Medicine strives to find the best place of care for patients, which can be defined as one that achieves the best clinical outcomes with minimal disruption for the patient, at a manageable cost (1, 2).

With the number of hematopoietic stem cell transplantations (HSCTs) increasing, due to the number of conditions treated and the incorporation of low and middle-income countries into the HSCT field, rising costs, staffing difficulties and hospital capacity shortages must be addressed. The Worldwide Network for Blood and Marrow Transplantation identified the major cost drivers as patient characteristics, laboratory and radiology, drugs, supportive care, quality management and staff training, and graft procurement (3).

Outpatient (OP) and at-home management, were adopted early during the inception of hematological therapies, including HSCT (4).

The advent of CAR-T platforms with an increased range of indications and more limited toxicity, together with the physician’s experience and confidence, has increased interest in early patient discharge while maintaining close patient monitoring (5).

Social trends, cost constraints, and the impact of COVID-19 (6) support the shift from inpatient (IP) care to more acceptable modalities, like home care for HSCT or CAR-T cell therapies (2).

However, safety concerns for outpatient modalities will always be extremely important until HSCT and cell therapy procedures cause less aggressive effects on the patient’s health.

Fortunately, emerging technological developments (i.e., wearable devices, artificial intelligence (AI), facial recognition) provide important opportunities to increase safety while reducing costs. This mini-review discusses HSCT and CAR-T as models for clinical out-of-hospital management and takes a prospective view of technologies that can help maximize clinical efficacy, contain costs, and enhance patients´ well-being.

In 1997, Jagannath reported 91 multiple myeloma autologous HSCT (auto-HSCTs) followed on an OP basis (7).

In the OP setting, patients receive the conditioning regimen and HSCT infusion at an outpatient clinic or the hospital, and are then discharged and followed up in an ambulatory day clinic.

Nowadays, several reports on the management of HSCTs on an OP basis have been published, but systematization and research are still lacking (8). Even the definition of OP setting can be controversial since several modalities exist, from OP to full at-home management (9).

Holbro (10) reported 91 auto-HSCTs in myeloma patients managed entirely at an OP clinic where 84% had to be readmitted during the first 100 days, mostly for febrile neutropenia. No patient died or required ICU care. Savings of nearly 20,000 Canadian dollars per patient were calculated compared with IP HSCT.

McDiarmid (11) retrospectively analyzed infections in 178 allogeneic (allo-HSCT) and 508 autologous OP HSCTs from 1,045 consecutive allo- and auto-HSCTs. The infection incidence was significantly lower in both OP auto- and allo- cohorts compared to IP setting. The 100-day non-relapse mortality (NRM) was significantly lower for OP allo-HSCT than for IP allo-HSCT. They concluded that OP allo- and auto-HSCT had comparable short-term outcomes and complications to IP HSCT.

Granot (12) retrospectively reported 1,037 OP allo-HSCT, and noted that 47% of OP patients were never hospitalized as well as having a lower 5-year risk of NRM than IP HSCT (13% OP vs. 23% IP, p<0.001). OPs evaluated the experience favorably. Shingal (13) reported 856 OP allo-HSCT (a third of whom were never hospitalized) with a median decreased stay of 6 days but no report on long-term results was made.

A Mexican group found that performing OP allo- and auto- HSCTs, with simplified stem cell conservation or conditioning regimens, amongst other measures, could be a solution for countries needing less resource-intense modalities (14, 15).

In the at-home model, patients equally receive the conditioning regimen and stem cell infusion at the hospital or outpatient clinic, spending the aplastic phase at home, where they are cared for by a healthcare team and only returned to hospital if severe complications appear.

A group in Barcelona (16, 17) performed 50 auto-HSCT at home, suggesting nearly 50% cost reduction with great patient satisfaction. Gonzalez-Barrera (18) reported 84 at-home auto- HSCTs with a median at-home stay of 17 days, 86% experienced neutropenic fever, 44% presented grade 3-4 mucositis, and 26% received parenteral nutrition. Hospital readmission occurred in 12% of patients, usually for sepsis, and lasted a median of 9 days, with no transplant-related mortality (TRM). The Durham group analyzed both auto- and allo-HSCTs, finding similar results and good preservation of quality of life for at-home HSCTs (19) compared to IP controls.

Svahn (20) analyzed at-home allo-HSCTs finding significantly reduced TRM (13% at-home vs. 44% IP controls), with improved four-year survival (63% at-home vs. 44% IP controls). They suggested that this advantage could be due to better oral nutrition, resulting in the reduced probability of acute graft-versus-host disease (GvHD) and bacteriemia (21). Pediatric at-home allo-HSCTs has also been performed with favorable results (22, 23). Jenkelowitz reported great caregiver satisfaction for at-home HSCT (24)

Gonzalez (8) summarized 29 auto- and allo-HSCT studies, finding evidence of improved health outcomes, quality of life, and at-home/OP models vs IP effectiveness. Overall survival rates comparing both models were similar for both autologous and allogeneic patients. They also found that OP and at-home HSCT were safe, perhaps more than conventional modalities. They estimated a shorter average stay with the OP/at-home models, being 55% and 19% shorter than the IP model for auto- and allo-HSCTs, respectively, which could ease hospital bed shortages and waiting times. The average cost reduction over the IP-HSCT model was 33.42% and 19.27% for auto- and allo-HSCTs, respectively (Appendix 1 and 2 update a published summary of the studies on allo -HSCT and their results).

As Gonzalez has indicated (8), the high-quality research in the field that is needed for evaluation and benchmarking is lacking. Research should include clinical trials with uniform defining criteria for the different HSCT care models, uniform cost analyses, and assessment of personal experiences and quality of life of staff and patients involved. Finally, the different HSCT modalities should be registered in the different HSCT databases.

In the OP CAR-T model, lymphodepletion, and CAR-T infusion are administered at an OP clinic, with patients staying at home and followed up at fixed intervals at the OP clinic, and admitted to hospital preemptively, or to monitor or treat adverse events (25, 26).

Several authors have reviewed the challenges and requirements for OP CAR-T (5, 27–29).

Borogovac (26) reported 21 patients treated at a CAR-T unit designed for the OP setting. Seventy-one percent were admitted after discharge to treat adverse effects and stayed a median of 8 days, but none needed ER or ICU care. None died. Similar experiences were reported by McGann (25) with 40 patients. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) had a similar incidence as with IPs (25, 26). Table 1 summarizes these findings.

Paludo (30) reported 123 OP CAR-T patients managed with a remote patient monitoring program (RPM), to monitor vital data and neurological symptoms (31). Sixteen percent could be completely managed in the OP setting, with a median stay of 8 days for those who were hospitalized to treat post CAR-T adverse effects, with 6% needing ICU. Most patients (83%) were satisfied with their RPM. Dwivedy (32)Shao (33) and Bachier (34) reported similar experiences. Appendix 3 summarizes these reports.

At-home/OP HSCT is a well-recognized management platform (9). Borogobac (26) defined the key components of an OP CAR-T model: create a multidisciplinary team, train nursing staff, educate community providers, increase patient knowledge and support, acquire physical space for CAR-T operations, adhere to standardized procedures and processes, review procedures, outcomes and finances. Similar considerations were made by an expert panel of the American Society of Transplantation and Cellular Therapy (28)

At-home/OP programs should define patient eligibility criteria, patient and caregiver information, and training. Appendix 4 summarizes and updates prior published provisional patient acceptance criteria for at-home/OP HSCT and CAR-T therapy programs.

A well-trained staff with on-call nurses and physicians to attend routine or emergency calls as well as an antibiotic policy adapted to the at-home/OP context and efficient transport for diagnostic samples are needed. Both routine and emergency operational scenarios must be assessed (8, 9).

Allo-HSCT presents a higher incidence of infections, including aspergillosis, and adverse events like GvHD or acute renal failure (20, 35), which should be detected and managed during the early stages. Common complications of HSCT [fever, mucositis (36, 37), GvHD, capillary leak syndrome, bleeding, diarrhea, nutrition (21)], or CAR-T (CRS, ICANS) should have defined prevention and treatment strategies, which must be planned and trained for. Decreased physical performance should be addressed with a specialized exercise program (38, 39).

Interventions (i.e., fluid therapy, transfusions, antibiotics, catheter care) should be designed to minimize clinical team visits, considering the distance of patients’ homes from the hospital. For example, the use of continuous infusion pumps (40) or self-administration could be contemplated (41). For OP CAR-T, special protocols for the early use (even while at home) of tocilizumab or dexamethasone in the treatment of complications should be implemented.

Table 2 summarizes critical issues when implementing an at-home HSCT/OP CAR-T program.

Emerging technologies provide means for improved patient safety monitoring, which is of special concern for at-home/OP HSCT and CAR-T therapy programs. Remarkably, many can potentially feed data to patients’ records and form networks with AI, resulting in early warning systems and better patient records, creating a continuous care ecosystem.

a. Staff and caregiver training: at-home/OP HSCT and CAR-T programs require specific and timely training for both caregivers and health staff.

b. Patient electronics:

i. Facial recognition technologies (FRT): Cheng showed that oxygen saturation can be measured by remote photoplethysmography using a general-purpose camera (46). Due to its sensitivity, FRT can be more sensitive than clinician judgment, creating early warning systems and enabling improved clinical decision-making.

ii. Point of care tests (POC):

iii. Wearables and remote follow-up:

iv. Drones: unmanned vehicles (drones) are flying devices used for automated transport. Ground drones also exist.

v. Virtual assistants (VA) or AI virtual assistants are embodied or disembodied conversational agents that allow patients to ask questions, receive information, and report their clinical evolution to a technical system in a natural language.

c. Artificial intelligence:

d. As technical advances improve communications and patient care, which in turn facilitate the implementation of at-home OP treatments; more diverse, patient- and process- centered organizational models will become necessary.

a. The feasibility of at-home HSCT is well established, and, in some instances, it could improve patient outcomes (infections, GvHD, survival), with reduced mortality (8, 16, 18, 20, 22). Outpatient management has been considered the future of CAR-T (5), with several dozens of patients already managed this way. However, those are usually single-center reports, so further research, including prospective comparative trials, is required to prove the advantages of at-home/OP management over IP treatment, in clinical and economic terms.

b. Safety and clinical efficacy are critical for at-home/OP HSCT and CAR-T operations. Clinicians must establish policies addressing the specific adverse events, adapted to the constraints of at-home/OP HSCT and CAR-T. An anticipatory approach must be taken, given the possible difficulties in managing patients outside the hospital setting. To this end, emerging technologies can create an improved ecosystem for HSCT/CAR-T.

i. Before HSCT/CAR-T:

ii. During HSCT/CAR-T:

c. Technical support holds significant promise for at-home/OP HSCT and CAR-T programs. Gatwood proposed telemedicine and wearables as requirements for OP CAR-T management (5). However, even if high sensitivity and specificity levels are demonstrated, many issues linger: patient and caregiver acceptability, data safekeeping, training, regulation, etc.

d. Staff education and training for routine and emergency responses must be an integral part of at-home/OP programs. Several barriers including psychological and personal factors, training opportunities or connectivity, as well as facilitators for the incorporation of digital technologies by healthcare staff should be addressed to implement real change (69).

e. Finally, at-home/OP HSCT and CAR-T therapies could result in improved clinical results and satisfaction rates for patients and staff over conventional hospitalization. Now is the time for further research. However, we should never forget that the ultimate objective of outpatient or at-home HCST and CAR-T programs is patient’s well-being (5), and not economics. The lessons learned in this demanding context could be expanded to the standard IP environment.

IR: Conceptualization, Supervision, Writing – original draft, Writing – review & editing. SG: Investigation, Writing – review & editing. CC: Conceptualization, Investigation, Writing – review & editing. EO: Investigation, Writing – review & editing. IS: Conceptualization, Investigation, Writing – review & editing.