Introduction
Chimeric antigen receptor T-cell (CAR-T) therapy is an immunotherapy that modifies T-cells to target and eliminate cancer cells and is fast becoming a standard of care for some relapsed or refractory haematological malignancies.1 Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are common side-effects of CAR-T.2 ICANS has been described in as high as over 60% of patients depending on a CAR-T product. The most commonly reported consequence is encephalopathy, which can range from mild cognitive and neurological deficits to obtundation, stupor and even coma.1 The onset tends to vary from days to weeks post infusion, with limited research available on neurocognitive recovery trajectory.3 Although the literature has documented a diverse range of clinical features of ICANS, the syndrome has not been holistically characterised.4
This paper describes a protocol of an Australian prospective longitudinal study of adult patients in the haematology service undergoing CAR-T therapy. The aim is to investigate neurological, cognitive, psychiatric and psychosocial outcomes of the treatment, with an emphasis on characterisation of acute neurocognitive features of ICANS. The study will determine a set of cognitive and neurological instruments necessary to identify and monitor the syndrome acutely and investigate predictors of differential outcomes post infusion. Recovery is examined from an acute, subacute and long-term perspective. This paper outlines the rationale, design and methodology of the research project. The protocol includes clinical and paraclinical tools to help guide the overall management of CAR-T patients.
Clinical features of ICANS
Accurate recognition of ICANS is essential for timely intervention and medical management. Description of clinical presentation varies across studies and can include focal weakness, apraxia, tremor, disturbance of speech and language, impaired attention, memory dysfunction, seizures, hallucinations, behaviour disturbance and emotional lability.5 There has been, however, little consensus regarding a syndrome underpinning these symptoms, which complicates early detection, severity classification and our understanding of recovery. Neurotoxicity is typically treated with corticosteroids, which have the drawback of potentially reducing efficacy of CAR-T cells.3 Understanding the syndrome evolution could help optimise dosage and duration of corticosteroid administration, subsequently improving therapy outcomes.
The commonly adopted measure of ICANS is the immune effector cell-associated encephalopathy (ICE) score.6 The instrument comprises brief items on orientation, attention, handwriting, simple naming and ability to follow simple commands. Severity of ICANS is determined according to the ICE score out of 10 and patients’ level of consciousness, motor function, evidence of seizures or elevated intracranial pressure.1 3 Herr et al,7 however, described a series of patients in whom neurocognitive symptoms predated decrease in the ICE score. Thus, this approach might adequately recognise early signs of mild impairment or capture recovery to complete resolution. Understanding syndromology of neurotoxicity is the first step in the development of new diagnostic instruments and evidence-based management strategies.
Baseline significance
One of the key challenges in understanding CAR-T-related neurotoxicity is distinguishing new symptoms from pre-existing dysfunction. Both disease itself and cancer treatments are commonly associated with neurological and cognitive presentation. Patients become eligible for CAR-T if their cancer is refractory to or has progressed following prior lines of systemic therapy or stem cell transplantation, with many previously exposed to central nervous system (CNS) penetrating agents. Schroyen et al’s8 systematic review demonstrated high prevalence of chemotherapy-induced leucoencephalopathy in patients with cancer, persisting for years following active treatment. Subjective cognitive complaints are prevalent in the oncology population, with physical and psychological factors (eg, poor sleep, fatigue, pain, anxiety and depression) commonly contributing to disruption in cognition. Thus, to adequately characterise ICANS, it is necessary to evaluate baseline cognitive, psychological and neurological status in patients pre-CAR-T.
Recovery trajectory
Although ICANS is understood as an acute event typically resolving within several weeks, persisting symptoms have been reported. Research investigating neurocognitive recovery has been limited.3 Maillet et al9 examined 27 adult patients with relapsed B-cell lymphoma prior to CAR-T and 6–12 months post infusion. Forty-four per cent of their cohort experienced acute neurotoxicity. The authors found no difference in participants’ neurocognitive status at review compared with baseline and a reduction in self-reported cognitive concerns, suggesting that ICANS had resolved. While these findings are consistent with the hypothesised acute nature of neurotoxicity, a large proportion of the cohort was excluded from follow-up due to disease progression. It is not clear if these patients followed the same trajectory. A wide follow-up interval also limits conclusions regarding ICANS duration.
Wang et al10 conducted a cross-sectional study of patient-reported concerns in 60 individuals in the first year post-CAR-T (28 were included at <30 days, 13 at 30–90 days and 19 at >90 days post infusion). Commonly reported symptoms included pain, fatigue, sleep disturbance, drowsiness, lack of energy, malaise, weakness, headache and difficulty concentrating. Those who experienced grade 2–4 CRS and/or ICANS had greater reports of physical symptoms, sadness, irritability, difficulty speaking and interference with enjoyment of life >30 days post-CAR-T. The authors did not exclude patients with disease progression or have information on symptom profiles prior to infusion. Thus, distinguishing CAR-T-related contribution from possible effects of disease and other treatment is difficult. These findings provide valuable insight into subjective experience of CAR-T patients. Self-report questionnaires could be used to screen for patients who require clinical consultation and subsequent intervention.
Risk of neurotoxicity
Identifying patients at risk of neurotoxicity is paramount for adequate medical management pre-CAR-T and post-CAR-T. Established risk factors for developing ICANS include older age, active CNS disease, CAR-T cell dose and product (eg, higher incidence has been reported following axicabtagene ciloleucel), early onset of CRS and high disease burden.11 12 The literature has suggested that serum markers, such as procalcitonin, ferritin, interleukin 6, C reactive protein and lactate dehydrogenase also might predict development of ICANS; however, the evidence is mixed.12 There are no known cognitive markers predictive of development or severity of neurotoxicity. Identifying new risk factors and prodrome markers of ICANS would help establish uniform guidelines for medical care and implementing preventative strategies for those at high risk.13
Project aims
The proposed research aims to investigate the neurocognitive, psychiatric and psychosocial outcomes of CAR-T therapy. By establishing a comprehensive neuropsychological and neurological baseline pretreatment, we will define acute neurocognitive features specific to ICANS and severe CRS. Characterisation of the baseline cognitive status will extend beyond psychometric investigation to evaluating semiology of the cognitive complaint. The project will examine early signs associated with neurotoxicity, as well as define a set of instruments necessary to detect and monitor ICANS. Neuropsychological examinations will be completed by a clinical neuropsychologist, who will distinguish primary cognitive impairment underpinned by CAR-T-related processes from secondary cognitive dysfunction resulting from psychopathology, poor sleep, fatigue or pain. The study will also investigate predictive factors for developing neurotoxicity to facilitate close monitoring and preventative management of patients who are at high risk. Finally, both acute and long-term recovery will be examined post-CAR-T from a neurological, cognitive and psychosocial perspective. It is hoped that the research will contribute to optimising the overall management of CAR-T patients and improve recognition and referral pathways for neurocognitive dysfunction in this cohort.