Background: Hemophagocytic Lymphohisticytosis (HLH) is an underestimated but potentially life-threatening CAR-T cell complication. Among anti-CD19 CAR-T cell recipients, secondary HLH (sHLH) incidence is reported around 3%. Due to its low frequency and the absence of unique diagnostic markers and established criteria, sHLH is often unrecognized, and the treatment is not standardized.

Objectives: This retrospective GoCART Coalition - EBMT registry study, aimed to assess the real-world sHLH incidence and characteristics after CAR-T administration.

Methods: EBMT centres were invited to participate to the study regarding all the patients treated with CAR-T cells from 2014 to 2022. We received data of all the consecutive patients from 21 EBMT centers. We retrieved clinical data from the EBMT registry and developed a specific questionnaire to collect additional information about indication for CAR-T cells, CAR-T cell product and outcomes including sHLH manifestations and treatment.

Results: Among a total of 817 CAR T recipients, the median follow-up was 1.8 years and 2-years Overall Survival and Progression Free Survival were 53.5% and 39.5% respectively. sHLH report was unknown for 14 patients and reported for 803 patients. Among them, 28 patients, (21 with B cell lymphoma and 7 with B-Acute Lymphoblastic Leukemia), experienced sHLH after CAR-T cell administration, with an sHLH incidence of 3.6% (95%CI: 2.5 - 5.1) at 90 days. No event occurred after 90 days. Secondary HLH occurred in 12 patients treated with tisagenlecleucel (42.9%), 10 with axicabtagene ciloleucel (35.7%), 4 with brexucabtagene autoleucel (14.3%), and 2 treated with other products (7.2%). Half of the sHLH patients received at least one Hematopoietic Stem Cell Transplantation before CAR-T (Table 1). sHLH occurred a median of 11 days (range 5-86) after CAR-T administration, and 93% of patients experienced a Cytokine Release Syndrome (34% grade 3-4), which was resolved in 60% of them before HLH onset. High-grade fever was the most prominent feature (n=18, 75% of patients), followed by liver (n=13, 54%), kidney (n=8, 32%), and lung toxicity (n=5, 22%). The median ferritin value was 10723 ng/ml (range 1558-50565). Increased liver enzymes, LDH and triglycerides and impaired coagulation test were also common findings. Eleven patients underwent a bone marrow aspirate, with evidence of hemophagocytosis in 45% of cases. Twenty patients (80%) received a treatment, with steroids and anakinra the most commonly used. The median follow-up post sHLH was 1.9 years. Of the 28 patients 4 died in absence of sHLH resolution at days 1, 27, 69 and 116 post sHLH diagnosis. Nine other patients died after resolution of sHLH: 7 after relapse including 2 within 30 days post resolution; and 2 without relapse within 30 days post sHLH resolution. The overall survival after sHLH was 80.9% at 90 days and 48.1% at 2 years.

Conclusion: Overall, this registry study reported an incidence of 3.6% of secondary HLH at 90 days after CAR-T cell treatment. Patients experienced heterogeneous clinical manifestations, mainly represented by fever and liver involvement. Anakinra and steroids represented the employed treatments and the overall survival was 80.9% at 90 days. These data will allow a better understanding of this poorly identified condition, helping to define better diagnostic criteria and standardized treatments.

REFERENCES: NIL.

Acknowledgements: NIL.

Disclosure of Interests: Matteo Doglio: None declared, Robert D Sandler: None declared, Jacques-Emmanuel Galimard: None declared, Eva Michel: None declared, Peter Dreger: None declared, Paul Chauvet: None declared, Didier Blaise: None declared, Peter Vandenberghe: None declared, Caroline Besley: None declared, Lucía López-Corral: None declared, Carlos Solano: None declared, Friedrich Stolzen: None declared, Fabio Ciceri: None declared, Hermann Einsele: None declared, Emanuele Angelucci: None declared, Alessandro Rambaldi: None declared, Ilaria Cutini: None declared, Krzysztof Kalwak: None declared, Massimo Martino: None declared, Aloysius Ho: None declared, Antonio Perez-Martinez: None declared, Al Schmidt: None declared, Jiri Sramek: None declared, Jana Mihalyova: None declared, Michel Schaap: None declared, Tobias Alexander: None declared, Jurgen Kuball JK is inventor on multiple patents dealing with genetic engineering and shareholder of Gadeta Founders, JK received research support from Miltenyi Biotech, Novartis and Gadeta, Zinaida Peric: None declared, Annalisa Ruggeri: None declared, Raffaella Greco: None declared.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.