Non-Pharmacological Interventions for Neurotoxicity in Hematologic Patients Receiving CAR-T Therapy

A parallel-group, multicenter and randomized controlled clinical trial will be conducted from July 2025 to July 2027. The study will evaluate the effectiveness of two non-pharmacological interventions in reducing neurotoxicity associated with CAR-T cell therapy in adult patients with hematologic cancer.

A total of 100 patients will be enrolled and randomly assigned into three groups using stratified randomization performed by an individual external to the research team.

The intervention will begin at least one month prior to CAR-T cell infusion. Participants will be followed weekly before, during, and for four weeks after therapy. Interventions and evaluations will be carried out in the same hospital where the patient receives treatment, and always by the same multidisciplinary team (hematologists, nurses, nutritionists, physiotherapists).

Primary and secondary outcomes will be assessed at baseline (prior to intervention), during treatment, and post-treatment follow-up. Written informed consent will be obtained from all participants before enrollment.

• Physical activity (Other): Patients assigned to intervention group A will follow a supervised programme of physical activity and exercise at home and during hospitalisation. All patients will follow the same exercise programme, which will be adapted to a basic, intermediate and advanced level to suit the patients' physical condition. The loads, intensity and number of sets will be adapted to each level. Aerobic exercise will consist of walking and/or cycling at an intensity of between two and five on the Borg perceived exertion (RPE) scale. Resistance exercise will consist of one session focusing on the trunk and upper limbs, and another on the lower limbs. Both sessions will include seven exercises, performed at an intensity of between three and four on the Borg RPE scale.
• Physical activity and nutrition (Other): The intervention integrates a structured physical activity programme with individualized nutritional recommendations based on the Mediterranean diet. Macronutrient distribution was 50-55% carbohydrates, 30-35% fats, and 10-15% proteins. The protocol emphasized the intake of vegetables (≥2 servings/day, 200 g each), fruits (1-2 servings/day, 150 g each), legumes (≥3 servings/week, 150 g cooked), whole grains (1-2 servings/meal, 40-60 g), and low-fat dairy products (1-2 servings/day; 200 ml milk or 125 g yoghurt). Lean meats were prescribed at 3-4 servings/week (100-125 g each), fish and seafood at 4 servings/week (150 g each), nuts at 3-7 servings/week (30 g each), and olive oil as the principal fat source (≤4 tbsp/day). Micronutrients and bioactive compounds from these foods, including antioxidants, polyphenols, and essential fatty acids, were recognized as pivotal for modulating protective mechanisms and mitigating toxicological effects.

Primary outcomes

• Incidence and severity of neurotoxicity as assessed by American Society for Transplantation and Cellular Therapy (ASCT) Immune Effector Cell-Associated Encephalopathy (ICE) consensus grading system [At baseline and from the infusion of treatment until 15 days after CAR-T therapy.]: Patients will undergo a standardised neurological evaluation. The American Society for Transplantation and Cellular Therapy (ASCT) classifies immune effector cell-associated encephalopathy (ICE), which grades the associated neurotoxicity from 1 to 4. It consists of five domains: ICE score, decreased level of consciousness, convulsions, motor findings and elevated intracranial pressure or cerebral oedema. The ICE score evaluates five cognitive domains (orientation, object naming, following instructions, writing and attention) with a maximum score of 10 points.

Secondary outcomes

• Functional independence as assessed by the Lawton and Brody Instrumental Activities of Daily Living (IADL) scale [At baseline and from the infusion of treatment until 15 days after CAR-T therapy.]: Functional capacity will be assessed using the Lawton and Brody Instrumental Activities of Daily Living (IADL) scale . This instrument evaluates the patient's ability to perform eight instrumental activities essential for independent living (e.g., using the telephone, shopping, preparing meals, housekeeping, laundry, transportation, medication management, and financial management). Each item is scored as 0 (dependent) or 1 (independent), yielding a total score ranging from 0 (total dependence) to 8 (complete independence). Higher scores indicate greater independence and better functional status.
• Physical activity level as assessed by the International Physical Activity Questionnaire (IPAQ) [At baseline and from the infusion of treatment until 15 days after CAR-T therapy.]: Physical activity will be quantified using the International Physical Activity Questionnaire (IPAQ). The instrument comprises seven items and provides information on the time spent walking, performing moderate-intensity activities, vigorous-intensity activities, and sedentary behaviour during the last seven days. The results are expressed in metabolic equivalent task minutes per week (MET-min/week) and categorised into three levels of physical activity: * Low: no or insufficient activity. * Moderate: ≥3 days of vigorous activity (20 minutes/day), ≥5 days of moderate activity or walking (30 minutes/day), or a combination reaching ≥600 MET-min/week. * High: vigorous activity on ≥3 days achieving ≥1,500 MET-min/week, or 7 days of any combination reaching ≥3,000 MET-min/week. This classification allows the identification of patients at risk of inactivity and facilitates monitoring of changes across the intervention.
• Nutritional status as assessed by the Patient-Generated Subjective Global Assessment (PG-SGA) [At baseline and from the infusion of treatment until 15 days after CAR-T therapy.]: Nutritional status will be evaluated using the Patient-Generated Subjective Global Assessment (PG-SGA), a tool that has been validated for the purpose of nutritional screening in oncohematology. The PG-SGA combines patient-reported data and clinician assessment, including weight changes, dietary intake, nutrition impact symptoms, functional capacity, and physical examination findings. Patients are categorised into three groups: well-nourished, moderately malnourished/at risk of malnutrition, or severely malnourished. The instrument facilitates the identification of patients requiring nutritional interventions, thereby providing a comprehensive overview of nutritional risk within the study population.
• Quality of life as assessed by the Short Form 12 (SF-12) [At baseline and from the infusion of treatment until 15 days after CAR-T therapy.]: Quality of life will be assessed using the Short Form 12 (SF-12) health survey. The SF-12 evaluates eight health domains, which are aggregated into two summary scores: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). Each domain is scored according to the SF-12 scoring algorithm, resulting in standardized scores ranging from 0 to 100, with higher scores indicating better health-related quality of life.
• Adherence to interventions [At baseline and from the infusion of treatment until 15 days after CAR-T therapy.]: The researcher collected attendance records, food records and self-reported activity levels as part of the follow-up of the subjects.

Other outcomes

• Length of initial hospital stay [From the infusion of treatment until 15 days after CAR-T therapy.]: Duration of the initial hospitalisation following CAR-T infusion will be documented from the day of admission until discharge (days).
• Number of hospital readmissions [From the infusion of treatment until 15 days after CAR-T therapy.]: Hospital readmissions related to the intervention will be documented, including cause and date of readmission (number of readmissions per participant).

Sex: All, ages: 18 Years to 80 Years

Inclusion Criteria:

* Male and female patients, aged 18 to 80 years.
* Diagnosed with a hematological condition.
* Initiating antineoplastic treatment with CAR-T cell therapy.

Exclusion Criteria:

* Presence of language barriers or physical and/or cognitive impairments that hinder the understanding of the interventions or prevent proper completion of the assessment tools used in the study.
* Pre-existing neurological or psychiatric comorbidities that may interfere with the evaluation of neurotoxic effects of the hematologic treatment.
* Concomitant treatment with additional neurotoxic drugs not related to the study protocol.
* History of abusive consumption of neurotoxic substances.

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• Marina Hernandez Aliaga, RN, MSc, PhD(c), Principal investigator, Instituto de Investigacion Sanitaria INCLIVA