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. 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 . 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).

Figure 1. The preferred reporting items for systematic reviews and meta-analysis (PRISMA) flow diagram.

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 and .

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 . The modified Downs and Black checklist with 27 items assessed eight non-randomized single-arm trials. 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) . 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

3.5. Economic Outcomes

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.

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