Cancer remains a worldwide health concern, resulting in a significant burden of disability-adjusted life years (DALYs). This burden amounts to 11.5 million DALYs, 82.2% of cases in low-to-middle-income countries [1]. The current conventional therapy has given acceptable outcomes, and improved the survival rate by more than 70% among children, adolescents, and young adults (CAYA) diagnosed with B-cell malignancies. However, 15%–40% of patients suffer from relapse and 2%–3% remain unresponsive to initial treatment. The prognosis of such patients is typically very poor, with a survival rate no higher than 20% [2,3].

Allogeneic stem cell transplantation (allo-SCT) arises as a potential curative treatment option by substituting the diseased bone marrow with healthy stem cells, effectively resetting the patient's hematopoietic system. Yet, among patients who did not attain minimal residual disease (MRD) negativity before undergoing allo-SCT, their 3-year overall survival (OS) and leukemia-free survival (LFS) stood at a mere 23.5% and 20.6%, respectively [4]. Recently, chimeric antigen receptor T-cell (CAR T-cell) therapy has successfully shown that up to 80% of patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) achieved complete remission with negative MRD [5,6]. Although CAR T-cell imposes substantial burdens on healthcare providers, it is still cost-effective, even in low-to-middle-income countries, suggesting its applicability in resource-limited settings [3,7,8]. A significant downside of CAR T-cell therapy likely involves the potential for relapse, with the most alarming type of relapse being lineage switch [2,3].

The reasoning behind integrating CAR T-cell therapy with SCT rests on their complementary modes of action. CAR T-cell therapy provides a potent, focused assault on leukemic cells, while SCT eliminates remaining malignant cells and encourages the establishment of a strong immune system. This potentially harmonious strategy shows significant potential for attaining more profound and long-lasting remissions, and perhaps even cures, in patients with R/R leukemia. Some suggest that using SCT after CAR T-cell therapy can increase survival and lower recurrence risks [5,6,9-16], while others argue the associated risks might overshadow potential benefits [17-21]. Therefore, our study aims to conduct a systematic review of contemporary clinical research and thoroughly assess the potential benefits of allo-SCT administered post-CAR T-cell infusion and their impact on treatment outcomes among pediatric, adolescent, and young adult populations.

A total of 3,408 records were identified from electronic databases. After removing duplicates and irrelevant articles, 115 records remained for screening and further assessed for eligibility. Ultimately, 12 studies which met the inclusion criteria were included in the review [9-20]. The search flowchart and study selection are illustrated in Fig. 1.

Twelve cohort studies involving 380 subjects were conducted across diverse regions, spanning America, Asia, and Europe. All studies enrolled participants aged 25 years or younger. Except for one study [13], all reported cases of R/R B-ALL, with or without extramedullary involvement, notably in the central nervous system. The blast cells' proportion before CAR T-cell infusion varied from 0.03% to 99.00%. Across all studies, CAR T-cell therapy targeted the CD19 epitope, with dosages ranging from 0.3 to 9.9×10⁶/kg in single infusions. The majority of patients responded well to the therapy and the decision of receiving SCT after CAR T-cell therapy were influenced by either disease relapse or physicians’ preference to consolidate remission. Neutrophil and platelet engraftment were achieved typically in 11–21 days and 8–89 days, respectively. All of the included studies showed good quality. Table 1 provides detailed characteristics of the included studies.

We observed a trend of higher complete remission (OR, 2.74; 95% CI, 0.88–8.54; P=0.08; I²=57%) (Fig. 2A) and lower mortality rate (OR, 0.58; 95% CI, 0.27–1.27; P=0.17; I²=0%) (Fig. 2B) in the CAR T-cell+SCT group compared to those who did not proceed to SCT, although the difference was not statistically significant. There was a significant reduction of relapse rate among patients who received SCT after CAR T-cell therapy (OR, 0.18; 95% CI, 0.06–0.56; P=0.003; I²=41%; Fig. 2C). In addition, both OS and LFS showed favorable trend towards the CAR T-cell+SCT group, respectively (HR, 0.44; 95% CI, 0.25–0.77; P=0.005; I²=0% and HR, 0.29; 95% CI, 0.17–0.49; P<0.00001; I²=0%) (Fig. 2D and E). Our meta-analysis also showed favorable outcomes of CAR T-cell therapy as a bridge before receiving consolidative SCT. Compared to the patients only receiving chemotherapy before SCT, those bridged with CAR T-cell therapy showed improvement of OS and LFS, respectively (HR, 0.16; 95% CI, 0.06–0.43; P=0.0003; I²=0% and HR, 0.30; 95% CI, 0.12–0.77; P=0.01; I²=0%) (Fig. 3).

In the CAR T-cell group, common posttransplant toxicities included manageable rates of acute and chronic graft-versus-host disease (GVHD). Hu et al reported the incidence of grade II–III and III–IV acute GVHD were 26% and 7%, respectively. In a long-term follow-up, severe chronic GVHD accounted for 11% (3 out of 26 subjects). Sun et al. [11] observed similar findings whereas the incidence of grade II–IV acute GVHD was 28.6%, while no patient experienced extensive chronic GVHD in 2 years. Serious adverse events were rare, but included thrombotic microangiopathy and infectious complications.

This meta-analysis included cohort studies, which initially provided low quality evidence. All except one study showed no concern in regards to imprecision. We detected no substantial risk of bias, heterogeneity, or indirectness among studies. Publication bias could not be evaluated as the number of included studies was less than 10. The evidence generated from this meta-analysis was judged to be very low-to-low, as outlined in Table 2.

Despite the presence of chemotherapy and allo-SCT, the prognosis for CAYA with R/R B-ALL remains highly unfavorable, especially for those unresponsive to initial treatment. The sustained survival of these individuals hinges on achieving complete remission through salvage chemotherapy followed by allo-SCT. Regrettably, a notable portion of patients never undergo potentially life-saving allo-SCT due to the inability to attain a second complete remission after salvage chemotherapy. Additionally, for patients who do undergo allo-SCT, those identified with MRD positivity confront a significantly poorer prognosis compared to individuals with no signs of MRD at the time of allo-SCT [29]. This emphasizes the critical need for innovative therapeutic strategies tailored to this patient demographic [30].

The observed trend of higher complete remission rates and lower mortality in the CAR T-cell+SCT group underscores the potential synergistic effects of combining these 2 innovative therapies [31]. The significant reduction in relapse rate among patients who received SCT after CAR T-cell therapy further reinforces the value of this sequential approach, as maintaining long-term disease control is crucial for improving patient prognosis [32]. Additionally, the favorable trends observed in OS and LFS for the CAR T-cell+SCT group suggest that this combination may enhance the durability of clinical responses, potentially leading to improved long-term outcomes [33]. The meta-analysis also highlights the potential benefits of using CAR T-cell therapy as a bridge to consolidative SCT. The safety profile of the CAR T-cell+SCT treatment was generally well-tolerated, as indicated in literature [29,34].

At the molecular level, CAR T-cells can initiate a rapid and highly specific cytotoxic response. Upon antigen engagement, these cells release perforin and granzymes to induce apoptosis in malignant targets, while also producing inflammatory cytokines, such as interferon-gamma and tumor necrosis factor-alpha that amplify anti-leukemic immunity [35,36]. This targeted immune response can lead to deep remissions and MRD negativity, effectively reducing tumor burden and creating an optimal immunologic window for allo-SCT. However, CAR T-cell efficacy can be limited by antigen escape, T-cell exhaustion, and limited persistence [6,14]. Allo-SCT addresses these gaps by reconstituting the immune system with donor-derived cells capable of exerting a broad graft-versus-leukemia effect. Unlike CAR T-cells, this response is not restricted to a single antigen and involves recognition of minor histocompatibility antigens and tumor-associated peptides by donor T-cells and natural killer cells [37,38]. This diverse and sustained immune surveillance is particularly effective when performed after CAR T-cell-induced cytoreduction, as it targets any residual leukemic cells that may have evaded initial therapy [39,40].

Together, this sequence leverages the potent, short-term cytotoxicity of CAR T-cells and the durable, systemic immunologic control of allo-SCT to achieve superior and sustained remission outcomes. This strategy also positions patients for better outcomes by mitigating the risks associated with bridge therapies like conventional chemotherapy, which have shown limitations in producing sustained responses in prior studies [9,11,41]. Not only addresses the critical need for effective pre-SCT therapies, but it also emphasizes the growing preference for immunotherapeutic strategies that minimize the associated toxicities of traditional treatments, ultimately improving the overall therapeutic landscape in oncology. Moreover, findings emphasize the necessity of optimizing the cell product quality in adoptive T-cell therapies, as this can further reduce adverse effects and clinical costs, making these therapies more accessible and practical for a broader range of patients. Furthermore, the integration of CAR T-cell therapy within treatment regimens is indicative of a significant shift towards personalized medicine in oncology, reflecting the need to develop individualized approaches that harness the patient's immune system to effectively combat malignancies, which is particularly crucial for improving outcomes in solid tumors [42].

Our study differs from existing literature by offering a targeted analysis of the synergistic potential of consolidative allo-SCT following CAR T-cell therapy. Additionally, we address gaps in prior research by systematically examining relapse rate, survival endpoints (OS and LFS), and treatment-related toxicities in post-CAR T SCT settings—an area still underrepresented in current literature, specifically in the CAYA population.

This meta-analysis has several limitations. First, the relatively small number of patients treated with CAR T-cell followed by allo-SCT limits the statistical power and generalizability of the results. It may reduce confidence in the observed treatment effects, increase susceptibility to bias, and restrict subgroup analyses. Second, available data reporting the safety profile was still limited. It is not clear whether the complications occurred following allo-SCT were purely related to the transplantation process itself or influenced by the previous treatments received and/or the comorbidities of the subjects. Finally, the studies were mainly conducted in developed regions, such as China, United States, and European countries which made its availability limited in low-to-middle-income countries.

In this study, we illustrate that employing a sequential approach involving CAR T-cell therapy followed by consolidative allo-SCT offers potential benefits as effective disease management in CAYA diagnosed with R/R B-ALL. Despite the constraints inherent in our study, additional clinical trials are warranted to ascertain the advantages of CAR T-cell therapy as a bridging intervention preceding allo-SCT fully.