The Neurocognitive Impact of CAR T Cell Therapy in Hematological Cancers: A Systematic Review of Cognitive Function, Quality of Life, and Psychological Outcomes.

Introduction

Chimeric antigen receptor (CAR) T‐cell therapy has fundamentally changed how we approach blood cancer treatment. CAR T‐cell therapy represents a revolutionary advance in oncology, achieving durable remissions that were previously unattainable for many patients [ 1 , 2 ]. The technology works by taking a patient's immune cells and engineering them with a CAR. This receptor combines several components: intracellular signaling domains, costimulatory molecules like CD28 and CD137, and an extracellular targeting system. Together, these allow the modified cells to hunt down cancer without requiring the usual immune recognition pathways [ 3 , 4 , 5 , 6 , 7 ]. Yet this breakthrough comes with serious complications. Two major side effects concern clinicians most: cytokine release syndrome and immune effector cell‐associated neurotoxicity syndrome (ICANS) [ 8 , 9 , 10 , 11 ]. CRS triggers body‐wide inflammation. ICANS, however, creates a more complex clinical picture. It affects brain function in ways that can be devastating ‐ from mild attention problems to severe neurological damage involving speech, memory, decision‐making, and spatial awareness [ 12 , 13 , 14 , 15 , 16 , 17 , 18 ].

Brain Function Under Attack

The cognitive problems we see after CAR T‐cell therapy involve complicated immune‐brain interactions. When these engineered cells activate, they release massive amounts of inflammatory molecules. IL‐6, IL‐1β, TNF‐α, and IFN‐γ flood the system, triggering damaging brain inflammation. This process breaks down the blood‐brain barrier ‐ normally our brain's protective shield and activates microglia, the brain's own immune cells. Different brain regions suffer distinct damage. The frontal cortex, which controls attention and executive function, becomes impaired. Memory and language processing in the temporal lobe deteriorate. Spatial processing abilities in the parietal regions also decline. Blood vessel dysfunction makes everything worse by reducing brain blood flow and allowing immune cells to invade neural tissue. Current data suggests roughly one in four patients (25%–35%) develops noticeable cognitive problems. Some recover within weeks. Others struggle with persistent deficits lasting well over a year. Memory, attention, language, and executive function take the biggest hits. These aren't just “test results”—they disrupt real life. Patients lose their ability to work effectively, manage daily tasks, or maintain relationships. Families often need extensive support systems to cope with these changes.

Assessment Problems We Face

Despite growing recognition of these cognitive complications, we're still struggling with major gaps in patient care. Different hospitals use completely different testing approaches. Some rely on quick screening tools like the MoCA. Others conduct extensive testing batteries including FACT‐Cog and Hopkins Verbal Learning assessments. This inconsistency makes comparing research findings nearly impossible and hampers guideline development. The relationship between early severe brain toxicity and long‐term cognitive outcomes remains puzzling. Some studies suggest severe early symptoms predict lasting problems. Other research contradicts this entirely. We also lack clear protocols for monitoring timing and frequency. When should patients see specialists? What constitutes appropriate intervention? These questions remain unanswered. Patient variability adds another layer of complexity. Children might recover differently than elderly patients. Someone's pretreatment cognitive status seems to matter. Different CAR T‐cell products may cause varying problems. A further challenge lies in the mismatch between patient‐reported difficulties and formal neurocognitive test results.

Why This Study Matters

CAR T‐cell therapy continues expanding to new patient groups across different ages and conditions. Healthcare providers desperately need reliable information about cognitive risks. How likely are these problems? Which patients face highest risk? How should we monitor effectively?

Doctors need this information for honest patient conversations and appropriate care planning. The situation becomes more complex because cognitive problems rarely occur alone. Many patients also develop anxiety, depression, and stress reactions from their cancer journey. These psychological challenges interact with cognitive difficulties in ways that affect recovery and quality of life. Unfortunately, we understand very little about these mental health complications ‐ their frequency, predictors, or specific relationships to cognitive problems.

Our Research Goals

This systematic review synthesizes all available evidence on cognitive function, psychological outcomes, and quality of life following CAR T‐cell therapy for blood cancers. We're addressing several critical questions: How common are cognitive problems across different CAR T‐cell treatments? What severity patterns emerge? Can we identify recovery trajectories over time? Which factors predict better outcomes? How do psychological complications like anxiety and depression affect patients? Does severe early brain toxicity reliably predict long‐term cognitive difficulties?

Our analysis aims to provide healthcare teams with evidence‐based information for accurate patient counseling, effective monitoring strategies, and comprehensive support systems. As CAR T‐cell use expands rapidly, a robust synthesis of neurocognitive and psychological outcomes is essential to optimize patient care, guide survivorship planning, and inform future research.

Methodology

This systematic review was conducted in accordance with the Cochrane Collaboration Handbook for Systematic Reviews of Interventions and the PRISMA guidelines.

Study Registration

This systematic review has been registered with the International Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42023491223.

Eligibility Criteria

Study eligibility was determined using predefined inclusion and exclusion criteria based on the PICO framework (Population, Interventions, Comparators, Outcomes) and study design requirements. Studies were included if they assessed neurocognitive, psychological, or quality‐of‐life outcomes in patients with hematological malignancies undergoing CAR T‐cell therapy. Detailed eligibility criteria are presented in Table 1 .

Search Strategy

A comprehensive literature search was conducted across PubMed, Embase, and Scopus to identify relevant studies on the neurocognitive impact of CAR T cell therapy in hematological cancers. The search was performed up to 2024 using a combination of controlled vocabulary (MeSH, Emtree) and free‐text terms to ensure comprehensiveness. The primary search terms included:

CAR T‐cell therapy.

Neurocognitive function.

Cognitive impairment.

Immune effector cell‐associated neurotoxicity syndrome (ICANS).

Psychological outcomes (anxiety, depression, PTSD).

Quality of life (QoL) in hematological malignancies.

Boolean operators (AND, OR) were used to optimize sensitivity and specificity. Detailed search strategy is shown in Supporting Information Table S1 . Filters were applied to include only human studies, full‐text articles, and publications in English from the last 25 years (2000–2024). A 25‐year search window (2000–2024) was adopted to ensure methodological completeness by capturing early translational and mechanistic studies on cellular immunotherapies, including pre‐approval CAR T research; however, no studies before 2010 met the inclusion criteria. In addition to database searches, a manual search was performed by screening the reference lists of included studies and previous systematic reviews to identify additional relevant publications. Gray literature sources, including conference proceedings and preprints, were also reviewed where applicable to minimize publication bias. The complete search strategy and selection of studies are depicted in Figure 1 .

Study Selection and Data Extraction

Selection Process

A two‐stage screening process was conducted using the Rayyan tool. Eight independent reviewers screened the titles and abstracts, with each article being evaluated by two reviewers to eliminate bias. Disagreements were resolved by a third independent reviewer. Full‐text screening was performed to confirm study eligibility.

Data Extraction

A standardized data extraction form was used to collect:

Study characteristics: Study design, sample size, publication year.

Patient demographics: Age, cancer type, CAR T‐cell therapy product used.

Neurocognitive outcomes: Memory, executive function, language, attention.

Psychological outcomes: Anxiety, depression, PTSD, emotional coping strategies.

Quality of life: Patient‐reported measures (EORTC QLQ‐C30, EQ‐5D‐5L).

Adverse effects: Incidence of ICANS, CRS, and cognitive toxicity.

Quality Assessment

The quality of included studies was evaluated using appropriate tools (Figure 2 and Table 2 ):

Cochrane Risk of Bias Tool (RoB‐2) Used in randomized controlled trials to evaluate different sources of bias, including selection, performance, and reporting bias.

Newcastle‐Ottawa Scale (NOS): Employed in cohort and case control studies to assess how subjects in studies are selected, similarity between study groups, and outcome measurement areas.

Studies were classified as low, moderate, or high risk of bias. A qualitative assessment of publication bias was conducted through examination of study features together with sponsorships and documented outcome choices. Studies funded by pharmaceutical companies or those lacking pre‐registered protocols were considered at a higher risk of selective reporting bias. The impact of potential publication bias on findings was considered in the interpretation of results.

Certainty of Evidence Assessment

The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach was used to determine the certainty of evidence based on:

Risk of bias.

Consistency of findings.

Indirectness.

Imprecision.

Publication bias Each outcome was classified as high, moderate, low, or very low certainty.

Study Amendments

During the review process, minor amendments were made to the inclusion criteria to accommodate newly published studies. Originally, only RCTs were considered, but observational cohort and case‐control studies were included to provide a more comprehensive assessment of CAR T‐cell therapy outcomes.

Data Synthesis and Analysis

Synthesis Approach: A narrative synthesis was conducted to summarize key findings on neurocognitive, QoL, and psychological outcomes.

Subgroup Analyzes: Additional analyzes were performed based on cancer type, CAR T‐cell therapy type (Axi‐cel, Tisa‐cel, Cilta‐cel), and patient age group (pediatric vs. adult).

Heterogeneity: Study heterogeneity was assessed based on differences in study design, population, and outcome measures.

Statistical Analysis: Effect measures such as risk ratios (RR), mean differences (MD), and standardized mean differences (SMD) were used where applicable. 95% confidence intervals (CI) were reported.

Outcomes of Interest

Primary Outcome

Impact of CAR T‐cell therapy on cognitive function, executive processing, memory, and attention.

Secondary Outcomes

Quality of Life (QoL): Changes in patient‐reported outcomes over time.

Psychological Impact: Prevalence of anxiety, depression, PTSD, and coping mechanisms.

Adverse Effects: Incidence of ICANS, CRS, and long‐term cognitive impairment.

This methodology ensures transparency, reproducibility, and alignment with best practices in systematic review reporting.

Results

Overview of Study Selection

A total of 18 studies were included in this systematic review, all focusing on the neurocognitive, psychological, and quality‐of‐life (QoL) outcomes following CAR T‐cell therapy in patients with hematological malignancies. Studies were selected based on predefined inclusion criteria, and a PRISMA flow diagram (not included in this section) was used to document the screening and selection process.

Characteristics of Included Studies

The 18 included studies comprised diverse designs across hematological malignancies, with sample sizes ranging from 40 to 419 patients (total N = 2847). Studies included 3 Phase 3 RCTs, 6 prospective studies, and 9 observational studies. Patient populations spanned multiple myeloma (5 studies), DLBCL/LBCL (8 studies), and mixed hematological malignancies (5 studies). CAR‐T products were predominantly axi‐cel (8 studies) and ide‐cel (4 studies), with age distributions favoring older adults (median ages 60–68 years in most studies). Further detailed in Table 3 .

Synthesis of Results

Neurocognitive Outcomes

Across the 18 included studies, neurocognitive changes after CAR T‐cell therapy were variably reported but clinically relevant in a subset of patients. In longitudinal cohorts, early cognition was often stable to 90 days, followed by small but persistent declines in domains such as memory, language, organization, and divided attention up to day 360, particularly among those who developed ICANS ≥ grade 2 [ 19 ]. In trial and cohort settings, unresolved cognitive/neurological events (e.g., confusion, tremor, mental status changes) were still observed at 30–90 days in older LBCL populations [ 20 ]. Patient‐reported cognitive difficulties among longer‐term survivors were also noted (≈38% in one cohort) and correlated with worse global mental health and symptom burden [ 21 ]. ICANS incidence varied widely across products and settings (e.g., ~24% grade 2–4 in one axi‐cel cohort; 56% in a single‐center axi‐cel series; 65% neurological events with 27% grade ≥ 3 in an older LBCL RCT subgroup), while severe ICANS ranged from ~10% to ≥ 27% where reported [ 20 , 22 , 23 ]. In contrast, myeloma cohorts frequently showed low investigator‐identified neurotoxicity with ide‐cel (≈3%–10%) [ 24 , 25 ], and cilta‐cel trials reported mostly grade 1–2 ICANS at low frequency [ 26 ].

Psychological Outcomes (Anxiety, Depression, PTSD)

Psychological morbidity was common. In prospective/observational cohorts, anxiety and depression were present in roughly 30%–35% of patients, and PTSD symptoms were reported in about 21% in one study [ 27 ]. Baseline psychological distress and coping profiles were consistently associated with subsequent outcomes: higher baseline fatigue, anxiety, or depression predicted worse perceived cognition at 90 days [ 19 ], and better emotional coping was linked to higher QoL and lower distress (depression, anxiety, PTSD) [ 27 ]. In acute PRO tracking after axi‐cel, concentration/memory problems peaked around day 14, with variable trajectories for mood symptoms by day 90 [ 23 ].

Quality of Life (QoL) and Patient‐Reported Outcomes

A biphasic QoL pattern emerged across multiple studies: deterioration in the first 2–3 weeks (fatigue, function, mood), followed by clinically meaningful improvement by ~day 90–100 or by month 2–3, with maintenance thereafter in many cohorts [ 23 , 24 , 25 , 28 ]. In randomized settings, axi‐cel recipients recovered QoL more rapidly than standard‐of‐care comparators and maintained gains over follow‐up [ 20 , 28 ]. In relapsed/refractory myeloma, ide‐cel cohorts showed significant improvements in global health status/HRQoL and physical well‐being by 2–3 months, sustained to 9–18 months in longitudinal analyzes [ 24 , 25 ]. Notably, patients experiencing moderate‐to‐severe ICANS exhibited worse cognitive trajectories up to 1 year, consistent with delayed functional recovery relative to those without ICANS [ 19 , 20 ]. Importantly, while most patients achieved QoL improvement by Day 90, those who experienced grade ≥ 2 ICANS showed persistent impairments in physical and emotional functioning, with some deficits extending to 12 months post‐treatment [ 19 , 20 , 29 ]. These findings indicate that ICANS severity is a major determinant of long‐term QoL outcomes, in contrast to patients without ICANS who typically returned to baseline by 3 months.

ICANS and EEG/Biomarker Findings

EEG abnormalities (e.g., background slowing, focal changes) tracked with ICANS severity in clinical series [ 30 ]. A quantitative EEG‐based score (EICANS) demonstrated strong correlations with ICANS severity and with neurotoxicity duration (Spearman's R² ≈ 0.69 and R² ≈ 0.31, respectively) in small cohorts [ 31 ]. Given the limited sample sizes and number of studies, these EEG markers should be interpreted as preliminary and require external validation before routine clinical adoption [ 30 , 31 ].

Subgroup Findings (Age, Product, Tumor Type)

Age: Older adults (> 65 y) demonstrated more persistent neurocognitive/neurologic sequelae at 30–90 days and beyond [ 20 ], whereas pediatric populations (where reported) showed higher acute ICANS risk but generally better long‐term cognitive recovery trajectories [ 29 ]. In one survivor cohort, younger adults reported worse mental‐health indices than older adults, highlighting heterogeneous psychological recovery by age [ 21 ].

CAR T product: Axi‐cel was associated with higher neurotoxicity/ICANS in LBCL settings, yet with faster QoL recovery versus standard care in randomized trials [ 20 , 22 , 23 , 28 ]. Ide‐cel cohorts demonstrated low severe neurotoxicity with early and sustained cognitive/HRQoL improvements [ 24 , 25 ]. Cilta‐cel showed low, mostly grade 1–2 ICANS with longer time to symptom worsening versus standard care in lenalidomide‐refractory myeloma [ 26 ].

Tumor type: LBCL cohorts (commonly treated with axi‐cel) showed higher ICANS/neurologic event rates than myeloma cohorts (frequently receiving ide‐cel or cilta‐cel), which generally reported lower severe neurotoxicity and steady HRQoL gains [ 20 , 24 , 25 , 26 ].

Modifiers and Predictors: Higher baseline symptom burden (fatigue, anxiety, depression) predicted worse perceived cognition at 90 days [ 19 ]. Emotional coping capacity was positively associated with QoL and inversely with distress [ 27 ]. Disease‐/treatment‐related factors also contributed: high tumor burden and severe CRS aligned with greater ICANS severity and prolonged dysfunction in several reports, and biochemical markers (e.g., fibrinogen, LDH) were associated with ICANS risk in a single‐center series [ 22 ].

Risk of Bias Assessment

Studies were assessed using RoB‐2 (Risk of Bias in RCTs) and categorized as low risk.

Studies used the Newcastle‐Ottawa Scale (NOS), with an average score of 7/9 (high quality).

No significant publication bias detected, but heterogeneity in cognitive assessment tools was noted.

Key Findings and Interpretation

CAR T‐cell therapy significantly improves progression‐free survival but is associated with short‐ and long‐term neurotoxicity.

ICANS and QoL deterioration peak within the first 14 days post‐treatment but show partial recovery by Day 100.

Persistent neurocognitive deficits affect a subset of patients, requiring long‐term monitoring and supportive interventions.

EEG‐based monitoring (EICANS Score) is a promising tool for early neurotoxicity detection.

Negative and Conflicting Findings

Contradictory reports on long‐term neurocognitive recovery: Some studies, such as Delforge et al. reported full cognitive recovery by 12 months, whereas others, such as Kuznetsova et al. noted persistent deficits in executive function.

No clear correlation between CRS severity and neurocognitive decline Eckhardt et al. suggesting independent pathways.

Publication Bias

We considered assessing publication bias using funnel plots and Egger's regression test. However, because fewer than eight studies reported ICANS outcomes using consistent grading (grade ≥ 3) or cognitive impairment with standardized assessment tools, the available data set was insufficient for robust quantitative testing. Formal application of Egger's regression to such small, heterogeneous datasets is underpowered and risks spurious results. Instead, we conducted a qualitative assessment of potential bias. Several included studies were industry‐funded pivotal trials, which may increase the likelihood of selective outcome reporting, while smaller single‐center cohorts tended to report higher ICANS rates. Taken together, these factors suggest that ICANS incidence in the published literature may represent an upper bound of the true population risk. In contrast, cognitive impairment findings were more evenly distributed across study sizes, reducing the likelihood of strong publication bias.

Discussion

Key Findings and Their Significance

This systematic review highlights the neurocognitive, psychological, and quality‐of‐life (QoL) outcomes associated with CAR T‐cell therapy in hematological malignancies. Three consistent patterns emerged across the 18 included studies. First, ICANS remains the most significant neurotoxic complication, occurring in 25%–70% of patients, with severe forms affecting 10%–20% [ 22 , 29 , 32 ]. The most impacted domains were working memory, attention, and executive function, with up to 44% of patients experiencing deterioration posttreatment [ 29 ]. While some patients recovered within months, others showed persistent dysfunction beyond 1 year [ 32 ]. Importantly, the EICANS Score showed promising correlations with ICANS severity (R² = 0.69, p < 0.001) in preliminary studies, though larger validation cohorts are needed to establish its clinical utility [ 22 ]. Second, QoL trajectories were biphasic. Early declines in fatigue, anxiety, and depression (Day 14) generally improved by Day 90, and patients treated with axi‐cel showed significant improvements by Day 100 (+18.1 points, p < 0.0001) [ 28 , 30 ]. However, patients with severe ICANS showed delayed or incomplete recovery, with prolonged deficits in emotional and physical functioning. Up to 35% of patients developed persistent anxiety or depression, and 21% of those with severe ICANS reported PTSD symptoms [ 27 , 32 ]. Third, age was an important modifier. Older patients (> 65 years) exhibited prolonged neurocognitive impairments, while pediatric patients—despite having a 25%–44% ICANS incidence—demonstrated more robust cognitive recovery [ 20 , 29 ]. These findings suggest that baseline cognitive reserve, neuroplasticity, and inflammatory burden influence recovery, emphasizing the need for age‐tailored rehabilitation strategies.

Comparison With Existing Literature

Our findings are consistent with prior studies (e.g., Santomasso et al., Neelapu et al.) that identified ICANS as a major adverse effect of CAR T‐cell therapy, with heterogeneous neurocognitive impacts. However, differences in recovery patterns remain. While studies such as Delforge et al. reported full cognitive recovery at 12 months, Kuznetsova et al. documented ongoing executive dysfunction, suggesting that patient characteristics, treatment variables, and inflammatory pathways may account for outcome heterogeneity. The relationship between CRS and ICANS also remains debated. While early reports suggested a direct correlation, our synthesis aligns with emerging evidence that ICANS arises from distinct neuroimmune mechanisms [ 31 ], likely involving endothelial activation and blood–brain barrier disruption. Similarly, while prior pivotal trials such as ZUMA‐7 emphasized early physical recovery, our review demonstrates that psychological recovery lags behind physical function in patients with severe ICANS. This highlights a gap in survivorship care, where neurocognitive and psychosocial sequelae remain under‐recognized.

Clinical Practice Implications

Our synthesis indicates that survivorship after CAR T therapy must extend beyond disease control to include cognitive and psychosocial monitoring.

Early Identification and Risk Stratification

EEG‐based screening using the EICANS Score should be considered during the first week post‐infusion, when neurotoxicity risk is highest. Patients with pre‐existing cognitive impairment, psychiatric comorbidities, or severe CRS may benefit from intensified surveillance.

Targeted Support

Patients who experience Grade ≥ 3 ICANS should undergo routine neuropsychological evaluation at 1, 3, and 12 months. Evidence‐based interventions such as CBT, mindfulness‐based therapy, and pharmacologic management of anxiety or depression should be integrated into care pathways.

Personalized Rehabilitation

Older patients with persistent deficits may require a multidisciplinary rehabilitation approach, incorporating cognitive training, aerobic and resistance exercise, and dietary strategies targeting neuroinflammation.

Research Priorities

Several urgent gaps demand immediate attention.

Assessment Standardization

The current testing heterogeneity makes meaningful comparisons nearly impossible. We desperately need consensus on core assessment batteries. Memory evaluation should include the Hopkins Verbal Learning Test and Wechsler Memory Scale. Executive function assessment requires the Trail Making Test Part B, Stroop Task, and Dimensional Change Card Sort. Processing speed and attention demand evaluation through the Digit Symbol Substitution Test, Continuous Performance Task (CPT‐3), and Flanker Inhibitory Control and Attention Test. Language abilities need assessment via the Boston Naming Test, Controlled Oral Word Association Test, and semantic fluency measures.

Objective Biomarkers

We can't continue relying solely on subjective assessments. EEG‐based monitoring using the EICANS Score shows real promise but needs validation in much larger populations. Neuroimaging approaches—MRI, fMRI, PET—should complement blood‐based markers like Neurofilament light chain and Glial Fibrillary Acidic Protein as neuroinflammation indicators.

Implementation Timeline

Every single patient deserves pretreatment baseline testing. No exceptions. Short‐term follow‐ups at 1, 3, and 6 months post‐CAR‐T are absolutely essential for capturing early trajectory changes. Long‐term assessments extending 12 months and beyond become critical for understanding actual recovery patterns.

Mechanistic Understanding

ICANS pathophysiology remains frustratingly incomplete. Future investigations must integrate cytokine profiling (IL‐6, IL‐1β, TNF‐α, IFN‐γ), microglial activation studies, endothelial dysfunction markers, and blood‐brain barrier assessments. Advanced neuroimaging using DTI and PET can reveal structural and functional changes that correlate with neurotoxicity severity. Vascular permeability markers—VEGF, sICAM‐1, Ang‐2—might serve as early warning signals for impending brain injury. We also need rigorous testing of whether targeted TNF‐α or IL‐1β inhibition can reduce ICANS without compromising antitumor efficacy. Diffusion Tensor Imaging studies should focus specifically on white matter changes and microstructural alterations that correspond with ICANS severity. The EICANS Score requires validation in substantially larger cohorts, though early results appear genuinely encouraging.

Neuroprotective Trials

Given how disturbingly common lasting dysfunction proves to be, randomized trials testing anti‐inflammatory agents (anakinra, tocilizumab), neuroprotective compounds (N‐acetylcysteine, omega‐3 fatty acids), and structured rehabilitation programs have become essential. These interventions should thoughtfully combine exercise, cognitive‐behavioral therapy, mindfulness training, and targeted dietary modifications.

Economic Impact

We must rigorously assess the cost‐effectiveness of routine monitoring and long‐term rehabilitation. Studies should quantify the true economic burden of cognitive impairment on healthcare systems, employment capacity, and caregiver support networks. This information becomes absolutely crucial for informing insurance coverage policies for survivorship care.

Expanding Research Into Understudied Populations

Critical knowledge gaps persist in several populations that deserve focused research attention. Pediatric patients need specialized assessment of long‐term neurodevelopmental outcomes and educational interventions. Their developing brains may respond quite differently to immune‐mediated injury—potentially offering valuable insights into protective mechanisms we could harness for older patients. Geriatric population (over 65 years) often enter therapy with already‐reduced cognitive reserve and may require entirely customized rehabilitation strategies. Our age‐related findings suggest this population faces unique challenges that standard approaches don't address adequately. Research must also include diverse ethnic and socioeconomic groups. Current evidence comes primarily from relatively homogeneous populations, potentially missing important disparities in post‐treatment cognitive care access. Equitable implementation of neurocognitive monitoring protocols absolutely depends on understanding these differences. This comprehensive approach to understanding CAR T‐cell therapy's cognitive consequences will ultimately serve patients far better by providing clinicians with the evidence‐based tools they actually need for optimal care planning and honest patient counseling. Table 4 summarizes the key focus areas identified for future research in this study.

Strengths and Limitations

Strengths

Comprehensive synthesis of 18 studies, encompassing diverse study designs (RCTs, cohort studies, observational studies).

Integration of objective neurocognitive measures (EEG biomarkers) with patient‐reported QoL outcomes, providing a multifaceted analysis.

Subgroup analysis of pediatric versus older populations, offering insights into age‐related variations in neurocognitive recovery.

Limitations and Publication Bias

Heterogeneity in cognitive outcome measures across studies, limiting direct comparability.

Variability in follow‐up durations, making long‐term recovery patterns difficult to establish.

Potential publication bias, as studies with negative findings on cognitive function may be underrepresented.

Limited cost‐effectiveness analysis, necessitating further research on the economic impact of neurocognitive monitoring.

A major limitation of this review is the inability to formally test for publication bias due to the limited number of eligible studies per outcome and the heterogeneity of ICANS and cognitive endpoints. Although qualitative assessment suggested that ICANS rates may be selectively overrepresented in smaller or single‐center series, this could also reflect genuine population differences or differences in ICANS grading thresholds. Conversely, cognitive impairment outcomes appeared less prone to selective reporting. Future studies should adopt standardized cognitive batteries and consistently report ICANS severity to enable formal bias testing (e.g., funnel plots, Egger's regression) and improve the reliability of pooled estimates.

To address these limitations, future studies should adopt standardized cognitive assessment protocols, longer follow‐up periods, and cost‐effectiveness evaluations.

Strength of Evidence Assessment

The strength of evidence for each major finding was assessed using the GRADE framework. The details are summarized in Table 5 .

Conclusion

CAR T‐cell therapy represents a major therapeutic advance, but its benefits must be weighed against significant neurocognitive and psychosocial risks. Up to 44% of patients experience cognitive impairments in memory, attention, and executive function, with 35% developing anxiety or depression and 21% of severe ICANS patients reporting PTSD symptoms. While most patients experience QoL improvements by Day 100, a subset face persistent deficits beyond 12 months. EEG‐based tools such as the EICANS Score show promise for early detection but require validation. These findings have immediate therapeutic applications for clinical practice. Routine neurocognitive monitoring using standardized assessment tools should be integrated into CAR‐T survivorship protocols, with age‐tailored rehabilitation strategies particularly for older patients. Early identification systems can guide timely interventions including cognitive‐behavioral therapy, targeted pharmacologic management, and multidisciplinary support to optimize long‐term functional recovery. Future research should prioritize standardized assessments, mechanistic studies, and neuroprotective strategies to enhance the safety profile of this transformative therapy.

Author Contributions

All authors have read and approved the final version of the article and have contributed significantly. Ashvath Arumugam Pillai, had full access to all data in this study and takes complete responsibility for data integrity and accuracy of data analysis.

Disclosure

All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

Conflicts of Interest

The authors declare no conflicts of interest.

Transparency Statement

The authors affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Generative AI Use Statement

Paperpal and ChatGPT‐4o, were utilized solely for language refinement, grammar enhancement, and stylistic refinements. These tools had no role in conceptualization, data analysis, interpretation of results, or substantive content development. All intellectual contributions, data analysis, and scientific interpretations remain solely the work of the authors. The final manuscript was critically reviewed and edited to ensure accuracy and originality. The authors take full responsibility for the integrity of the work presented.

Supporting information

Supporting Table S1 : Search strategies of the databases searched along with the number of results.

Acknowledgments

The authors extend their gratitude to Medicos In Research, Nautanwa, UP 273164, India, for their unwavering guidance and support throughout the development of this manuscript. Their invaluable contributions provided a platform for us to learn research methodologies, collaborate effectively, expand our professional network, and gain additional insights that significantly enriched this work. We deeply appreciate their efforts in fostering an environment of academic growth and scientific inquiry.

Pillai A. A., Tiwari M., Patil S. B., et al., “The Neurocognitive Impact of CAR T Cell Therapy in Hematological Cancers: A Systematic Review of Cognitive Function, Quality of Life, and Psychological Outcomes,” Health Science Reports 8 (2025): 1‐14, 10.1002/hsr2.71571.

Data Availability Statement

The authors confirm that all data supporting the findings of this study are available within the article and its supporting information S1 . Additional data sets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Associated Data

Supplementary Materials

Supporting Table S1 : Search strategies of the databases searched along with the number of results.

Data Availability Statement

The authors confirm that all data supporting the findings of this study are available within the article and its supporting information S1 . Additional data sets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.