High-Dose Anakinra Shows Promise in Treating CRS/ICANS Post CAR T-Cell Therapy

Significant toxicities, including cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS), continue to be associated with chimeric antigen receptor-engineered (CAR) T-cell therapy. Because of this, clinical trial investigators are exploring new treatment options.

In a retrospective study, patients with B-cell or plasma cell malignancies were treated across 9 institutions with the recombinant interleukin-1 receptor antagonist, anakinra (Kineret). Within the study, patients were administered either a high-dose (8mg/kg/day) or low-dose (100-200mg/day) regimen to evaluate the efficacy and safety of anakinra.

According to one of the study authors, Nicolas Gazeau, MD, this agent has shown potential in this patient population after CAR T cell therapies, including tocilizumab (Actemra) and corticosteroids, fail to treat patients with refractory CRS and/or ICANS.

Findings revealed that after failure of CAR T-cell therapy, early administration of high-dose anakinra was associated with promising results, including rapid resolution of CRS/ICANS symptoms after use of tocilizumab and/or corticosteroids, a manageable toxicity profile, and a non-relapse mortality rate at day 30 of 0%, while treated with low-dose anakinra ended up dying from infections.

In an interview with Targeted OncologyTM, Gazeau, hematology resident, post-doctoral research fellow at Fred Hutchinson Cancer Research Center, further discusses his analysis of anakinra when administered at 2 different dose regimens for patients with refractory CRS/ICANS after CAR T-cell therapy.

Can you discuss CAR T-cell toxicity and which patients might not be eligible for this form of treatment?

The 2 main toxicities with CAR T-cell that we know of CRS. Specifically, toxicities because there are also infections, but as a risk of CRS with the clinical signs are fever and hypotension, hypoxia that we treat with tocilizumab or steroid. Then, there is ICANS, which is the neurotoxicity, which is rarer, but we treat for now with just a steroid. The 2 main toxicities and the fact that we have just steroids right now to treat eye cancer are why we are looking for a number of treatments.

Can you explain the mechanism of action of anakinra? What led to your study of its use in patients with refractory CRS and ICANS after CAR T-cell therapy?

Anakinra is a recombinant human interleukin-1 receptor antagonist that inhibits the pro-inflammatory, interleukin-1 alpha and beta to binds the receptor. It has already been used in in other diseases like rheumatoid arthritis. It also has been proved in first team marine model that is one is an important interleukin involved in the icons NCRs. Anakinra is working to treat, those CRS in the marine model. Now we have some clinical studies showing that anakinra can play a role in the treatment of neurotoxicity and CRS after CAR T-cell therapy.

What were the methods used to conduct your analysis?

It is a retrospective study with 9 different institutions, from US and from Spain. In Seattle, where I am working right now, and Portland, and 7 different centers in Spain. We have 43 patients with severe or refractory CRS, most of them were treated for ICANS. They were all treated by anakinra with different doses. The efficacy of anakinra, depending of the dose of anakinra as a practitioner, chose to add an amount of the toxicity.

What were the findings of the study?

We separated as a group as the quality of participation in 2 different groups. Some patients received low dose-anakinra between 100 mg and 200 mg by day, and some patients received a high-dose around 8 mg/kg. This first showed that there was no difference between the peak of CRS and the peak of ICANS between the 2 groups, from time to first anakinra or even a steroid duration. We showed faster resolution of CRS or ICANS in the high-dose group, and we also showed a lower rate of non-relapse mortality in the high-dose group. The result at the end is anakinra seems to have efficacy on ICANS and CRS after therapy. This efficacy looks more pertinent and more interesting.

What are the implications of your findings? What do they mean for the future of research?

It is an interesting and good result. It's encouraging for patients and treatment for those toxicities because CAR T-cell therapy is a very good and new therapy, and we have to know how to manage such toxicities. We have to keep in mind that it's a retrospective study with 43 patients.

We can keep in mind that in a clinical point of view, if we have a patient with refractory ICANS of CRS with a lot of steroids, we can think about anakinra as a treatment. If we use anakinra in the clinic, it is probably more relevant to use it with a high dose. We have to wait for sure to get the FDA approved for the treatment, with a prospective study.

What other research do you think will be important for patients with refractory CRS and ICANS in the near future?

We need prospective students with a control group to prove if our patients have the benefits of this treatment. We have to think more about the CAR T-cell construct to keep the good efficacy of CAR T-cell and try to avoid the side effects. We have to find another way to manage these toxicities. There is tocilizumab and now, maybe anakinra. There are also molecules that can could be interesting. We have to proceed with that for sure.