANA19NAUnplanned hospitalization: 26.0%NANANA
Palomba (2020) [52]Liso-cel47100%62.0%NANATotal: 7.8 (SD, 13.1) days
ICU: 0.6 (SD, 2.8) days
6.0%25693.0%~100%NATotal: 20.1 (SD, 15.1) days
ICU: 1.1 (SD, 5.5) days
7.0%
Sehgal (2022) [39]Liso-cel20NATotal: 45.0%
Within 72 h: 10.0%
Median: 6.0 (IQR, 5.0–10.0) daysAEs: 78.0%
Other: 22.0%
Initial hospitalization:
Mean: 2.5 (SD, 3.2) days
Median: 5.0 (IQR, 4.0–7.0) days
ICU:
Mean: 3.0 days Median: 3.0 (IQR, 3.0–3.0) days
5.0%41NATotal: 100%NAInitial hospitalization:
Mean: 11.9 (SD, 5.1) days
Median: 12.0 (8.0–15.0) days
ICU:
Mean: 2.5 (SD, 0.7) days
Median: 2.5 (IQR, 2.0–3.0) days
20.0%
Yang (2022) [26]Tisa-cel, axi-cel50NAWithin the 1st month: 52.0%NANALOS for months 1, 2, 3, 4, 5, 6, and 7: 5.2, 1.6, 1.2, 1.3, 1.4, 0.7, and 0.9 days, respectively
ICU LOS:
for months 1, 2, 3, 4, 5, 6, and 7: 0.6, 0.1, 0.1, 0.3, 0, 0, and 0.1 days, respectively
NA380NAWithin the 1st month: 100% (by definition)NALOS for months 1, 2, 3, 4, 5, 6 and 7: 20.4, 4.6, 2.4, 2.0, 1.4, 1.1 and 1.0 days, respectively
ICU LOS:
for months 1, 2, 3, 4, 5, 6 and 7: 2.4, 0.1, 0.1, 0.1, 0.1, 0.1, and 0.1 days, respectively
NA
Fowler (2023) [67]Tisa-cel17NA59.0%5.8 (SD, 7.1) daysCRS: 53.0%Total:
Mean: 4.3 (SD, 1.4) days
Median: 4.5 days
ICU: 0.0 days
0.0%80NA100%NATotal:
Mean: 13.8 (SD, 8.5) days
Median: 12.5 days
ICU:
Median: 4.0 days
9.0%
Linhares (2022) [37]Liso-cel54NAOverall hospitalization: 76.0%
Within 4 days: 31.0%
Median: 5.0 days (2.0–310.0 days)AEs: 83.0%
Other: 17.0%
Initial hospital stay:
Median: 6.0 (1.0–28.0) days
ICU:
Median: 3.5 (2.0–5.0) days
4.0%25NA100%NAInitial hospital stay:
Median initial stay: 13.0 days (1.0–31.0)
NA
McGarvey (2022) [65]Liso-cel19NANANANAMedian: 9.0 (range, 4.0–33.0) daysNA71NANANAMedian: 15.0 (range, 1.0–164.0) daysNA
Denlinger (2022) [53]Tisa-cel, axi-celTisa-cel: 18NANANANATisa-cel: 9.0 daysNAAxi-cel: 45NANANAAxi-cel: 14.0 daysNA
Maziarz (2022) [61]Tisa-cel, axi-celTisa-cel: 8100%63.0%NANAMean: 1.7 days
ICU: 0.4 days
38.0%Axi-cel: 86 Tisa-cel: 25Axi-cel: 52.0%
Tisa-cel: 76.0%
NANAAxi-cel: 6.9 days
Tisa-cel: 4.6 days
Axi-cel: 30.0%
Tisa-cel: 16.0%
Myers (2020) [46]Tisa-cel198 *NAWithin 30 days: 70.0%NANAMedian: 7.0 (IQR, 4.0–13.0) days23.0%15 *NANANANANA
Kamdar (2022) [64]Liso-cel19NA68.0%Median: 9.0 (IQR, 4.0–19.0) daysCRS: 38.0%
Other AEs: 38.0%
PD: 8.0%
Other: 15.0%
Median: 9.0 (IQR, 5.0–9.0) days0.0%NANANANANANA
Kirby (2022) [63]Tisa-cel, axi-cel, liso-cel, brexu-cel20NAWithin 1st month of therapy:
Overall: 50.0%
Axi-cel: 67.0%
Liso-cel: 36.0%
Tisa-cel: 100%
Brexu-cel: 100%
NANANANANANANANANANA
Nasta (2022) [60]Tisa-cel68NAWithin 72 h: 19.4%
Within 30 days: 36.1%
NACRS: 85%
Infection: 8%
Colitis: 4%
Catatonia: 4%
Median: 5.0 daysNA4NANANANANA
Shao (2021) [57]Tisa-cel12NAWithin 30 days: 50.0%Median: 4.0 days (2.0–12.0 days)CRS: 83.0%
Colitis: 17.0%
Median: 5.5 days (2.0–9.0) daysNANANANANANANA
Borogovac (2022) [55]Axi-cel, tisa-cel, brexu-cel, liso-cel21NAPost therapy: Within 72 h/within 1st month:
Overall: 24.0%/71.0%
Axi-cel: 23.0%/76.0%
Liso-cel: 0.0%/0.0%
Tisa-cel: 33.0%/67.0%
Brexu-cel: 0.0%/100%
Median: 4.0 (1.0–28.0) daysFever: 87.0%
CNS toxicity: 13.0%
Median: 8.0 days (1.0–30.0)NA2NANANANANA
Farooqui (2022) [59]Axi-celWith AKI: 14
Without AKI: 69
NANANANANAWith AKI: 42.9%
Without AKI: 29.0%
NANANANANANA
* In Myers et al., 93% of all patients (198 of 213) received CAR-T in the outpatient setting. Hence, these data were reported under the outpatient cohort. Abbreviations: AE, adverse event; AKI, acute kidney injury; axi-cel, axicabtagene ciloleucel; brexu-cel, brexucabtagene autoleucel; CAR-T, chimeric antigen receptor T-cell; CNS, central nervous system; CRS, cytokine release syndrome; ER, emergency room; ICU, intensive care unit; IQR, interquartile range; liso-cel, lisocabtagene maraleucel; LOS, length of stay; NA, not available; OP, outpatient; PD, progressive disease; SD, standard deviation; tisa-cel, tisagenlecleucel.
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Hansen, D.K.; Liu, Y.-H.; Ranjan, S.; Bhandari, H.; Potluri, R.; McFarland, L.; De Braganca, K.C.; Huo, S. The Impact of Outpatient versus Inpatient Administration of CAR-T Therapies on Clinical, Economic, and Humanistic Outcomes in Patients with Hematological Cancer: A Systematic Literature Review. Cancers 2023, 15, 5746. https://doi.org/10.3390/cancers15245746

AMA Style

Hansen DK, Liu Y-H, Ranjan S, Bhandari H, Potluri R, McFarland L, De Braganca KC, Huo S. The Impact of Outpatient versus Inpatient Administration of CAR-T Therapies on Clinical, Economic, and Humanistic Outcomes in Patients with Hematological Cancer: A Systematic Literature Review. Cancers. 2023; 15(24):5746. https://doi.org/10.3390/cancers15245746

Chicago/Turabian Style

Hansen, Doris K., Yi-Hsuan Liu, Sandip Ranjan, Hitesh Bhandari, Ravi Potluri, Lindsay McFarland, Kevin C. De Braganca, and Stephen Huo. 2023. "The Impact of Outpatient versus Inpatient Administration of CAR-T Therapies on Clinical, Economic, and Humanistic Outcomes in Patients with Hematological Cancer: A Systematic Literature Review" Cancers 15, no. 24: 5746. https://doi.org/10.3390/cancers15245746

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