Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-like Syndrome (IEC-HS) for Chimeric Antigen Receptor T-Cell Therapy (CAR-T) and T-Cell Engager Antibody (TCE) in Myeloma and Lymphoma
Authors: Ayoobkhan Fathima Shehnaz , Qureshi Raabia , Rahman Raeef L , Faiz Zohaa , Irfan Sohaib , Iftikhar Ahmad , Ansari Briha , Mushtaq Muhammad Umair , Abdallah Al-Ola , Raza Shahzad , Shaikh Hira , Lutfi Forat , Atrash Shebli , McGuirk Joseph P. , Hashmi Hamza , Anwer Faiz , Ahmed Nausheen 
Published: December 2024

Introduction:
Chimeric Antigen Receptor T-cell therapy (CAR-T) and T-cell engager antibody (TCE) revolutionized relapsed refractory multiple myeloma (RRMM) and non-hodgkin lymphoma (NHL) and acute lymphoblastic leukemia (ALL) treatment. Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) is a potentially fatal rare complication characterized by cytopenia, coagulopathy, transaminasemia, and hyperferritinemia. We aim to analyze the IEC-HS incidence, patterns, and outcomes in RRMM and NHL patients undergoing CAR-T and TCE therapy utilizing the FDA Adverse Event Reporting System (FAERS) database.
Methods:
We conducted a retrospective post-marketing pharmacovigilance inquiry using the FDA Adverse Event Reporting System (FAERS) database and the Medical Dictionary for Regulatory Activities (MEDRA). The database was accessed on 3/1/2024 to examine the adverse effects of CAR-T using the keywords “Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome” : idecabtagene vicleucel (ide-cel), ciltacabtagene autoleucel (cilta-cel), axicabtagene ciloleucel (axi-cel), brexucabtagene autoleucel (brexu-cel), tisagenlecleucel (tisa-cel) and lisocabtagene maraleucel (liso-cel) and TCE (teclistamab, elranatamab, talquetamab, mosunetuzumab, glofitamab, and epcoritamab) since their FDA approval in the US and non-US populations using the R software. Descriptive analysis was used to describe incidence and outcomes. Mortality per product was calculated for patients with IEC-HS.
Results :
A total of 15,852 adverse events were reported in the FAERS, of which there were 263 (1.7%) IEC-HS events. The highest incidence of IEC-HS was observed with tisa-cel (n=92, 34.9%), followed by axi-cel (n=89, 33.8%), brexu-cel (n=22, 8.4%), cilta-cel (n=19, 7.2%), ide-cel (n=15, 5.7%), liso-cel (n=11, 4.2%), epcoritamab (n=7, 2.6%), mosunetuzumab (n=4, 1.5%), and teclistamab (n=4, 1.5%). Glofitamab, talquetamab, and elranatamab recorded no IEC-HS events and were omitted from further analysis.
There were 116 IEC-HS cases associated with infections, with the highest rates in axicel and tisa-cel (n=39,33.6 %), followed by ide-cel (n=9, 7.7%), brexu-cel (n=7, 6%), cilta-cel (n=4, 3.4%), liso-cel (n=3, 2.5%), and teclistamab (n=1, 0.8%).
Half the cases of IEC-HS had concurrent Cytokine Release Syndrome (CRS)(n=133, 50%). Amongst these, the highest incidence was with tisa-cel (44.4%), followed by axi-cel (30.8%), cilta-cel (8.3%), brexu-cel (7.5%), liso-cel (3.8%) and ide-cel ( 3.8%). Only 1 (0.8%) patient who recieved teclistamab and 1 (0.8%) who received mosunetuzumab experienced IEC-HS. Epcoritamab reported no incidences of IEC-HS with CRS.
IEC-HS with immune effector cell-associated neurotoxicity syndrome (IECHS) and CRSwas present in 61 (23.2%) patients, with the highest incidence in axi-cel recipients (41%), followed by tisa-cel (29.5%), ide-cel (13.1%), brexu-cel (11.5%), liso-cel (1.6%), cilta-cel (1.6%), and teclistamab (1.6%). mosunetuzumab and epcoritamab reported no incidences of IEC-HS with CRS and ICANS. Only 2.7% hadIEC-HS and ICANS without CRS, which was mostly seen with axi-cel (57.1%), followed by brexu-cel (28.6%) and ide-cel (14.3%).
Isolated IEC-HS without CRS or ICANS occurred in 23.6%, mostly in axi-cel recipients (42.3%) followed by tisa-cel (24.2%), cilta-cel (11.3%), epcoritamab (11.3%), liso-cell (8.1%), brexu-cel (4.8%), mosunetuzumab (4.8%), teclistamab (3.2%), and ide-cel (1.6%).
The mortality was high in patients with IEC-HS (58.1%).The IEC-HS-associated mortality was highest in teclistamab recipients(n=3, 75%), followed by axi-cel (n=64, 71.9%), brexu-cel (n=14, 63.6%), ide-cel (n=9, 60%), tisa-cel (n=50, 54.3%), mosunetuzumab (n=2, 50%), cilta-cel (n=8, 42.1%), and liso-cel (n=3, 27.2%). Epcoritamab had no IEC-HS-related deaths.
Conclusion:
IEC-HS is a rare but potentially fatal complication with both CAR-T and TCE for NHL and RRMM. In NHL, the incidence appears higher with tisa-cel, with the highest IEC-HS associated mortality with axi-cel. For RRMM, cilta-cel had the highest incidence of IEC-HS, while associated mortality was highest with teclistamab. No IEC-HS was observed with talquetamab, glofitamab, and elranatamab. However, these therapies were recently approved and not yet widely available, and longer follow-ups will be needed.