Managing CAR T-Cell Therapy in Patients With Hematologic Malignancies

Today we are speaking with Stephanie Jackson, MSN, RN, AOCNS, BMTCN, an oncology and bone marrow transplant clinical nurse specialist at UCLA Medical Center, Los Angeles, about the role oncology nurses play in managing adult patients with hematologic malignancies who are undergoing chimeric antigen receptor (CAR) T-cell therapy. This is a type of genetically modified autologous T-cell immunotherapy that is generated from the patient’s own cells.

Two CAR T-cell therapies are currently approved by the US Food and Drug Administration (FDA) for adults with blood cancers. Tisagenlecleucel is indicated as a treatment for adult patients with relapsed or refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL) after two prior systemic therapies. The second is axicabtagene ciloleucel, which is also indicated for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including those with DLBCL.

-Interviewed by Anna Azvolinsky

Cancer Network: First, can you describe how CAR T-cell therapy is generated, specifically for each patient?

Ms. Jackson: Yes, and thank you for having me. CAR T cells are considered a modified autologous transplant in which we use the patient’s own T cells, which are extracted through apheresis. Once collected, the T cells are shipped to the manufacturer, where they are genetically engineered with a specific, disarmed virus that allows them to produce receptors that are specific to defective B cells once they are placed back into the patient’s body. That is where the name comes from: chimeric antigen receptor therapy.

The T cells are modified over a period of about 2 to 4 weeks, and they multiply and divide in the lab. Once that division happens, they are then shipped back to the treatment site and cryopreserved until the patient is ready to receive them. Once ready, the patients are brought into the inpatient or outpatient setting, depending on the institution, to receive what is considered conditioning, chemo-depleting chemotherapy. Either 3 or 4 days of fludarabine will also be administered. On day 0, the patients are given back their modified T cells and are kept in the hospital under close supervision, until they are deemed stable to be discharged. Once they are discharged, they receive close monitoring in the outpatient setting. Depending on the institution, some may receive follow-up 2 to 3 times per week until they are deemed stable, and they are required to stay local for 3 to 4 weeks post-transplant.

Cancer Network: Although CAR T cells can be very effective, there are risks of complications. Can you talk about some of those complications and the role of oncology nurses like yourself in managing these patients? In addition, are there specific times during the course of therapy when patients are most vulnerable to these risks?

Ms. Jackson: There are two major “black box” warning complications that you will always hear about. One is cytokine release syndrome, and the other is neurological toxicity. Cytokine release syndrome is considered a life-threatening reaction to the T cells that usually occurs about 2 to 7 days after the patient has received his or her T cells back. It can last as long as 58 days. Cytokine release syndrome is usually linked to those patients who have a high tumor burden, and it’s caused when the T cells connect with the defective B cells; the malignant B cells go through rapid apoptosis [cell death], and all of the intracellular components of the B cells are released into the bloodstream, causing a systemic inflammatory response that is usually triggered as a result of interleukin-6 (IL-6). These patients can have very high fevers of up to 104°F, as well as hypotension, tachycardia, tachypnea, and/or capillary leak syndrome. Renal failure, impaired clotting, and elevated C-reactive protein are also possible, and sometimes the latter can even result in cardiac arrest if their tumor burden is high enough. So, as you can imagine, the role of the oncology nurse is critical with these patients, because they require trained staff to closely monitor them.

Neurological toxicity is the other “black box” warning that is commonly seen in these patients, and this is also triggered by the release of IL-6, which is thought to deposit into the brain. We see this about 4 to 17 days post-transplant, and it can have long-term effects. In clinical trials, this side effect was seen up to 43 days after transplant in 87% of patients. It also requires trained staff to recognize it. Some of the clinical manifestations we see in these patients include headaches; tremors that can lead to or be indicative of cerebral bleeds; seizures; encephalopathy; and sometimes delirium or aphasia.

Following the FDA approval of these two CAR T-cell therapies, clinical sites that offer this therapy are required to train all staff that will be involved in the care of these patients. This helps ensure that clinicians have the skillset and competency to be able to recognize symptoms of the “black box” warnings in patients receiving modified T cells.

Cancer Network: Are there any other signs and symptoms to watch out for when managing these patients, or that patients should look out for once they are dismissed from the hospital?

Ms. Jackson: This is considered a modified transplant, so patients will have a weakened immune system afterward. Some of the patients that we see in the first few days have tumor lysis, and their potassium, creatinine, or uric acid levels can go up. However, again, this is usually seen in the inpatient setting, when the patient is being closely monitored. For this therapy, the nurses and even the patient’s caregivers are a huge component of monitoring. The nursing staff look closely at patients’ lab results, particularly at trends in their complete blood count, as well as at clotting factors, tumor lysis lab results, and their vital signs. For example, tachycardia can be a heart rate of less than 100 if a patient has a baseline heart rate of about 80 beats per minute. We also look at trends in the patient’s temperature, which is a huge component of care. If patients have a normal baseline temperature of 97°F, then a fever may be 99°F. So, this is something that nurses need to really monitor and educate the patient and family members to monitor after the patient is discharged. Fluid intake and output is also important to watch because, as I discussed earlier, these patients can go into renal failure. We make sure that their output is maintained at 30 cc’s per hour to ensure that they are having adequate perfusion to their kidneys.

Regarding neurological symptoms, it’s important that nurses educate the caregivers so they can monitor for subtle changes. For example, sudden vision or auditory hallucinations, slight tremors, or headaches could be indicative of cerebral bleeding. When discharging these patients, outpatient nurses should remind caregivers to watch for these symptoms daily; they can also make the clinicians’ phone numbers readily available to them in the event of an emergency.

Cancer Network: Lastly, are there still unknown questions about these therapies-potential long-term side effects or other concerns to highlight? And, are there side effects or anything else that were not seen in the clinical trials, but that you as a nurse see in caring for these patients?

Ms. Jackson: The two adverse events I described are the biggest. We have seen that when patients are discharged, most of these side effects subside. Some patients have long term B-cell aplasia and require IV Ig. I think that one of the biggest things that hematology and transplant divisions as a whole have to start thinking about is what to do in the event of relapse. These patients are refractory, with relapsed disease; many who qualify for these therapies are older, so in the event that they relapse, what do we do? Are the patients then eligible for clinical trials? Do we think about giving them a stem cell transplant, a haplo-transplant, or an umbilical cord transplant? Do we give these patients a second transplant? Is it safe to give a patient a transplant within a year of their receiving CAR T-cell therapy?

CAR T-cell therapy is comprised of the patient’s own cells, so we don’t have to worry about graft versus host disease, but is it safe to then give a transplant? Do the risks outweigh the potential benefits?

These are some of the things we are seeing in clinical practice that will be a concern, considering that these patients already tend to be somewhat fragile and have received prior therapies, are advanced in age, and have very aggressive disease. What are we going to do with them in the future? That is something we are thinking about as a community of transplant and hematology clinicians, and we may start to see new clinical trials that address these questions.

Cancer Network: Thank you so much for joining us today, Stephanie!

Ms. Jackson: Thank you!