Neurotoxicity and CRS Remain and Issue in Lymphoma After CAR T-Cell Therapy

Mazyar Shadman, MD, MPH

While a number of immunotherapy options have been developed and designed to eliminate malignant cells, including chimeric antigen receptor (CAR) T-cell therapy, toxicities linked with these products remains an issue in the lymphoma space.

Over the past decade, numerous CAR T-cell products have been approved by the FDA and even more clinical trials are in progress. Products currently on the market include axicabtagene ciloleucel (axi-cel; Yescarta), brexucabtagene autoleucel (Tecartus), tisagenlecleucel (Kymriah), lisocabtagene maraleucel (Breyanzi), idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti).

The product was investigated early on in pediatric patients with B-cell acute lymphoblastic lymphoma (ALL) and aimed to target CD19. Now, CAR T-cell therapies have been approved for use in adult relapsed/refractory non-Hodgkin lymphoma, multiple myeloma, and relapsed B-cell ALL.

Though different CAR T-cell therapies are available to patients with lymphomas, the rate and characteristics of toxicity differ depending on each product. In the follicular lymphoma space, in particular, there are no therapies that results in cure and novel treatments with both high efficacy and low toxicity are needed.

With CAR T cells, toxicities like cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome may be limiting.

In an interview with Targeted OncologyTM, Mazyar Shadman, MD, MPH, physician, Seattle Cancer Care Alliance, associate professor, Division of Medical Oncology, University of Washington School of Medicine, associate professor, Clinical Research Division, Fred Hutchinson Cancer Research Center, discussed what community oncologists should keep in mind when treating patients who are viable for CAR T-cell therapy.

Can you discuss the rate of cytokine release syndrome in patients who receive CAR T-cell therapy?

We have different CAR T-cell products for lymphoma patients now. The rate and characteristics of cytokine release syndrome is different depending on which product we use. Significant or severe cytokine release syndrome, which we call grade 3 or 4, ranges somewhere between 5%-6%, to around 15%, depending on what product we use. The timing that the CRS starts, the duration of it, and the type of treatments we provide is going to be different depending on the product.

In general, the idea is to suppress the immune storm that's happening. If the grade is high, and if the patient is clinically unstable, meaning that if they require oxygen, or if their blood pressure is unstable, we will be very aggressive, using more than 1 medication or intervention to slow down that cytokine release. In lighter or less significant cases, we try to provide supportive care. Sometimes controlling a patient's fever or mild pain that they're experiencing is all we need to do. It also depends on the setting that the patient is in, meaning whether or not they're in the inpatient setting or in the clinic.

For some of these CAR T-cell products, we start the treatment in the outpatient setting, and we only admit the patient if they develop adverse events. In those cases, we may need to start the intervention of at least the first dose of some of our drugs in the clinic and while they're being admitted. For patients who are in the hospital, the intervention is much faster and is done by the inpatient service.

With severe toxicity in mind, when should treatment with CAR T-cell therapy be stopped?

As part of the assessment, we try to get an idea of the likelihood of patients developing cytokine release syndrome or neurological toxicities before starting the CAR T-cell process. If there is any indication that the patient may have an additional risk, for example, if they have baseline comorbidities, either cardiac or pulmonary or some neurological problems, we first discuss that risk and benefit with the patient. Unfortunately, there are occasions that we find that the patient may not be a good candidate for CAR T. At the end of the day, we want to make sure that the risk and benefit is justified like any other treatment in medicine.

After CAR T-cell therapy, the level of care that we provide depends on the severity of the toxicity. In severe cases in patients who are unstable from the hemodynamic standpoint or from the neurological standpoint, we do our best. We use high doses of corticosteroids or some other anti-inflammatory drugs. There are many new drugs that are in clinical trials for management of toxicities from CAR T-cell therapy, with CAR T-cell therapy being a 1-time treatment. It's not reversible, so it's not possible for us to stop the treatment. It's a done deal. There are ongoing clinical trials, mainly with the allogeneic product, that consider more than 1 time treatment, and sometimes toxicity from 1 infusion may indicate or impact one's decision of repeating the therapy.

Can you discuss some of the safety aspects of CAR T-cell therapy?

Some of the relevant adverse events from CAR T-cell therapy that our colleagues who refer patients to see more than us are being recognized more these days. For example, cytopenias or low blood counts and poor or delayed counts recovery has become a known problem and issue and we are paying special attention to this. There are many studies trying to predict which patients may develop cytopenia and these patients require supportive care. These are mainly done by our colleagues in the community because by the time patients are 2,3, or 4 months out of the CAR T-cell therapy, most of the time we no longer take care of them.

Being familiar with adverse events from CAR T-cell therapy and supportive care using growth factors for different types of cytopenia is important. Also, risk of infections after CAR T is important to know. We keep our patients on prophylactic antibiotics for 6 to 12 months with different agents. Institutions guidelines regarding COVID-19 are different, but we recommend revaccination for COVID-19 3 months after. We support our patients with their monoclonal anti-COVID antibodies before starting treatment to provide some coverage during the lymphopenia and immunosuppression after lymphodepleting chemotherapy and CAR T.

What is important for community oncologists to know about managing patients who receive CAR T-cell therapy?

Most of the time, our community oncology colleagues do not take care of patients immediately after CAR T, but I think it's important for them to be familiar with the type of adverse events that patients may develop after CAR T-cell therapy. This is both because of risk/benefit assessment before referring a patient for CAR T-cell therapy, to make sure patients have a good understanding of the adverse events and the toxicity that's associated with it, and sometimes when we send patients back to their primary oncologists, some of the toxicities are ongoing. I think it's very important for them to be familiar with the rate and for the type of adverse events that patients may develop after CAR T-cell therapy.