Chimeric antigen receptor T‐cell therapy: Challenges and framework of outpatient administration

Abstract Adoptive cellular therapy has made a landmark change within the treatment paradigm of several hematologic malignancies, and novel cellular therapy products, such as chimeric antigen receptor T‐cell therapy (CART), have demonstrated impressive efficacy and produced durable responses. However, the CART treatment process is associated with significant toxicities, healthcare resource utilization, and financial burden. Most of these therapies have been administered in the inpatient setting due to their toxicity profile. Improved toxicity management strategies and a better understanding of cellular therapy processes are now established. Therefore, efforts to transition CART to the outpatient setting are warranted with the potential to translate into enhanced patient quality of life and cost savings. A successful launch of outpatient CART requires several components including a multidisciplinary cellular therapy team and an outpatient center with appropriate clinical space and personnel. Telemedicine should be incorporated for closer monitoring. Additionally, clear criteria for admission upon clinical decompensation, a pathway for prompt inpatient transition, and clear toxicity management guidelines should be implemented. Effective education about cellular therapy and toxicity management is imperative, especially for the Emergency Department and Intensive Care Unit teams. Here, we have outlined the various logistical and clinical considerations required for the care of CART patients, which will aid centers to establish an outpatient CART program.

the years and the rates of acute higher grade toxicity have dropped significantly with early intervention with corticosteroids and tocilizumab [4,5]. The ongoing evolution of management guidelines and its rapid adoption to clinical practice calls into question whether inpatient therapy with its attendant cost is truly necessary for all CART recipients [4]. It is anticipated that CART therapy will eventually be an outpatient process at least for the products where we have clear evidence-based management guidelines for early intervention. Optimal patient selection is also a key in excluding the patients who are at high risk for complications after CART therapy in the outpatient setting.
Outpatient therapy can be provided in the ambulatory clinic setting where equipment and personnel are available to deal with semiemergent situations like infusion reactions. It is also open for an extended period but not continuously for 24 h. All the currently approved CART products are autologous with little risk of immediate infusion reaction, although premedication is always given. This suggests that the infusion of the product can be done in the clinic setting.
A successful outpatient program will have mastery of the time frame that each potential complication of CART is likely to occur, and institute-specific measures for early detection and intervention. It will also have suitable lodging facilities that are sufficiently proximal to the hospital, reliable caregiver support, a direct line of communication to the clinical team, and immediate availability of inpatient beds to admit based on specific symptoms and signs. It will also have a seamless system for rapid resuscitation and administration of tocilizumab, corticosteroids, and extended-spectrum antibiotics.

HISTORICAL PERSPECTIVE AND RATIONALE
Cellular therapy with CART falls under the auspices of the newly created immune effector cell therapy category. Autologous and allogeneic hematopoietic stem cell transplant (HCT) is a form of cellular therapy that has become standard of care for many diseases for many years and many centers are routinely performing HCT in the outpatient setting.
Some data suggest that outpatient HCT can be done as safely as in the inpatient setting [6,7]. Outpatient HCT can be more cost efficient and may be associated with improved patient satisfaction compared to inpatient HCT [6,7].
There are a few published reports where CART was said to have been given in the outpatient setting. Abramson reported that 25 of 344 patients received their CART in the outpatient setting. The low number suggests that these were highly selected patients and by far the minority of those who could have been treated [8].

Regulatory
Traditionally, HCT is regulated by the Foundation for the Accredi-

Personnel
A cohesive cellular therapy multidisciplinary healthcare team is by far the most important component of an outpatient cellular therapy program. This core group should consist of multiple entities including cellular therapy physicians plus a medical director, cellular therapy coordinators, advanced practice providers (APPs), clinical and research nurses, financial coordinators, apheresis and cellular therapy processing lab personnel, clinical pharmacy specialists, social workers, case managers, and procurement personnel. Alliances to this central group include pharmacy informatics, emergency department (ED) staff and intensive care unit (ICU) staff, and hospitalists [11].
The members of the core CART team will assume certain roles and responsibilities, but the cellular therapy program should ensure each responsibility has a designated member to be carried out appropriately. The CART physicians and APPs should confirm that patients meet the criteria to proceed with outpatient treatment. These

Infrastructure
The implementation of a successful outpatient CART program requires significant logistical planning and execution. Regarding the physical location, an outpatient cellular therapy center should be a dedi- The process for admission will also vary by institution. One recommendation is to implement a "scatter" hospital bed that can be made available for the patient to be admitted. Additionally, this bed should be in a designated unit where specific interventions like tocilizumab and high-dose corticosteroids are available. Admission through the ED is an option so long as the ED is set up as able to rapidly evaluate the patient and administer specific interventions. The ED physicians will also need to be REMS trained and keep up with other regulatory requirements. Additionally, some centers may be able to offer patients wearable devices. They can be worn for prolonged periods (for up to 30 days), and they can give valuable real-time data that are actionable. It is recommended to use devices that measure at least heart rate, body surface temperature, and blood pressure. Furthermore, some CAR Tcell therapy pharmaceutical companies provide support for outpatient treatments with digital platforms to provide pertinent information on personalized products and patient support (e.g., Cell Therapy 360) [21].
As with a variety of other clinical applications, SOPs and policies should be created to document and follow appropriate practices.

SETTING UP THE STRUCTURE
Education is imperative to having a successful CART program. Education should take place in all areas of the treatment facility where CAR T patients may be treated, including the ED. Any staff that will be caring for these patients will be required to be REMS certified as stated in previous sections. Individual roles of providers should be clearly defined.
It is beneficial to have a specific coordinator that will be responsible for these CART patients that will help patients, caregivers, and the facility navigate the logistics of CART therapy. The CART coordinator is responsible for coordinating with the pharmaceutical company to secure manufacturing dates for the cellular products and communicating these dates with the treating facility's ancillary departments to ensure adequate time to schedule. A designated service line for overseeing CART patients can be helpful by providing the extra oversight in taking care of these patients and their unique adverse events.
While the CART service line may not be the primary admitting team for these CART patients, they should be a consulting service to oversee the CART-related side effects. This service line should be composed of both physicians and APPs.
Historically, CART administration has fallen under the purview of HCT, but as the number of FDA-approved CART products increases in the future, there will be an increased demand to build programs that are specifically focused on CART and other immune effector cell prod- review potential patients for eligibility [20]. It is also imperative to conduct periodic evaluations to ensure that they remain eligible as disease status may change quickly with some leukemias and high-grade lymphomas. Carefully selected bridging therapy may help reduce tumor growth in certain instances [20,22].

Currently, the Center for International Blood & Marrow Transplant
Research (CIBMTR) collects data that pertains to quality assurance for not only stem cell transplant patients, but also CART patients. This data is typically reported by each facility's quality manager/quality team. In the process of building a CART program, there should be a plan for having a well-equipped quality team. The team will also need to establish which data points, in addition to the CIBMTR data points, that the facility also wants to capture, if any.

MONITORING, EXPANDING, AND METRICS FOR SUCCESS
Evaluating metrics with outpatient CAR T-cell therapy programs will provide meaningful points of data for performance as well as areas of expansion or improvement. Immune effector cell accreditation is recommended to be able to provide cellular therapies at cancer centers, and thus periodic reviews should be performed to be able to meet the regulatory standards. Beyond these requirements, cellular therapy programs could have internal outcomes to measure such as rates and grades of CRS/ICANS, number of doses of tocilizumab and corticosteroids, time to tocilizumab administration, rate of hospital admission, and rates and types of infections. Cancer centers can adopt additional metrics to track as they gain experience with outpatient CAR T-cell therapy for improved quality [11,20,23,24]. Furthermore, the data metrics are essential to leverage additional resources for the cellular therapy program. Increased patient volume in the outpatient services may require a redistribution of resources or increased healthcare professional positions to support the growing cellular therapy program. For example, a business plan to request additional pharmacists, nurses, APPs, or physicians for an area of unmet need may include these program metrics. These may be especially more indispensable with added telemedicine responsibilities among cellular therapy program personnel. Additionally, tocilizumab inventory may need to be redistributed to have adequate supply per REMS requirements for both outpatient and inpatient CART patients [11,20].

CONCLUSION
Outpatient administration and monitoring represent the future for CART. Being able to administer and monitor CART in the outpatient setting requires careful planning and attention to detail to preserve patient safety. It also requires appropriate oversight and adaptability to optimize patient satisfaction. The method of dealing with emergencies should be well thought out and systems in place to rapidly intervene, including admission to the hospital at the first sign of toxicity whether day or night. Quality metrics need to be developed and tracked (e.g., time from fever to tocilizumab). Hospital resource utilization will also be reduced, and the financial implications of cellular therapy delivery will show a more favorable profile. It is anticipated that the distance to the hospital will be extended, and more patients will be able to access this life-saving intervention from the comfort of their homes.
The implementation of outpatient CART requires an outpatient infusion center able to support the needs of the patients during each phase of treatment. Most importantly, the cellular therapy program should have a core workgroup of members with dedicated roles and responsibilities to provide optimal care for these patients from start to finish. The members encompassing this workgroup consist of cellular therapy physicians, cellular therapy coordinators, APPs, nurses, financial coordinators, apheresis and cellular therapy lab personnel, clinical pharmacy specialists, social workers, case managers, and procurement personnel. Pharmacy informatics, emergency department staff, and ICU staff, and hospitalists are also healthcare professionals who may care for these patients and will require education on how to manage toxicities of cellular therapies including CART. Additional steps may be necessary to logistically prepare and administer tocilizumab and other supportive care agents for non-oncology providers. Institutions should also incorporate telemedicine visits to be able to guide outpatient CART patients if signs/symptoms of CRS or ICANS arise. Wearable technology and other pharmaceutical company-specific platforms could be useful to track vital signs on these patients. The cellular therapy program should also document the workflow for outpatient cellular therapy via policies and SOPs and perform routine updates with dynamic changes based on experience. Additionally, successful implementation of an outpatient cellular therapy program requires extensive patient and caregiver education as the share of responsibility in providing care shifts substantially onto the patient and caregiver. All members of the healthcare team should be involved in providing this education at multiple crucial time points along the cellular therapy journey.