CAR T-cell Infusion in an Outpatient Setting: An Ideal Option for Selected Patients When Available

This is a 36-year-old male with refractory follicular lymphoma who had previously received two lines of therapy, including rituximab and bendamustine, as well as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) plus obinutuzumab. At his second relapse, he was referred to the CAR T-cell therapy program for evaluation and treatment. Considering the patient's preference to avoid hospitalization and stay at home with his family, he expressed interest in the outpatient cell therapy program. 

A comprehensive psychosocial assessment conducted by the social worker confirmed that the patient is in a safe environment to receive outpatient cell therapy treatment. He was considered for lisocabtagene maraleucel (liso-cel) due to its low-risk adverse event profile and longer median time to onset of cytokine release syndrome (CRS) compared with other CAR T-cell therapy products. 

After reviewing the patient's case, he met the institutional eligibility criteria for the outpatient cell therapy program. These criteria included having an excellent performance status, low disease burden, a reliable caregiver (his wife, who resides with him and is involved in his care), living within a specified distance from the hospital (in this case, 2 miles), reliable transportation, and no other significant co-morbidities. The patient and his wife underwent a comprehensive educational session with the transplant cellular therapy nurse coordinator, where they were provided with information about the entire process, adverse events to monitor, daily logs to maintain, and when to seek medical attention for routine, urgent, and emergent matters. Additionally, the patient was given a product wallet card and agreed to refrain from driving and engaging in hazardous occupations or activities for at least 8 weeks following the infusion. 

The patient's case was presented to the transplant and cell therapy interdisciplinary team meeting, where there was unanimous consensus for him to receive cell therapy on an outpatient basis. He successfully underwent the collection process and did not require bridging therapy. On Day 0, the patient received the infusion in the outpatient infusion unit, administered by a competent infusion nurse who had received training in cellular therapy administration as part of the Risk Evaluation and Mitigation Strategy (REMS) program.  

Each day, the treating team conducted an interval history and physical examination, assessed vital signs, weight, and reviewed the patient's medication (prescription and nonprescription). They also reviewed the vital signs and symptom log provided by the patient. During each visit, a neurologic examination and Immune Effector Cell-associated Encephalopathy (ICE) score assessment were performed. For CRS assessment, the following laboratory tests were conducted: complete blood count, comprehensive metabolic panel, coagulation panel, venous lactate, C-reactive protein (CRP), ferritin, albumin, fibrinogen, and D-dimer, interleukin-6, interleukin-10, tumor necrosis factor-alpha, and interleukin-1 beta. 

At each visit, the patient was deemed clinically stable and was discharged with instructions for follow-up care, symptom monitoring, fluid intake, and guidance on when to seek medical attention. This ongoing monitoring and assessment ensured the patient's safety and well-being throughout the outpatient cell therapy treatment process. 

Outpatient Follow Up 

The patient was seen daily up until Day 14 after infusion and three times weekly in clinic until day 28. On Day 20, the patient was seen in clinic, and the assigned outpatient APP noted normal temperatures, blood pressure, and temperatures. While performing the routine ICE score assessment, the APP recognized a slight tremor of the patient’s right hand. The caregiver noted that the patient had seemed distracted during the physical examination and was scored as an 8/10 due to sentence penmenship changes and trouble naming one out of the three objects. The assigned APP and the attending IEC cellular therapy physician consulted and agreed to directly admit the patient to the bone marrow transplant and cellular therapy service for management and observation. The patient was prescribed dexamethasone and anti-seizure medications; brain MRI, EEG, and neurologic consult were unremarkable, and the symptoms resolved upon discharge. The patient was discharged after 4 days and provided with instructions regarding the next scheduled follow-up in 2 days after being discharged.  

Discussion 

Several large academic centers, as well as numerous community hospitals and CAR T-cell infusion centers now offer outpatient programs based on data showing acceptable safety of the procedure as outpatient provided that complex systems are in place to provide education, monitor patients closely, and provide immediate care as needed.  

There are several center-related requirements for outpatient administration, and each individual patient’s case must be approved for the outpatient setting based on comorbidities, disease burden, insurance provider, and other factors. All outpatients must have a 24/7 caregiver, who is able to remain within close proximity to the center with the patient for the specified period of time.  

From a center or program perspective, education must be provided to the full multidisciplinary team outside of center staff including staff in the ED and ICU, as well as pharmacists and social workers. Education also must be provided to the patient and caregiver regarding the product, procedures for off-hours symptom management, and completion of logs for temperature, fluid intake, and medication administration. Product-specific wallet cards must be provided to the patient in case of an emergency medical event.¹

Centers must ensure that all policies and procedures follow those dictated by the Foundation for the Accreditation of Cellular Therapy (FACT), REMS, and any institutional biosafety committees, as well as manufacturer-specific product procedures. To ensure all staff is familiar with all the procedures, as well as to discuss any changes to protocols or new developments in patient care, center staff should meet weekly¹ and electronic medical record tags should be used. 

Outpatient infusions of tisagenlecleucel (tisa-cel) were described in both the ELIANA and JULIET studies for patients with B-cell ALL and DLBCL, respectively.^2,3 In addition, Dwivedy Nasta and colleagues⁴ reported the University of Pennsylvania at the experience with tisa-cel for patients with lymphoma. They found an admission rate of 31%, with a median of 5 days post-infusion—mostly due to low-grade fevers and one due to altered mental status. Liso-cel was reported to be safe in the outpatient setting by Bachier et al.,⁵who looked at a compilation of data from five trials and found that 46% of patients who received liso-cel as an outpatient did not require hospitalization after infusion; ICU-level care was needed for only 3% of patients. In addition, the median number of days of hospitalization for patients who received infusion in the outpatient setting was 6 days, which was 9 days fewer than patient who received liso-cel in the inpatient setting (15 days, range, 2-98 days, n = 272).   

A recent real-world retrospective analysis presented as a poster at the 2023 Transplantation & Cellular Therapy Meeting explored outcomes of both inpatient and outpatient CAR T-cell therapy for patients with mantle cell lymphoma (MCL) and follicular lymphoma (FL). Patients received brexucabtagene autoleucel (brexu-cel), liso-cel, tisa-cel, anicabtagene ciloleucel (axi-cel), or an unspecified agent (for patients with FL). In the MCL cohort, 151 total patients were included. Of these, 72% were infused in the inpatient setting. A total of 113 patients experienced AEs—68% inpatient vs. 32% outpatient. Of all patients with MCL who experienced AEs, the AE occurred within 30 days of infusion for 68%. Hospitalization rates for outpatients due to AEs occurred within 0-3 days for 79% and 0-30 days for 88%. Only 17% of all patients with MCL required ICU-level care due to an AE. In the FL cohort, 81% of the total 267 patients were infused in the inpatient setting. A total 182 patients had observable AEs, with only 18% of these occurring in outpatients. AEs occurred within 30 days post-infusion for 59% of all patients with FL; outpatient rates for hospitalization due to an AE were 57% for within 0-3 days and 80% for within 0-30 days. Of all patients with FL, ICU-level care by day 30 was required for 18 patients with an observable AE.⁶

Another single-institution experience with outpatient transfusion of axi-cel, tisa-cel, brex-cel, and liso-cel was favorable, with an overall admission rate of just 24% within 72 hours after infusion. The admission rates were consistent across products, and all patients requiring admission were triaged either through the 24/7 cellular therapy hotline or the patient’s regular follow-up visit. There were no ED visits.¹

The topic of costs for inpatient vs outpatient CAR T-cell infusion is complex and out of the scope of this discussion. However, it should be noted that there is less strain on hospital resources when CAR T-cell infusions are done on an outpatient basis, which has become more important since the beginning of the COVID-19 pandemic.^7,8

References: 

1. Borogovac A, Keruakous A, Bycko M, et al. Safety and feasibility of outpatient chimeric antigen receptor (CAR) T-cell therapy: Experience from a tertiary care center. Bone Marrow Transplant. 2022;57:1025-1027. 
2. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378:439-448. 
3. Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380:45-56. 
4. Dwivedy Nasta S, Namoglu EC, Hughes ME, et al. Hospitalization patterns with commercial CAR T-cell therapy: a single institution experience. Blood. 2019;134:3240.  
5. Bachier CR, Godwin JE, Andreadis C, et al. Outpatient treatment with lisocabtagene maraleucel (liso-cel) across a variety of clinical sites from three ongoing clinical studies in relapsed/refractory (R/R) large B-cell lymphoma (LBCL). J Clin Oncol. 2020;38:8037. 
6. Seyedin R, Hasegawa, Rajagopalan K, et al. Chimeric antigen receptor (CAR) T-cell therapy setting of care: a retrospective cohort analysis of MCL and FL patients in the United States (US). Presented at: 2023 Transplantation & Cellular Therapy Meetings; February 15-19, 2023; Orlando, FL. Poster 509. 
7. Amorosi D. Outpatient therapy: Bringing CAR T cells closer to home. Cell Therapy Next. December 20, 2021. Accessed May 26, 2023. https://www.healio.com/news/hematology-oncology/20211220/outpatient-therapy-bringing-car-t-cells-closer-to-home  
8. Fischer L. Moving CAR T-cell treatment to outpatient setting: A real-world case study. Oncology Nursing News. March 3, 2023. Accessed May 26, 2023. https://www.oncnursingnews.com/view/moving-car-t-cell-treatment-to-outpatient-setting-a-real-world-case-study