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. 2025 Apr 25;15(2):9–19. doi: 10.62347/WDWE6603

Chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed, refractory CLL: a systematic review and meta-analysis

Mohammad Amin Karimi 1,*, Motahareh Rouhparvarzamin 2,*, Reza Kahdemi 3, Parisa Alsadat Dadkhah 4, Narges Karimi 5, Parisa Nasiri 1, Arash Azizinezhad 6, Aseman Mashhadian 7, Haleh Alizadeh 8, Faezeh Arghidash 9, Pooyan Valizadegan 1, Shayan Ehsani Ziary 10, Ata Akhtari Kohnehshahri 11, Kamyar Feyzi 1, Omid Salimi 12, Seyed Hadi Hashemi 13, Mohammad Sadra Gholami Chahkand 14, Yaser Khakpour 15, Melika Arab Bafrani 16, Niloofar Deravi 17
PMCID: PMC12089925  PMID: 40401080

Abstract

Objectives: Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by the excessive production of lymphocytes in the bone marrow. One of the emerging therapeutic strategies for CLL is chimeric antigen receptor (CAR) T-cell therapy, wherein T-cells are genetically modified to recognize and target cancer cells more effectively. The present study aims to systematically compare the therapeutic impact of high-dose versus low-dose status of CAR T-cell therapy targeting CD19 (CART-19) in patients with relapsed or refractory CLL. Methods: To identify relevant studies, a comprehensive literature search was conducted in PubMed, Scopus, and Web of Science databases up to April 2023. The primary outcome measures included treatment response rates, assessed as complete response (CR) and partial response (PR), and toxicity, as indicated by the incidence of cytokine release syndrome (CRS). Additionally, sensitivity and bias analyses were performed to evaluate the robustness of the findings. Results: Four randomized controlled trials (RCTs) comprising 89 patients with relapsed or refractory CLL met the inclusion criteria. Comparison of treatment response rates between high-dose and low-dose CART-19 therapy demonstrated a significantly higher complete and partial response rate in the high-dose group (SMD [95% CI]: 1.02 [0.10, 1.94]; P<0.05). However, no significant association was observed between CTL019 dosage and the incidence of CRS (P>0.05). Conclusion: This meta-analysis suggests that high-dose CART-19 is associated with improved response rates and survival outcomes in patients with CLL compared to low-dose therapy. However, due to variability in study results, further large-scale, well-designed trials are required to establish the optimal therapeutic dosing strategy for CART-19 therapy in CLL.

Keywords: Chronic lymphocytic leukemia, chimeric antigen receptor, CAR T-cell therapy, CART-19, dose-response relationship, treatment efficacy, toxicity, cytokine release syndrome

Introduction

Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia among adults, affecting an estimated 200,000 individuals in the United States, with approximately 4,410 deaths annually. It accounts for 1.1% of all newly diagnosed cancers in the U.S., with a median age at diagnosis of 70 years and a male-to-female ratio of 1.7:1. In 2022, approximately 20,160 new cases of CLL were expected in the U.S. The five-year survival rate is 90%, while the ten-year survival rate is estimated at 82% [1]. The progression of CLL varies significantly, with 70-80% of patients being asymptomatic at diagnosis, and some never requiring treatment. The disease’s natural history depends on molecular factors, with time to first treatment ranging from months to decades [2,3].

CLL is often incidentally diagnosed during routine blood testing, with unexplained lymphocytosis as a hallmark finding. Among symptomatic patients, 50% present with lymphadenopathy, while 20-50% develop splenomegaly or hepatomegaly. Constitutional “B symptoms” such as unintentional weight loss (>10% over 6 months), fever, and night sweats are reported in 5-10% of cases [4]. Additionally, complications include autoimmune hemolytic anemia (≤10%) and immune thrombocytopenia (≤2%). Given its impact on humoral immunity, frequent infections, particularly affecting the respiratory tract, occur in up to 10% of patients [5,6]. Diagnosis is typically confirmed using peripheral blood flow cytometry, with a requirement of ≥5 × 109/L monoclonal B cells for a definitive CLL diagnosis [7-9].

CLL is characterized by the accumulation of dysfunctional, monoclonal B lymphocytes, which exhibit an aberrant immunophenotype, including CD5, CD23, and CD19 positivity, alongside dim expression of CD20, CD22, and CD79b [10]. A major driver of CLL pathogenesis is the overexpression of B-cell lymphoma 2 (BCL2), which inhibits apoptosis and promotes clonal expansion [11]. The B-cell receptor (BCR) signaling pathway is constitutively active, contributing to proliferation and survival [12,13]. Immunoglobulin heavy chain variable region (IGHV) mutational status is a critical prognostic factor, with unmutated IGHV (≤2% deviation from germline) being associated with more aggressive disease [14-16]. Additionally, CLL is marked by impaired humoral and cellular immune responses, increasing susceptibility to infections, and reducing vaccine efficacy [17].

First-line treatment for CLL includes Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib or the BCL2 inhibitor named venetoclax [18,19]. In relapsed or refractory CLL, non-covalent BTK inhibitors such as pirtobrutinib have demonstrated response rates >70%, while phosphoinositide 3-kinase (PI3K) inhibitors, including idelalisib and duvelisib, remain alternative options [20,21]. Chimeric antigen receptor T-cell (CAR-T) therapy has shown a 45% complete response rate, and allogeneic hematopoietic cell transplantation remains the only curative option [22]. The status of CAR T-cell therapy targeting CD19 (CART-19) in CLL remains an area of ongoing investigation, with emerging data on its efficacy yet to be fully established.

CART-19 therapy is an advanced immunotherapeutic approach in which T-cells are genetically modified to enhance their ability to recognize and eliminate cancer cells. Recent studies indicate that CAR T-cell therapy demonstrates superior efficacy compared to conventional treatments previously utilized [23]. This therapy functions similarly to an active drug, meaning that rather than acting solely at a localized target, CAR T-cells actively seek out, bind to, and eliminate cancer cells [24].

While CART-19 therapy has shown promise in CLL, determining the optimal dosage remains a challenge. Higher doses may enhance anti-tumor activity but are associated with increased toxicity, particularly cytokine release syndrome (CRS) and neurotoxicity. Conversely, lower doses may reduce these risks but could compromise therapeutic efficacy. Given the lack of a standardized dosing protocol, this systematic review and meta-analysis aim to provide the first comprehensive comparison of high-dose versus low-dose CART-19 in relapsed and refractory CLL, evaluating both treatment response and safety outcomes.

Material and method

Study aim and design

This study aims to evaluate the efficacy of high-dose versus low-dose CART-19 in patients with relapsed or refractory CLL. A standardized checklist was used to guide the study design, screening process, and data selection. The study was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines to ensure methodological rigor. The research protocol was registered on the Open Science Framework (OSF) and can be accessed at https://osf.io/j5d9x.

Search strategy

A systematic literature search was performed across PubMed, Scopus, and Web of Science up to April 2023. Advanced search techniques, including Boolean operators and database-specific tags, were applied to refine search results (Table 1). The search strategy incorporated key terms related to chimeric antigen receptor (CAR) T-cell therapy, CD19, chronic lymphocytic leukemia (CLL), B-cell malignancies, and immunotherapy to ensure comprehensive coverage of relevant literature. The selection process was conducted in two phases: (1) Study retrieval, where potentially relevant studies were identified based on titles, abstracts, and keywords, and (2) Screening and selection, in which three independent reviewers assessed the titles and abstracts after duplicate removal. Studies meeting the inclusion criteria were shortlisted for full-text review and final inclusion in the analysis.

Table 1.

The search strategy of the included databases

Database Search strategy Additional filters
PubMed ((“Receptors, Chimeric Antigen”[Mesh]) OR (“Receptors, Antigen, T-Cell”[Mesh])) AND (“Antigens, CD19”[Mesh]) AND (“Leukemia, Lymphocytic, Chronic, B-Cell”[Mesh]) English, April 28th, 2023
Scopus (TITLE-ABS-KEY(Chimeric antigen receptor-modified t-cells)) AND (TITLE-ABS-KEY(CD19)) AND ((TITLE-ABS-KEY(CLL) OR TITLE-ABS-KEY(Chronic lymphocytic leukemia))) English, April 28th, 2023
Web of Science 1: chimeric Antigen receptor-modified T-cell (All Fields) English, April 30th, 2023
2: CD19 (All Fields)
3: CLL (All Fields) OR Chronic lymphocytic leukemia (All Fields)
4: #1 AND #2 AND #3
5: #1 AND #2 AND #3
6: #1 AND #2 AND #3
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Inclusion and exclusion criteria

Studies were eligible for inclusion if they included observational and interventional studies that examined the response to CART-19 therapy in relapsed or refractory CLL patients, comparing high-dose versus low-dose administration. Exclusion criteria included review articles, case reports, case series, letters to the editor, and conference abstracts or posters, as these did not provide primary data relevant to treatment efficacy.

Quality assessment

The methodological quality of the included studies was assessed using the critical appraisal checklist provided by the Joanna Briggs Institute (JBI) (https://jbi.global/critical-appraisal-tools) (Figure 2). Full-text articles meeting the inclusion criteria were independently reviewed for quality by two researchers (M.R & R.K). Any disagreements with the reviewer were resolved through discussion to reach a consensus (M.A.K). A standardized data extraction sheet was then developed to systematically collect relevant study details, including authors’ names, study location, study design, sample size, participant demographics (age and gender), treatment protocols, follow-up duration, and key outcomes related to treatment response and toxicity.

Figure 2.

Figure 2

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Quality assessment of the included studies.

Statistical analysis

This meta-analysis evaluated the efficacy of high-dose versus low-dose CART-19 in patients with relapsed or refractory CLL. Data analysis was conducted using Stata version 13.1 (Stata Corp, College Station, TX, USA). The results were reported as standardized mean difference (SMD) with 95% confidence intervals (CI) and visualized in a forest plot. Heterogeneity among studies was assessed using the I2 statistic, with a random-effects model applied when significant heterogeneity was detected (I2>50%). To evaluate the robustness of findings, sensitivity analysis was performed by sequentially excluding individual studies and repeating the meta-analysis. Additionally, potential publication bias was examined through funnel plot asymmetry and Egger’s regression analysis.

Results

A systematic literature search was conducted in PubMed, Scopus, and Web of Science, yielding a total of 101 articles. After removing 14 duplicate records, 34 studies remained following title and abstract screening. Subsequently, 4 studies met the full-text eligibility criteria and were included in the final review, while the remaining studies were excluded due to irrelevance (Figure 1).

Figure 1.

Figure 1

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PRISMA 2020 flow diagram. Flowchart depicting the study selection process for the systematic review and meta-analysis. A total of 101 records were identified from PubMed, Scopus, Google Scholar, and Web of Science. After the removal of 14 duplicate records, 87 studies were screened based on title and abstract. Following the exclusion of 53 studies due to irrelevance, 34 full-text articles were assessed for eligibility. Of these, 30 were excluded for not meeting the inclusion criteria. Ultimately, 4 studies were included in the final systematic review and meta-analysis.

This systematic review and meta-analysis incorporated four randomized controlled trials (RCTs) involving 89 participants with relapsed or refractory CLL in the active disease stage. All trials were conducted in the United States, specifically in Philadelphia and New York. The follow-up period ranged from one month to two years, with participants’ ages varying between 54 and 76 years; approximately 30% of the cohort was female. Lymphodepleting regimens were administered before T-cell infusion in all RCTs, commonly using regimens such as Fludarabine/Cyclophosphamide, Pentostatin/Cyclophosphamide, or Bendamustine.

The included trials evaluated response parameters, including complete response (CR), partial response (PR), and overall response rate (ORR), comparing high-dose infusion (5 × 108) versus low-dose infusion (5 × 107) of CART-19. The safety profile of CART-19 therapy was assessed in all trials, with CRS being the most frequently reported adverse event. Table 2 presents the detailed characteristics of the included studies.

Table 2.

Baseline characteristics of the included studies

Author (Year) Country Study design Duration of follow up (months) Participants Age (years) Sex % (female) Side effects Response
Porter et al. (2013) [25] USA RCT 3 (1.3-5) Total (n=10) 63 (59-76) 30% • CRS (n=7) • Overall: 2 CR, 2 PR
• HD1: 4 • HD: 3 • HD: 2 (CR or PR)
• LD2: 6 • LD: 4 • LD: 2 (CR or PR)
Porter et al. (2014) [26] USA RCT 7.3 (1-16) Total (n=23) 62 (54-76) 33% • CRS (n=13) • Overall: 5 CR, 4 PR (3/9 later progressed)
• HD: 11 • HD: 6 • HD: 6 (CR or PR)
• LD: 12 • LD: 7 • LD: 3 (CR or PR)
Frey et al. (2020) [28] USA RCT 31.5 (2-75) Total (n=32) 61.3 (48.8-76.1) 22% • HD: 5 pts with infection, 1 pt with second malignancy, 5 pts with CRS • Overall: 9 CR, 5 PR, 15 PD, 2 Died
• HD: 19 • LD: 4 pts with infection, 3 pts with CRS • HD: 7 CR, 3 PR, 7 PD, 1 Died
• LD: 13   • LD: 2 CR, 2 PR, 8 PD, 1 Died
Porter et al. (2016) [27] USA RCT 9 (1-34) Total (n=24) 62 NM CRS (numbers not specified by dosage) • Overall: 5 CR, 5 PR
• HD: 11 • HD: 4 CR, 2 PR
• LD: 13 • LD: 1 CR, 3 PR
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Abbreviations: RCT, Randomized Controlled Trial; HD, High Dose; LD, Low Dose; CR, Complete Response; PR, Partial Response; CRS, Cytokine Release Syndrome; PD, Progressive Disease; NM, Not Mentioned.

1

HD: single dose of 5 × 108 CART-19.

2

LD: single dose of 5 × 107 CART-19.

A pooled analysis of four RCTs demonstrated a statistically significant improvement in complete and partial response rates in patients receiving high-dose CAR-T19 therapy compared to those in the low-dose group (SMD [95% CI]: 1.02 [0.10, 1.94]; P<0.05, Figure 3). Importantly, no heterogeneity was detected among the included studies (I2=0.00%). In contrast, the incidence of cytokine release syndrome (CRS) did not differ significantly between the high-dose and low-dose groups (SMD [95% CI]: 0.21 [-0.78, 1.20]; P>0.05, Figure 4), with similarly low heterogeneity (I2=0.00%).

Figure 3.

Figure 3

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Forest plot comparing complete/partial response between low-dose and high-dose CAR-T19 treatment.

Figure 4.

Figure 4

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Forest plot comparing cytokine release syndrome (CRS) between low-dose and high-dose CAR-T19 treatment.

Publication bias

Publication bias was assessed in the comparison of high-dose versus low-dose CART-19 therapy in relapsed CLL. The funnel plot revealed asymmetry (Figure 5), raising concerns about potential bias. However, Begg’s test (P=1.00) and Egger’s test (P=0.78) indicated no statistically significant publication bias.

Figure 5.

Figure 5

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Assessment of publication bias in the included studies.

Outlier detection and sensitivity analysis

An L’Abbé plot was constructed to assess patient remission rates between high-dose and low-dose groups, revealing no outlier studies (Figure 6). Sensitivity analysis was conducted by systematically removing individual studies and reassessing the pooled results. The findings demonstrated that no single study significantly influenced the overall effect size, confirming the robustness and stability of the results.

Figure 6.

Figure 6

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Outlier detection in the included studies.

Discussion

CAR T-cell therapy has demonstrated promising outcomes in the treatment of relapsed and refractory CLL. However, the optimal dosage of CART-19 treatment remains a subject of ongoing debate among researchers. This systematic review aimed to assess the efficacy and safety of high-dose (5 × 108 cells) and low-dose (5 × 107 cells) of CART-19 therapy in patients with relapsed or refractory CLL. A comprehensive literature search was conducted to identify relevant clinical trials evaluating CART-19 in this patient population. The review included four RCTs with a total of 89 participants. The findings indicate that patients receiving high-dose CART-19 exhibited a higher rate of complete or partial remission compared to those receiving low-dose CART-19. Moreover, the incidence of CRS did not differ significantly between the two dosage groups, suggesting comparable safety profiles.

Our findings suggests a potential advantage of high-dose CART-19 therapy over low-dose therapy in achieving complete or partial remission in relapsed or refractory CLL, although differences favored the high-dose group, they did not reach statistical significance in all studies. Porter et al., in two separate studies conducted in 2013 [25] and 2014 [26], reported higher response rates in the high-dose groups, with 6 out of 13 (46.2%) and 7 out of 19 (36.8%) patients achieving remission, respectively, compared to 3 out of 13 (23.1%) and 2 out of 13 (15.4%) in the low-dose groups. In contrast, Porter et al. [27] and Frey et al. [28] did not observe a substantial difference, reporting response rates of 6 out of 11 (54.5%) vs. 4 out of 13 (30.8%) and 2 out of 4 (50%) vs. 2 out of 4 (50%) for high-dose and low-dose groups, respectively.

While these findings suggest a potential benefit of high-dose CART-19 therapy, the lack of statistical significance and the variability in response rates across studies indicate that dosing may not be the sole determinant of therapeutic efficacy. Factors such as patient-specific immune responses, disease burden, and prior treatments may contribute to the observed differences. Additionally, the absence of heterogeneity among the included studies (I2=0.00%) suggests methodological consistency, yet the relatively small sample sizes limit the generalizability of the findings. Given the marginal statistical significance (P=0.03) and wide confidence intervals, further well-powered, multi-center clinical trials with longer follow-up periods are necessary to establish a definitive dosing strategy for CART-19 therapy in relapsed or refractory CLL.

Over the past few decades, cell-based immunotherapy has emerged as a promising strategy for treating malignant diseases. This approach utilizes patient-derived immune cells, which are expanded in vitro and genetically modified to enhance their ability to identify and eliminate tumor cells [29]. Several T cell-based therapeutic modalities have been developed for malignancies, including tumor-infiltrating lymphocytes (TILs), T-cell receptor (TCR)-engineered T cells, and CAR T-cells [29,30]. Among these, CAR T-cell therapy has demonstrated superior and more sustained clinical responses compared to TIL and TCR-modified T-cell therapies [30,31]. CAR T-cells are genetically engineered lymphocytes equipped with synthetic receptors that facilitate the recognition and destruction of tumor cells expressing the target antigen. These receptors, known as CARs (chimeric antigen receptors), are artificial constructs that include a single-chain variable fragment (ScFv) of an antibody for antigen recognition and an intracellular T-cell activation domain [32].

While CAR T-cell therapy has shown promising results, it may also be associated with adverse effects, including cytokine release syndrome (CRS) and neurological complications such as headaches, ataxia, and tremors [33,34]. CRS emerged as the predominant adverse reaction observed in hematologic cancer research involving CAR-T cell therapy. CRS is a systemic inflammatory response triggered by various factors, including infections and certain immunotherapies. It is notably associated with CAR T-cell treatments, where rapid activation of T cells leads to the release of pro-inflammatory cytokines. Clinically, CRS presents with symptoms ranging from fever and fatigue to more severe manifestations like hypotension and multi-organ dysfunction [35]. This side effect, which is distinctive and frequently severe, was commonly documented in the studies. Nevertheless, our data analysis did not reveal any correlation between this unfortunate occurrence and doses of CART-19, and the incidence of CART-19 doses of CRS was not significant in these two groups.

This systematic review and meta-analysis is the first to comprehensively evaluate the effects of high-dose and low-dose CART-19 therapy in relapsed and refractory CLL, directly comparing their impact on partial remission, complete remission, and cytokine release syndrome. By synthesizing data from multiple studies, this analysis offers valuable insights into the potential benefits of high-dose CART-19 therapy, suggesting that it may be associated with higher response rates and improved survival outcomes compared to low-dose therapy. Furthermore, including multiple randomized trials enhances the robustness of the findings, contributing to a more comprehensive understanding of dosing strategies in CART-19 therapy.

Despite its strengths, this review has several limitations. The variability in study outcomes highlights the need for further research to determine the optimal dosage of CART-19, particularly considering the balance between efficacy and toxicity, such as CRS and neurotoxicity. Additionally, the small number of included studies limits the statistical power and generalizability of the findings. The lack of large-scale, multi-center trials with diverse patient populations restricts the applicability of the results across different racial and geographical groups. Therefore, further methodologically rigorous RCTs with larger sample sizes and extended follow-up periods are necessary to validate these findings and establish more definitive dosing guidelines for CART-19 therapy in relapsed and refractory CLL.

Conclusion

This systematic review and meta-analysis assessed the efficacy and safety of high-dose and low-dose CART-19 therapy in patients with relapsed and refractory CLL. The findings suggest that high-dose CART-19 may be associated with higher response rates and improved survival outcomes compared to low-dose therapy. However, the observed differences were not consistently significant across studies, and the variability in results underscores the need for further investigation. Given the limited number of included studies and small sample sizes, additional well-designed, large-scale RCTs are necessary to establish the optimal CART-19 dosage while ensuring a balance between therapeutic efficacy and safety. Expanding research to include diverse populations and longer follow-up periods will further enhance the generalizability and clinical applicability of these findings.

Acknowledgements

The authors would like to thank the researchers whose work was included in this study.

Disclosure of conflict of interest

None.

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