Case report: Successful use of emapalumab in adult B-cell acute lymphoblastic leukemia experiencing severe neurotoxicity and hemophagocytic lymphohistiocytosis-like features after CAR-T cell therapy

Beatrice Manghisi ¹ Giulia Cotilli ^1,2 Marilena Fedele ¹ Paola Perfetti ¹ Elisabetta Terruzzi ¹ Luisa Verga ¹ Lorenza Maria Borin ¹ Andrea Carrer ¹ Monica Fumagalli ¹ Maria Beatrice Ferrari ^1,2 Alex Moretti ^2,3 Roberto Rona ⁴ Annalisa Benini ⁴ Beatrice Vergnano ⁴ Giovanni Palumbo ⁵ Alessandra Zincone ⁶ Oscar Maglia ⁷ Chiara Scollo ⁸ Carolina Steidl ⁹ Lorenzo Iovino ¹⁰ Adriana Balduzzi ^2,3 Rocco Piazza ^1,2 Carlo Gambacorti-Passerini ^1,2 Matteo Parma ¹ Andrea Aroldi ^1,2*

• ¹ Hematology Division, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy., Monza, Italy
• ² Department of Medicine and Surgery, University of Milano Bicocca, Monza, Italy
• ³ Pediatric Stem Cell Transplant Unit, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy, Monza, Italy
• ⁴ Department of Emergency and Intensive Care, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy, Monza, Italy
• ⁵ Neuroradiology Department, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy, Monza, Italy
• ⁶ Department of Neurology, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy, Monza, Italy
• ⁷ Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy, Monza, Italy
• ⁸ Transfusion Medicine Unit, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy, Monza, Italy
• ⁹ Lymphoma Unit, Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute, Milan, Italy., Milan, Lombardy, Italy
• ¹⁰ Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States

Chimeric antigen receptor (CAR)-T cell therapy is a powerful adoptive immunotherapy associated with significant toxicity, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). As CAR-T usage expands, hyperinflammatory toxicities resembling hemophagocytic lymphohistiocytosis (HLH) syndrome are increasingly recognized. Immune effector cell-associated HLH-like syndrome (IEC-HS) describes HLH-like symptoms attributable to CAR-T cell therapy, often presenting as CRS resolves. Treatments for IEC-HS are adapted from primary HLH, including corticosteroids, the recombinant human interleukin (IL)-1 receptor antagonist anakinra and the Janus Kinase inhibitor ruxolitinib. Emapalumab, an anti-IFN-γ antibody, is promising but underexplored in adult IEC-HS cases.We report an adult B-cell acute lymphoblastic leukemia (B-ALL) patient treated with brexucabtagene autoleucel (brexu-cel). The patient developed CRS, refractory neurotoxicity, and IEC-HS with worsening multiorgan failure and hyperinflammatory markers. Treatment included tocilizumab, highdose corticosteroids, anakinra, siltuximab, and ruxolitinib. Despite aggressive management, hyperinflammation and neurotoxicity persisted. Emapalumab was initiated on day +11, resulting in normalization of the biochemical parameters and full neurological recovery by day +21. The patient recovered from IEC-HS and underwent allogeneic stem cell transplantation. This case highlights the role of emapalumab in managing refractory IEC-HS and persistent neurotoxicity in adults, underscoring the need for targeted interventions in severe CAR-T complications.