Anakinra for Treatment and Prevention of CAR-T Neurotoxicity: A Systematic Review of Evidence to Inform SIE-GITMO-Sidem Guidelines

Background Patients with aggressive B-cell lymphomas may achieve prolonged survival after treatment with chimeric antigen receptor T-cells (CAR-T). Nevertheless, after CAR-T infusion 22-43% of the patients develop cytokine-mediated neurotoxicity (ICANS) (Meng 2021, Belin 2020). Steroids are commonly used to treat patients who develop ICANS, which, however, is still fatal in 16-27% of overall patients developing neurotoxicity (Dolladille 2021). Moreover, a warning to a higher rate of infections after prolonged exposure to high-dose steroids has been launched. For the above reasons Anakinra, a monoclonal neutralizing antibody against interleukin-1 (IL-1), has been tested in such a clinical scenario.

Aims of the study The present study is aimed at revising the available literature regarding Anakinra use for the prevention or treatment of ICANS in order to support the development of evidence-based recommendations for the CAR-T guideline program started by three national scientific societies, namely SIE, GITMO and SIDEM.

Methods On 1^st April 2022 EMBASE, PubMed and Cohrane Library databases were scanned with standard queries in order to identify overall records (published since Jan 2019) reporting clinical outcomes of CAR-T in adult patients with lymphoma. Out of 730 identified records, those reporting Anakinra use after CAR-T therapy were identified. The search also included studies presented uniquely in abstract form. Case series including less than 5 treated patients were excluded. Response rates were reported in 8 treatments and 3 prophylaxis studies.

Results We collected 15 studies reporting the use of Anakinra in 189 recipients of CAR-T for refectory/relapsed aggressive B-cell lymphomas: 132 patients received off-label Anakinra for severe (grade 3-4) or steroid-refractory ICANS, while 57 patients were enrolled into 3 prospective studies aimed at ICANS prevention. The commercial CAR-T products employed included axi-cel (63/120), brexu-cel (30/120), tisa-cel (37/120), and liso-cel (9/120). Grade 5 ICANS were reported in 4/84 (4.7%) patients treated with Anakinra and amelioration of the neurological status was reported in 46-100% of the patients. Higher response rates were reported for doses higher than 200 mg per day and early mortality declined from 84% to 7% in patients receiving high vs low doses in one study. The rate of ICANS in patients receiving prophylaxis with Anakinra was 14% and only transient grade 3 ICANS developed. As a consequence a significant reduction of the hospital stay from 38 to 24 days was reported in one study comparing two paired cohorts. Several limitations were reckoned in the available evidence including small sample size and huge heterogeneity of patient population and CAR-T products. Moreover different ICANS grading systems were used and cumulative steroid doses were provided only by a few studies. Finally, a high rate of infection-related deaths were reported in this patient population, including viral encephalitis, which deserves a better insight, in particular regarding titration of steroids in patients starting Anakinra.

Conclusions A growing body of evidence has been reporting the outcomes of Anakinra in lymphoma patients who developed ICANS after CAR-T, higher Anakinra doses proving the most satisfactory results. Preliminary studies also tested an early adoption of Anakinra for the prevention of severe ICANS. The above systematic review confirms the need of randomized clinical trials to assess the effectiveness (grade 5 ICANS, duration of ICANS, steroid cumulative dose) of Anakinra in different patients subgroups, i.e. severe ICANS, steroid-refractory ICANS, ICANS with concurrent CRS, patients at high risk of developing ICANS (Rubin 2020).

Marchetti:GILEAD srl: Honoraria. Chiappella:Celgene-Bristol Myers Squibb: Other: lecture fee, advisory board; Gilead Sciences: Other: lecture fee, advisory board; Clinigen: Other: lecture fee, advisory board; Takeda: Other: lecture fee, advisory board; Roche: Other: lecture fee, advisory board; Janssen-Cilag: Other: lecture fee, advisory board; Incyte: Other: lecture fee; SecuraBIO: Other: advisory board; Ideogen: Other: advisory board; Novartis: Other: lecture fee; Astrazeneca: Other: lecture fee. Ferreri:BMS: Research Funding; Beigene: Research Funding; Pharmacyclics: Research Funding; Hutchison Medipharma: Research Funding; Amgen: Research Funding; Genmab: Research Funding; ADC Therapeutics: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; PletixaPharm: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Adienne: Speakers Bureau; Pfizer: Research Funding; Ospedale San Raffaele srl: Patents & Royalties: NGR-hTNAF/RCHOP in relapsed/refractory PCNSL; SNGR-hTNF in brain tumours. Zinzani:EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Secura Bio: Membership on an entity's Board of Directors or advisory committees.

Anakinra is licensed for rheumatoid arthritis, while its off-label use for ICANS is discussed in the abstract