Primary Analysis of a Pilot Study of Prophylactic Anakinra to Mitigate CAR T Cell-Associated Toxicity in Patients with Relapsed or Refractory Large B-Cell Lymphoma

Introduction. Chimeric antigen receptor (CAR) T-cell therapy can result in significant acute toxicity, including grade >3 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). We previously demonstrated that myeloid-like ICANS-associated cells (IACs) expressing high levels of interleukin-1-beta (IL-1B) are enriched within infusion products of relapsed or refractory large B-cell lymphoma (r/r LBCL) patients who develop high grade ICANS following treatment with axicabtagene ciloleucel (axi-cel)(Deng et al., Nat. Med. 2020). Other studies have shown that IL-1B levels increase early after axi-cel infusion, and that anakinra, an IL-1 receptor antagonist, may abrogate CRS and ICANS without negatively impacting CAR T cell function. We conducted a single center, open label, prospective pilot study to determine whether prophylactic anakinra can mitigate CRS and/or ICANS in r/r LBCL patients treated with standard of care axi-cel (NCT04432506).

Methods. Anakinra was administered subcutaneously at a dose of 100 mg daily (N=10) or 100 mg BID (N=10) for 7 days, starting on day 0, 6 hours before axi-cel infusion. A 3+3 design was used for a safety run-in phase within each dose level cohort, and dose limiting toxicity (DLT) was evaluated during the first 30 days after axi-cel infusion. CRS and ICANS were graded as per ASTCT consensus grading system and tumor response was determined according to the 2014 Lugano Classification. The primary endpoint was to assess safety and tolerability of anakinra to prevent CRS and/or ICANS, and secondary endpoint was efficacy. Single-cell RNA sequencing with capture-based cell identification was performed to quantify IACs in the infusion products. To assess the effectiveness of anakinra, an exploratory comparison was also performed to a historical cohort of axi-cel-treated r/r LBCL patients who were matched for baseline tumor burden by total metabolic tumor volume (TMTV).

Results. All 20 patients treated at dose levels 1 and 2 completed the full course of anakinra and were evaluable for safety and efficacy. At baseline, median age was 58 years (range, 26-81 years), 10 (50%) were male, 14 (70%) had an IPI >3, 15 (75%) had LDH levels above upper limit of normal, median TMTV was 31 mL (range, 3-226), median number of prior systemic therapies was 3 (range, 2-8), 12 (60%) patients received bridging therapy, and all patients had refractory disease to prior therapy. At data cut-off, median follow-up was 8 months (95% CI, 2-14 months). There were no DLTs noted in either cohort. Grade 3-4 adverse events (AEs) occurring in >3 patients included neutropenia (65%), thrombocytopenia (45%), anemia (45%), infections (15%) and hypertension (15%). AEs possibly attributed to anakinra included grade 2 nausea (1) and grade 3 diarrhea (1). Five (25%) patients had ongoing grade 3-4 cytopenia at day 30. CRS of any grade, grade 2-4, and grade 3-4 were observed in 95%, 40%, and 5%, respectively. ICANS of any grade and grade 3-4 occurred in 35% and 20%, respectively. Median CRS duration was 5 days and median ICANS duration was 2 days. The overall and complete response (CR) rates were 85% and 65%, respectively, and 6-month PFS rate was 67%.

As compared to the TMTV-matched historical cohort, patients treated with anakinra experienced lower rates of CRS grade 2-4 (40% vs 70%), ICANS of any grade (35% vs 70%), ICANS grade 3-4 (20% vs 50%), a shorter median ICANS duration (2 vs 10 days), and required a lower median dexamethasone cumulative dose (100 vs 195 mg). CRS of any grade, median CRS duration, and overall and CR rates were similar between cohorts and consistent with prior reports (Table). IACs were detected in the infusion product of 9/15 (60%) patients treated with anakinra (mean of 0.56% of cells), of whom 3 (33%) had grade 3-4 ICANS. In a historical cohort not treated with anakinra, IACs were detected in 19/43 (44%) patients (mean of 0.47% of cells), of whom 13 (68%) had grade 3-4 ICANS (Table).

Conclusion. Prophylactic use of anakinra is safe and may mitigate CRS and ICANS in patients with r/r LBCL treated with axi-cel, including those with detectable IACs, without impacting CR rate. Longer follow-up and prospective randomized clinical trials are needed to confirm these findings. Correlative studies are ongoing to further characterize the CAR T products, CAR T expansion in vivo, and serum cytokine profile.

Strati:ALX Oncology: Research Funding; Astrazeneca Acerta: Research Funding; Kite Gilead: Consultancy; TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Hutchinson MediPharma: Consultancy; Sobi: Research Funding; Roche Genentech: Consultancy. Steiner:BMS: Research Funding; Seagen: Research Funding; GSK: Research Funding; Rafael Pharmaceuticals: Research Funding. Ahmed:Chimagen: Consultancy, Research Funding; Seagen: Research Funding; Tessa Therapeutics: Consultancy, Research Funding; Xencor: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Myeloid Therapeutics: Consultancy; Merck: Research Funding. Nastoupil:ADC Therapeutics, BMS, Caribou Biosciences, Epizyme, Genentech/Roche, Gilead/Kite, Genmab, Janssen, MEI, Morphosys, Novartis, Takeda: Honoraria; Genentech/Roche, MEI, Takeda: Other: DSMC; BMS, Caribou Biosciences, Epizyme, Genentech, Gilead/Kite, Genmab, Janssen, IGM Biosciences, Novartis, Takeda: Research Funding. Nair:Incyte Corporation: Honoraria. Hawkins:Bristol Myers Squibb Cell Therapy: Membership on an entity's Board of Directors or advisory committees. Samaniego:TG Therapeutics: Honoraria. Shpall:Navan: Consultancy; Fibroblasts and FibroBiologics: Consultancy; Bayer: Honoraria; axio: Consultancy; Affimed: Other: License agreement; adaptimmune: Consultancy; Takeda: Patents & Royalties; NY blood center: Consultancy. Kebriaei:Amgen: Research Funding; Ziopharm: Research Funding; Pfizer: Consultancy; Kite: Consultancy; Jazz: Consultancy. Flowers:TG Therapeutics: Research Funding; Xencor: Research Funding; V Foundation, Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Takeda: Research Funding; 4D: Research Funding; NPower: Current holder of stock options in a privately-held company; Adaptimmune: Research Funding; Amgen: Research Funding; Cellectis: Research Funding; Karyopharm: Consultancy; Guardant: Research Funding; Janssen Pharmaceutical: Research Funding; Pharmacyclics/Janssen: Consultancy; Genmab: Consultancy; Gilead: Consultancy, Research Funding; Foresight Diagnostics: Consultancy, Current holder of stock options in a privately-held company; Genentech/Roche: Consultancy, Research Funding; Spectrum: Consultancy; Allogene: Research Funding; Acerta: Research Funding; EMD: Research Funding; SeaGen: Consultancy; Sanofi: Research Funding; National Cancer Institute: Research Funding; Pfizer: Research Funding; Iovance: Research Funding; Kite: Research Funding; Eastern Cooperative Oncology Group: Research Funding; BeiGene: Consultancy; Celgene: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Pharmacyclics: Research Funding; Ziopharm: Research Funding; Morphosys: Research Funding; Burroughs Wellcome Fund: Research Funding; Abbvie: Consultancy, Research Funding; Bayer: Consultancy, Research Funding. Westin:MonteRosa: Consultancy; Novartis: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Merck: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; MorphoSys/Incyte Corporation: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Iksuda: Consultancy; Calithera: Consultancy, Research Funding; Abbvie/GenMab: Consultancy; SeaGen: Consultancy. Neelapu:Merck: Consultancy, Honoraria, Other: Personal fees, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Other: Personal fees, Research Funding; Novartis: Consultancy, Honoraria, Other: Personal fees; Celgene: Consultancy, Honoraria, Other: Personal fees, Research Funding; Incyte: Consultancy, Honoraria, Other: Personal fees; Cell Medica/Kuur: Consultancy, Honoraria, Other: Personal fees; Calibr: Consultancy, Honoraria, Other: Personal fees; Allogene Therapeutics: Consultancy, Honoraria, Other: Personal fees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Personal fees, Research Funding; Kite: Consultancy, Honoraria, Other: Personal fees, Research Funding; Adicet Bio: Consultancy, Honoraria, Other: Personal fees, Research Funding; Aptitude Health: Consultancy, Research Funding; Unum Therapeutics: Consultancy, Honoraria, Other: Personal fees, Research Funding; Bluebird Bio: Consultancy, Honoraria; Medscape: Consultancy, Honoraria; Legend Biotech: Consultancy, Honoraria, Other: Personal fees; Pfizer: Consultancy, Honoraria, Other: Personal fees; Bio Ascend: Consultancy, Honoraria; Poseida: Research Funding; Cellectis: Research Funding; Karus Therapeutics: Research Funding; Acerta: Research Funding; Takeda Pharmaceuticals: Patents & Royalties: related to cell therapy.. Green:KDAc Therapeutics: Current equity holder in private company; Tessa Therapeutics: Honoraria; Monte Rosa Therapeutics: Honoraria; Allogene: Research Funding; Sanofi: Research Funding; Kite/Gilead: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees.

Anakinra is approved for the treatment of RA and CAPS. In this trial it is used experimentally to prevent CRS and ICANS associated with CART