Limiting severe toxicity, mortality after CAR T-cell therapy
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In this installment of In Practice, Marco L. Davila, MD, PhD, and Rawan G. Faramand, MD, of H. Lee Moffitt Cancer Center and Research Institute in Tampa, discuss the importance of developing a patient-specific management strategy to limit severe toxicities and mortality after chimeric antigen receptor T-cell therapy.
Davila, an associate member of the Blood & Marrow Transplant and Cellular Immunotherapy program, and Faramand, an assistant member, were two of the coauthors of a recent study in Clinical Cancer Research that aimed to identify factors that can predict severe toxicities in patients undergoing CAR T-cell therapy.
Davila and Faramand share the results of their research and make recommendations on how to develop mitigation strategies in patients who may be at a higher risk for treatment-related toxicities.
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Q: How important is developing a patient-specific strategy to manage the toxicities that can result from CAR T-cell therapy?
Faramand: CAR T-cell therapy has shown significant promise for hematologic malignancies, leading to the FDA approval of three CAR T-cell therapies for the treatment of B-cell acute lymphoblastic leukemia, large B-cell lymphoma (LBCL) and, most recently, for mantle cell lymphoma. Although durable response rates are encouraging for patients with relapsed/refractory disease, the widespread use of these therapies is limited by toxicities such as cytokine release syndrome (CRS) and neurologic toxicity. Despite earlier recognition of these toxicities and the use of corticosteroids and interleukin (IL)-6 antagonists, such as tocilizumab, patients unfortunately still die as a result of these unique immune-related adverse effects. Therefore, it is critical to identify patients who are at highest risk for developing these toxicities and develop individualized strategies to mitigate them.
Q: Has research revealed factors associated with increased mortality risk for patients considering CAR T-cell therapy?
Faramand: Yes. We evaluated 75 patients at our institution with LBCL who were treated with standard-of-care axicabtagene ciloleucel (Yescarta; Kite Pharma/Gilead). In our analysis, patient and tumor characteristics, such as disease stage, International Prognostic Index score or age, were not associated with the development of severe grade 3 or higher toxicities. However, we found that baseline levels of cytokines measured before lymphodepleting chemotherapy — particularly IL-6 — were associated with the development of severe CRS and neurotoxicity.
Q: Which patients are at the greatest risk for death according to your research?
Davila: We identified elevated IL-6 levels (greater than or 40 pg/mL) at baseline to be associated with severe toxicity and death in patients treated with axicabtagene ciloleucel (axi-cel). Although most patients in our analysis died of disease progression, three patients with elevated IL-6 died of treatment-related mortality. This highlights the importance of identifying these patients early, before CAR T-cell infusion, and designing risk-adapted clinical trials to mitigate these toxicities.
Q: Should patients at high risk for toxicities still undergo CAR-T, or consider alternative therapies?
Faramand: CAR T-cell therapy offers heavily pretreated patients encouraging durable response rates. We observed these findings in our patients, despite most of them being ineligible for treatment under the pivotal ZUMA-1 clinical trial. Given limited treatment options for patients with relapsed or refractory disease, these patients would still benefit from CAR T-cell therapy but I would encourage enrollment in clinical trials aimed at mitigating toxicity.
Q: Can the results of your research have an impact on clinical practice?
Faramand: Building on our current work, we are creating and prospectively validating a predictive model to risk-stratify patients and guide management of severe toxicities. As more and more cellular therapies demonstrate efficacy and obtain FDA approval, predictive models of toxicity incorporating baseline cytokines will be very important in informing which patients can be safely treated in the outpatient setting.
Q: Would the factors your research revealed be limited to patients with diffuse LBCL?
Davila: Our analysis was limited to patients with DLBCL. Although similar cytokine elevations have been observed in patients with acute lymphoblastic leukemia, there are inherent key differences between the diseases and the findings will need to be confirmed in a cohort of patients with ALL. With the recent FDA approval of brexucabtagene autoleucel (Tecartus; Kite Pharma/Gilead), these findings will also need to be validated in patients with mantle cell lymphoma.
Q: Would the risk factors you identified be limited to axi-cel?
Faramand: Because the risk for toxicity differs among the various CAR T-cell constructs, the factors we identified are limited to axi-cel. An analysis is planned for patients treated with standard-of-care tisagenlecleucel (Kymriah, Novartis).
Q: What is the role of the tumor microenvironment in influencing the toxicity of CAR T-cell therapy?
Davila: We observed that recipient myeloid cells and regulatory T cells may play an important role in the pathogenesis of severe neurotoxicity and CRS. In our analysis, patients who experienced severe neurotoxicity had lower T cell type scores and higher macrophage scores. This brings up another potential strategy of reducing toxicity by reducing systemic inflammation and polarizing the tumor microenvironment toward a T-cell infiltration phenotype.
Further, we observed a novel association between peak levels of the catecholamine norepinephrine and severe CRS. Because catecholamines can be inhibited by agents such as metyrosine, this brings up another potential therapeutic strategy to mitigate toxicity.
Q: What is the next step, after you identify potential risk factors?
Faramand: By early identification of risk factors, we can design clinical trials aimed at mitigating toxicity. We and others have shown that patients develop severe life-threatening toxicities despite earlier and more frequent use of corticosteroids and tocilizumab than was used in the pivotal ZUMA-1 trial. Therefore, novel approaches are needed that balance the benefit of reducing toxicity with the potential risk for impacting efficacy.
Q: What are some of the mitigation strategies a clinician should consider?
Faramand: There are several approaches to mitigating toxicity that are currently being investigated in clinical trials. The cytokine GM-CSF has recently been associated with the development of CRS. An ongoing clinical trial is evaluating the combination of lenziluzimab, a humanized monoclonal antibody that targets GM-CSF, with axi-cel in patients with relapsed or refractory LBCL is (NCT04314843). Similarly, IL-1 secreted by macrophages or monocytes has been shown to play a key role in CRS. A phase 2 clinical trial is currently accruing patients to evaluate the efficacy of anakinra, an IL-1 receptor antagonist, in reducing severe CRS and neurotoxicity in patients with LBCL treated with axi-cel (NCT 04150913).
Q: Do you consult professional guidelines on the topic during your decision-making process?
Faramand: Our institutional guidelines are based on the most recent American Society for Transplantation and Cellular Therapy consensus grading guidelines and the CARTOX working group recommendations. Because this is a rapidly evolving field, new evidence and studies are incorporated into our best practices and discussed during a weekly tumor board focused on patients treated with CAR-T and other cellular therapies.
Q: Are there certain red flags clinicians should keep in mind when evaluating patients for treatment-related toxicities?
Faramand: Because cytokine analysis is currently only available in a research setting, clinicians will need to rely on clinical factors. Regarding red flags, those include factors described in a recent report from the U.S. Lymphoma CAR T consortium. Patients with Eastern Cooperative Oncology Group grade 2 to 4 performance status and those with elevated bilirubin had more severe CRS, whereas those with depressed left ventricular ejection fraction less than 50% and bulky tumors greater than 10 cm were more likely to have severe neurotoxicity.
Q: Is there anything else you want clinicians to know about the need for patient-specific strategies to manage treatment toxicity?
Davila: I encourage all CAR T-cell providers to engage the CAR T-cell community at large with questions and interesting cases. With small numbers of patients treated to date, the best way to advance our knowledge and improve outcomes for patients is if we rapidly share our collective experiences with this exciting technology.
For more information:
Marco L. Davila, MD, PhD, can be reached at marco.davila@moffitt.org.
Rawan G. Faramand, MD, can be reached at rawan.faramand@moffitt.org
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