Siltuximab Resolves CRS/ICANS After CAR T-cell Therapy for Hematologic Malignancies

Mayur Narkhede, MD

Siltuximab (Sylvant) induced complete resolution of CAR T-cell therapy–induced cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) in patients with hematologic malignancies, according to data presented at the 2023 Transplantation and Cellular Therapy Meetings.

The results come from an interim analysis of an ongoing, single-center phase 2 trial (NCT04975555) of 6 total patients with diffuse large B-cell lymphoma (DLBCL; n = 3), follicular lymphoma (n = 1), and multiple myeloma (n = 2). Siltuximab elicited a complete resolution of CRS at 14 days in 5 of 6 patients (83%) with a median time to complete response of 1 hour (range, 1-3). Of the 5 responding patients, 2 required a second dose of siltuximab at 12 hours.

Additionally, among 4 patients who had ICANS, 3 (75%) had a complete resolution at 28 days, with a median time to complete response of 45 hours (range, 9-65). All CRS/ICANS events were grade 1 or 2 prior to siltuximab administration. No patients experience worsening of CRS after onset.

“The patient population in our 6-patient interim analysis was of an extremely high-risk phenotype. The majority of them had high c-reactive protein, ferritin, and lactate dehydrogenase pre-lymphodepletion. These patients are supposed to have higher-grade CRS or ICANS, which we did not observe this in our study, other than 1 patient. [Siltuximab] looks promising, and we will present more data [in the future],” lead study author Mayur Narkhede, MD, said in an interview with OncLive^®.

Narkhede, an assistant professor at the University of Alabama, Birmingham (UAB) in the Division of Hematology/Oncology at UAB Medicine, discussed the early findings for the use of siltuximab to manage CRS and ICANS in patients following CAR T-cell therapy and expanded on the next steps for investigating this agent during the phase 2 trial and beyond.

OncLive^®: What was the rationale for investigating siltuximab for CRS and ICANS following CAR T-cell therapy?

Narkhede: CRS and ICANS are the 2 most unique adverse effects [AEs] that we see with CAR T-cell therapy. Currently, tocilizumab (Actemra), an interleukin-6 [IL-6] receptor blocker, is used to mitigate severity [of CRS]. However, preclinical studies showed that there may be a paradoxical increase in the IL-6 levels after you block the receptors, leading to the worsening of either CRS or ICANS.

In our study, we used siltuximab, which directly binds to IL-6 and neutralizes it. We hypothesized that the CRS and ICANS would be less severe than one would normally see with the use of tocilizumab.

What was the patient population enrolled and evaluated in this study?

This was a single-center phase 2 study. We decided to enroll any patient who was supposed to get a commercial CAR T-cell therapy. Patients were screened when they planned to get the CAR T-cell therapy and [subsequently] enrolled when they developed their first CRS or ICANS.

In this interim analysis, we had 6 patients enrolled, of which 3 had a diagnosis DLBCL, 1 had follicular lymphoma, and 2 had multiple myeloma.

What were some of the key findings from this interim analysis?

The study [is designed to include] 20 [total] patients. The study was meant to be conducted in 2 phases. [In] the first phase, after 7 patients enrolled, we assessed for futility. If we saw that 3 or fewer patients did not have a complete resolution of CRS with siltuximab and required rescue tocilizumab, then the trial would be futile.

However, what we showed the results from the first 6 patients, of which 5 had a complete resolution of their CRS, with a median time of resolution of 1 hour from infusion completion. Two patients needed 2 doses of siltuximab to achieve that.

Based on these results, how might this agent potentially affect quality of life [QOL] for patients who receive CAR T-cell therapy?

We are evaluating neurocognitive function, as the whole rationale for using siltuximab is to see if it decreases the severity of both CRS and ICANS. We are trying to see if there is an impact on neurocognitive functioning of patients.

What we're using is a National Institutes of Health neurocognitive toolbox, which is an iPad-based questionnaire that patients [complete] before and after CAR T-cell infusion. These [QOL evaluations] also include patients that were supposed to get CAR T-cell therapy and do not have CRS or ICANS, so we have a comparator arm, as well.

When we have more patients, we hope to provide updates with the results of this [QOL] testing. We hope that siltuximab has some better effects on the neurocognitive functioning.

What have you observed about the safety profile of siltuximab?

It's very hard to assess for AEs that are related to siltuximab in the setting of receiving CAR T-cell therapy. However, we did not observe any infusion-related reactions. There were no other new or surprising AEs noted in these patients, understanding that most of these patients are recuperating from lymphodepleting chemotherapy. There was nothing really surprising [regarding safety].

Can you expand on the next steps for investigating siltuximab in this setting? What could be the potential clinical implications for this research?

The first step is always completion of the trial, getting and publishing more data. [The interim analysis] serves as a good starting point. Earlier, we didn't have any published data for the use of siltuximab. However, we now do have some data, and we will provide more data.

Although I’m not sure about this, the future direction [of this research could evaluate whether] siltuximab reduces the severity [of CRS or ICANS], and the only way to measure that is to compare it with tocilizumab, and that could be the future implication of this research.

Based on the data reported thus far, what is your stance on the role of siltuximab for patients who may experience CRS or ICANS following CAR T-cell therapy?

Now we have some preliminary prospective data for the use of siltuximab in the treatment of CRS and ICANS with promising response rates. However, I would still be very cautious in using it before tocilizumab, given that our experience is very good with tocilizumab. This is something in the future where we may consider replacing tocilizumab, but not at this time point.

Reference

Narkhede M, Di Stasi A, Bal S, et al. Interim analysis of investigator-initiated phase 2 trial of siltuximab in treatment of cytokine release syndrome and immune effector cell associated neurotoxicity related to CAR T-Cell therapy. Presented at: 2023 Transplantation and Cellular Therapy Meetings. February 15-19, 2023; Orlando, FL. Abstract 165.