CAR T Cells May Be Safely Administered in Outpatient Setting for Patients With B-Cell Lymphomas

David G. Maloney, MD, PhD

Two chimeric antigen receptor (CAR) T-cell therapies are currently FDA-approved for the treatment of adult patients with relapsed/refractory large B-cell lymphomas. These include axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah). While these treatments have excited the treatment landscape, patients receiving CAR T-cell therapy must be closely monitored, which poses a challenge for administration in the outpatient setting.

Two major adverse events of concern with CAR T cells are cytokine release syndrome (CRS) and neurotoxicity. Patients must be monitored closely for the potential onset of either of these events. With liso-cel, however, onset of CRS appears more delayed than with axi-cel in this patient population.

A study presented at the 2020 Transplantation & Cellular Therapy Meetings of the American Society for Transplantation and Cellular Therapy showed the feasibility of administering liso-cel in the outpatient setting. About 30% to 40% of patients did not require hospitalization after receiving the CAR T-cell therapy, but many still did. For CAR T cells to be administered safely in the outpatient setting, the center must be prepared for patients to come to the hospital at any time with toxicity and be prepared to treat very sick patients.

CAR T cells were administered in the outpatient setting at select academic centers that are equipped for handling these patients in admission to the hospital at any time. While this therapy is not ready for the community setting or other centers that are not equipped for 24/7 triage, physicians should know these therapies are available for these patients, and they can refer their patients to local centers that can administer CAR T-cell therapy safely to their patients.

In an interview with Targeted Oncology, David G. Maloney, MD, PhD, medical director of the Immunotherapy Clinic and Program, Fred Hutchinson Cancer Research Center, discussed findings from administration of CAR T-cell therapy in the outpatient setting for patients with B-cell lymphomas.

TARGETED ONCOLOGY: For patients treated in these trials in the outpatient setting, what was the process for CAR T-cell production and administration that differed from the process in academic centers?

Maloney: The approach of doing CAR T cells in the outpatient setting requires a very robust clinical ability in the centers. These patients can still get very sick, so for my situation, we are doing this in an academic situation, which is where we pioneered the use of outpatient administration of CAR T cells. There have been a few other academic centers that have been able to do this, and the liso-cel product appears to be a CAR T-cell construct that has a lower rate of toxicity. There is a lower rate of severe grade 3 CRS, and the onset of the toxicity is slower than what we would typically see with axi-cel. The difference in a 4-1BB construct in this setting is we have been able to give it in the outpatient setting with very close monitoring of our patients with admission to the hospital at the first sign of fever.

What we pioneered in Seattle was the ability to do this, again in a transplant program that had a very robust system. What is very important for a center to even be able to consider doing CAR T cells in the outpatient setting is they need to have the patients stay within 30 minutes of the center, they have to be seen essentially daily after CAR T-cell administration for the first couple of weeks, and they need to be able to be admitted in the middle of the night with 24/7 triage directly to the hospital to a team that has access to take care of very sick patients. That includes admission to the intensive care unit (ICU) for CRS or neurologic toxicity. It’s not quite fair to call it outpatient in a community center; it is outpatient in a very select group of centers who are very well qualified and have a robust team that is capable of taking care of patients who can get very ill following CAR T cells.

TARGETED ONCOLOGY: What did you observe in this study?

Maloney: We showed that in a variety of outpatient settings that this product, liso-cel, in this patient population which was largely aggressive lymphomas that it can be done safely but with the caveat that this is done in centers that have the ability for 24/7 triage and get people to the hospital. We found that around 30% to 40% of patients did not ever require hospitalization, which is quite interesting in that a lot of these patients can go through lymphodepletion, receive their CAR T cells, and still be monitored in the outpatient setting without requiring hospitalization.

Since about 30% to 40% did not require hospitalization, that means the remaining number did, so 60% to 70% did have to go into the hospital. This was almost always for fever, and this was almost always the onset of a low-grade CRS. The advantage of this product is that it is more delayed. That onset is not in the first 24 to 48 hours like it is with axi-cel. It is more delayed in the 3- to 5-day range. We were able to get patients safely into the hospital, and it was very rare we would have to do escalation of care when people got admitted. Most of the time patients could be managed essentially out of the ICU with rare exceptions. Again, you still have to have the ability to get people into the ICU potentially for aggressive care if needed.

That was the main finding, that not everyone required hospital admission and if just add up to the total resources that would be used in caring for patients in the CAR T-cell setting, you would think it would be lower with less days in the hospital and less days in the ICU and more days in the outpatient center.

TARGETED ONCOLOGY: Do the findings from this analysis indicate that there is hope for the use of CAR T-cell in the community setting?

Maloney: With reservation, I think you can do this in a very select community setting that has access to all those things I said, such as 24/7 care, middle of the night care, direct admission to the hospital, and ready access to ICU care.

TARGETED ONCOLOGY: What should the community know right now about CAR T cells?

Maloney: The key thing for community oncologists is to get your patients to the center that can provide this service. Right now, CAR T cells appear to be the most active treatment that we have for relapsed/refractory aggressive lymphomas. Many of the studies are trying to move this treatment up, and there are now 3 randomized studies challenging the role of autologous transplant for the first relapse in large B-cell lymphoma. We know that in clinical trials tumor burden matters, so if you can get patients to a center that can deliver CAR T-cell therapy with any of the approved products before they have widespread bulky disease, then this will be associated with a higher response duration than many of the other trials. If we can treat people with the lowest disease burden, that should translate into better outcomes and longer survival, as well as a higher chance of being in remission 1 to 2 years later.

This is a very exciting field, and we are seeing a lot of new molecules come in that will be challenging the role of CAR T cells as well, such as the bispecific antibodies, which may even work in cases of CAR T-cell failure. We are still learning how to make these treatments more effective and safer.