Managing Cytokine Release Syndrome in Patients on CAR T-Cell Therapy

Ahead of the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, we are speaking with Elizabeth Shpall, MD, of the University of Texas MD Anderson Cancer Center, about the management of cytokine release syndrome in patients receiving chimeric antigen receptor (CAR) T-cell therapy. Dr. Shpall will be speaking at an Education Session titled, “Assessment and Management of Cytokine Release Syndrome” on Friday, May 31, at the meeting, which is being held May 31–June 4 in Chicago.

Cancer Network: Cytokine release syndrome needs to be assessed for and managed in patients undergoing chimeric antigen receptor (CAR) T-cell therapy. For which cancer types has CAR T-cell therapy been investigated? In addition, how many patients benefit from it, and how durable are their responses?

Dr. Shpall: I think acute lymphoblastic leukemia (ALL) was the first cancer type for which CAR T-cell therapy was evaluated. The most stunning data come from individuals younger than age 26 years, in highly refractory situations where patients had failed many therapies, including an allogeneic transplant, which is the most aggressive option. In this setting, the use of CAR T–targeting CD19 produced a 90% complete remission rate, which is very impressive.

Depending on which studies you read, including the characteristics of the patients and the actual construct itself, about 60% of patients who achieved a complete remission appear to be in long-term remission at this time. Some studies found that this rate was lower, while other studies found it to be similar. So, I think the jury is still out on the long-term results, since many patients are still being followed and treated. That said, this research led to the US Food and Drug Administration (FDA) approval of the first CAR T-cell therapy, tisagenlecleucel, for the treatment of patients with ALL.

Research evaluating CAR T-cell therapy for non-Hodgkin lymphoma and diffuse large B-cell lymphomas in patients aged 18 to 75 years started shortly after the studies looking into this therapy for ALL. Now, even patients in their 80s are being treated. The categories of disease in this population include high-grade B-cell lymphoma, diffuse large B-cell lymphoma, primary mediastinal large cell lymphoma, and diffuse large B-cell lymphoma arising from follicular lymphoma. These are the four subclassifications of patients who appear to benefit from CAR T-cell therapy. In clinical trials, approximately 70% of patients studied responded to axicabtagene ciloleucel, and the complete remission rate was about 54%. Long term, about 40% of these patients have remained in remission. Following critical studies led by Sattva Neelapu, MD, of MD Anderson Cancer Center, the FDA approved the CAR T-cell therapy axicabtagene ciloleucel for the previously listed individuals in October of 2017.

Researchers continue to evaluate tisagenlecleucel for various lymphoma categories and have seen good results. Many other therapies are being evaluated at different institutions across the country, including the TRANSCEND protocol, which is evaluating JCAR17 CAR T-cell therapy. The data look very promising so far, but it's not yet at the FDA for approval. In addition, there are some very impressive CAR T-cell constructs developed in individual academic centers that are moving forward and producing similar results to the ones I just discussed.

Lastly, data on the use of bb2121, a CAR T-cell therapy that targets B-cell maturation antigen, in multiple myeloma patients were just published in The New England Journal of Medicinel. The follow-up period was shorter, so it's not as robust as other studies and there's not as much information to tell us about the response durability, but the results are exciting.

Cancer Network: Some patients taking CAR T-cell therapy experience cytokine release syndrome (CRS). Why does this happen, and what proportion of patients will experience CRS?

Dr. Shpall: Although CAR T-cell therapy is very impressive and produces extraordinary results, it is also very potent in terms of the unique toxicities it produces. Cytokine release syndrome is the most common side effect associated with this treatment, and it is characterized by high fevers, hypertension, hypoxia, and multi-organ damage. About one-quarter to two-thirds of patients experience some sort of CRS. However, high-grade CRS-grade 4 or 5, which can be very dangerous or even fatal-is rare. Grade 3 and 4 CRS occurs in approximately 20% to 50% of patients.

Fortunately, the fatality due to CRS is very low, less than 5%-actually, less than 4% in most studies. But about half the patients who have been recorded in these early studies have required very intensive care management for at least a few days to ride out the cytokine release that has occurred. Management includes interleukin-6 inhibitors and corticosteroids. Neurotoxicity is fortunately not as common as CRS, but when it does occur, it has to be managed by a very astute team of investigators who understand how to diagnose and manage it (primarily with corticosteroids).

Cancer Network: How are patients monitored for CRS and neurotoxicity during CAR T-cell therapy? What are the early symptoms?

Dr. Shpall: The patients are followed very carefully. They need to be seen every day. Institutions often have a team in place to do so, including an evaluation for fever and monitoring of blood pressure and heart rate. These vital signs are very early signals that the patient may be developing CRS. Fever is typically the first warning sign of CRS followed by changes to blood pressure and heart rate. The patient’s respiratory status is also monitored because an increased use of oxygen and other clinical parameters can also indicate that a patient is developing CRS and needs immediate treatment.

For neurotoxicity, our team at MD Anderson and around the country has developed very simple neurologic testing to assess whether patients are developing any kind of neurologic compromise. It’s what we call the immune effector cell-associated encephalopathy (ICE) score, which is a simple 10-point score that involves asking the patient several questions (eg, name three objects, count backwards from 100 to 0, etc). If the patient can complete all of them and can write a sentence without any changes in handwriting, that confirms no early signs of neurotoxicity are present. Any perturbation in any of those parameters can heighten the team’s awareness that neurotoxicity may be developing, which can prompt more sophisticated testing such as electroencephalograms and scans of the brain.

Cancer Network: Are there any predictive factors or biomarkers that might help identify which patients are at risk for high-grade CRS?

Dr. Shpall: Many researchers are looking into this now. The academic centers are studying all of the different cytokines, including interleukin-6, interleukin-1, tumor necrosis factor alpha, and interferon gamma. However, baseline cytokine levels are not yet a perfect predictor.

Cancer Network: Can you tell us a little about how CRS should be managed, including more about MD Anderson’s recently proposed guidelines for managing CRS and other CAR T-cell therapy toxicities?

Dr. Shpall: It's important to underscore that published in the Biology of Blood and Marrow Transplantation in 2018 is the American Society for Transplantation and Cellular Therapy’s consensus grading by Lee et al. About 50 investigators from around the country were brought together to try to develop a now consensus screening criteria that will be used at every institution in the United States. This is a major improvement in the field, since before there were four or five different grading systems, and it was hard to compare patients and CAR T-cell products from different institutions. Now that this consensus grading is published, almost every center has adopting the criteria. At MD Anderson, we are also using this consensus grading.

In terms of how we evaluate for CRS, there are different symptoms that define grade 1, 2, 3, or 4 CRS, and these symptoms dictate the patient’s immune cell–associated neurotoxicity score. If patients have grade 1 CRS with a temperature, we watch them. If it's grade 2 CRS, we also continue to watch them, and if they develop more serious fevers or continued fevers, we may treat them with tocilizumab. For grade 3 and 4 CRS, we definitely treat patients with tocilizumab and corticosteroids.

We have been using tocilizumab and corticosteroids earlier in the course of CRS because studies have shown that they do not compromise the ultimate response rates in our patients, and they really do help abrogate early CRS and neurotoxicity. Patients developing grade 2 or 3 CRS are moved to the intensive care unit for careful monitoring and then are moved right back as soon as they are stabilized. If neurotoxicity alone is present without CRS, tocilizumab is not helpful, so we treat these patients with corticosteroids. Many groups in the country are looking at other potential blockades of these syndromes. One of them is the interleukin-1 inhibitor anakinra, which appears to be quite effective in mouse models; however, we don't have much clinical data yet.

Cancer Network: What else would you like to tell readers about CAR T-cell therapy, CRS, and neurotoxicity?

Dr. Shpall: I think it's a new day in the treatment of our patients. It's a gratifying time now to be able to achieve meaningful complete remissions and long-term responses when we have never had these opportunities in the past. However, we have to have the expertise in-house to be able to safely manage patients taking CAR T-cell therapy because, without that, we can have really unacceptable toxicities. So, clinical teams need to be trained, and clinicians from neurology, cardiology, and intensive care need to be part of a team that helps to manage these patients.

Many centers, including MD Anderson, are finding that the Foundation for the Accreditation of Cell Therapy (FACT) has developed very comprehensive standards to manage these patients. These are the Immune Effector Cell (IEC) Standards, published a year and a half ago. These standards go through each section of treatment, including collection, processing, infusion, and management. They have been invaluable in getting our team organized, and in providing a roadmap of what things should be instituted to optimize the quality management and care of patients taking CAR T-cell therapy. I highly recommend the IEC Standards for any center entertaining treating patients with CAR T cells.

Centers can also become accredited by FACT to be an immune effector cells center when they meet certain standards, which can be downloaded on the FACT website. The FACT IEC inspection and accreditation program is going a long way to making this therapy safe for patients treated with CAR T-cell therapy throughout the United States.