Neurocognitive Assessment in Adults Undergoing CD19 Targeted CAR-T Cell Therapy

Primary outcomes

1. Self-assessed neurocognitive performance

   Time frame: The endpoint wil be evaluated at screening (before starting CAR-T therapy), at 6, 12 and 24 months after CAR-T infusion (from the beginning of the study at least 24 months after CAR-T infusion)

   Self-assessed neurocognitive performance will be evaluated through Functional Assessment of Cancer Therapy - Cognitive questionnaire (FACT-Cog Version 3). The FACT-Cog (Version 3) is a self-report questionnaire developed within the measurement system of FACIT.org (Functional Assessment of Chronic Illness Therapy) to assess perceived cognitive functioning in individuals with cancer. The instrument includes 37 items in total, although the most commonly reported total score is based on 33 scored items. Each item is rated on a 5-point Likert scale (0-4) (0 = not at all; 4 = very much / very often, depending on the item). Total score (33-item scoring): Minimum: 0, Maximum: 132. Score interpretation: higher scores indicate better perceived cognitive functioning, lower scores indicate greater perceived cognitive impairment.

2. Neurocognitive performance evaluation: Cognitive Status - Mini-Mental State Examination (MMSE)

   Time frame: The endpoint wil be evaluated at screening (before starting CAR-T therapy), at 6, 12 and 24 months after CAR-T infusion (from the beginning of the study at least 24 months after CAR-T infusion)

   Cognitive status will be assessed using the Mini-Mental State Examination (MMSE).

   Unit of Measure: Total score (points) Range: 0 to 30 Interpretation: Higher scores indicate better cognitive performance.

3. Quality of Life (QoL)

   Time frame: The endpoint wil be evaluated at screening (before starting CAR-T therapy), at 6, 12 and 24 months after CAR-T infusion (from the beginning of the study at least 24 months after CAR-T infusion)

   Quality of life will be evaluated through EORTC QLQ-C30 questionnaire (European Organisation for Research and Treatment of Cancer-Quality of life Questionnaire-Core 30). The EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30) is a 30-item instrument used to assess health-related quality of life in people with cancer.

   All scales and single items are linearly transformed to a 0-100 scale (Minimum: 0 and Maximum: 100).

4. Psychological status

   Time frame: The endpoint wil be evaluated at screening (before starting CAR-T therapy), at 6, 12 and 24 months after CAR-T infusion (from the beginning of the study at least 24 months after CAR-T infusion)

   Psychological status will be evaluated through HADS questionnaire (Hospital Anxiety and Depression Scale). The Hospital Anxiety and Depression Scale consists of two subscales: anxiety (HADS-A) and depression (HADS-D). Each subscale ranges from 0 to 21, with higher scores indicating worse psychological outcomes (greater anxiety or depression symptoms).

5. Resilience

   Time frame: The endpoint wil be evaluated at screening (before starting CAR-T therapy), at 6, 12 and 24 months after CAR-T infusion (from the beginning of the study at least 24 months after CAR-T infusion)

   Resilience will be evaluated through RS-14 questionnaire (Resilience scale-14 questionnaire). The Resilience Scale-14 produces a total score ranging from 14 to 98, with higher scores indicating a better outcome (greater resilience).

6. Adverse events

   Time frame: The endpoint wil be evaluated at 6, 12 and 24 months after CAR-T infusion (from the beginning of the study at least 24 months after CAR-T infusion)

   CRS (Cytokine Release Syndrome), ICANS (Immune Effector Cell-Associated Neurotoxicity Syndrome) and IEC-HS (Immune Effector Cell associated HLH-like Syndrome) will be graded according to ASBMT (American Society for Blood and Marrow Transplantation ) consensus grading, ICAHT (Immune effector cell-associated hematotoxicity) will be graded according to EHA/EBMT (European Hematology Association/European Society for Blood and Marrow Transplantation) consensus grading, other extrahematological toxicities will be graded according to the latest version of CTCAE criteria (Common Terminology Criteria for Adverse Events).

7. Treatment characteristics: Previous Central Nervous System Prophylaxis

   Time frame: The endpoint wil be evaluated at screening (before starting CAR-T therapy)

   History of Central Nervous System prophylaxis prior to CAR-T therapy, including intrathecal methotrexate and/or high-dose methotrexate, collected from medical records. Unit of Measure: Participants with previous CNS prophylaxis (%).

8. Overall Survival (OS)

   Time frame: The endpoint will be evaluated from the beginning to the end of the study (at least 24 months after CAR-T infusion)

   Overall Survival for all patients included in the study: defined as the time between the start of CAR-T until death from any cause.

9. Neurocognitive performance evaluation: Praxic Abilities - Rey-Osterrieth Complex Figure Test (Copy Condition)

   Time frame: The endpoint wil be evaluated at screening (before starting CAR-T therapy), at 6, 12 and 24 months after CAR-T infusion (from the beginning of the study at least 24 months after CAR-T infusion)

   Praxic and visuoconstructive abilities will be assessed using the copy condition of the Rey-Osterrieth Complex Figure Test (ROCF).

   Unit of Measure: Total score (points) Range: 0 to 36 Interpretation: Higher scores indicate better praxic/visuoconstructive performance.

10. Neurocognitive performance evaluation: Verbal Memory - Rey Auditory Verbal Learning Test (Word List 3 Recall)

    Time frame: The endpoint wil be evaluated at screening (before starting CAR-T therapy), at 6, 12 and 24 months after CAR-T infusion (from the beginning of the study at least 24 months after CAR-T infusion)

    Verbal memory will be assessed using Word List 3 recall from the Rey Auditory Verbal Learning Test (RAVLT).

    Unit of Measure: Number of words correctly recalled Range: 0 to 15 Interpretation: Higher scores indicate better verbal memory performance.

11. Neurocognitive performance evaluation: Visual Memory - Rey-Osterrieth Complex Figure Test (Delayed Recall)

    Time frame: The endpoint wil be evaluated at screening (before starting CAR-T therapy), at 6, 12 and 24 months after CAR-T infusion (from the beginning of the study at least 24 months after CAR-T infusion)

    Visual memory will be assessed using the delayed recall condition of the Rey-Osterrieth Complex Figure Test (ROCF).

    Unit of Measure: Total score (points) Range: 0 to 36 Interpretation: Higher scores indicate better visual memory performance.

12. Neurocognitive performance evaluation: Language - Verbal Fluency Test

    Time frame: The endpoint wil be evaluated at screening (before starting CAR-T therapy), at 6, 12 and 24 months after CAR-T infusion (from the beginning of the study at least 24 months after CAR-T infusion)

    Language function will be assessed using a Verbal Fluency Test (phonemic and/or semantic, as applicable).

    Unit of Measure: Number of correct words generated within the allotted time Range: No fixed maximum value Interpretation: Higher scores indicate better language performance.

13. Neurocognitive performance status: Attention and Processing Speed - Trail Making Test Part A

    Time frame: The endpoint wil be evaluated at screening (before starting CAR-T therapy), at 6, 12 and 24 months after CAR-T infusion (from the beginning of the study at least 24 months after CAR-T infusion).

    Attention and processing speed will be assessed using Part A of the Trail Making Test (TMT-A).

    Unit of Measure: Completion time (seconds) Range: Continuous variable (no fixed maximum) Interpretation: Lower scores indicate better performance.

14. Neurocognitive performance evaluation: Executive Function - Trail Making Test Part B.

    Time frame: The endpoint wil be evaluated at screening (before starting CAR-T therapy), at 6, 12 and 24 months after CAR-T infusion (from the beginning of the study at least 24 months after CAR-T infusion)

    Executive function will be assessed using Part B of the Trail Making Test (TMT-B).

    Unit of Measure: Completion time (seconds) Range: Continuous variable (no fixed maximum) Interpretation: Lower scores indicate better performance.

15. Neurocognitive performance evaluation: Attention and Processing Speed - Symbol Digit Modalities Test (Oral Version)

    Time frame: The endpoint wil be evaluated at screening (before starting CAR-T therapy), at 6, 12 and 24 months after CAR-T infusion (from the beginning of the study at least 24 months after CAR-T infusion).

    Attention and processing speed will be assessed using the oral version of the Symbol Digit Modalities Test (SDMT).

    Unit of Measure: Number of correct substitutions Range: No fixed maximum value (administration time-dependent) Interpretation: Higher scores indicate better attention and processing speed.

16. Neurocognitive performance evaluation: Executive Function - Frontal Assessment Battery

    Time frame: The endpoint wil be evaluated at screening (before starting CAR-T therapy), at 6, 12 and 24 months after CAR-T infusion (from the beginning of the study at least 24 months after CAR-T infusion).

    Executive function will be assessed using the Frontal Assessment Battery (FAB). Unit of Measure: Total score (points) Range: 0 to 18 Interpretation: Higher scores indicate better executive functioning.

17. Treatment characteristics: Cumulative Anthracycline Dose

    Time frame: The endpoint wil be evaluated at screening (before starting CAR-T therapy).

    Total cumulative dose of anthracycline chemotherapy received prior to CAR-T therapy, collected from medical records.

    Unit of Measure: Milligrams per square meter (mg/m²).

18. Treatment characteristics: Prior Radiotherapy Field

    Time frame: The endpoint wil be evaluated at screening (before starting CAR-T therapy).

    Anatomical field of radiotherapy received prior to CAR-T therapy as recorded in medical records (e.g., mediastinal, cranial, total body irradiation, or other).

    Unit of Measure: Participants by radiotherapy field (%).

19. Treatment characteristics: Prior Radiotherapy Dose

    Time frame: The endpoint wil be evaluated at screening (before starting CAR-T therapy).

    Total radiation dose delivered during previous radiotherapy treatments before CAR-T therapy, obtained from medical records.

    Unit of Measure: Gray (Gy).