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Amelia Langston, MD: I'm Dr Amelia Langston from Emory University. Welcome to Medscape's InDiscussion series on chimeric antigen receptor (CAR)T-cell therapy. Today we're going to be discussing the monitoring and management of complications of CAR T-cell therapy with Dr Jean Koff. Dr Koff is an assistant professor here at Emory in the department of Hematology and Medical Oncology, and she is one of my most trusted colleagues. In the first episode, we talked about CAR T-cell therapy to reprogram a person's T cells to kill tumor cells. This is a very attractive concept to potentially offer curative therapy for patients with B-cell and plasma cell disorders. Today we're going to focus more on the unintended consequences of this therapy. Dr Koff, this therapy is offered only in specialized centers, typically centers specializing in transplant and cell therapies, and there's a reason for this. Can you talk about some of the complications that can occur, particularly early in the aftermath of CAR T-cell therapy?
Jean L. Koff, MD, MS: There are two main toxicities that we worry about in the first days to weeks following a CAR T infusion: cytokine release syndrome (CRS) and neurotoxicity, which is also known more specifically as immune effector cell-associated neurotoxicity syndrome (ICANS). I'll start with CRS. This is usually due to on-targeted effects induced by the CAR T-cell receptor binding to its target with subsequent activation of bystander immune cells and non-immune cells, like endothelial cells. When these bystander cells get overactivated, there can be a massive release of a range of cytokines, including IL-6 and various interferons, and thus, the CAR T-cell infusion can set off what's known as an inflammatory circuit that overwhelms the body's usual regulatory homeostatic mechanisms. It can result in a cytokine storm that can have detrimental effects on the patient who receives the CAR T infusion. The initial presenting symptoms may look like the flu, but if this manifestation is severe, untreated, or not treated aggressively enough, patients can have a shock-like syndrome — a profound elevation in the cytokine levels. The main manifestations of this, especially in the early stages, but even in the later stages or later grades, are fever, vascular leakage (which can cause low blood pressure and increased fluid in the lungs), and pulmonary edema (which can cause low oxygen saturation and, again, in later grades with a more progressive process dysfunction of other organs). What's special to note about CRS is that even though these symptoms of fever, low blood pressure, organ dysfunction that mimics sepsis, and infection risk are concerns in patients who get CAR T, how you manage CRS is quite different than the management of sepsis.
Langston: How do we manage this problem when it occurs?
Koff: The first thing is that it's important to be in a center where there's a lot of experience in administering CAR T therapy and managing these types of complications. One great way to manage this is to prevent it or at least monitor very closely, so you can catch CRS when it's in the early grades, when there are just fever and maybe a little hypertension that's responsive to fluids. Monitoring in an experienced center is a good first step. We've become more experienced with using these types of CAR T products, both on clinical trials and now that they're commercially available. We've been able to develop protocols where we can monitor patients closely and use treatments at earlier stages of the clinical picture to help prevent more severe forms of CRS. A couple of the mainstays in terms of CRS management include tocilizumab, which targets IL-6 signaling, and steroids in more severe grades. What we've seen with more data coming out in in the last few years since we've begun using these products is that the initial concerns about these types of treatments decreasing the efficacy of the CAR T cells actually hasn't been borne out. We've been using these therapies earlier in the course of CRS, which helps prevent the more severe grades of this developing.
Langston: The other big complication is neurotoxicity. Let's talk about the forms that neurotoxicity can take.
Koff: The mechanisms that underlie the pathophysiology of neurotoxicity are not as well described as what we know about CRS. This type of manifestation can range from some mild confusion to frank delirium — and even seizures, cerebral edema, coma. We know that neurotoxicity incidence increases with increased dose of the product, increased patient age, and numbers of prior therapies. It also most often develops within 3 to 10 days of infusion. There are some cases where these neurologic symptoms last beyond that time point. A lot of what we focus on when patients are receiving CAR T is monitoring for early signs of neurotoxicity. The initial symptoms usually include inattention and deficits in language. Part of what we do when we monitor these patients is assess a kind of mini mental status exam known as the CARTOX 10 that we administer to patients every 4 hours. It assesses relatively simple neurologic and cognitive functioning in areas like orientation, naming, following simple commands, and writing a sentence. That way, we're able to detect whether a patient may be developing early neurotoxicity and intervene sooner rather than later.
Langston: When people manifest neurotoxicity, we use steroids to manage that. I think there was a lot of concern that might compromise the efficacy of the CAR T product that has not really been borne out. One of the things that is of major concern in both early and in an ongoing basis is the risk of seizures. Talk about how we deal with that and some of the precautions patients need to take.
Koff: One of the precautions that we can use is medical therapy with Keppra (levetiracetam). We use Keppra as a prophylaxis against seizures. Another method that we often employ and highly recommend is having patients take precautions even when they're discharged from their admission for CAR T. We recommend that they have a 24-hour caregiver who's monitoring them. And, like any other patient who's at risk for seizures, that they refrain from activities like driving or operating machinery in case they have some late-developing neurotoxicity.
Langston: The things that we've talked about so far — CRS and neurotoxicity — the primary period of risk is the first month after therapy. We generally require that patients stay near the transplant center during that first month. It's very rare that patients will have these kinds of problems after they go home, but some of the problems can occur later on. Let's talk about blood counts. Although the lymphodepleting chemotherapy that's given just before the CAR T infusion is relatively low dose and has a pretty limited effect on the blood counts, there's a subset of patients who have very prolonged cytopenias.
Koff: That's right. We think about the cytopenias in terms of when they occur relative to the CAR T infusion. Most of the early cytopenias are usually attributed to the lymphodepleting chemotherapy, although you have to have a high index of suspicion for something like infections that can also cause these issues in these immunocompromised patients. Rarely, you can have something like an immune effector cell–associated hemophagocytic syndrome that can cause cytopenias in that early period within 30 days of the CAR T infusion. It's worth noting that most people on the clinical trials looking at CAR T infusion did experience some degree of cytopenias within that first month. It's very common. Most patients will experience the nadir of their counts within that first week after the CAR T infusion and then rapidly recover their counts. However, it's also common for cytopenias to either continue beyond that 30-day mark or recur at a later date after recovery, beyond what's expected for the lymphodepleting therapy alone. For that reason, cytopenias after CAR T infusion have sometimes been described as biphasic because you get that second decrease in the neutrophil count at a later point, usually about a month out from CAR T. There are several different causes for this. One of the main causes seems to be a poorly understood immune-mediated stem cell suppression. Of course, there are other causes in these complicated patients when they're immunosuppressed. There are infections, such as viral infections, that can cause low cell counts. As you get further out from CAR T infusion, you also have to have a high index of suspicion of entities like disease relapse, because these are disorders that often involve the bone marrow as well as a secondary bone marrow neoplasm. Again, these patients are heavily pretreated and at risk for myeloid disorders. There's that rare incidence of an immune effector cell-associated hemophagocytic syndrome. There are lots of etiologies to consider and lots of ways that we can think about working up these patients and then also managing them, so they're not at increased risk for infections when they're cytopenic.
Langston: The commercially available CAR T products are all targeting either B cells or plasma cells. As a consequence of that, patients often have prolonged B-cell and plasma-cell aplasia, and that certainly can predispose patients to infections. Let's talk about how we monitor these patients and what we need to do after patients go home because of this humoral immune deficit.
Koff: This is basically an on-target effect for these patients because the CAR T doesn't discriminate between malignant and benign B cells or plasma cells. One of the side effects from this can be hypogammaglobulinemia, and that puts people at risk for infection. One way that we can monitor this in our patients is by assessing their immunoglobulin G (IgG) levels over time and based on whether they have IgG levels that are lower than normal or if they have recurrent infections that are signaling that they may have deficits in humoral immunity. Even if they do have normal or borderline normal IgG levels, these would be indications to start supplementation with intravenous immune globulin (IVIG) to try and support their immune system, so they're not as at risk for these types of infections that can result when somebody doesn't have B cells or immunoglobulins.
Langston: Generally, we also prescribe prophylactic antiviral and pneumocystis prophylaxis for these patients for a minimum of 6 months and sometimes longer, depending upon what their immune profiles look like. There's also the issue of the potential for loss of prior immunity to things that we've either had or been vaccinated against. This is more of an uncharted area, but how we may approach that issue?
Koff: Like you said, this is an evolving field. We're learning more and more about the incidence of loss of prior immunity from vaccines or prior exposure to infections in patients who get CAR T infusion, but the immunogenicity and safety of vaccines after CAR T is largely unknown. Even working with that limited amount of data to guide vaccination approaches, I think we can still draw some inferences from our experience using other treatment modalities, such as stem cell transplant or even B-cell depleting therapy like rituximab. Even though patients treated with CAR T may have lower vaccine responses compared with healthy individuals, we still think that vaccination can help prevent infections, decrease their severity, help patients avoid hospitalizations, and save lives. The general recommendation is that for patients who are in remission and don't require additional chemo or stem cell therapy, vaccinations should be strongly considered if you're at least 6 months out from a CAR T infusion — that's for chilled or inactivated vaccines. We recommend patients wait at least 1 year for live and non-live adjuvant vaccines. Again, that recommendation is based on studies of vaccine responses in patients who have been treated with rituximab, which is an anti-T-cell agent targeting CD20 and also the kinetics of immune reconstitution in patients who've received CD19-directed CAR T.
Langston: In my experience, I think taking B-cell numbers in the peripheral blood and immunoglobulin levels into account is a good way to say, "Maybe we're ready to revaccinate," because there is a subset of these patients who have very long-term persistence of the CAR T cells and may have very prolonged B-cell aplasia, particularly the acute lymphocytic leukemia (ALL) patients. We can't emphasize enough how immunocompromised these patients sometimes are, even after they go home from CAR T-cell therapy. A wake-up call for me was reading a recent publication looking at patients with mantle cell lymphoma (MCL) in the real-world experience, and there was about a 10% risk of non-relapse mortality, with most of that being due to late infections. This really illustrates the need for diligence and continued monitoring of these patients well after the acute phase.
Koff: I completely agree. Having a good plan for prophylaxis and monitoring IgG levels or B-cell subsets is important. Patient counseling is also important, so that patients are taking measures to help isolate themselves and decrease situations that may be associated with increased risk of contagion.
Langston: With all of these things we've talked about today in mind, talk about how you approach a patient who's referred for consideration of CAR T as far as candidacy for this treatment, because it is not for the faint of heart.
Koff: A lot of what we assess when we're looking at a new patient for CAR T candidacy is actually limiting their risk of having some of these more severe toxicities related to CAR T. One of the first items we look at is their disease state. I'm a lymphoma doctor, so I'm usually looking at patients with large cell lymphoma or MCL. In order for the CAR T to be effective, we want to have relative stability of the disease in the time prior to CAR T manufacturing, which takes a few weeks between apheresis and the delivery of the cells. You're going to consider things like bridging therapy to make sure that you can keep your patient's disease from progressing in that time while you're waiting for the cells to be manufactured. Patients who have a very large burden of disease at time of CAR T, as might be expected, are at increased risk for having severe CRS, because it's that exaggerated, inflammatory, systemic response. That's certainly at the top of my mind. There are lots of patient-specific factors that we assess to limit a patient's risk for these side effects. Patients need to have adequate cell counts before they're infused with CAR T therapy, otherwise they're at increased risk for prolonged or severe cytopenias and the issues that arise from that. Patients who have a history of thrombus, persistent or recurrent infections, bleeding, and dialysis have a higher risk for some of the toxicities we've talked about today. And then older patients and people who have a preexisting neurologic disorder or a cognitive defect are at increased risk for ICANS, and it also makes it difficult to monitor for progression or manifestation of ICANS when you have a preexisting issue. Like you said, this is not for the faint of heart. Patients' functional status at the time of screening for CAR T and just before CAR T infusion is important. We want patients to have pretty good performance status, so that they can get through this therapy and the potential toxicities. The final piece I look at is dealing with the infusion and toxicities doesn't stop once you leave the hospital. Having a good caregiver and a good amount of social support is important for patients undergoing this therapy. You can't do it by yourself. You need someone who's monitoring you, who can take you to appointments, and who can make sure to notify your treatment team if you are having any of the issues that we discuss after you leave the hospital for infusion. Finally, we both practice at a stem cell and cell therapy center at a large academic cancer center. As we've mentioned, that is part of the puzzle. Part of CAR T management is being at a facility where providers are very experienced in the management of the infusion and also of the toxicities. Having tocilizumab on hand and ready to give in case of CRS, for example, is not something that's readily available at all sites.
Langston: Today we've had Dr Jean Koff discussing the monitoring and management of complications of CAR T therapy. Thank you for joining us today. This is Dr Amelia Langston for InDiscussion.
Resources
Cancer Immunotherapy With Chimeric Antigen Receptor (CAR) T Cells
Immune Effector Cell Associated Neurotoxicity Syndrome in Chimeric Antigen Receptor-T Cell Therapy
On-target and Off-target-based Toxicologic Effects
CARTOX 10 Point Neurological Assessment
Cytopenia After CAR-T Cell Therapy-A Brief Review of a Complex Problem
Immune Effector Cell-associated Hemophagocytic Lymphohistiocytosis-like Syndrome
Management of Hypogammaglobulinaemia and B-cell Aplasia
Chimeric Antigen Receptor (CAR) T-cell Treatment for Mantle Cell Lymphoma (MCL)
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Cite this: Monitoring and Management of CAR T-Cell Therapy Complications - Medscape - May 11, 2023.
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