Treatment with Siltuximab for Short Term Complications after Chimeric Antigen Receptor T-Cell Therapy: A Multicenter Retrospective Analysis
Authors: Sanchez-Pina Jose M. , Silva Pablo , López-Corral Lucía , Chinea Anabelle , Martin Lopez Ana Africa , Martinez-Cibrian Nuria , Hernani Rafael , Noriega Victor , Filaferro Silvia , Balsalobre Pascual , Calbacho Maria , Pérez-Martínez Antonio , Barba Pere , Kwon Mi 
Published: December 2024

Background

CAR-T cell therapy is associated with severe and potentially fatal complications and entails significant resource consumption. The most characteristic and frequent short-term complications include Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). The standard treatment for CRS consists of the use of steroids and anti-interleukin 6 (IL-6). Tocilizumab binds to the IL-6 receptor but can paradoxically increase IL-6 levels, potentially favoring or worsening ICANS. There is increasing evidence supporting the use of siltuximab, a monoclonal antibody that binds directly to IL-6, as an alternative treatment for these complications.

Methods

This GETH-TC multicenter and retrospective study was aimed to review the Spanish experience with siltuximab in patients with several hematological malignancies treated with CAR T-cells. We compared its use in first-line therapy (FLT) for patients (pts) at high risk of developing ICANS with its use in subsequent lines as salvage treatment (ST) for refractory CRS/ICANS. High risk was defined as having active CNS involvement due to the neoplastic disease.

Results

From January 2019 to July 2024, 39 pts were identified at four centers: 10 FLT and 29 ST. Median age was 45.5 years (18-68) vs 55.5 years (21-73) (p=0.2) and females comprised 30% vs 55.2% (p=0.170) respectively. Most frequent diseases were diffuse large B cell lymphoma (DLBCL) (82%) and acute lymphoblastic leukemia (ALL) (5,1%). CAR-T products in the FLT vs ST groups were Axi-Cel 60% vs 79,4%; Tisa-Cel 10% vs 17,2%; Brexu-Cel 10% vs 3,4%; academic products 20% vs 0%.

Comparing FLT vs ST at the time of lymphodepletion, 8 (80%) vs 24 (82.8%) of pts were in progression (p=0.4) and 5 (50%) vs 14 (48.3%) pts had bulky disease (p=0,66). There were no differences in LDH or ferritin baseline levels. 5 (50%) FLT pts presented parenchymal CNS disease, 9 (90%) CSF involvement and both in 4 (40%). 9 (90%) of them also had systemic disease.

All pts presented CRS. Only one patient in each group presented CRS grade 3-4. Median CRS duration was the same in each group (5 days). In terms of neurotoxicity, 5 (50%) pts who received siltuximab in FLT presented ICANS vs. 27 (93.1%) (p=0.002) in ST. Grades 3-4, 1 pts (20%) vs 16 (64%). The were no differences in ICANS duration (6 days vs 5 days).

For FLT pts: 9 (90%) of received 2 doses of 11 mg/kg of siltuximab for the treatment of CRS and 1 (10%) received one dose. Max CRS grade prior to siltuximab administration was grade 1-2 in 8 (80%) and grade 3-4 in 2 (20%). For the ST group, indications for siltuximab administration included steroid and tocilizumab refractory CRS in 8 pts (27,6%) and refractory ICANS in 21 pts (73,4%). All received a single dose of 11 mg/kg. The response rate to siltuximab was similar (6 (60%) vs 19 (65.5%) p=0.75).

None of the FLT pts received tocilizumab, compared to 100% of pts in the second group as first-line treatment for CRS (8 mg/kg); median number of tocilizumab doses was 2. The need for steroid treatment was: 80% in FLT vs. 79.5% in ST (p=0.79), and 50% vs. 62.1% received anakinra (p=0.5).

During admission infections were documented in 3 (30%) vs 13 (44.8%) pts (p=0.41). In FLT group, one pts presented a fatal pseudomonas aeruginosa bacteremia, and 2 pts developed CMV reactivations. In the ST group, there were 3 GPC bacteremia, 1 of pseudomonas bacteremia, 3 CMV reactivations, 1 esophageal CMV disease, and 1 breakthrough fungal infection.

Concerning non-relapse-related mortality, there were no differences (1 (10%) vs 5 (17.2%) p=0.58). 2 patients died from macrophage activation syndrome and 3 from severe ICANS.

Admission duration was similar, 20.5 (10-43) vs 28.5 (11-95) (p=0.13) as was ICU admission rate (5 (50%) vs 16 (55.2%) p=0.77) and duration (7 days (1-21) vs. 6 days (6-52) p=0.87).

Response rate was FLT 90% vs 72% (p=0.25). Median follow up for FLT vs ST was 3,97 months (1,44-17,97) vs 9,83 months (1,21-51,21). Median PFS was 7.1 (0.4-14.62) vs 2.39 (0.31-4.47) (p=0.73) and median OS was not reached for the first group (70% of pts were still alive at last FU) and was 5.87 months (1.49-10.25) for ST (p=0.19).

Conclusions

To our knowledge, this is the first report of siltuximab for CRS including pts with CNS active disease. Siltuximab appeared to be effective and safe for both CRS and ICANS in both settings. These findings highlight the need for further prospective studies to establish optimal role of siltuximab on CAR-T cell therapy.