Immune Effector Cell Associated Neurotoxicity Syndrome

The aim of this study is to determine the effectiveness of DCog Short, a self-reporting, iPad-based application tool, in assessing neurotoxicity in participants undergoing CAR-T cell therapy.

The proposed multimodal telerehabilitation model allows a rehabilitation therapy team to set up individualized rehabilitation plans using a web-based care management portal and monitor patient progress online. Patients at home follow a safe and effective personalized exercise and nutrition plan guided by interactive touch-screen technology combined with behavioral counseling, social support, and interactive education and empowerment. The design of the telerehabilitation system is based on the cloud-based Internet-of-Things architecture allowing real-time monitoring of cardiovascular parameters and exercise performance. The patient's level of exertion during exercise is automatically identified by a validated AI-driven algorithm supporting exercise safety and efficacy. The ultimate goal of this pilot feasibility project is to establish the extent of the impact of the proposed patient-centered cancer telerehabilitation model on disease-specific quality of life, and functional and symptom outcomes and to obtain sufficient evidence for a definitive randomized clinical trial evaluating this approach in a multi-center study.

Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS) is a common and serious neurological complication associated with the use of CAR-T cells. The mechanisms involved are still poorly understood but studies suggest that inflammation during treatment leads to an increase in the permeability of the barrier between the brain and the blood vessels and the emission of extracellular vesicles (EVs) circulating between the brain and the blood vessels. EVs are biological particles that play an important role in cellular communication and the modulation of several physiological processes. The VESICANS study aims to characterize the EVs released before and during CAR-T cells treatment and upon the occurrence of ICANS, using flow cytometry, electron microscopy, Nanoparticle Tracking Analysis associated with MRI assessment of the barrier between the brain and blood. This study will ultimately contribute to facilitating the prevention and treatment of this toxicity which affects the prognosis of patients.

Objectives: The primary objective of this study will be to evaluate the impact of pre-emptive use of anakinra on the rate of severe cytokine release syndrome (CRS) following CD19-directed chimeric antigen receptor (CAR) T-cell therapy for B-acute lymphoblastic leukemia (B-ALL) in children and young adults. Patient Population: Children and young adults \<25 years of age undergoing CAR T-cell therapy for B-ALL with bone marrow disease burden of ≥5% involvement or detectable peripheral blasts within 2 weeks of the initiation of lymphodepleting chemotherapy. Study Design: This is a pilot single arm study. The investigators will inquire into the efficacy and safety of using anakinra pre-emptively to reduce the rate of severe CRS in patients with \>/=5% bone marrow blasts or lymphoblasts in the peripheral blood. Treatment Plan: This is a single arm unblinded study in which patients will receive anakinra, 2.5 mg/kg (max 100mg), IV every 12 hours starting at the onset of persistent fever (fever \>38.5⁰ C x 2 occurrences separated by at least 4 hours in a 24 hour period). If there is persistence or progression of CRS, anakinra frequency will be increased to 2.5mg/kg IV (max 100mg), every 6 hours. Anakinra will be continued until 48 hours after resolution of CRS and ICANS, and at least 7 days post-CAR T infusion. If dose and frequency of anakinra is increased, the increased dose of anakinra will be continued until 48 hours after resolution of CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) and at least 7 days post-CAR T infusion. For CRS worsening beyond dose escalation of anakinra, CRS will be managed as per standard of care management. Participants will be followed for 12 months following enrollment in the study and disease evaluations will be performed as per routine clinical care following CAR T-cell therapy.

CAR T-cell therapy is a promising innovative therapy for hematological malignancies. Immune effectors cells-associated neurotoxicity syndrome (ICANS) is a significant complication of CAR therapy. The goal of this study is to understand what brain mechanisms become disrupted when patients experience ICANS. The study will test the hypothesis that cerebrospinal fluid catecholamines and multimodal magnetic resonance imaging are affected in this disorder. To test this hypothesis, the study will measure cerebrospinal fluid catecholamines in ICANS patients and evaluate brain magnetic resonance imaging for these participants. This study may contribute to knowledge about brain biomarkers and imaging of ICANS, which will greatly aid in ICANS detection and prevention.