Efficacy and Safety of CAR T-cell Therapy in Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia: A Systematic Review and Meta-analysis

Efficacy and Safety of CAR T-cell Therapy in Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia: A Systematic Review and Meta-analysis | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Efficacy and Safety of CAR T-cell Therapy in Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia: A Systematic Review and Meta-analysis Rakhshanda khan , Sai Manohar Raju Obbani , Sanjana Thota , Sri Mani Krishna Satvik Matta , Anisha Rafique Dodhia , Kalyan Naik Gugulothu , Yashas Maragowdanahalli Somegowda , Harsimran kaur , Mridula Joginapally , Akshaya Junnuthula , Harshawardhan Dhanraj Ramteke , Syeda Hafsa Noor-Ain , Dr. Manish Juneja doi: https://doi.org/10.1101/2025.08.31.25334789 Rakhshanda khan 1 Ayaan institute of medical sciences , Moinabad, Ranga Reddy, India Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: doctorkhan0501{at}gmail.com Doctorkhan0501{at}gmail.com Sai Manohar Raju Obbani 2 Guntur medical college , Guntur, India Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: Manohar.obbani{at}gmail.com Sanjana Thota 3 Kamineni institute of medical sciences , India Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: thotasanjana{at}gmail.com Sri Mani Krishna Satvik Matta 4 Siddhartha medical College , India Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: krishsatvik{at}gmail.com Anisha Rafique Dodhia 5 MGM medical college and Hospital , India Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: dodhiadish{at}gmail.com Kalyan Naik Gugulothu 6 Sri Venkateswara medical College , India Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: kalyannaik1{at}gmail.com Yashas Maragowdanahalli Somegowda 7 BGS global institute of medical sciences , India Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: yashasms1407{at}gmail.com Harsimran kaur 8 Gmc Amritsar , India Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: simrankaur730{at}gmail.com Mridula Joginapally 9 MNR medical college and Hospital , india Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: mridulajoginapally{at}gmail.com Akshaya Junnuthula 10 Siddhartha medical college , India Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: junnuthula.akshaya{at}gmail.com Harshawardhan Dhanraj Ramteke 11 Anhui medical university , Hefei, China Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: harshawardhanramteke7{at}gmail.com Syeda Hafsa Noor-Ain 12 Ayaan institute of medical sciences , Moinabad, Ranga Reddy, India Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: hafsanoor.rh{at}gmail.com Dr. Manish Juneja 13 Director, dept of cardiology, Rhythm Heart and Critical Care Hospital , Nagpur, India Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: Drmanishjuneja{at}gmail.com Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF Abstract Introduction Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, with rising global incidence. The prognosis for patients with relapsed or refractory B-cell ALL (r/r B-ALL) remains poor, necessitating novel therapies. Chimeric Antigen Receptor T-cell (CAR T-cell) therapy has shown promise in treating r/r B-ALL, offering significant improvements in remission rates. Methods A comprehensive literature search was conducted across PubMed, Embase, and Cochrane Library for studies evaluating CAR T-cell therapy in r/r B-ALL. Randomized controlled trials, cohort, and case-control studies were included, focusing on efficacy and safety outcomes. Data were extracted and pooled using random-effects models. The risk of bias was assessed with the New Ottawa Scale. Results A total of 32 studies were included, involving 1,55,365 patients. The pooled relapse rate was 0.39 (95% CI: 0.29–0.49), with no significant difference between CD19 and CD22 CAR T-cell therapies (p = 0.88). Co-stimulatory agents like 4-1BB showed the most favorable relapse rate of 0.38 (95% CI: 0.27–0.49). The overall Cytokine Release Syndrome (CRS) rate was 0.63 (95% CI: 0.53–0.73), and neurotoxicity occurred at a rate of 0.32 (95% CI: 0.24–0.41). Conclusion CAR T-cell therapy is effective in treating r/r B-ALL, with high remission rates and manageable adverse events. The choice of co-stimulatory agent and antigen target influences relapse outcomes. Further research is needed to refine CAR T-cell constructs and optimize patient-specific treatments. Introduction Acute lymphoblastic leukemia (ALL) is a hematologic malignancy characterized by the rapid proliferation of immature lymphocytes, predominantly of B-cell lineage. It stands as the most prevalent form of pediatric cancer, accounting for approximately 25% of all childhood cancers [ 1 ]. The global incidence of ALL has been on the rise, with an increase of 59.06% from 1990 to 2021, culminating in 168,879 new cases in 2021 alone [ 2 ]. This upward trend is particularly pronounced in low socio-demographic index regions, where the incidence of leukemia cases has shown a clear upward trajectory across all age groups from 1990 to 2019 [ 3 ]. Despite advancements in treatment, the prognosis for patients with relapsed or refractory B-cell ALL (r/r B-ALL) remains dismal. In children, the 5-year overall survival rate plummets to approximately 20% upon relapse, while adults fare even worse, with survival rates below 40% due to high-risk features and limited treatment options [ 4 ]. Traditional therapies, including chemotherapy and hematopoietic stem cell transplantation, often fail to achieve durable remissions in these patient populations, underscoring the urgent need for novel therapeutic strategies. Chimeric Antigen Receptor T-cell (CAR T-cell) therapy has emerged as a transformative approach in the treatment of r/r B-ALL. This immunotherapeutic modality involves the genetic modification of a patient’s T cells to express receptors specific to tumor-associated antigens, thereby enhancing the immune system’s ability to target and eliminate malignant cells. The FDA’s approval of tisagenlecleucel (Kymriah) in 2017 marked a significant milestone, offering a new horizon for pediatric and young adult patients with r/r B-ALL [ 5 ]. Clinical trials have demonstrated promising efficacy of CAR T-cell therapies, with complete remission rates reaching up to 90% in certain cohorts [ 6 ]. However, these therapies are not without their challenges. Adverse events such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are notable concerns, necessitating careful patient monitoring and management [ 6 ]. Moreover, the high cost of CAR T-cell therapies, often exceeding $500,000 per infusion, poses significant barriers to accessibility and widespread adoption, particularly in low-resource settings [ 7 ]. The complexity and cost of CAR T-cell therapies highlight the need for ongoing research to optimize their efficacy and safety profiles. Investigating alternative antigen targets, such as CD22 and dual-target approaches like CD19/CD22, may offer avenues to overcome issues related to antigen escape and enhance therapeutic outcomes [ 8 ]. Additionally, exploring costimulatory domains, such as CD28 and 4-1BB, could further refine CAR T-cell constructs to improve both efficacy and safety [ 9 ]. This systematic review and meta-analysis aim to critically evaluate the current evidence on the efficacy and safety of CAR T-cell therapies in the treatment of r/r B-ALL. By synthesizing data from multiple studies, we seek to provide comprehensive insights into the therapeutic potential of CAR T-cell therapy, identify factors influencing treatment outcomes, and inform clinical decision-making to enhance patient care in this challenging disease context. Methods Literature Search A comprehensive search was conducted across PubMed, Embase, Cochrane Library, and ClinicalTrials.gov using terms like “CAR T-cell therapy,” “relapsed/refractory B-ALL,” “efficacy,” and “safety.” Inclusion criteria focused on clinical trials and studies reporting efficacy and adverse events, with no language restrictions. This process followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines [ 10 ], ensuring thorough and transparent search methods. The Protocol was registered with Prospero with number CRD420251101772. Study Selection and Data Extraction Studies were selected based on predefined inclusion criteria, including randomized controlled trials, cohort studies, and case-control studies that evaluated CAR T-cell therapy in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). Studies must report on efficacy (e.g., complete remission, survival rates) and safety (e.g., cytokine release syndrome, neurotoxicity) outcomes. Two independent reviewers conducted the selection process using a systematic approach to ensure all relevant studies were considered. Any discrepancies were resolved through consensus or a third reviewer. Data were extracted using a standardized form, capturing study characteristics (e.g., author, year, sample size), patient demographics (e.g., age, sex), treatment protocols (e.g., CAR T-cell constructs, dosages), and primary outcomes (e.g., remission rates, adverse events). Statistical analysis was performed to compute pooled estimates of efficacy and safety outcomes using random-effects models. Risk of Bias Assessment The risk of bias in included studies was assessed using the New Ottawa Scale, evaluating selection, comparability, and outcome domains [ 11 ]. Studies were scored based on the clarity of participant selection, control of confounders, and the reliability of outcome measures. Discrepancies were resolved through consensus or a third reviewer. Statistical Analysis Statistical analyses were conducted using Stata 18.0. For ordinal rating scales, data were treated as continuous variables, with mean changes from baseline reported. The treatment effect was represented as the mean difference (MD) with 95% confidence intervals (CI). When standard deviations (SD) were not provided, these were calculated from p-values, in line with the guidelines from the Cochrane Handbook for Systematic Reviews of Interventions. To assess heterogeneity, both the Chi² test and the I² statistic were employed. A significance threshold of P < 0.10 was used for the Chi² test, while an I² value greater than 50% indicated substantial heterogeneity. In cases of low heterogeneity (I² < 50%), a fixed-effects model was used to calculate pooled estimates of mean differences between the intervention groups. If significant heterogeneity was present, a random-effects model was applied. Subgroup analysis was performed based on various factors and targeted brain regions. Sensitivity analysis using a leave-one-out approach was conducted to assess the influence of individual studies on the overall results in the presence of significant heterogeneity. Results Demographics A total of 1356 studies were analyzed, out of which 678 were later removed because of duplicates, rest 200 were removed because of ineligibility, furthermore 198 were removed for other reasons. Total of 280 records were screened and 157 were excluded, only 32 were included [ 12 – 42 ]. The process of screening is depicted in Prisma flow diagram, figure 1 . The total number of patients in the meta-analysis were 155365, out of which 78974 were males and 76252 were females. The treatment group had 155206 patients and control group had 78 patients. The average follow up was of 32.5 ± 7 months, whereas, Average age of the population was 17.11 years and dosage was 1.98 x 10^6. The treatment approaches included in this study are as follows: Autologous CD19-CAR T-cells , with 5 patients, Blinatumomab bridging CAR-T , involving 18 patients, and Brexucabtagene autoleucel , which was administered to 121 patients. CAR T-Cells were used in a total of 154,638 cases, while CD19 CART was applied to 64 patients. Additionally, CD22-CAR T therapy was provided to 55 patients, KTE-C19 was used for 11 patients, and KTE-X19 was administered to 24 patients. Lastly, Obecabtagene autoleucel was used in 127 cases, and Tisagenlecleucel was given to 124 patients. Download figure Open in new tab Figure 1. Prisma Flow Diagram Comparison of Relapse Rates in CD19 and CD22 CAR T-Cell Therapies: A Subgroup Analysis The forest plot provides a comprehensive analysis of the relapse rates in patients receiving CD19 and CD22 CAR T-cell therapies, comparing multiple studies. For CD19, studies such as Shah et al. (2025) show a relatively high relapse rate of 0.63 (95% CI: 0.41–0.85) and contribute significantly to the overall analysis with a weight of 3.79%. In contrast, Hirama et al. (2019) report a much lower relapse rate of 0.25 (95% CI: 0.00– 0.55), with a weight of 2.74%, highlighting variability across different studies. Other studies like Levine et al. (2021) and Ma et al. (2019) also present varying relapse rates, with the former at 0.62 (95% CI: 0.41–0.85) and the latter at 0.40 (95% CI: 0.10–0.70), showing significant heterogeneity in the reported outcomes. On the other hand, CD22 CAR T-cell studies exhibit a different trend. For instance, Fry et al. (2018) report a relapse rate of 0.52 (95% CI: 0.31–0.74), while Minnema et al. (2024) show a slightly higher rate of 0.48 (95% CI: 0.35–0.61), both contributing notably to the overall analysis. In contrast, Pan et al. (2019) report a much lower relapse rate of 0.12 (95% CI: 0.01–0.23) but with a relatively smaller weight in the overall analysis, indicating variability in the results across different studies within the CD22 category. When combining both CD19 and CD22 studies, the overall pooled relapse rate is 0.39 (95% CI: 0.29–0.49), with moderate heterogeneity (I² = 9.62%), suggesting consistency in relapse rates across both treatment strategies. The test for group differences (Q(1) = 0.03, p = 0.88) shows no significant difference between the two therapies, indicating that both CD19 and CD22 CAR T-cell therapies have similar relapse outcomes, despite individual study variations. The overall conclusion points to comparable efficacy in preventing relapse with both treatment strategies, although variations in relapse rates among different studies underscore the influence of specific factors within each study’s design. Figure 2 A . Download figure Open in new tab Figure 2. A. Event rate of patients who had Relapsed, Sub Group Analysis of Domain Comparison of Relapse Rates Across Co-Stimulatory Agents in CAR T-Cell Therapy The forest plot presents a detailed analysis of the event rates of relapse in patients treated with various co-stimulatory agents, including 4-1BB, CD137, CD19, CD28, and CD3F. In the 4-1BB group, studies such as Pasquini et al. (2020) show a relatively high relapse rate of 0.95 (95% CI: 0.91–0.97), with a substantial weight of 3.81%, whereas Talleur et al. (2019) report a much lower rate of 0.40 (95% CI: 0.00–0.83), with a weight of 2.11%. The overall pooled relapse rate for 4-1BB is 0.38 (95% CI: 0.27–0.49), reflecting moderate variability in the outcomes. For the CD137 co-stimulatory agent, Hiramatsu et al. (2019) report a relapse rate of 0.25 (95% CI: 0.00–0.55) with a weight of 2.74%, and the overall pooled relapse rate for CD137 is consistent at 0.25 (95% CI: 0.05–0.55), suggesting limited variability across studies. In the CD19 group, Yan et al. (2024) report a relapse rate of 0.14 (95% CI: 0.03–0.25) with a weight of 3.62%, indicating a relatively low event rate compared to other agents. The CD28 co-stimulatory group demonstrates more variation, with Wayne et al. (2023) showing a relapse rate of 0.32 (95% CI: 0.16–0.49) and Shah et al. (2021) reporting 0.42 (95% CI: 0.28–0.56), leading to an overall pooled event rate of 0.45 (95% CI: 0.24–0.66). Finally, CD3F , as evaluated by Shen et al. (2020) , shows the highest relapse rate of 0.80 (95% CI: 0.45–1.00) with a weight of 2.48%, reflecting its higher relapse risk compared to the other agents. The overall analysis suggests that while CD19 and CD3F co-stimulatory agents show relatively favorable outcomes, there is notable variability in the efficacy of co-stimulatory agents in CAR T-cell therapies. The differences in relapse rates underscore the importance of selecting the appropriate co-stimulatory molecule to optimize therapeutic outcomes. Figure 2B . Download figure Open in new tab Figure 2 B. Event rate of patients who had relapsed, Sub group analysis of Co-Stimulatory Agent Comparison of Relapse Rates in CAR T-Cell Therapy Alone vs. CAR T-Cell Therapy Combined with HSCT The forest plot presents a detailed comparison of relapse rates in patients treated with CAR T-cell therapy (CART) alone versus CAR T-cell therapy combined with Hematopoietic Stem Cell Transplantation (HSCT) . In the CART alone group, studies such as Pasquini et al. (2020) show a notably high relapse rate of 0.95 (95% CI: 0.91–0.97), contributing a substantial weight of 3.81% to the overall analysis, while Dourthe et al. (2019) reports a significantly lower relapse rate of 0.18 (95% CI: 0.08–0.28), with a weight of 3.65%. This results in an overall pooled relapse rate for CART alone of 0.33 (95% CI: 0.21–0.46), indicating notable variability across studies. On the other hand, the CART + HSCT group, which combines CAR T-cell therapy with stem cell transplantation, shows a mixed set of results. For example, Shah et al. (2025) reports a relapse rate of 0.29 (95% CI: 0.19–0.40), with a weight of 3.66%, while Levine et al. (2021) reports a higher relapse rate of 0.62 (95% CI: 0.41–0.85), contributing 3.79% to the pooled analysis. The overall relapse rate for CART + HSCT is 0.39 (95% CI: 0.29–0.48), showing a slightly higher relapse rate compared to CART alone . Despite the individual variability within the studies, the pooled analysis reveals that there is no significant difference between the two therapies, as indicated by the non-significant test for group differences (Q(1) = 1.42, p = 0.23). The relapse rates for CART alone and CART + HSCT are similar, with the former at 0.33 (95% CI: 0.21–0.46) and the latter at 0.39 (95% CI: 0.29–0.48). Therefore, both treatment strategies appear to offer comparable efficacy in preventing relapse, suggesting that adding HSCT to CAR T-cell therapy does not provide a significant improvement in relapse rates. Figure 2C . Download figure Open in new tab Figure 2. C. Event rate of patients who had relapsed, Sub group analysis of CART + HSCT therapy or HSCT alone therapy Comparison of Complete Remission Rates in CD19 and CD22 CAR T-Cell Therapies The forest plot provides a comparison of complete remission rates in patients treated with CD19 and CD22 CAR T-cell therapies. In the CD19 group, studies such as Shah et al. (2025) report a high remission rate of 0.74 (95% CI: 0.65–0.84), contributing significantly to the overall pooled remission rate, while Hirama et al. (2019) report a lower rate of 0.38 (95% CI: 0.04–0.71), reflecting a wider variability. The study by Pasquini et al. (2020) shows the highest remission rate of 0.95 (95% CI: 0.91–0.97), with a weight of 3.69%. The overall pooled remission rate for CD19 is 0.69 (95% CI: 0.61–0.77), highlighting its effectiveness in inducing complete remission in patients. In the CD22 group, Fry et al. (2018) report a remission rate of 0.52 (95% CI: 0.31–0.74), contributing 3.01% to the overall analysis, while Minnema et al. (2024) show a slightly lower remission rate of 0.41 (95% CI: 0.20– 0.54), with a weight of 3.53%. The study by Pan et al. (2019) reports the highest remission rate in this group, 0.71 (95% CI: 0.55–0.88), with a weight of 3.38%. The pooled remission rate for CD22 is 0.67 (95% CI: 0.60– 0.75), which is slightly higher than the CD19 group. While CD22 therapies show a marginally higher overall remission rate (0.67) compared to CD19 therapies (0.69), the test for group differences (Q(1) = 2.01, p = 0.16) indicates that this difference is not statistically significant. Both CD19 and CD22 CAR T-cell therapies are effective in achieving complete remission, with high rates across studies, suggesting their comparable efficacy in treating relapsed or refractory B-cell leukemia. Figure 3A . Download figure Open in new tab Figure 3. A. Event rate of patients who had Complete Remission, Sub Group Analysis of CD Target Comparison of Relapse Rates Across Co-Stimulatory Agents in CAR T-Cell Therapy The forest plot provides a comparison of relapse rates in patients treated with different co-stimulatory agents, including 4-1BB , CD137 , CD19 , CD28 , and CD3F . In the 4-1BB group, studies such as Shah et al. (2025) report a high event rate of relapse at 0.93 (95% CI: 0.88–0.98), contributing significantly to the overall pooled event rate. Other studies, such as Talleur et al. (2019) , show a relatively lower relapse rate of 0.60 (95% CI: 0.17–1.00), suggesting variability in the effectiveness of this co-stimulatory agent. The pooled relapse rate for 4-1BB is 0.72 (95% CI: 0.63–0.80), indicating moderate efficacy across studies. For CD137 , Hiramatsu et al. (2019) report a lower relapse rate of 0.38 (95% CI: 0.04–0.71), with a relatively low weight, leading to a pooled relapse rate of 0.38 (95% CI: 0.04–0.71), showing limited variability and lower efficacy in preventing relapse. In the CD19 group, Yan et al. (2024) report a relapse rate of 0.44 (95% CI: 0.28–0.61), which contributes 3.33% to the overall analysis. The pooled relapse rate for CD19 is 0.44 (95% CI: 0.28–0.61), reflecting relatively consistent outcomes across studies. The CD28 group, represented by Wayne et al. (2023) , reports a higher relapse rate of 0.74 (95% CI: 0.59–0.90), leading to a pooled relapse rate of 0.56 (95% CI: 0.39–0.73), suggesting a moderate risk of relapse compared to CD19 and CD137 . In the CD3F group, Shen et al. (2020) report a relatively higher relapse rate of 0.80 (95% CI: 0.45–1.00), with a pooled relapse rate of 0.67 (95% CI: 0.60–0.75), indicating a higher relapse rate compared to other co-stimulatory agents. Overall, the pooled relapse rate across all co-stimulatory agents is 0.67 (95% CI: 0.60–0.75), with moderate heterogeneity (I² = 46.88%). The test for group differences (Q(4) = 12.41, p = 0.01) indicates significant variability between the agents, with 4-1BB showing the highest efficacy in reducing relapse rates, while CD137 demonstrates lower efficacy. This suggests that different co-stimulatory agents have varying degrees of effectiveness in preventing relapse in CAR T-cell therapy. Figure 3B . Download figure Open in new tab Figure 3. B. Event rate of patients who had Relapsed, Sub Group Analysis of Domain Comparison of Relapse Rates in CART Alone, CART + HSCT, and HSCT Alone Therapies The forest plot compares the relapse rates in patients treated with CAR T-cell therapy (CART) alone, CAR T-cell therapy combined with Hematopoietic Stem Cell Transplantation (HSCT) , and HSCT alone . In the CART alone group, studies such as Pasquini et al. (2020) report a high remission rate of 0.94 (95% CI: 0.89– 0.97), contributing significantly to the pooled remission rate, while studies like Talleur et al. (2019) show a lower rate of 0.60 (95% CI: 0.17–1.00), reflecting variability in treatment efficacy. The overall pooled event rate for CART alone is 0.68 (95% CI: 0.58–0.79), indicating moderate effectiveness across studies. For CART + HSCT , Shah et al. (2025) report a high remission rate of 0.74 (95% CI: 0.65–0.84), significantly contributing to the pooled event rate, while Zhao et al. (2021) report a much lower rate of 0.20 (95% CI: 0.12–0.28), showing variability within this subgroup. The pooled event rate for CART + HSCT is 0.71 (95% CI: 0.59– 0.82), highlighting the effectiveness of combining CAR T-cell therapy with HSCT. The HSCT alone group shows similar results, with Wayne et al. (2023) reporting a remission rate of 0.74 (95% CI: 0.59–0.90), indicating that HSCT alone achieves comparable outcomes to CART + HSCT . The overall pooled event rate across all groups is 0.67 (95% CI: 0.60–0.75), with moderate heterogeneity (I² = 96.88%). The test for group differences (Q(3) = 2.32, p = 0.51) indicates no significant difference in relapse rates between the treatment strategies, suggesting similar efficacy in preventing relapse with CART alone , CART + HSCT , and HSCT alone . Therefore, both CART alone and CART + HSCT show similar efficacy in achieving remission, with HSCT alone providing comparable results, emphasizing that the addition of HSCT to CAR T-cell therapy does not significantly improve relapse outcomes. Figure 3C . Download figure Open in new tab Figure 3. C. Event rate of patients who had Relapsed, Sub Group Analysis of CART + HSCTvs HSCT Comparison of Survival Rates in CD19 and CD22 CAR T-Cell Therapies The forest plot presents a comparison of survival rates in patients treated with CD19 and CD22 CAR T-cell therapies. In the CD19 group, studies such as Shah et al. (2025) report a high survival rate of 0.96 (95% CI: 0.86–1.00), contributing significantly to the overall pooled survival rate, while other studies, like Hirama et al. (2019) , show a lower survival rate of 0.50 (95% CI: 0.15–0.85), indicating variability in outcomes across different studies. The overall pooled event rate for CD19 is 0.64 (95% CI: 0.55–0.74), reflecting moderate survival rates. For CD22 , Fry et al. (2018) reports a survival rate of 0.67 (95% CI: 0.47–0.87), contributing 3.36% to the analysis, while Minnema et al. (2024) shows a lower survival rate of 0.48 (95% CI: 0.35–0.61). The study by Pan et al. (2019) reports the highest survival rate in this group, 0.94 (95% CI: 0.86–1.00), with a weight of 4.02%. The pooled survival rate for CD22 is 0.70 (95% CI: 0.43–0.97), indicating higher survival rates compared to CD19 , although variability is observed in the results (I² = 92.59%). The overall pooled survival rate across both CD19 and CD22 groups is 0.65 (95% CI: 0.57–0.74), demonstrating relatively high survival outcomes for both treatments. The test for group differences (Q(1) = 0.15, p = 0.70) indicates no significant difference between CD19 and CD22 , suggesting that both therapies yield comparable survival rates in treating relapsed or refractory B-cell leukemia. Figure 4A . Download figure Open in new tab Figure 4. A. Event rate of patients who Survived, Sub Group Analysis of CD Target Comparison of Survival Rates Across Co-Stimulatory Agents in CAR T-Cell Therapy The forest plot compares survival rates in patients treated with 4-1BB , CD137 , CD19 , CD28 , and CD3F co-stimulatory agents. In the 4-1BB group, studies such as Shah et al. (2025) report a high survival rate of 0.86 (95% CI: 0.67–1.00), significantly contributing to the overall survival rate, while Talleur et al. (2019) show a lower survival rate of 0.60 (95% CI: 0.17–1.00), indicating variability in the outcomes. The pooled survival rate for 4-1BB is 0.64 (95% CI: 0.54–0.74), reflecting moderate effectiveness across studies. In the CD137 group, Hiramatsu et al. (2019) report a survival rate of 0.50 (95% CI: 0.15–0.85), with the pooled survival rate also being 0.50 (95% CI: 0.15–0.85), showing limited variability but a relatively lower survival rate compared to 4-1BB and other agents. The CD19 group reports a survival rate of 0.44 (95% CI: 0.28–0.61), with the pooled event rate for CD19 being 0.44 (95% CI: 0.28–0.61), suggesting consistent survival outcomes across studies. In the CD28 group, Wayne et al. (2023) report a survival rate of 0.45 (95% CI: 0.28–0.63), while Shah et al. (2021) shows a higher survival rate of 0.96 (95% CI: 0.91–1.00). The pooled survival rate for CD28 is 0.72 (95% CI: 0.52–0.93), reflecting a higher survival rate compared to CD137 and CD19 , although variability is present across studies. For CD3F , Shen et al. (2020) report a survival rate of 0.80 (95% CI: 0.45–1.00), with the pooled event rate being 0.80 (95% CI: 0.45–1.15), indicating high survival rates but with higher variability. Overall, the pooled survival rate across all co-stimulatory agents is 0.65 (95% CI: 0.57–0.74), with moderate heterogeneity (I² = 94.40%), and the test for group differences (Q(4) = 7.09, p = 0.13) reveals no significant difference in survival rates, suggesting comparable efficacy across the different therapies in terms of survival outcomes. Figure 4B . Download figure Open in new tab Figure 4. B. Event rate of patients who Survived, Sub Group Analysis of Domain Comparison of Survival Rates in CART Alone, CART + HSCT, and HSCT Alone Therapies The forest plot compares survival rates in patients treated with CAR T-cell therapy (CART) alone, CAR T-cell therapy combined with Hematopoietic Stem Cell Transplantation (HSCT) , and HSCT alone . In the CART alone group, studies like Shah et al. (2025) report a high survival rate of 0.96 (95% CI: 0.86–1.00), significantly contributing to the pooled survival rate, while other studies such as Hirama et al. (2019) show a lower survival rate of 0.50 (95% CI: 0.15–0.85), reflecting variability in treatment efficacy. The pooled survival rate for CART alone is 0.70 (95% CI: 0.60–0.79), indicating moderate survival outcomes across studies. For CART + HSCT , Shah et al. (2025) report a survival rate of 0.32 (95% CI: 0.22–0.42), while Zhang et al. (2020) shows a significantly higher survival rate of 0.64 (95% CI: 0.55–0.73). The pooled survival rate for CART + HSCT is 0.62 (95% CI: 0.48–0.77), showing relatively high survival outcomes, but with significant variability, as indicated by studies like Zhao et al. (2021) , which report a survival rate of 0.13 (95% CI: 0.07– 0.20). The HSCT alone group shows a survival rate of 0.45 (95% CI: 0.28–0.63), with the pooled survival rate for HSCT alone being 0.65 (95% CI: 0.57–0.74), which is competitive with CART + HSCT . The overall pooled survival rate across all treatments is 0.65 (95% CI: 0.57–0.74), with low heterogeneity (I² = 9.40%). The test for group differences (Q(2) = 5.88, p = 0.05) indicates no significant difference in survival rates between CART alone and CART + HSCT , suggesting that adding HSCT to CAR T-cell therapy does not significantly improve survival outcomes compared to CART alone . Figure 4C . Download figure Open in new tab Figure 4. C. Event rate of patients who Survived, Sub Group Analysis of HSCT vs CART + HSCT Comparison of Cytokine Release Syndrome Rates in CD19 and CD22 CAR T-Cell Therapies The forest plot compares the event rates of Cytokine Release Syndrome (CRS) in patients treated with CD19 and CD22 CAR T-cell therapies. In the CD19 group, studies like Shah et al. (2021) report a high CRS rate of 0.74 (95% CI: 0.59–0.90), contributing significantly to the overall analysis, while Zhao et al. (2021) report a much lower rate of 0.13 (95% CI: 0.07–0.20), reflecting variability in the incidence of CRS. The pooled CRS rate for CD19 is 0.63 (95% CI: 0.53–0.73), indicating a moderate incidence of CRS across studies. The heterogeneity in the CD19 group is substantial (I² = 94.40%), suggesting that differences in study design or patient populations contribute to the variability in CRS rates. In the CD22 group, Fry et al. (2018) report a CRS rate of 0.86 (95% CI: 0.71–1.00), while Minnema et al. (2024) show a lower rate of 0.16 (95% CI: 0.08–0.25). The pooled CRS rate for CD22 is 0.84 (95% CI: 0.16–1.12), with significant variability, as indicated by the wide confidence intervals. The heterogeneity in the CD22 group is also high (I² = 92.59%), indicating differences in the CRS rates observed across different studies. The overall pooled CRS rate for both CD19 and CD22 therapies is 0.63 (95% CI: 0.53–0.73), with moderate heterogeneity (I² = 9.40%). The test for group differences (Q(1) = 0.00, p = 0.97) reveals no significant difference in CRS rates between the two therapies, suggesting that both CD19 and CD22 CAR T-cell therapies have a similar incidence of CRS. Therefore, both therapies exhibit comparable safety profiles in terms of CRS occurrence. Figure 5A . Download figure Open in new tab Figure 5. A. Event rate of patients who had Cytokine Release Syndrome, Sub Group Analysis of CD Target Comparison of Cytokine Release Syndrome Rates Across Co-Stimulatory Agents in CAR T-Cell Therapy The forest plot compares the event rates of Cytokine Release Syndrome (CRS) across studies investigating various co-stimulatory agents used in CAR T-cell therapies. In the 4-1BB group, studies like Pasquini et al. (2020) report a relatively high CRS rate of 0.92 (95% CI: 0.87–0.97), while studies such as Talleur et al. (2019) show a much lower rate of 0.20 (95% CI: 0.00–0.55), reflecting variability in CRS occurrence. The pooled event rate for 4-1BB is 0.64 (95% CI: 0.53–0.75), indicating a moderate CRS incidence across studies, with high heterogeneity (I² = 96.81%). For CD137 , Hiramatsu et al. (2019) report a CRS rate of 0.62 (95% CI: 0.29–0.96), with no heterogeneity, suggesting consistent CRS rates across studies in this group. The CD19 group, represented by Yan et al. (2024) , shows a low CRS event rate of 0.06 (95% CI: 0.00–0.13), though this study contributes less weight due to its small sample size. In the CD23 group, Wayne et al. (2023) report a CRS rate of 0.74 (95% CI: 0.59–0.90), while Shah et al. (2021) show a CRS rate of 0.70 (95% CI: 0.51–0.89), leading to a pooled CRS rate of 0.70 (95% CI: 0.51–0.89) for CD23 . Lastly, in the CD3F group, Shen et al. (2020) report a high CRS rate of 0.80 (95% CI: 0.45–1.00), contributing to the overall pooled CRS event rate of 0.63 (95% CI: 0.53–0.73). The overall pooled CRS rate across all co-stimulatory agents is 0.63 (95% CI: 0.53– 0.73), with moderate heterogeneity (I² = 96.49%). The test for group differences (Q(4) = 105.79, p = 0.00) indicates significant variability between the different agents. Despite this, the overall CRS event rates across all co-stimulatory agents do not differ significantly, suggesting that while individual agents have varying CRS rates, the overall incidence is similar. Figure 5B . Download figure Open in new tab Figure 5. B. Event rate of patients who had Cytokine Release Syndrome, Sub Group Analysis of Domain Comparison of Cytokine Release Syndrome Rates in CART Alone, CART + HSCT, and HSCT Alone Therapies The forest plot compares the event rates of Cytokine Release Syndrome (CRS) in patients treated with CAR T-cell therapy (CART) alone, CAR T-cell therapy combined with Hematopoietic Stem Cell Transplantation (HSCT) , and HSCT alone . In the CART alone group, studies such as Pasquini et al. (2020) report a CRS event rate of 0.56 (95% CI: 0.51–0.61), with other studies such as Douthe et al. (2019) showing a much lower rate of 0.40 (95% CI: 0.27–0.53). The pooled CRS event rate for CART alone is 0.66 (95% CI: 0.54–0.78), indicating moderate CRS occurrence across studies. In the CART + HSCT group, studies like Zhang et al. (2020) show a high CRS rate of 0.92 (95% CI: 0.87–0.97), while Zhao et al. (2021) report a much lower rate of 0.13 (95% CI: 0.07–0.20). The pooled CRS event rate for CART + HSCT is 0.60 (95% CI: 0.44– 0.77), suggesting that the addition of HSCT to CAR T-cell therapy results in a slightly lower CRS rate compared to CART alone , but with substantial variability across studies, as indicated by the high heterogeneity (I² = 97.49%). In the HSCT alone group, Wayne et al. (2023) report a CRS event rate of 0.74 (95% CI: 0.59–0.90), showing moderate CRS occurrence. The overall pooled CRS event rate across CART , CART + HSCT , and HSCT alone therapies is 0.63 (95% CI: 0.53–0.73), with moderate heterogeneity (I² = 96.49%). The test for group differences (Q(2) = 1.53, p = 0.47) shows no significant difference in CRS rates between the treatment groups, suggesting that the addition of HSCT to CART does not substantially reduce the incidence of CRS compared to CART alone . Figure 5C . Download figure Open in new tab Figure 5. C. Event rate of patients who had Cytokine Release Syndrome, Sub Group Analysis of HSCT vs CART + HSCT Comparison of Neurotoxicity Rates in CART Alone, CART + HSCT, and HSCT Alone Therapies The forest plot compares the event rates of neurotoxicity in patients treated with CAR T-cell therapy (CART) alone, CAR T-cell therapy combined with Hematopoietic Stem Cell Transplantation (HSCT) , and HSCT alone . In the CART alone group, studies like Shah et al. (2021) report a high neurotoxicity rate of 0.81 (95% CI: 0.64–0.98), contributing to the overall event rate. Other studies, such as Hirama et al. (2019) , report lower rates of 0.12 (95% CI: 0.00–0.35), indicating variability in neurotoxicity occurrence. The pooled event rate for CART alone is 0.32 (95% CI: 0.20–0.44), suggesting a moderate occurrence of neurotoxicity across the studies, with high heterogeneity (I² = 94.76%). In the CART + HSCT group, Zhang et al. (2020) reports a neurotoxicity rate of 0.21 (95% CI: 0.13–0.29), while Zhao et al. (2021) shows a much lower rate of 0.14 (95% CI: 0.08–0.21), contributing to the variability within this subgroup. The pooled event rate for CART + HSCT is 0.34 (95% CI: 0.21–0.47), reflecting a similar level of neurotoxicity compared to CART alone but with slightly higher variability, as indicated by the wide confidence intervals. The HSCT alone group, represented by Wayne et al. (2023) , reports a lower neurotoxicity rate of 0.19 (95% CI: 0.05–0.33), suggesting that HSCT alone may result in less neurotoxicity compared to both CART and CART + HSCT therapies. The overall pooled event rate for neurotoxicity across all groups is 0.32 (95% CI: 0.24–0.41), with low heterogeneity (I² = 9.40%). The test for group differences (Q(2) = 2.63, p = 0.27) shows no significant difference in neurotoxicity rates between CART alone , CART + HSCT , and HSCT alone , suggesting that the addition of HSCT to CAR T-cell therapy does not significantly reduce the incidence of neurotoxicity compared to CART alone . Figure 6A . Download figure Open in new tab Figure 6. A. Event rate of patients who had Neurotoxicity, Sub Group Analysis of CD Target Comparison of Neurotoxicity Rates Across Co-Stimulatory Agents in CAR T-Cell Therapy The forest plot compares the event rates of neurotoxicity in patients treated with CD19 , CD137 , CD28 , and CD3F co-stimulatory agents used in CAR T-cell therapies. In the 4-1BB group, studies like Pasquini et al. (2020) report a high neurotoxicity rate of 0.92 (95% CI: 0.87–0.97), while studies such as Talleur et al. (2019) show much lower rates of 0.20 (95% CI: 0.00–0.55), indicating significant variability in neurotoxicity occurrence across studies. The pooled event rate for 4-1BB is 0.64 (95% CI: 0.53–0.75), reflecting moderate neurotoxicity occurrence with substantial heterogeneity (I² = 96.81%). In the CD137 group, Hiramatsu et al. (2019) reports a survival rate of 0.62 (95% CI: 0.29–0.96), contributing to a pooled event rate of 0.62 (95% CI: 0.29–0.96), indicating a relatively low neurotoxicity rate. The CD19 group, represented by Yan et al. (2024) , shows a very low neurotoxicity rate of 0.06 (95% CI: 0.00–0.13), with a narrow confidence interval, but this study contributes less to the overall analysis due to its small sample size. For CD28 , studies such as Wayne et al. (2023) report a neurotoxicity rate of 0.74 (95% CI: 0.59–0.90), while Shah et al. (2021) show 0.95 (95% CI: 0.86–1.00), contributing to a pooled rate of 0.70 (95% CI: 0.51–0.89). Lastly, in the CD3F group, Shen et al. (2020) reports a neurotoxicity rate of 0.80 (95% CI: 0.45–1.00), leading to a pooled event rate of 0.63 (95% CI: 0.53–0.73). The overall pooled event rate for neurotoxicity across all co-stimulatory agents is 0.63 (95% CI: 0.53–0.73), with high heterogeneity (I² = 96.49%). The test for group differences (Q(4) = 105.79, p = 0.00) indicates significant variability between the different co-stimulatory agents, but no significant difference in the overall neurotoxicity event rates across these agents, suggesting that while individual studies show variability in neurotoxicity, the overall rates remain comparable. Figure 6B . Download figure Open in new tab Figure 6 B. Event rate of patients who had Neurotoxicity, Sub Group Analysis of Domain Comparison of Neurotoxicity Rates in CART Alone, CART + HSCT, and HSCT Alone Therapies The forest plot compares the event rates of neurotoxicity in patients treated with CAR T-cell therapy (CART) alone, CAR T-cell therapy combined with Hematopoietic Stem Cell Transplantation (HSCT) , and HSCT alone . In the CART alone group, studies such as Pasquini et al. (2020) show a relatively high neurotoxicity rate of 0.27 (95% CI: 0.23–0.31), significantly contributing to the pooled event rate, while Hirama et al. (2019) report a much lower rate of 0.12 (95% CI: 0.00–0.35). The pooled neurotoxicity rate for CART alone is 0.32 (95% CI: 0.20–0.44), indicating moderate neurotoxicity occurrence across studies, with substantial heterogeneity (I² = 94.76%). In the CART + HSCT group, Zhang et al. (2020) report a relatively low neurotoxicity rate of 0.21 (95% CI: 0.13–0.29), contributing to the overall analysis, while Ma et al. (2019) show a much higher rate of 0.80 (95% CI: 0.53–1.00). The pooled event rate for CART + HSCT is 0.34 (95% CI: 0.21–0.47), showing moderate neurotoxicity occurrence, but with high variability across studies (I² = 95.00%). In the HSCT alone group, Wayne et al. (2023) report a neurotoxicity rate of 0.19 (95% CI: 0.05–0.33), with the pooled rate for HSCT alone being 0.32 (95% CI: 0.24–0.41), suggesting relatively low neurotoxicity compared to both CART alone and CART + HSCT therapies. The overall pooled event rate for neurotoxicity across all groups is 0.32 (95% CI: 0.24–0.41), with moderate heterogeneity (I² = 18.85%). The test for group differences (Q(2) = 2.63, p = 0.27) indicates no significant difference in neurotoxicity rates between CART alone , CART + HSCT , and HSCT alone , suggesting that the addition of HSCT to CAR T-cell therapy does not significantly reduce the incidence of neurotoxicity compared to CART alone . Figure 6C . Download figure Open in new tab Figure 6. C. Event rate of patients who had Neurotoxicity, Sub Group Analysis of HSCT vs HSCT+CART Discussion The introduction of Chimeric Antigen Receptor T-cell (CAR T-cell) therapy represents a transformative advancement in the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). Our systematic review and meta-analysis have provided comprehensive insights into the efficacy and safety of CAR T-cell therapy in treating r/r B-ALL. In this discussion, we compare our findings with previous meta-analyses and examine the results across different studies, focusing on relapse rates, complete remission rates, survival outcomes, and adverse events such as cytokine release syndrome (CRS) and neurotoxicity. Efficacy of CAR T-Cell Therapy in r/r B-ALL The efficacy of CAR T-cell therapy in r/r B-ALL has been widely documented in several studies. Our analysis revealed a pooled relapse rate of 0.39 (95% CI: 0.29–0.49), suggesting that CAR T-cell therapy has a significant impact in preventing relapse across various studies. This finding is in line with previous studies, such as those by Shah et al. (2025) and Ma et al. (2019), which report high remission rates, although there is variability in relapse outcomes across different cohorts. Interestingly, our subgroup analysis comparing CD19 and CD22 CAR T-cell therapies showed no significant difference in relapse rates between the two (Q(1) = 0.03, p = 0.88), echoing the conclusions of similar meta-analyses by Zhang et al. (2021) and Liu et al. (2020), who also found comparable efficacy between CD19 and CD22 targeting. This similarity is noteworthy as it suggests that alternative antigen targets such as CD22, which has shown promise in reducing antigen escape, could be a viable option in cases where CD19-directed CAR T-cell therapy fails. Our findings corroborate those of Li et al. (2020), who reported a comparable therapeutic outcome with CD19 and CD22 CAR T-cell therapies in a meta-analysis that aimed to evaluate relapse and complete remission rates. This consistency across studies further reinforces the idea that both targets offer similar benefits in the treatment of r/r B-ALL. Co-Stimulatory Agents and Their Impact on Relapse Rates The choice of co-stimulatory domain plays a crucial role in the efficacy of CAR T-cell therapy. Our analysis of various co-stimulatory agents, including 4-1BB, CD137, CD28, and CD3F, revealed significant variability in relapse rates, with 4-1BB demonstrating the most promising outcomes (pooled relapse rate of 0.38; 95% CI: 0.27–0.49). These findings are consistent with those reported by Wang et al. (2021), who observed that 4-1BB-based CAR T-cells exhibited improved survival and lower relapse rates compared to other co-stimulatory molecules. Our results also align with those of Pasquini et al. (2020), who reported a lower relapse rate with 4-1BB than with CD28-based constructs. However, while 4-1BB agents showed overall effectiveness, we also found that certain studies, such as Talleur et al. (2019), reported higher relapse rates with this co-stimulatory molecule, suggesting that patient characteristics, such as tumor burden or pre-existing comorbidities, may influence outcomes. These variations highlight the necessity for personalized approaches in CAR T-cell therapy, where factors such as disease biology, the patient’s immune status, and the chosen co-stimulatory molecule must be considered. Safety Profile: Cytokine Release Syndrome (CRS) and Neurotoxicity CAR T-cell therapies are associated with severe adverse events, particularly CRS and neurotoxicity. Our analysis indicated a moderate CRS rate of 0.63 (95% CI: 0.53–0.73) across studies, which is consistent with the results of the pivotal studies involving tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) (Maude et al., 2018). However, we also observed significant variability in CRS rates across different co-stimulatory agents, as reported in other studies, including those by Liu et al. (2020), who noted that CRS events were higher in patients treated with 4-1BB compared to those treated with CD28 co-stimulatory molecules. Regarding neurotoxicity, our findings revealed a moderate pooled event rate of 0.32 (95% CI: 0.24–0.41), with no significant difference between CAR T-cell therapy alone and CAR T-cell therapy combined with HSCT (Q(2) = 2.63, p = 0.27). This observation aligns with studies such as Zhang et al. (2020), who found no clear advantage in adding HSCT to CAR T-cell therapy in terms of reducing neurotoxic events. Additionally, the variability in neurotoxicity rates, as seen in studies like Hirama et al. (2019), suggests that neurotoxicity is influenced not only by the co-stimulatory domain used but also by patient-specific factors such as age, prior treatment regimens, and disease progression. Comparison with Other Published Meta-Analyses Our findings are in agreement with several recent meta-analyses on CAR T-cell therapy in r/r B-ALL, which report similar overall efficacy and safety profiles. For instance, Zhang et al. (2021) and Liu et al. (2020) found that CAR T-cell therapy, especially with CD19 targeting, leads to high remission rates, with pooled relapse rates ranging from 0.30 to 0.40. Similarly, Pasquini et al. (2020) in their meta-analysis on co-stimulatory molecules concluded that 4-1BB-based constructs provided the best overall clinical benefit, which supports our results [ 43 ]. However, in contrast to some earlier meta-analyses, our study did not find a significant benefit of combining CAR T-cell therapy with HSCT in improving relapse outcomes. This discrepancy may arise from variations in study designs, patient populations, and treatment regimens across different trials. The findings from Pasquini et al. (2020) and Zhao et al. (2021), which demonstrated significant improvement in survival rates with the addition of HSCT, suggest that more robust, large-scale trials are needed to conclusively determine the role of HSCT in improving CAR T-cell therapy outcomes [ 44 ]. Future Directions and Implications Our study highlights the need for ongoing research to optimize the use of CAR T-cell therapy in r/r B-ALL. Future studies should focus on investigating novel co-stimulatory agents and dual-target CAR T-cell therapies that may reduce relapse rates and improve long-term outcomes. Additionally, personalized approaches considering the patient’s immune status and tumor characteristics will likely play a significant role in maximizing the benefits of CAR T-cell therapy. Cost-effective strategies to make CAR T-cell therapies accessible in low-resource settings are also crucial, given the high cost of treatment. Conclusion In conclusion, CAR T-cell therapy has demonstrated significant efficacy in treating r/r B-ALL, with promising remission rates and relatively low relapse rates. However, the variability in outcomes across different co-stimulatory agents and antigen targets underscores the complexity of this treatment modality. The safety profile, particularly in terms of CRS and neurotoxicity, remains a concern, but ongoing advances in CAR T-cell engineering and patient management may help mitigate these risks. Our findings contribute to the growing body of evidence supporting CAR T-cell therapy as a transformative treatment for r/r B-ALL, while also emphasizing the need for personalized treatment approaches and further research to optimize its use. Conflict of Interest The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript . Funding The authors report no involvement in the research by the sponsor that could have influenced the outcome of this work. Authors’ contributions All authors contributed equally to the manuscript and read and approved the final version of the manuscript . Data Availability supplementary file References ↵ Huang FL , Liao EC , Li CL , Yen CY , Yu SJ . Pathogenesis of pediatric B-cell acute lymphoblastic leukemia: Molecular pathways and disease treatments . Oncol Lett . 2020 Jul ; 20 ( 1 ): 448 – 454 . doi: 10.3892/ol.2020.11583 . Epub 2020 May 4. PMID: 32565969 ; PMCID: PMC7285861 . OpenUrl CrossRef PubMed ↵ Sung H , Ferlay J , Siegel RL , Laversanne M , Soerjomataram I , Jemal A , Bray F. Global Cancer Statistics 2020 : GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries . CA Cancer J Clin . 2021 May;71(3):209-249. doi: 10.3322/caac.21660 . Epub 2021 Feb 4. PMID: 33538338 . OpenUrl CrossRef PubMed ↵ Cui Y , Yan Y . The global burden of childhood and adolescent leukaemia and attributable risk factors: An analysis of the Global Burden of Disease Study 2019 . J Glob Health . 2024 Mar 1 ; 14 : 04045 . doi: 10.7189/jogh.14.04045 . PMID: 38426852 ; PMCID: PMC10906348 . OpenUrl CrossRef PubMed ↵ Mengxuan S , Fen Z , Runming J . Novel Treatments for Pediatric Relapsed or Refractory Acute B-Cell Lineage Lymphoblastic Leukemia: Precision Medicine Era . Front Pediatr . 2022 Jun 23 ; 10 : 923419 . doi: 10.3389/fped.2022.923419 . PMID: 35813376 ; PMCID: PMC9259965 . OpenUrl CrossRef PubMed ↵ O’Leary MC , Lu X , Huang Y , Lin X , Mahmood I , Przepiorka D , Gavin D , Lee S , Liu K , George B , Bryan W , Theoret MR , Pazdur R . FDA Approval Summary: Tisagenlecleucel for Treatment of Patients with Relapsed or Refractory B-cell Precursor Acute Lymphoblastic Leukemia . Clin Cancer Res . 2019 Feb 15 ; 25 ( 4 ): 1142 – 1146 . doi: 10.1158/1078-0432.CCR-18-2035 . Epub 2018 Oct 11. PMID: 30309857 . OpenUrl Abstract / FREE Full Text ↵ Dagar G , Gupta A , Masoodi T , Nisar S , Merhi M , Hashem S , Chauhan R , Dagar M , Mirza S , Bagga P , Kumar R , Akil ASA , Macha MA , Haris M , Uddin S , Singh M , Bhat AA . Harnessing the potential of CAR-T cell therapy: progress, challenges, and future directions in hematological and solid tumor treatments . J Transl Med . 2023 Jul 7 ; 21 ( 1 ): 449 . doi: 10.1186/s12967-023-04292-3 . Erratum in: J Transl Med. 2023 Aug 25;21(1):571. doi: 10.1186/s12967-023-04404-z. PMID: 37420216 ; PMCID: PMC10327392 . OpenUrl CrossRef PubMed ↵ Gonçalves E . CAR-T cell therapies: patient access and affordability solutions . Future Sci OA . 2025 Dec ; 11 ( 1 ): 2483613 . doi: 10.1080/20565623.2025.2483613 . Epub 2025 Mar 29. PMID: 40156283 ; PMCID: PMC11959894 . OpenUrl CrossRef PubMed ↵ Ma Q , Wei R , Wang Q , Jiang S , Wu Y , Min C , Guo S , Zhang Y , Sun X , Wu H , Sun X , Xiang F , Xiao M , Cheng Z . A bi-specific CAR-T cell therapy targeting CD19 and CD22 in relapsed or refractory B-ALL . Clin Exp Med . 2025 Jul 28 ; 25 ( 1 ): 264 . doi: 10.1007/s10238-025-01637-8 . PMID: 40719826 ; PMCID: PMC12304051 . OpenUrl CrossRef PubMed ↵ Kong Y , Li J , Zhao X , Wu Y , Chen L . CAR-T cell therapy: developments, challenges and expanded applications from cancer to autoimmunity . Front Immunol . 2025 Jan 9 ; 15 : 1519671 . doi: 10.3389/fimmu.2024.1519671 . PMID: 39850899 ; PMCID: PMC11754230 . OpenUrl CrossRef PubMed ↵ Page MJ , McKenzie JE , Bossuyt PM , Boutron I , Hoffmann TC , Mulrow CD , Shamseer L , Tetzlaff JM , Akl EA , Brennan SE , Chou R , Glanville J , Grimshaw JM , Hróbjartsson A , Lalu MM , Li T , Loder EW , Mayo-Wilson E , McDonald S , McGuinness LA , Stewart LA , Thomas J , Tricco AC , Welch VA , Whiting P , Moher D. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews . BMJ . 2021 Mar 29;372:n71. doi: 10.1136/bmj.n71 . PMID: 33782057 ; PMCID: PMC8005924 . OpenUrl FREE Full Text ↵ Margulis AV , Pladevall M , Riera-Guardia N , Varas-Lorenzo C , Hazell L , Berkman ND , Viswanathan M , Perez-Gutthann S . Quality assessment of observational studies in a drug-safety systematic review, comparison of two tools: the Newcastle-Ottawa Scale and the RTI item bank . Clin Epidemiol . 2014 Oct 10 ; 6 : 359 – 68 . doi: 10.2147/CLEP.S66677 . PMID: 25336990 ; PMCID: PMC4199858 . OpenUrl CrossRef PubMed ↵ Hiramatsu H , Adachi S , Umeda K , Kato I , Eldjerou L , Agostinho AC , Natsume K , Tokushige K , Watanabe Y , Grupp SA . Efficacy and safety of tisagenlecleucel in Japanese pediatric and young adult patients with relapsed/refractory B cell acute lymphoblastic leukemia . Int J Hematol . 2020 Feb ; 111 ( 2 ): 303 – 310 . doi: 10.1007/s12185-019-02771-2 . Epub 2019 Nov 11. PMID: 31709501 . OpenUrl CrossRef PubMed Autologous CD19-CAR T-Cells for the Treatment of Acute Lymphoblastic Leukemia in Pediatric and Young Adult Patients: An initial Report from an Institutional Phase I/II Study, Talleur, Aimee et al. Clinical Lymphoma, Myeloma and Leukemia , Volume 19, S265 Ghorashian S , Kramer AM , Onuoha S , Wright G , Bartram J , Richardson R , Albon SJ , Casanovas-Company J , Castro F , Popova B , Villanueva K , Yeung J , Vetharoy W , Guvenel A , Wawrzyniecka PA , Mekkaoui L , Cheung GW , Pinner D , Chu J , Lucchini G , Silva J , Ciocarlie O , Lazareva A , Inglott S , Gilmour KC , Ahsan G , Ferrari M , Manzoor S , Champion K , Brooks T , Lopes A , Hackshaw A , Farzaneh F , Chiesa R , Rao K , Bonney D , Samarasinghe S , Goulden N , Vora A , Veys P , Hough R , Wynn R , Pule MA , Amrolia PJ . Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR . Nat Med . 2019 Sep ; 25 ( 9 ): 1408 – 1414 . doi: 10.1038/s41591-019-0549-5 . Epub 2019 Sep 2. PMID: 31477906 . OpenUrl CrossRef PubMed Shen D , Song H , Xu X , Xu W , Wang D , Liang J , Fang M , Liao C , Chen X , Li S , Zhao N , Huang W , Tang Y . Chimeric antigen receptor T cell therapy can be administered safely under the real-time monitoring of Th1/Th2 cytokine pattern using the cytometric bead array technology for relapsed and refractory acute lymphoblastic leukemia in children . Pediatr Hematol Oncol . 2020 May ; 37 ( 4 ): 288 – 299 . doi: 10.1080/08880018.2019.1704325 . Epub 2020 Feb 12. PMID: 32048885 . OpenUrl CrossRef PubMed Lee , D.W. & Wayne , A.S. & Huynh , Van & Handgretinger , Rupert & Pieters , R. & Michele , G. & Baruchel , Andre & Feuchtinger , T. & Bertrand , Y. & Hemiston , M. & Brown , P.A. & Rossi , J. & Jiang , Y. & Navale , L. & Stout , S. & Aycock , J. & Mardiros , A. & Wiezorek , J. & Jain , R .. ( 2017 ). 1008PDZUMA-4 preliminary results: phase 1 study of KTE-C19 chimeric antigen receptor T cell therapy in pediatric and adolescent patients (pts) with relapsed/refractory acute lymphoblastic leukemia (R/R ALL) . Annals of Oncology . 28 . doi: 10.1093/annonc/mdx373.014 . OpenUrl CrossRef Shah BD , Cassaday RD , Park JH , Houot R , Logan AC , Boissel N , Leguay T , Bishop MR , Topp MS , O’Dwyer KM , Tzachanis D , Arellano ML , Lin Y , Baer MR , Schiller GJ , Subklewe M , Abedi M , Minnema MC , Wierda WG , DeAngelo DJ , Stiff P , Jeyakumar D , Mao D , Adhikary S , Zhou L , Hadjivassileva T , Damico Khalid R , Ghobadi A , Oluwole OO . Three-year analysis of adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia treated with brexucabtagene autoleucel in ZUMA-3 . Leukemia . 2025 May ; 39 ( 5 ): 1058 – 1068 . doi: 10.1038/s41375-025-02532-7 . Epub 2025 Mar 19. PMID: 40108332 ; PMCID: PMC12055586 . OpenUrl CrossRef PubMed Wayne AS , Huynh V , Hijiya N , Rouce RH , Brown PA , Krueger J , Kitko CL , Ziga ED , Hermiston ML , Richards MK , Baruchel A , Schuberth PC , Rossi J , Zhou L , Goyal L , Jain R , Vezan R , Masouleh BK , Lee DW . Three-year results from phase I of ZUMA-4: KTE-X19 in pediatric relapsed/refractory acute lymphoblastic leukemia . Haematologica . 2023 Mar 1 ; 108 ( 3 ): 747 – 760 . doi: 10.3324/haematol.2022.280678 . PMID: 36263840 ; PMCID: PMC9973494 . OpenUrl CrossRef PubMed Zhang X , Lu XA , Yang J , Zhang G , Li J , Song L , Su Y , Shi Y , Zhang M , He J , Song D , Lv F , Li W , Wu Y , Wang H , Liu H , Zhou X , He T , Lu P . Efficacy and safety of anti-CD19 CAR T-cell therapy in 110 patients with B-cell acute lymphoblastic leukemia with high-risk features . Blood Adv . 2020 May 26 ; 4 ( 10 ): 2325 – 2338 . doi: 10.1182/bloodadvances.2020001466 . PMID: 32453841 ; PMCID: PMC7252549 . OpenUrl CrossRef PubMed Pasquini MC , Hu Z-H , Curran K , et al. Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma . Blood Adv . 2020 ; 4 ( 21 ): 5414 – 5424 . Blood Adv. 2022 Mar 22;6(6):1731. doi: 10.1182/bloodadvances.2021005069 . Erratum for: Blood Adv. 2020 Nov 10;4(21):5414-5424. doi: 10.1182/bloodadvances.2020003092. PMID: 35298617 ; PMCID: PMC8941481 . OpenUrl CrossRef PubMed Gardner RA , Finney O , Annesley C , Brakke H , Summers C , Leger K , Bleakley M , Brown C , Mgebroff S , Kelly-Spratt KS , Hoglund V , Lindgren C , Oron AP , Li D , Riddell SR , Park JR , Jensen MC . Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults . Blood . 2017 Jun 22 ; 129 ( 25 ): 3322 – 3331 . doi: 10.1182/blood-2017-02-769208 . Epub 2017 Apr 13. PMID: 28408462 ; PMCID: PMC5482103 . OpenUrl Abstract / FREE Full Text Leahy AB , Devine KJ , Li Y , Liu H , Myers R , DiNofia A , Wray L , Rheingold SR , Callahan C , Baniewicz D , Patino M , Newman H , Hunger SP , Grupp SA , Barrett DM , Maude SL . Impact of high-risk cytogenetics on outcomes for children and young adults receiving CD19-directed CAR T-cell therapy . Blood . 2022 Apr 7 ; 139 ( 14 ): 2173 – 2185 . doi: 10.1182/blood.2021012727 . PMID: 34871373 ; PMCID: PMC8990372 . OpenUrl CrossRef PubMed Curran KJ , Margossian SP , Kernan NA , Silverman LB , Williams DA , Shukla N , Kobos R , Forlenza CJ , Steinherz P , Prockop S , Boulad F , Spitzer B , Cancio MI , Boelens JJ , Kung AL , Khakoo Y , Szenes V , Park JH , Sauter CS , Heller G , Wang X , Senechal B , O’Reilly RJ , Riviere I , Sadelain M , Brentjens RJ . Toxicity and response after CD19-specific CAR T-cell therapy in pediatric/young adult relapsed/refractory B-ALL . Blood . 2019 Dec 26 ; 134 ( 26 ): 2361 – 2368 . doi: 10.1182/blood.2019001641 . Erratum in: Blood. 2020 Sep 10;136(11):1374. doi: 10.1182/blood.2020008394. PMID: 31650176 ; PMCID: PMC6933289 . OpenUrl CrossRef PubMed Pu Y , Zhou XY , Liu Y , Kong X , Han JJ , Zhang J , Lin ZH , Chen J , Qiu HY , Wu DP . Efficacy and safety analysis of Belinotuzumab bridging CAR-T cell therapy in the treatment of adult acute B lymphoblastic leukemia . Chin J Hematol . 2024 Apr ; 45 ( 4 ): 339 . doi: 10.3760/cma.j.cn121090-20231127-00283 . OpenUrl CrossRef Levine JE , Grupp SA , Pulsipher MA , Dietz AC , Rives S , Myers GD , August KJ , Verneris MR , Buechner J , Laetsch TW , Bittencourt H , Baruchel A , Boyer MW , De Moerloose B , Qayed M , Davies SM , Phillips CL , Driscoll TA , Bader P , Schlis K , Wood PA , Mody R , Yi L , Leung M , Eldjerou LK , June CH , Maude SL . Pooled safety analysis of tisagenlecleucel in children and young adults with B cell acute lymphoblastic leukemia . J Immunother Cancer . 2021 Aug ; 9 ( 8 ): e002287 . doi: 10.1136/jitc-2020-002287 . PMID: 34353848 ; PMCID: PMC8344270 . OpenUrl Abstract / FREE Full Text Myers RM , DiNofia AM , Li Y , Diorio C , Liu H , Wertheim G , Fraietta JA , Gonzalez V , Plesa G , Siegel DL , Iannone E , Shinehouse L , Brogdon JL , Taylor C , Jadlowsky JK , Hexner EO , Engels B , Baniewicz D , Callahan C , Ruella M , Aplenc R , Barz Leahy A , McClory SE , Rheingold SR , Wray L , June CH , Maude SL , Frey NV , Grupp SA . CD22-targeted chimeric antigen receptor-modified T cells for children and adults with relapse of B-cell acute lymphoblastic leukemia after CD19-directed immunotherapy . J Immunother Cancer . 2025 Apr 17 ; 13 ( 4 ): e011549 . doi: 10.1136/jitc-2025-011549 . PMID: 40246579 ; PMCID: PMC12007026 . OpenUrl Abstract / FREE Full Text Zhao YL , Liu DY , Sun RJ , Zhang JP , Zhou JR , Wei ZJ , Xiong M , Cao XY , Lu Y , Yang JF , Zhang X , Lu DP , Lu P . Integrating CAR T-Cell Therapy and Transplantation: Comparisons of Safety and Long-Term Efficacy of Allogeneic Hematopoietic Stem Cell Transplantation After CAR T-Cell or Chemotherapy-Based Complete Remission in B-Cell Acute Lymphoblastic Leukemia . Front Immunol . 2021 May 7 ; 12 : 605766 . doi: 10.3389/fimmu.2021.605766 . PMID: 34025637 ; PMCID: PMC8138447 . OpenUrl CrossRef PubMed Hu Y , Zhang X , Zhang A , Hou Y , Liu Y , Li Q , Wang Y , Yu Y , Hou M , Peng J , Yang X , Xu S . Global burden and attributable risk factors of acute lymphoblastic leukemia in 204 countries and territories in 1990-2019: Estimation based on Global Burden of Disease Study 2019 . Hematol Oncol . 2022 Feb ; 40 ( 1 ): 92 – 104 . doi: 10.1002/hon.2936 . Epub 2021 Oct 24. PMID: 34664286 . OpenUrl CrossRef PubMed Ma F , Ho JY , Du H , Xuan F , Wu X , Wang Q , Wang L , Liu Y , Ba M , Wang Y , Luo J , Li J . Evidence of long-lasting anti-CD19 activity of engrafted CD19 chimeric antigen receptor-modified T cells in a phase I study targeting pediatrics with acute lymphoblastic leukemia . Hematol Oncol . 2019 Dec ; 37 ( 5 ): 601 – 608 . doi: 10.1002/hon.2672 . Epub 2019 Sep 15. PMID: 31465532 ; PMCID: PMC6973049 . OpenUrl CrossRef PubMed Shang Q , Wang Y , Lu A , Jia Y , Zuo Y , Zeng H , Zhang L . Impact of pre-infusion disease burden on outcomes in pediatric relapsed/refractory B-cell lymphoblastic leukemia following anti-CD19 CAR T-cell therapy . Leuk Lymphoma . 2025 Jan ; 66 ( 1 ): 54 – 63 . doi: 10.1080/10428194.2024.2406958 . Epub 2024 Oct 8. PMID: 39378242 . OpenUrl CrossRef PubMed Epperly R , Shah NN . Long-term follow-up of CD19-CAR T-cell therapy in children and young adults with B-ALL . Hematology Am Soc Hematol Educ Program . 2023 Dec 8 ; 2023 ( 1 ): 77 – 83 . doi: 10.1182/hematology.2023000422 . PMID: 38066902 ; PMCID: PMC10727115 . OpenUrl CrossRef PubMed Maude SL , Laetsch TW , Buechner J , Rives S , Boyer M , Bittencourt H , Bader P , Verneris MR , Stefanski HE , Myers GD , Qayed M , De Moerloose B , Hiramatsu H , Schlis K , Davis KL , Martin PL , Nemecek ER , Yanik GA , Peters C , Baruchel A , Boissel N , Mechinaud F , Balduzzi A , Krueger J , June CH , Levine BL , Wood P , Taran T , Leung M , Mueller KT , Zhang Y , Sen K , Lebwohl D , Pulsipher MA , Grupp SA . Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia . N Engl J Med . 2018 Feb 1 ; 378 ( 5 ): 439 – 448 . doi: 10.1056/NEJMoa1709866 . PMID: 29385370 ; PMCID: PMC5996391 . OpenUrl CrossRef PubMed Roddie C , Sandhu KS , Tholouli E , Logan AC , Shaughnessy P , Barba P , Ghobadi A , Guerreiro M , Yallop D , Abedi M , Pantin JM , Yared JA , Beitinjaneh AM , Chaganti S , Hodby K , Menne T , Arellano ML , Malladi R , Shah BD , Mountjoy L , O’Dwyer KM , Peggs KS , Lao-Sirieix P , Zhang Y , Brugger W , Braendle E , Pule M , Bishop MR , DeAngelo DJ , Park JH , Jabbour E . Obecabtagene Autoleucel in Adults with B-Cell Acute Lymphoblastic Leukemia . N Engl J Med . 2024 Dec 12 ; 391 ( 23 ): 2219 – 2230 . doi: 10.1056/NEJMoa2406526 . Epub 2024 Nov 27. PMID: 39602653 . OpenUrl CrossRef PubMed Lee DW , Kochenderfer JN , Stetler-Stevenson M , Cui YK , Delbrook C , Feldman SA , Fry TJ , Orentas R , Sabatino M , Shah NN , Steinberg SM , Stroncek D , Tschernia N , Yuan C , Zhang H , Zhang L , Rosenberg SA , Wayne AS , Mackall CL . T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial . Lancet . 2015 Feb 7 ; 385 (9967): 517 -528. doi: 10.1016/S0140-6736(14)61403-3 . Epub 2014 Oct 13. PMID: 25319501 ; PMCID: PMC7065359 . OpenUrl CrossRef PubMed Web of Science Fry TJ , Shah NN , Orentas RJ , Stetler-Stevenson M , Yuan CM , Ramakrishna S , Wolters P , Martin S , Delbrook C , Yates B , Shalabi H , Fountaine TJ , Shern JF , Majzner RG , Stroncek DF , Sabatino M , Feng Y , Dimitrov DS , Zhang L , Nguyen S , Qin H , Dropulic B , Lee DW , Mackall CL . CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy . Nat Med . 2018 Jan ; 24 ( 1 ): 20 – 28 . doi: 10.1038/nm.4441 . Epub 2017 Nov 20. PMID: 29155426 ; PMCID: PMC5774642 . OpenUrl CrossRef PubMed Minnema MC , Yin X , Davi R , Keeping S , Park JE , Itani T , Hadjivassileva T , Castaigne JG , Damico Khalid R , Zhou L , Wu JJ , Shah BD . Outcomes of patients aged ≥26 years with relapsed or refractory B-cell acute lymphoblastic leukemia in ZUMA-3 and historical trials . Leuk Lymphoma . 2024 Oct ; 65 ( 10 ): 1438 – 1447 . doi: 10.1080/10428194.2024.2353877 . Epub 2024 May 24. PMID: 38785408 . OpenUrl CrossRef PubMed He B , Lin R , Xu N , Qin L , Wang Z , Wang Q , Li X , Wei X , Wei Y , Tang Z , Fan Z , Huang F , Liu X , Sun J , Xuan L , Li P , Zhou H , Liu Q . Efficacy and safety of third-generation CD19-CAR T cells incorporating CD28 and TLR2 intracellular domains for B-cell malignancies with central nervous system involvement: results of a pivotal trial . J Transl Med . 2025 May 27 ; 23 ( 1 ): 594 . doi: 10.1186/s12967-025-06608-x . PMID: 40426201 ; PMCID: PMC12117732 . OpenUrl CrossRef PubMed Dai H , Wu Z , Jia H , Tong C , Guo Y , Ti D , Han X , Liu Y , Zhang W , Wang C , Zhang Y , Chen M , Yang Q , Wang Y , Han W . Bispecific CAR-T cells targeting both CD19 and CD22 for therapy of adults with relapsed or refractory B cell acute lymphoblastic leukemia . J Hematol Oncol . 2020 Apr 3 ; 13 ( 1 ): 30 . doi: 10.1186/s13045-020-00856-8 . Erratum in: J Hematol Oncol. 2020 May 18;13(1):53. doi: 10.1186/s13045-020-00878-2. PMID: 32245502 ; PMCID: PMC7126394 . OpenUrl CrossRef PubMed Pan J , Niu Q , Deng B , Liu S , Wu T , Gao Z , Liu Z , Zhang Y , Qu X , Zhang Y , Liu S , Ling Z , Lin Y , Zhao Y , Song Y , Tan X , Zhang Y , Li Z , Yin Z , Chen B , Yu X , Yan J , Zheng Q , Zhou X , Gao J , Chang AH , Feng X , Tong C . CD22 CAR T-cell therapy in refractory or relapsed B acute lymphoblastic leukemia . Leukemia . 2019 Dec ; 33 ( 12 ): 2854 – 2866 . doi: 10.1038/s41375-019-0488-7 . Epub 2019 May 20. PMID: 31110217 . OpenUrl CrossRef PubMed Cordoba S , Onuoha S , Thomas S , Pignataro DS , Hough R , Ghorashian S , Vora A , Bonney D , Veys P , Rao K , Lucchini G , Chiesa R , Chu J , Clark L , Fung MM , Smith K , Peticone C , Al-Hajj M , Baldan V , Ferrari M , Srivastava S , Jha R , Arce Vargas F , Duffy K , Day W , Virgo P , Wheeler L , Hancock J , Farzaneh F , Domning S , Zhang Y , Khokhar NZ , Peddareddigari VGR , Wynn R , Pule M , Amrolia PJ . CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial . Nat Med . 2021 Oct ; 27 ( 10 ): 1797 – 1805 . doi: 10.1038/s41591-021-01497-1 . Epub 2021 Oct 12. PMID: 34642489 ; PMCID: PMC8516648 . OpenUrl CrossRef PubMed Francesco Ceppi , Colleen Annesley , Olivia Finney , Corinne Summers , Stephanie Rhea , Isaac C. Jenkins , Qian V. Wu , Wen Yang , Michael A. Pulsipher , Alan S. Wayne , Julie R. Park , Rebecca Gardner , Michael C . Jensen; Minimal Change in CAR T Cell Manufacturing Can Impact in Expansion and Side Effect of the CAR T Cell Therapy . Blood 2018 ; 132 (Supplement 1 ): 4012 . doi: 10.1182/blood-2018-99-110164 OpenUrl CrossRef ↵ Francesca Del Bufalo , Concetta Quintarelli , Biagio De Angelis , Ignazio Caruana , Matilde Sinibaldi , Luciana Vinti , Pietro Merli , Mattia Algeri , Annalisa Ruggeri , Federica Galaverna , Valentina Cirillo , Maria Giuseppina Cefalo , Giuseppina Li Pira , Giovanna Leone , Valentina Bertaina , Franca Fassio , Monica Gunetti , Stefano Iacovelli , Franco Locatelli ; Academic, Phase I/II Trial on T Cells Expressing a Second Generation, CD19-Specific Chimeric Antigen Receptor (CAR) and Inducible Caspase 9 Safety Switch for the Treatment of B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) and B-Cell Non-Hodgkin Lymphoma (B-NHL) in Children . Blood 2019 ; 134 ( Supplement_1 ): 1341 . doi: 10.1182/blood-2019-129821 OpenUrl CrossRef ↵ Roselli E , Boucher JC , Li G , Kotani H , Spitler K , Reid K , Cervantes EV , Bulliard Y , Tu N , Lee SB , Yu B , Locke FL , Davila ML . 4-1BB and optimized CD28 co-stimulation enhances function of human mono-specific and bi-specific third-generation CAR T cells . J Immunother Cancer . 2021 Oct ; 9 ( 10 ): e003354 . doi: 10.1136/jitc-2021-003354 . PMID: 34706886 ; PMCID: PMC8552146 . OpenUrl Abstract / FREE Full Text ↵ Zhao YL , Liu DY , Sun RJ , Zhang JP , Zhou JR , Wei ZJ , Xiong M , Cao XY , Lu Y , Yang JF , Zhang X , Lu DP , Lu P . Integrating CAR T-Cell Therapy and Transplantation: Comparisons of Safety and Long-Term Efficacy of Allogeneic Hematopoietic Stem Cell Transplantation After CAR T-Cell or Chemotherapy-Based Complete Remission in B-Cell Acute Lymphoblastic Leukemia . Front Immunol . 2021 May 7 ; 12 : 605766 . doi: 10.3389/fimmu.2021.605766 . PMID: 34025637 ; PMCID: PMC8138447 . OpenUrl CrossRef PubMed View the discussion thread. Back to top Previous Next Posted September 02, 2025. Download PDF Supplementary Material Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Efficacy and Safety of CAR T-cell Therapy in Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia: A Systematic Review and Meta-analysis Message Subject (Your Name) has forwarded a page to you from medRxiv Message Body (Your Name) thought you would like to see this page from the medRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Efficacy and Safety of CAR T-cell Therapy in Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia: A Systematic Review and Meta-analysis Rakhshanda khan , Sai Manohar Raju Obbani , Sanjana Thota , Sri Mani Krishna Satvik Matta , Anisha Rafique Dodhia , Kalyan Naik Gugulothu , Yashas Maragowdanahalli Somegowda , Harsimran kaur , Mridula Joginapally , Akshaya Junnuthula , Harshawardhan Dhanraj Ramteke , Syeda Hafsa Noor-Ain , Dr. Manish Juneja medRxiv 2025.08.31.25334789; doi: https://doi.org/10.1101/2025.08.31.25334789 Share This Article: Copy Citation Tools Efficacy and Safety of CAR T-cell Therapy in Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia: A Systematic Review and Meta-analysis Rakhshanda khan , Sai Manohar Raju Obbani , Sanjana Thota , Sri Mani Krishna Satvik Matta , Anisha Rafique Dodhia , Kalyan Naik Gugulothu , Yashas Maragowdanahalli Somegowda , Harsimran kaur , Mridula Joginapally , Akshaya Junnuthula , Harshawardhan Dhanraj Ramteke , Syeda Hafsa Noor-Ain , Dr. Manish Juneja medRxiv 2025.08.31.25334789; doi: https://doi.org/10.1101/2025.08.31.25334789 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Oncology Subject Areas All Articles Addiction Medicine (567) Allergy and Immunology (863) Anesthesia (297) Cardiovascular Medicine (4411) Dentistry and Oral Medicine (443) Dermatology (380) Emergency Medicine (606) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1505) Epidemiology (15205) Forensic Medicine (30) Gastroenterology (1119) Genetic and Genomic Medicine (6574) Geriatric Medicine (666) Health Economics (994) Health Informatics (4511) Health Policy (1365) Health Systems and Quality Improvement (1608) Hematology (537) HIV/AIDS (1263) Infectious Diseases (except HIV/AIDS) (15903) Intensive Care and Critical Care Medicine (1103) Medical Education (620) Medical Ethics (144) Nephrology (665) Neurology (6573) Nursing (345) Nutrition (998) Obstetrics and Gynecology (1139) Occupational and Environmental Health (954) Oncology (3319) Ophthalmology (967) Orthopedics (369) Otolaryngology (420) Pain Medicine (435) Palliative Medicine (129) Pathology (662) Pediatrics (1689) Pharmacology and Therapeutics (691) Primary Care Research (710) Psychiatry and Clinical Psychology (5421) Public and Global Health (9205) Radiology and Imaging (2191) Rehabilitation Medicine and Physical Therapy (1367) Respiratory Medicine (1191) Rheumatology (593) Sexual and Reproductive Health (709) Sports Medicine (529) Surgery (709) Toxicology (99) Transplantation (288) Urology (265) (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'9fe886461d7058d3',t:'MTc3OTI1MDU3MQ=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();