Psychiatric, cognitive, psychosocial, and neurological outcomes of chimeric antigen receptor T-cell therapy: protocol for a prospective study

Background Immune effector cell-associated neurotoxicity syndrome (ICANS) is a common side-effect of chimeric antigen receptor T-cell (CAR-T) therapy, with symptoms ranging from mild to occasionally life-threatening. The psychiatric, cognitive, psychosocial, and neurological sequalae of ICANS are diverse and not well-specified, posing a challenge for diagnosis and management. The recovery trajectory of the syndrome is uncertain. Psychiatric, cognitive, psychosocial, and neurological status is rarely examined in this population pre-therapy, adding a layer of complexity to specifying symptoms pertinent solely to CAR-T treatment. Aims The aim is to investigate psychiatric, cognitive, psychosocial, and neurological outcomes in patients after CAR-T therapy, particularly among those who develop ICANS. The project will establish a comprehensive pre-treatment baseline and will longitudinally monitor for therapy-associated change. Methods A prospective longitudinal study of all adult patients in a single Australian haematology service undergoing CAR-T therapy. Neuropsychological and neurological examinations occur prior to CAR-T, and patients are reviewed during the acute post-treatment period, 28 days, 6 months, and 12 months post-infusion. Data will be sourced from objective psychometric measures, clinical examinations, self-report questionnaires, and accounts of subjective cognitive complaint to capture a broad spectrum of dysfunction and its daily functional impact. Conclusions We present a protocol of a research study that will describe the neurocognitive features specific to ICANS, characterise the underlying syndrome, identify predictors of differential post-infusion outcomes, and contribute to optimising the overall management of CAR-T patients. The protocol will serve as the basis of guidance regarding clinical and paraclinical follow-up of patients undergoing CAR-T cell therapy. ### Competing Interest Statement Ms Kuznetsova reports no disclosures. Dr Oza reports no disclosures. Dr Rosenfeld reports no disclosures. Dr Anderson reports honoraria from AstraZeneca, Janssen, Abbvie, Beigene, Takeda, CSL, Novartis, Kite, Gilead, and Roche. Employee of the Walter and Eliza Hall institute which receives Milestone payments in relation to venetoclax. Dr Sales reports no disclosures. Ms van der Linde reports honoraria from Kite. Dr Roos served on scientific advisory boards, received conference travel support and/or speaker honoraria from Roche, Novartis, Merck and Biogen. Izanne Roos is supported by MS Australia and the Trish Multiple Sclerosis Research Foundation. Ms Roberts reports no disclosures. Ms DAprano reports no disclosures. A/Prof Loi reports honoraria from Otsuka and Lundbeck. She has received research support from the National Health and Medical Research Council and Royal Melbourne Hospital. Dr Dowling reports honoraria and conference support from Kite and Gilead and honoraria from Novartis. Dr Dowling also receives royalties from Abbvie in relation to venetoclax via the Walter and Eliza Hall institute. A/Prof Dickinson reports advisory boards, research funding from Novartis, Kite, BMS and Gilead. Prof Kalincik served on scientific advisory boards for MS International Federation and World Health Organisation, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Roche, Sanofi-Genzyme, Teva, BioCSL and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck. Prof Harrison reports the following disclosures: AbbVie: consultancy, advisory board, Amgen: consultancy, honoraria, advisory board, research funding, Celgene: consultancy, honoraria, advisory board, research funding, CSL Bering: honoraria, GSK: consultancy, research funding, advisory board Janssen Cilag: consultancy, honoraria, advisory board, research funding, Novartis: consultancy, honoraria, advisory board, research funding, Roche/Genetec: consultancy, honoraria, advisory board, Takeda: consultancy, honoraria, advisory board Haemalogix: scientific advisory board, research funding, Sanofi: consultancy/advisory role Terumo: consultancy/advisory role/expert testimony A/Prof Malpas has received conference travel support from Merck, Novartis, and Biogen. He has received research support from the National Health and Medical Research Council, Multiple Sclerosis Australia, The University of Melbourne, The Royal Melbourne Hospital Neuroscience Foundation, and Dementia Australia. ### Funding Statement V.K. received a graduate scholarship from the University of Melbourne. There were no other sources of funding obtained for this research. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of Peter MacCallum Cancer Centre gave ethical approval for this work (21/145). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes