Anakinra prophylaxis did not significantly decrease the incidence or severity of CRS or ICANS in patients with LBCL treated with liso-cel.

Using the interleukin-1 receptor antagonist anakinra as prophylaxis for cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) in patients with large B-cell lymphoma (LBCL) receiving lisocatagene autoleucel (liso-cel; Breyanzi) did not significantly reduce the incidence or severity of these toxicities, according to findings from a phase 2 trial (NCT04359784) presented at the 2025 Tandem Meeting.

Despite being well-tolerated, anakinra did not meet the primary end point of lowering CRS rates in patients with LBCL treated with liso-cel.

Further, while intravenous (IV) administration of anakinra appeared to shorten ICANS duration, it did not prevent toxicity progression and was associated with lower complete response (CR) rates.

“We observed that prophylactic anakinra, including IV dosing with up-titration, was feasible and safe. However, our primary end point of reducing any-grade CRS to 15% was not met. This end point was based on a benchmark from a clinical trial, where conditions may not exactly match real-world settings. In fact, in our non-trial patient cohort receiving liso-cel alone, we observed a CRS rate of 63% compared with 40% in the TRANSCEND study [NCT02631044],” Emily Liang, MD, Fred Hutch Cancer Center, said in an oral presentation of the data during the meeting.

The phase 2 trial enrolled 25 patients with LBCL receiving liso-cel. Patients were given anakinra either subcutaneously (SC; n = 15) or via IV infusion (n = 10) at 200 mg daily from day 0 through day +13 post-infusion. In the IV cohort, step-up dosing was allowed in cases of worsening CRS or ICANS:

1. 8 mg/kg/day IV in 3 divided doses
2. 1 mg/kg/hour continuous infusion for 72 hours

Patients were monitored for CRS and ICANS using ASTCT criteria. The primary end point of the study was a reduction in CRS incidence, with a goal of lowering rates from the 40% observed in the TRANSCEND study to 15%. Secondary end points consisted of ICANS severity, hospitalization rates, steroid use, and overall response rates. In addition, the study retrospectively compared outcomes to 72 patients who had received liso-cel alone at the same institution.

A total of 32 patients were screened, and 25 received liso-cel with anakinra prophylaxis. Baseline disease burden, histologic subtypes, and pre-treatment inflammatory markers were comparable between the anakinra and control groups.

All patients completed the planned anakinra regimen without dose interruptions or adverse events attributable to anakinra. Three infections were reported, including 2 mild Clostridium difficile infections in the SC cohort and 1 cytomegalovirus reactivation in the IV cohort.

Key Findings

All patients completed the planned anakinra regimen without dose interruptions or adverse events attributable to anakinra. Three infections were reported, including 2 mild Clostridium difficile infections in the SC cohort and 1 cytomegalovirus reactivation in the IV cohort.

CRS occurred in 68% of patients (n = 17) who received anakinra (SC: 53%; IV: 90%), compared with 63% in the retrospective liso-cel alone cohort (n = 47). ICANS was observed in 36% of the patients treated with anakinra (n = 9) vs 34% in the control group (n = 25%). Rates of severe CRS deemed grade 2 or higher and grade 3 or higher ICANS were similar across groups.

“Of note, no patients who received IV and anakinra developed grade 3 or higher ICANS, despite having the highest rate of CRS at 90%, though we acknowledge the small numbers in this group,” said Liang.

IV dosing was associated with lower ICANS severity and shorter duration at a median of 2 days vs 5 days in controls. However, step-up dosing did not prevent CRS progression from grade 1 to grade 2 in patients requiring escalation.

A total of 8 patients developed CRS. Two patients required up-titration to step-up dose number 1 only, and 5 patients required up-titration to step-up dose number 2. For all cases of CRS, up-titration to step-up dose number 2 did not prevent progression from grade 1 to grade 2.

While the need for tocilizumab and steroids was similar across groups, anakinra-treated patients required lower cumulative dexamethasone doses (10 vs 27) and shorter steroid courses at a median of 3 days (IQR, 2-5.5 days) vs 6 days (IQR 3-11 days) with liso-cel alone. Nine patients in the liso-cel plus SC or IV anakinra arm required tocilizumab vs 22 patients in the liso-cel only arm.

In addition, anakinra was linked to lower CR rates. Overall response rates (ORR) were 74% in the anakinra cohort vs 80% in the liso-cel alone group, and CR rates were 42% in anakinra-treated patients vs 51% in the control group. In the IV cohort, CR rates were lowest at just 38%.

“Our primary end point of any grade CRS reduction to 15% was not met. However, our end point was based on a benchmark from a clinical trial where conditions may not exactly match real-world conditions. In fact, in our non-trial patient cohort of liso-cel only, we observed a CRS rate of 63% compared with 40% in the TRANSCEND study,” added Liang.

Implications and Next Steps

While anakinra prophylaxis was well-tolerated and did not lead to treatment-related adverse events, it failed to reduce CRS or ICANS incidence. The finding that IV anakinra was associated with lower CR rates raises concerns about its potential impact on CAR T-cell function and persistence.

Researchers are now focusing on correlative studies to understand anakinra’s effects on CAR T-cell kinetics and inflammatory pathways. These findings highlight the need for alternative strategies to mitigate CAR T-cell toxicities, particularly for high-risk patients. Future research will also explore other immune-modulating agents and refined patient selection criteria for toxicity prevention.

“Further studies are needed to assess whether there might be greater benefit of prophylactic anakinra in patients with a higher risk of toxicities,” concluded Liang.

Reference

Liang E, Basom R, Hirayama A, et al. Phase 2 trial of SC versus IV anakinra to prevent CRS and neurotoxicity in LBCL patients receiving lisocabtagene maraleucel: final analysis and comparison to historical control. Presented at: 2025 Transplantation & Cellular Therapy Meetings; February 12-15, 2025; Honolulu, HI. Abstract 17.