Leukemia burden impacts the efficacy and toxicity of blinatumomab in pediatric B-cell acute lymphoblastic leukemia

Leukemia burden impacts the efficacy and toxicity of blinatumomab in pediatric B-cell acute lymphoblastic leukemia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (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],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Leukemia burden impacts the efficacy and toxicity of blinatumomab in pediatric B-cell acute lymphoblastic leukemia Weiling Yan, Shaoyan Hu, Wenjin Gao, Lihua Yang, Yan Gu, Yufeng Liu, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5197329/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Blinatumomab has demonstrated its efficacy and safety in pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL). The objective of this analysis was to describe the responses and toxicities of blinatumomab in pediatric patients with different leukemic burdens in the bone marrow. Methods We enrolled patients aged 0-18 years who were diagnosed with CD19-positive B-ALL and treated with blinatumomab between January 2021 and May 2023 from 14 centers in China. Results A total of 307 patients were enrolled in this analysis. The complete remission (CR) rate was 72.1% among 61 patients with ≥5% blasts(non-complete remission, NCR group), of whom 90.9% achieved minimal residual disease (MRD) negativity. Among 93 patients with <5% blasts but multiparametric flow cytometry MRD (MFC-MRD) positive(MRD+ group), 96.8% achieved MRD negativity. Of the 153 MFC-MRD negative patients(MRD- group), 60.0% and 65.5% turned quantitative polymerase chain reaction MRD (qPCR-MRD) or next-generation sequencing MRD (NGS-MRD) negative, respectively. Additionally, Patients in the MRD+ and MRD- groups had significantly better outcomes than those in the NCR group, with 30-month OS rates of 91.6% (95% CI: 0.857-0.979), 95.3% (95% CI: 0.915-0.993), and 77.6% (95% CI: 0.674-0.894), respectively (P<0.001), and 30-month RFS rates of 90.7% (95% CI: 0.847-0.972), 93.3% (95% CI: 0.890-0.979), and 64.4% (95% CI: 0.495-0.837), respectively (P<0.001). There was no statistically significant difference in OS between the patients who achieved MFC-MRD negativity in the NCR group and those in the MRD+ group, with 30-month OS rates of 85.7% (95% CI: 0.745-0.987) and 93.2% (95% CI: 0.881-0.986), respectively (P=0.270). In this study, 41% of patients experienced grade ≥3 adverse events (AEs), with hematological toxicity being the most common (32.9%). The severe adverse events, such as cytokine release syndrome (CRS) and neurotoxicity, occurred at a low rate, particularly grade ≥3, at 3.6% and 2.6%, respectively. Conclusion Overall, these results indicate that blinatumomab is effective and well-tolerated. Patients with a lower leukemia burden before blinatumomab administration tend to have better overall survival and relapse-free survival with fewer AEs. acute lymphoblastic leukemia pediatric blinatumomab real-world study Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction B-cell acute lymphoblastic leukemia (B-ALL) is a prevalent and potentially life-threatening hematologic malignancy primarily affecting pediatric populations. With risk-adapted protocols, the 5-year overall survival (OS) rate exceeds 90%.[ 1 , 2 ] Nevertheless, 15–20% of patients still relapse with standard first-line chemotherapy, and only about 50% of these can survive long-term.[ 3 , 4 ] Patients who experience second or further relapses, or relapses after hematopoietic stem cell transplantation (HSCT), have a worse prognosis and lower quality of life. Minimal residual disease (MRD) is an important prognostic factor in childhood ALL, and persistent MRD positivity is associated with a high relapse rate and poor overall survival.[ 5 ] The ability of a treatment to induce MRD negativity is often considered a surrogate marker for long-term outcomes. Increasing the intensity of chemotherapy is accompanied by significant toxicity and adverse effects. Thus, there is a critical need for innovative and targeted therapies to enhance treatment outcomes while minimizing side effects. Blinatumomab, a bispecific T-cell engager (BiTE) construct that links CD19 + malignant B cells to CD3 + T cells, has been approved by the US Food and Drug Administration for the treatment of adult and childhood relapsed/refractory (R/R) B-ALL and persistent MRD in B-ALL. Several clinical randomized studies have demonstrated the efficacy and safety of blinatumomab in children with R/R ALL.[ 6 – 8 ] Additionally, several studies have evaluated the real-world survival outcomes and toxicities of blinatumomab in R/R B-ALL or primary B-ALL in children.[ 9 – 11 ] In a phase II trial of adult patients, blinatumomab induced MRD negativity in most patients and resulted in high rates of relapse-free survival (RFS) and OS.[ 12 ] However, research in pediatric patients is relatively limited. In this retrospective multicenter observational study, the largest to date, we describe the responses and toxicities of blinatumomab in patients with different leukemic burdens in the bone marrow. Methods Study design The main objective of this retrospective multicenter study was to analyze the application of blinatumomab in Chinese pediatric B-ALL patients, including clinical characteristics, treatment patterns, and the efficacy and toxicity of blinatumomab. We enrolled patients aged 0–18 years who were diagnosed with CD19-positive B-ALL and treated with blinatumomab between January 2021 and May 2023 from 14 centers in China. The study received approval from the Ethics Committee of the Children's Hospital, Zhejiang University School of Medicine (2023-IRB-0115-P-01). Long-term follow-up was performed for all enrolled patients until the end of the study period or death. Patients who participated in any interventional clinical trial or had a history of other tumors were excluded. Additionally, patients who discontinued blinatumomab for economic reasons were not included in the statistical analysis. Outcome measures The evaluation of efficacy included morphologic complete remission (CR) and MRD response. CR was defined as 100×10 9 /L and absolute neutrophil count > 1×10 9 /L); those with partial recovery of peripheral blood counts (platelets > 50×10 9 /L and absolute neutrophil count > 0.5×10 9 /L) and incomplete recovery of peripheral blood counts (platelets > 100×10 9 /L or absolute neutrophil count > 1×10 9 /L) were defined as CRh and CRi. MRD was assessed using multiparametric flow cytometry (MFC), quantitative polymerase chain reaction (qPCR) analysis (threshold 10 − 4 /0.01%), or next-generation sequencing (NGS, threshold 10 − 6 /0.0001%). A complete MRD response was defined as no leukemia cells detected in the bone marrow after treatment with blinatumomab. OS was defined as the time from the beginning of blinatumomab treatment to death for any reason or the last follow-up. RFS was the time from the beginning of blinatumomab treatment to the date of relapse or death, or the last follow-up. Adverse events (AEs) were recorded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Statistical analyses Patients were divided into three groups based on the bone marrow blast percentage and MFC-MRD status at the initiation of blinatumomab: bone marrow blasts ≥ 5% (non-complete remission, NCR group), bone marrow blasts < 5% with MFC-MRD positive (MRD + group), and bone marrow blasts < 5% with MFC-MRD negative (MRD- group). Descriptive statistics were used for demographic and disease characteristics. Continuous variables were presented as medians (ranges), and categorical variables were summarized as frequencies (percentages). Chi-square test or Fisher’s exact tests were used to examine differences between categorical parameters, with statistical significance set at p < 0.05. Survival analyses were conducted using the Kaplan-Meier (KM) method. Median OS and RFS were reported in months with 95% confidence intervals. Results Baseline characteristics From January 2021 to May 2023, a total of 307 patients were enrolled. The median age of the patients at the initiation of blinatumomab treatment was 6.2 years (range: 0.4 to 17.3 years), with 184 male patients (59.9%). Among them, 113 patients (36.8%) received blinatumomab for R/R B-ALL, of whom 50 patients were non-remission before blinatumomab, 76 (24.8%) for positive MRD, and 58 (18.9%) with high-risk to improve the outcome despite having achieved MRD negativity. The remaining patients received blinatumomab as an alternative to chemotherapy due to severe infection or drug intolerance. Four patients had previously undergone allogeneic hematopoietic stem cell transplantation (allo-HSCT) and seven patients had received CAR-T cell therapy before blinatumomab. Thirty-six patients (11.7%) had KMT2A rearrangement, and 32 (10.4%) had the BCR::ABL1 fusion gene. The baseline characteristics of the patients are shown in Table 1 . Table 1 Baseline characteristics of the patients Characteristics NCR group (n, %) MRD + group (n, %) MRD- group (n, %) All patients (n, %) Total number N = 61 N = 93 N = 153 N = 307 Age, median (range), y 7.3 (0.4–16.6) 6.7 (0.5–17.3) 6.1 (0.4–17.3) 6.2 (0.4–17.3) Sex, (male) 33 (54.1) 53 (57.0) 98 (64.1) 184 (59.9) Molecular abnormalities KMT2Ar 10 (16.4) 13 (14.0) 13 (8.5) 36 (11.7) TEL::AML1 3 (4.9) 12 (12.9) 15 (9.8) 30 (9.8) E2A::PBX1 3 (4.9) 3 (3.2) 8 (5.2) 14 (4.6) BCR::ABL1 4 (6.6) 5 (5.4) 23 (15.0) 32 (10.4) Ph-like 2 (3.3) 2 (2.2) 6 (3.9) 10 (3.3) Other mutations 19 (31.1) 42 (45.2) 65 (42.5) 126 (41.0) Absence of mutations 20 (32.8) 18 (19.4) 23 (15.0) 61 (19.9) Extramedullary involvement Testis 3 (4.9) 2 (2.2) 1 (0.7) 6 (2.0) CNSL 2 (3.3) 8 (8.6) 7 (4.6) 17 (5.5) Relapse 0 13 (21.3) 69 (74.2) 138 (90.2) 220 (71.7) ≥1 48 (78.7) 24 (25.8) 15 (9.8) 87 (28.3) HSCT before blinatumomab initiation 1 (1.6) 3 (3.2) 0 4 (1.3) CART before blinatumomab initiation Yes 7 (11.5) 0 0 7 (2.3) KMT2Ar: KMT2A rearrangement; MFC-MRD: flow cytometry MRD; qPCR MRD: quantitative polymerase chain reaction MRD; NGS MRD: next-generation sequencing MRD; CNSL:central nervous system leukemia; HSCT:hematopoietic stem cell transplantation In this cohort, 185 patients received blinatumomab with a dosage stepwise escalation from 5 to 15 µg/m²/day, and 17 patients with an escalation from 9 to 28 µg/day. The remaining 105 patients began treatment directly at the full dosage, two of whom received 28 µg/day from day one. Sixty-one patients with bone marrow blasts ≥ 5% at the time of blinatumomab administration were assigned to the NCR group, with 13 (21.3%) patients had blast between 5% and 20% in the bone marrow, 11 (18.0%) between 20% and 50%, and 37 (60.7%) equal to or higher than 50%. Additionally, 93 patients were included in the MRD + group, and 153 patients were included in the MRD- group. In the NCR group, the median interval from diagnosis to the initiation of blinatumomab was 7.3 months, with 78.7% of patients more than 6 months and 41% more than 24 months (Fig. 1 ). Response In the NCR group, 44 (72.1%) out of the 61 patients achieved CR/CRh/CRi after blinatumomab treatment, and 2 patients (3.3%) achieved PR. A total of three patients discontinued blinatumomab, including one abandoned treatment on the 6th day due to the family's decision, one discontinued on day 3 due to severe CRS, and the other withdrew on the first day of application due to high fever. Of the 10 patients with KMT2A rearrangement, 8 (80.0%) achieved CR. All four patients with positive BCR::ABL1 achieved CR. Among the 44 patients who achieved CR/CRh/CRi, 40 (90.9%) achieved MFC-MRD negativity after blinatumomab treatment (Table 2 ). Of the 44 CR patients, 7 (15.9%) relapsed thereafter, with two dying from relapse and one dying after allo-HSCT. All these relapsed patients had a history of 1–2 previous relapses and had presented an MRD response after blinatumomab treatment, with a median relapse interval of 3.9 months (range: 0.8 to 14.2 months). A total of 26 patients (42.6%) proceeded to allo-HSCT during follow-up, of whom 24 achieved CR after blinatumomab. Table 2 Adverse events of all patients Adverse events Total, n(%) Grade 1–2, n(%) Grade ≥ 3, n(%) Patients with at least one adverse event 262 (85.3) 136 (44.3) 126 (41.0) Cytokine release syndrome 85 (27.7) 74 (24.1) 11 (3.6) Infections 48 (15.6) 22 (7.2) 26 (8.5) Neurotoxicity 24 (7.8) 16 (5.2) 8 (2.6) Hematological toxicity 153 (49.8) 52 (16.9) 101 (32.9) Hepatotoxicity 49 (16.0) 43 (14.0) 6 (2.0) Pyrexia 142 (46.3) 138 (45.0) 4 (1.3) In the MRD + group, among 93 cases, 91 were evaluated for MRD after blinatumomab, with an MRD clearance rate of 98.9% (n = 90). The patient who did not achieve MRD negativity proceeded to allo-HSCT. Of the 90 patients who achieved MRD negativity, three relapsed, ranging from 5.5 to 11.2 months after blinatumomab, and two died. Of the two patients who were not evaluated, one discontinued blinatumomab on day 4 due to severe neurological events. In the MRD- group, 20 patients were MRD positive when evaluated by qPCR, and 29 were MRD positive by NGS. After blinatumomab treatment, 60.0% (n = 12) and 65.5% (n = 19) of patients turned qPCR-MRD or NGS-MRD negative, respectively. One patient whose qPCR-MRD turned negative relapsed 1.5 months later. No case relapsed among patients who achieved NGS-MRD negativity. However, two patients with persistent NGS-MRD relapsed at 1.2 and 2.8 months after the treatment of blinatumomab, respectively. Outcome analysis The median follow-up duration for all patients was 16.1 months (range: 0.1 to 33.7 months). Patients in the MRD + and MRD- groups had significantly better outcomes than those in the NCR group, with 30-month OS rates of 91.6% (95% CI: 0.857–0.979), 95.3% (95% CI: 0.915–0.993), and 77.6% (95% CI: 0.674–0.894), respectively (P < 0.001), and 30-month RFS rates of 90.7% (95% CI: 0.847–0.972), 93.3% (95% CI: 0.890–0.979), and 64.4% (95% CI: 0.495–0.837), respectively (P < 0.001). The OS and RFS were similar between the MRD- and MRD + groups (P = 0.246 and P = 0.461) (Fig. 2). In the subgroup analysis of the NCR group, the OS at 30 months for the CR/CRh/CRi patients was higher than for those who only reached PR or non-remission (NR) were 87.0% (95% CI: 0.765–0.988) and 50.0% (95% CI: 0.296–0.844), respectively (P = 0.001), and the 30-month RFS for the CR/CRh/CRi group was higher than that of the NR/PR group as well, with rates of 78.5% (95% CI: 0.669–0.922) and 33.3% (95% CI: 0.128–0.867), respectively (P = 0.008, Fig. 3 ). Furthermore, We also compared the RFS of patients who achieved MRD negativity in the NCR group and the MRD + group. There was no statistically significant difference in OS between the patients who achieved MFC-MRD negativity in the NCR group and those in the MRD + group, with 30-month OS rates of 85.7% (95% CI: 0.745–0.987) and 93.2% (95% CI: 0.881–0.986), respectively (P = 0.270). However, the relapse rate in the NCR group was higher than that in the MRD + group, with 30-month RFS rates of 76.4% (95% CI: 0.638–0.914) and 92.1% (95% CI: 0.866–0.979), respectively (P = 0.015) (Fig. 4 ). Adverse events A total of 262 patients (85.3%) experienced at least one drug-related adverse event (AE), with 126 patients (41.0%) experiencing grade ≥ 3 toxicities. Only one patient developed grade 5 CRS with IL-6 levels > 5000 pg/mL and died of multiple organ failure (Table 2 ). The main adverse events were hematological toxicity and pyrexia, observed in 49.8% and 46.3% of patients, respectively. The most common grade ≥ 3 adverse event was hematological toxicity (32.9%). Most CRS and neurotoxicity events were grade 1 or 2, observed in 74 (24.1%) and 16 (5.2%) cases, respectively. Grade ≥ 3 CRS was observed in 11 patients (3.6%) and grade ≥ 3 neurotoxicity in 8 patients (2.6%). In this study, a total of 36 patients (11.7%) temporarily discontinued treatment with blinatumomab due to AEs, and six patients (2.0%) permanently discontinued treatment. Among those who temporarily discontinued, four patients interrupted their dosage due to hepatotoxicity with elevated alanine aminotransferase levels, and six due to CRS. Additionally, five patients temporarily discontinued treatment for neurotoxicity, and seven for fever. Nine patients temporarily discontinued treatment due to multiple AEs (Fig. 5 ). As for permanent discontinuation, three patients stopped blinatumomab due to neurological events, with two of them experiencing seizures. One patient had to discontinue treatment due to grade ≥ 3 neutropenia complicated by infection. Two patients each had to discontinue blinatumomab due to CRS and acute pancreatitis (Fig. 5 ). In the subgroup analysis, 96.7% of patients in the NCR group experienced adverse events, which was higher than the 83.9% in the MRD + group (P = 0.012) and 81.7% in the MRD- group (P = 0.004). Additionally, the incidence of grade ≥ 3 AEs in the NCR, MRD+, and MRD- groups was 62.3%, 34.4%, and 36.6%, respectively (P < 0.001), indicating that patients in the NCR group experienced more severe AEs. Regarding specific AEs, patients in the NCR group exhibited significantly higher rates of hematological toxicity, CRS, pyrexia, infections, and hepatotoxicity compared to the other two groups, with the exception of neurotoxicity (Fig. 5 ). Discussion Despite the high cure rate of pediatric patients with B-ALL, the prognosis for patients with R/R B-ALL or persistent MRD positivity remains poor. Numerous prospective studies and retrospective real-world data have confirmed the efficacy and relative safety of blinatumomab in treating R/R B-ALL and inducing MRD negativity.[ 10 , 12 – 16 ] This retrospective analysis is the largest multicenter real-world study in children to date, providing valuable insights into the real-world application of blinatumomab in the treatment of pediatric B-ALL in China. In our study, the application of blinatumomab therapy achieved a high CR rate of 72.1% in patients with bone marrow blasts ≥ 5% at the initiation of treatment, with 90.9% of these responders also achieving MRD negativity, which is comparable to or higher than multiple previous pediatric studies.[ 6 , 9 , 10 , 17 ] This inspiring result indicates that blinatumomab is effective in inducing remission for relapsed/refractory or high-risk patients. Similarly, for patients with persistent MRD, blinatumomab has demonstrated excellent efficacy, with 98.9% of patients in the MRD + group achieving MFC-MRD negativity after one cycle of treatment, consistent with other pediatric studies.[ 7 , 13 , 16 ] We divided the patients into three groups based on leukemia burden before the application of blinatumomab and found that patients in the NCR group with higher leukemia burden had a lower probability of achieving MRD negativity, with a rate of 65.6% (n = 40/61). In contrast, the MRD + group with lower leukemia burden achieved a 96.8% MRD negativity rate. A similar result was found in the study by Locatelli and colleagues, where 79% of patients with ≥ 5% blasts at baseline achieved MRD response, compared to 92% of patients with < 5% blasts during the first two cycles of blinatumomab.[ 17 ] Several other trials also demonstrated that a low leukemia burden improved survival and response to blinatumomab.[ 6 , 7 , 9 , 18 ] The improved MRD response to blinatumomab is associated with a low baseline leukemia burden, which may be explained by the function and number of T cells. When the leukemia burden is high, T cells may be more prone to exhaustion. Therefore, patients receiving blinatumomab at a relatively low leukemia burden may benefit more. Consequently, some studies are evaluating the role of blinatumomab in children with chemotherapy-sensitive leukemia, including newly diagnosed or low-risk first-relapse B-ALL. This is also why blinatumomab is currently used for first-line treatment of patients with MRD positivity or even MRD negativity. Additionally, we found that achieving MRD negativity after blinatumomab treatment is related to prognosis. However, although achieving negative MRD, patients from NCR group still presented higher relapse rate than those from MRD + group, with 17.5% (7/40) of patients experiencing relapse later on, indicating that patients with low MRD burden were more likely to benefit from blinatumomab treatment. Apart from MFC-MRD, we also monitored MRD in some patients in the MRD- group using PCR or NGS, and the MRD response for these two methods was not as high as that for MFC. This may explain the relapse in patients achieving MFC-MRD negativity after blinatumomab application and why patients with MFC-MRD negativity still benefit from blinatumomab. Current studies have shown that undetectable NGS-MRD indicates a better prognosis than undetectable MFC-MRD in B-ALL.[ 19 , 20 ] The study by Min'er Gu and colleagues demonstrated that blinatumomab could further eradicate MRD after patients achieve MFC-MRD undetectable in B-ALL patients.[ 21 ] As MFC is not a very precise method for monitoring deep MRD, using other deeper MRD monitoring methods like PCR or NGS to guide blinatumomab application and subsequent treatment choices could lead to more accurate clinical decision-making. Toxicity was noted in our study, with 85.3% of patients experiencing at least one adverse event (AE), and 41% experiencing grade ≥ 3 AEs, consistent with previous studies.[ 6 , 15 , 17 ] The most common AEs were pyrexia and cytopenia, while the most feared adverse events, such as CRS and neurotoxicity, occurred at a low rate, particularly grade ≥ 3 (3.6% and 2.6%, respectively), consistent with data from other studies, confirming the relative safety of blinatumomab.[ 6 , 13 , 22 ] However, in the study by Beneduce and colleagues[ 9 ], a significant number of neurological events were observed, while the rates of CRS and hematological toxicity were lower. This might be attributed to the higher number of patients with < 5% blasts recruited in their cohort, supporting the hypothesis that a low leukemic burden is associated with an off-target effect of blinatumomab due to non-specific T cell activation.[ 23 ] Furthermore, we conducted a subgroup analysis and found that AEs, except for neurotoxicity, were significantly higher in the NCR group than in the other two groups, similar to the previous study, further supporting the hypothesis. As a retrospective study, it is subject to inherent biases and limitations in data collection and reporting that may affect the validity of the findings. Additionally, as a multicenter retrospective study, physicians from different centers may be more flexible in the use of blinatumomab, potentially lacking a unified standard in terms of treatment options and duration. Although long-term follow-up was performed, the duration of follow-up may not be sufficient to capture all long-term effects and outcomes. In conclusion, this study investigates the impact of leukemia burden on the efficacy and toxicity of blinatumomab in pediatric B-ALL in a real-world setting in China. All patients treated with blinatumomab achieved a high rate of CR and MRD response. Patients with a lower leukemia burden before the administration of blinatumomab tend to have better OS and RFS, with fewer AEs, especially severe toxicities. However, regardless of the leukemia burden before treatment with blinatumomab, achieving MRD negativity after treatment indicates a favorable OS. Furthermore, the use of blinatumomab may lead to deeper remission. Employing more sensitive detection methods, such as PCR or NGS, to monitor MRD can better guide treatment. Abbreviations B-ALL B-cell acute lymphoblastic leukemia OS Overall survival HSCT Hematopoietic stem cell transplantation MRD Minimal residual disease RFS Relapse-free survival CR Complete remission MFC Multiparametric flow cytometry qPCR Quantitative polymerase chain reaction NGS Next-generation sequencing AEs Adverse events NCR Non-complete remission CNSL: Central nervous system leukemia Declarations Author information: Weiling Yan 1# , Shaoyan Hu 2# , Wenjin Gao 3# , Lihua Yang 4 , Yan Gu 5 , Yufeng Liu 6 , Yunyan He 7 , Dunhua Zhou 8 , Wenting Hu 9 , Xue Tang 10 , Ming Sun 11 , Lili Song 12 , Wenyu Yang 13 , Yalan You 14 , Yongmin Tang 1 *, Xiaojun Xu 1 * 1 Department of Hematology & Oncology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China 2 Department of Hematology, Children's Hospital of Soochow University, Suzhou, Jiangsu, China 3 Department of Hematology & Oncology, Xi'an Children's Hospital, Xi'an, Shaanxi, China 4 Department of Pediatric Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China 5 Department of Pediatric Hematology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China 6 Department of Pediatric Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China 7 Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China 8 Department of Pediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China 9 Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China 10 Department of Hematology, Shenzhen Children's Hospital, Shenzhen, Guangdong, China 11 Department of Hematology, Wuhan Children's Hospital, Wuhan, Hubei, China 12 Department of Hematology, Henan (Zhengzhou) Children's Hospital, Zhengzhou, Henan, China 13 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China 14 Department of Hematology and Oncology, Children's Medical Center, Hunan Provincial People's Hospital（The First Affifiliated Hospital of Hunan Normal University）,Changsha, China # These authors contributed equally to this work and share first authorship * Corresponding author Yongmin Tang, Department of Hematology & Oncology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. E-mail: [email protected] Xiaojun Xu, Department of Hematology & Oncology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. E-mail: [email protected] Ethical approval This retrospective study was approved by the Ethics Committee of the Children's Hospital, Zhejiang University School of Medicine (2023-IRB-0115-P-01). Consent for publication Not applicable. Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Competing Interests The authors have no relevant financial or non-financial interests to disclose. Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Author contributions Xiaojun Xu and Yongmin Tang designed the study. Weiling Yan analyzed the data and wrote the manuscript. 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Locatelli F, Zugmaier G, Mergen N, Bader P, Jeha S, Schlegel PG, et al. Blinatumomab in pediatric relapsed/refractory b-cell acute lymphoblastic leukemia: rialto expanded access study final analysis. Blood Adv. 2022;6(3):1004–14. Gore L, Locatelli F, Zugmaier G, Handgretinger R, O'Brien MM, Bader P, et al. Survival after blinatumomab treatment in pediatric patients with relapsed/refractory b-cell precursor acute lymphoblastic leukemia. Blood Cancer J. 2018;8(9):80. Locatelli F, Zugmaier G, Rizzari C, Morris JD, Gruhn B, Klingebiel T, et al. Improved survival and mrd remission with blinatumomab vs. Chemotherapy in children with first high-risk relapse b-all. Leukemia. 2023;37(1):222–25. Locatelli F, Eckert C, Hrusak O, Buldini B, Sartor M, Zugmaier G, et al. Blinatumomab overcomes poor prognostic impact of measurable residual disease in pediatric high-risk first relapse b-cell precursor acute lymphoblastic leukemia. Pediatr Blood Cancer. 2022;69(8):e29715. Locatelli F, Zugmaier G, Mergen N, Bader P, Jeha S, Schlegel PG, et al. Blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia: results of the rialto trial, an expanded access study. Blood Cancer J. 2020;10(7):77. Gokbuget N, Dombret H, Bonifacio M, Reichle A, Graux C, Faul C, et al. Blinatumomab for minimal residual disease in adults with b-cell precursor acute lymphoblastic leukemia. Blood. 2018;131(14):1522–31. Short NJ, Kantarjian H, Ravandi F, Konopleva M, Jain N, Kanagal-Shamanna R, et al. High-sensitivity next-generation sequencing mrd assessment in all identifies patients at very low risk of relapse. Blood Adv. 2022;6(13):4006–14. Pulsipher MA, Carlson C, Langholz B, Wall DA, Schultz KR, Bunin N, et al. Igh-v(d)j ngs-mrd measurement pre- and early post-allotransplant defines very low- and very high-risk all patients. Blood. 2015;125(22):3501–08. Gu M, Xia Y, Zhang J, Tang Y, Xu W, Song H, et al. The effectiveness of blinatumomab in clearing measurable residual disease in pediatric b-cell acute lymphoblastic leukemia patients detected by next-generation sequencing. Cancer Med. 2023;12(24):21978–84. Queudeville M, Ebinger M. Blinatumomab in pediatric acute lymphoblastic leukemia-from salvage to first line therapy (a systematic review). J Clin Med. 2021;10(12). Klinger M, Zugmaier G, Nagele V, Goebeler ME, Brandl C, Stelljes M, et al. Adhesion of t cells to endothelial cells facilitates blinatumomab-associated neurologic adverse events. Cancer Res. 2020;80(1):91–101. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5197329","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":363659044,"identity":"7f6446dc-a658-4856-943f-b84233b3976e","order_by":0,"name":"Weiling Yan","email":"","orcid":"","institution":"Department of Hematology \u0026 Oncology, Children's Hospital, Zhejiang University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Weiling","middleName":"","lastName":"Yan","suffix":""},{"id":363659045,"identity":"13383dbf-448e-45ea-84a6-9b8e579e7da7","order_by":1,"name":"Shaoyan Hu","email":"","orcid":"","institution":"Department of Hematology, Children's Hospital of Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Shaoyan","middleName":"","lastName":"Hu","suffix":""},{"id":363659046,"identity":"88044159-23db-4dc5-8e19-67b78825cea2","order_by":2,"name":"Wenjin Gao","email":"","orcid":"","institution":"Department of Hematology \u0026 Oncology, Xi'an Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wenjin","middleName":"","lastName":"Gao","suffix":""},{"id":363659047,"identity":"48f704d3-ec14-4e0d-91c4-5833c073fb80","order_by":3,"name":"Lihua Yang","email":"","orcid":"","institution":"Department of Pediatric Hematology, Zhujiang Hospital, Southern Medical University","correspondingAuthor":false,"prefix":"","firstName":"Lihua","middleName":"","lastName":"Yang","suffix":""},{"id":363659048,"identity":"95e9bd52-38b2-4b05-a410-e5ce3f19abcb","order_by":4,"name":"Yan Gu","email":"","orcid":"","institution":"Department of Pediatric Hematology, The First Affiliated Hospital of Shandong First Medical University \u0026 Shandong Provincial Qianfoshan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"Gu","suffix":""},{"id":363659049,"identity":"c46579c0-1ed0-4a08-8851-1ddb798d4e86","order_by":5,"name":"Yufeng Liu","email":"","orcid":"","institution":"Department of Pediatric Hematology, The First Affiliated Hospital of Zhengzhou University","correspondingAuthor":false,"prefix":"","firstName":"Yufeng","middleName":"","lastName":"Liu","suffix":""},{"id":363659050,"identity":"2596e530-134f-44be-adfc-754c99e8d194","order_by":6,"name":"Yunyan He","email":"","orcid":"","institution":"Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yunyan","middleName":"","lastName":"He","suffix":""},{"id":363659051,"identity":"d5c34d4c-08df-415a-8cb4-815e45e79485","order_by":7,"name":"Dunhua Zhou","email":"","orcid":"","institution":"Department of Pediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Dunhua","middleName":"","lastName":"Zhou","suffix":""},{"id":363659052,"identity":"53710b4f-dd2b-4e4d-9346-e071cfacaf0a","order_by":8,"name":"Wenting Hu","email":"","orcid":"","institution":"Department of Hematology \u0026 Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University","correspondingAuthor":false,"prefix":"","firstName":"Wenting","middleName":"","lastName":"Hu","suffix":""},{"id":363659053,"identity":"ab9144f8-3d50-44da-bd6b-2f090ba79316","order_by":9,"name":"Xue Tang","email":"","orcid":"","institution":"Department of Hematology, Shenzhen Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xue","middleName":"","lastName":"Tang","suffix":""},{"id":363659054,"identity":"4e5a32bd-5d86-453e-bdd2-3b9f6c3ebc1e","order_by":10,"name":"Ming Sun","email":"","orcid":"","institution":"Department of Hematology, Wuhan Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ming","middleName":"","lastName":"Sun","suffix":""},{"id":363659055,"identity":"21840dcf-286d-46d0-a866-6964fae495fa","order_by":11,"name":"Lili Song","email":"","orcid":"","institution":"Department of Hematology, Henan (Zhengzhou) Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lili","middleName":"","lastName":"Song","suffix":""},{"id":363659056,"identity":"f43d8b4e-7fc6-4a21-8162-ff7342a4d94b","order_by":12,"name":"Wenyu Yang","email":"","orcid":"","institution":"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases","correspondingAuthor":false,"prefix":"","firstName":"Wenyu","middleName":"","lastName":"Yang","suffix":""},{"id":363659057,"identity":"05781768-e273-48fc-a95f-5a9354c55aa6","order_by":13,"name":"Yalan You","email":"","orcid":"","institution":"Department of Hematology and Oncology, Children's Medical Center, Hunan Provincial People's Hospital（The First Affifiliated Hospital of Hunan Normal University）","correspondingAuthor":false,"prefix":"","firstName":"Yalan","middleName":"","lastName":"You","suffix":""},{"id":363659058,"identity":"ca6a161b-2ce0-4828-9799-808e8960df59","order_by":14,"name":"Yongmin Tang","email":"","orcid":"","institution":"Department of Hematology \u0026 Oncology, Children's Hospital, Zhejiang University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yongmin","middleName":"","lastName":"Tang","suffix":""},{"id":363659059,"identity":"82f6230e-eaee-4ff9-81a9-58fb9fb30a8f","order_by":15,"name":"Xiaojun Xu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6ElEQVRIiWNgGAWjYJCCAwwMbAwM7A0MBkAOYwPxWngOkKAFAiQSwBRhLQY3cgwP/KjgS9wu+fxBMQ+DjeyGA8zPHuDTIjkjLeFgzxm2xJ2zExKMeRjSjDccYDM3wKeFXyL5wAHeNrbEDbcTDgC1HE7ccICHTQKfFjaJxIaDf0Fabh5sAGr5T1gLyJbDYFtuMDMAtRwgrEWy51nCYZkzbMYbzqQxGM4xSDaeeZjNDK8Wg+M5xh/fVByT3XD8+DODNxV2sn3Hm5/h1QIFx8D+MgBHJjMR6oGgBkQwPyBO8SgYBaNgFIw0AADtFEsFmxu0zgAAAABJRU5ErkJggg==","orcid":"","institution":"Department of Hematology \u0026 Oncology, Children's Hospital, Zhejiang University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Xiaojun","middleName":"","lastName":"Xu","suffix":""}],"badges":[],"createdAt":"2024-10-03 09:38:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5197329/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5197329/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":68716366,"identity":"ed403402-e905-4cf1-b3b6-e77b679933e2","added_by":"auto","created_at":"2024-11-11 09:58:06","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":224737,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe interval from diagnosis to the initiation of blinatumomab\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNCR, non-complete remission\u003c/p\u003e","description":"","filename":"image1.tiff.png","url":"https://assets-eu.researchsquare.com/files/rs-5197329/v1/2dc557746df857c6ab0eccf6.png"},{"id":68716367,"identity":"98c535ee-9a4a-4bf6-bf74-b6757accc795","added_by":"auto","created_at":"2024-11-11 09:58:06","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1060018,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSurvival analysis of the whole cohort\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e, overall survival (OS) after blinatumomab treatment for the whole cohort; \u003cstrong\u003eB\u003c/strong\u003e, Comparison of OS rates after blinatumomab treatment in NCR, MRD+ and MRD- groups; \u003cstrong\u003eC\u003c/strong\u003e, Recurrent free survival (RFS) after blinatumomab treatment for the whole cohort; \u003cstrong\u003eD\u003c/strong\u003e Comparison of RFS rates after blinatumomab treatment in NCR, MRD+ and MRD- groups.\u003c/p\u003e","description":"","filename":"image2.tiff.png","url":"https://assets-eu.researchsquare.com/files/rs-5197329/v1/dd8ea6fb1faa1d8e07527210.png"},{"id":68716369,"identity":"dacdae83-9153-4adf-9598-18b90f4d5b73","added_by":"auto","created_at":"2024-11-11 09:58:06","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2970958,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSurvival analysis of patients in non-complete remission (NCR) group\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eComparison of OS (\u003cstrong\u003eA\u003c/strong\u003e) and RFS (\u003cstrong\u003eB\u003c/strong\u003e) after blinatumomab treatment between patients who achieving CR/CRh/CRi and those remaining NR or PR.\u003c/p\u003e","description":"","filename":"image3.tiff.png","url":"https://assets-eu.researchsquare.com/files/rs-5197329/v1/a5f58cbd8d5d8b94e1beb6d0.png"},{"id":68716365,"identity":"f6aad843-a725-4bea-92be-348b49748812","added_by":"auto","created_at":"2024-11-11 09:58:06","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":682225,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSurvival analysis of patients who achieved MRD negativity after Blinatumomab treatment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe OS (\u003cstrong\u003eA\u003c/strong\u003e) and RFS (\u003cstrong\u003eB\u003c/strong\u003e) were compared between patients from MRD+ group and non-complete remission (NCR) group who achieved MRD negativity after Blinatumomab treatment.\u003c/p\u003e","description":"","filename":"image4.tiff.png","url":"https://assets-eu.researchsquare.com/files/rs-5197329/v1/d2c5313f9a3c4ac11f4b15fd.png"},{"id":68716368,"identity":"5f242576-9979-40ac-8894-a86e94f6c99a","added_by":"auto","created_at":"2024-11-11 09:58:06","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1124162,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAdverse events (AEs)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e, AEs leading to discontinuation of blinatumomab; \u003cstrong\u003eB\u003c/strong\u003e, Comparison of the occurrences of AEs≥grade 3 in three groups. * P＜0.05; ** P＜0.001.\u003c/p\u003e","description":"","filename":"image5.tiff.png","url":"https://assets-eu.researchsquare.com/files/rs-5197329/v1/3b6f7516666e160a0b6be64d.png"},{"id":80378532,"identity":"3ab26081-3e58-4321-907b-b4999dea9c68","added_by":"auto","created_at":"2025-04-11 08:32:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":7211796,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5197329/v1/d6b3b3f7-ed17-48c3-a056-ac3476d715b0.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Leukemia burden impacts the efficacy and toxicity of blinatumomab in pediatric B-cell acute lymphoblastic leukemia","fulltext":[{"header":"Introduction","content":"\u003cp\u003eB-cell acute lymphoblastic leukemia (B-ALL) is a prevalent and potentially life-threatening hematologic malignancy primarily affecting pediatric populations. With risk-adapted protocols, the 5-year overall survival (OS) rate exceeds 90%.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] Nevertheless, 15\u0026ndash;20% of patients still relapse with standard first-line chemotherapy, and only about 50% of these can survive long-term.[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] Patients who experience second or further relapses, or relapses after hematopoietic stem cell transplantation (HSCT), have a worse prognosis and lower quality of life. Minimal residual disease (MRD) is an important prognostic factor in childhood ALL, and persistent MRD positivity is associated with a high relapse rate and poor overall survival.[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] The ability of a treatment to induce MRD negativity is often considered a surrogate marker for long-term outcomes. Increasing the intensity of chemotherapy is accompanied by significant toxicity and adverse effects. Thus, there is a critical need for innovative and targeted therapies to enhance treatment outcomes while minimizing side effects.\u003c/p\u003e \u003cp\u003eBlinatumomab, a bispecific T-cell engager (BiTE) construct that links CD19\u0026thinsp;+\u0026thinsp;malignant B cells to CD3\u0026thinsp;+\u0026thinsp;T cells, has been approved by the US Food and Drug Administration for the treatment of adult and childhood relapsed/refractory (R/R) B-ALL and persistent MRD in B-ALL. Several clinical randomized studies have demonstrated the efficacy and safety of blinatumomab in children with R/R ALL.[\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] Additionally, several studies have evaluated the real-world survival outcomes and toxicities of blinatumomab in R/R B-ALL or primary B-ALL in children.[\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eIn a phase II trial of adult patients, blinatumomab induced MRD negativity in most patients and resulted in high rates of relapse-free survival (RFS) and OS.[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] However, research in pediatric patients is relatively limited. In this retrospective multicenter observational study, the largest to date, we describe the responses and toxicities of blinatumomab in patients with different leukemic burdens in the bone marrow.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThe main objective of this retrospective multicenter study was to analyze the application of blinatumomab in Chinese pediatric B-ALL patients, including clinical characteristics, treatment patterns, and the efficacy and toxicity of blinatumomab. We enrolled patients aged 0\u0026ndash;18 years who were diagnosed with CD19-positive B-ALL and treated with blinatumomab between January 2021 and May 2023 from 14 centers in China. The study received approval from the Ethics Committee of the Children's Hospital, Zhejiang University School of Medicine (2023-IRB-0115-P-01). Long-term follow-up was performed for all enrolled patients until the end of the study period or death. Patients who participated in any interventional clinical trial or had a history of other tumors were excluded. Additionally, patients who discontinued blinatumomab for economic reasons were not included in the statistical analysis.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eOutcome measures\u003c/h3\u003e\n\u003cp\u003eThe evaluation of efficacy included morphologic complete remission (CR) and MRD response. CR was defined as \u0026lt;\u0026thinsp;5% bone marrow blasts, without evidence of extramedullary leukemia, and complete recovery of peripheral blood counts (platelets\u0026thinsp;\u0026gt;\u0026thinsp;100\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L and absolute neutrophil count\u0026thinsp;\u0026gt;\u0026thinsp;1\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L); those with partial recovery of peripheral blood counts (platelets\u0026thinsp;\u0026gt;\u0026thinsp;50\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L and absolute neutrophil count\u0026thinsp;\u0026gt;\u0026thinsp;0.5\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L) and incomplete recovery of peripheral blood counts (platelets\u0026thinsp;\u0026gt;\u0026thinsp;100\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L or absolute neutrophil count\u0026thinsp;\u0026gt;\u0026thinsp;1\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L) were defined as CRh and CRi. MRD was assessed using multiparametric flow cytometry (MFC), quantitative polymerase chain reaction (qPCR) analysis (threshold 10\u003csup\u003e\u0026minus;\u0026thinsp;4\u003c/sup\u003e/0.01%), or next-generation sequencing (NGS, threshold 10\u003csup\u003e\u0026minus;\u0026thinsp;6\u003c/sup\u003e/0.0001%). A complete MRD response was defined as no leukemia cells detected in the bone marrow after treatment with blinatumomab.\u003c/p\u003e \u003cp\u003eOS was defined as the time from the beginning of blinatumomab treatment to death for any reason or the last follow-up. RFS was the time from the beginning of blinatumomab treatment to the date of relapse or death, or the last follow-up. Adverse events (AEs) were recorded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.\u003c/p\u003e\n\u003ch3\u003eStatistical analyses\u003c/h3\u003e\n\u003cp\u003ePatients were divided into three groups based on the bone marrow blast percentage and MFC-MRD status at the initiation of blinatumomab: bone marrow blasts\u0026thinsp;\u0026ge;\u0026thinsp;5% (non-complete remission, NCR group), bone marrow blasts\u0026thinsp;\u0026lt;\u0026thinsp;5% with MFC-MRD positive (MRD\u0026thinsp;+\u0026thinsp;group), and bone marrow blasts\u0026thinsp;\u0026lt;\u0026thinsp;5% with MFC-MRD negative (MRD- group). Descriptive statistics were used for demographic and disease characteristics. Continuous variables were presented as medians (ranges), and categorical variables were summarized as frequencies (percentages). Chi-square test or Fisher\u0026rsquo;s exact tests were used to examine differences between categorical parameters, with statistical significance set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Survival analyses were conducted using the Kaplan-Meier (KM) method. Median OS and RFS were reported in months with 95% confidence intervals.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n\u003ch2\u003eBaseline characteristics\u003c/h2\u003e\n\u003cp\u003eFrom January 2021 to May 2023, a total of 307 patients were enrolled. The median age of the patients at the initiation of blinatumomab treatment was 6.2 years (range: 0.4 to 17.3 years), with 184 male patients (59.9%). Among them, 113 patients (36.8%) received blinatumomab for R/R B-ALL, of whom 50 patients were non-remission before blinatumomab, 76 (24.8%) for positive MRD, and 58 (18.9%) with high-risk to improve the outcome despite having achieved MRD negativity. The remaining patients received blinatumomab as an alternative to chemotherapy due to severe infection or drug intolerance. Four patients had previously undergone allogeneic hematopoietic stem cell transplantation (allo-HSCT) and seven patients had received CAR-T cell therapy before blinatumomab. Thirty-six patients (11.7%) had KMT2A rearrangement, and 32 (10.4%) had the BCR::ABL1 fusion gene. The baseline characteristics of the patients are shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eBaseline characteristics of the patients\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCharacteristics\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNCR group (n, %)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eMRD\u0026thinsp;+\u0026thinsp;group (n, %)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eMRD- group (n, %)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAll patients (n, %)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTotal number\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eN\u0026thinsp;=\u0026thinsp;61\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eN\u0026thinsp;=\u0026thinsp;93\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eN\u0026thinsp;=\u0026thinsp;153\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eN\u0026thinsp;=\u0026thinsp;307\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge, median (range), y\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.3 (0.4\u0026ndash;16.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.7 (0.5\u0026ndash;17.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.1 (0.4\u0026ndash;17.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.2 (0.4\u0026ndash;17.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSex, (male)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33 (54.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e53 (57.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e98 (64.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e184 (59.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMolecular abnormalities\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eKMT2Ar\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (16.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (14.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (8.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e36 (11.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTEL::AML1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (4.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12 (12.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (9.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30 (9.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eE2A::PBX1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (4.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (3.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (5.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14 (4.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBCR::ABL1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (6.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (5.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23 (15.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32 (10.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePh-like\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (3.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (2.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (3.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (3.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOther mutations\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19 (31.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e42 (45.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e65 (42.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e126 (41.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAbsence of mutations\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20 (32.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18 (19.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23 (15.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e61 (19.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003eExtramedullary involvement\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTestis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (4.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (2.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (0.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (2.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCNSL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (3.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (8.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (4.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17 (5.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRelapse\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (21.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e69 (74.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e138 (90.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e220 (71.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e48 (78.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24 (25.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (9.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e87 (28.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003eHSCT before blinatumomab initiation\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (1.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (3.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (1.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003eCART before blinatumomab initiation\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eYes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (11.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (2.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003eKMT2Ar: KMT2A rearrangement; MFC-MRD: flow cytometry MRD; qPCR MRD: quantitative polymerase chain reaction MRD; NGS MRD: next-generation sequencing MRD; CNSL:central nervous system leukemia; HSCT:hematopoietic stem cell transplantation\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eIn this cohort, 185 patients received blinatumomab with a dosage stepwise escalation from 5 to 15 \u0026micro;g/m\u0026sup2;/day, and 17 patients with an escalation from 9 to 28 \u0026micro;g/day. The remaining 105 patients began treatment directly at the full dosage, two of whom received 28 \u0026micro;g/day from day one.\u003c/p\u003e\n\u003cp\u003eSixty-one patients with bone marrow blasts\u0026thinsp;\u0026ge;\u0026thinsp;5% at the time of blinatumomab administration were assigned to the NCR group, with 13 (21.3%) patients had blast between 5% and 20% in the bone marrow, 11 (18.0%) between 20% and 50%, and 37 (60.7%) equal to or higher than 50%. Additionally, 93 patients were included in the MRD\u0026thinsp;+\u0026thinsp;group, and 153 patients were included in the MRD- group. In the NCR group, the median interval from diagnosis to the initiation of blinatumomab was 7.3 months, with 78.7% of patients more than 6 months and 41% more than 24 months (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003eResponse\u003c/h2\u003e\n\u003cp\u003eIn the NCR group, 44 (72.1%) out of the 61 patients achieved CR/CRh/CRi after blinatumomab treatment, and 2 patients (3.3%) achieved PR. A total of three patients discontinued blinatumomab, including one abandoned treatment on the 6th day due to the family's decision, one discontinued on day 3 due to severe CRS, and the other withdrew on the first day of application due to high fever. Of the 10 patients with KMT2A rearrangement, 8 (80.0%) achieved CR. All four patients with positive BCR::ABL1 achieved CR. Among the 44 patients who achieved CR/CRh/CRi, 40 (90.9%) achieved MFC-MRD negativity after blinatumomab treatment (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Of the 44 CR patients, 7 (15.9%) relapsed thereafter, with two dying from relapse and one dying after allo-HSCT. All these relapsed patients had a history of 1\u0026ndash;2 previous relapses and had presented an MRD response after blinatumomab treatment, with a median relapse interval of 3.9 months (range: 0.8 to 14.2 months). A total of 26 patients (42.6%) proceeded to allo-HSCT during follow-up, of whom 24 achieved CR after blinatumomab.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eAdverse events of all patients\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAdverse events\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTotal, n(%)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eGrade 1\u0026ndash;2, n(%)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3, n(%)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePatients with at least one\u003c/p\u003e\n\u003cp\u003eadverse event\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e262 (85.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e136 (44.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e126 (41.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCytokine release syndrome\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e85 (27.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e74 (24.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (3.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInfections\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e48 (15.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22 (7.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26 (8.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNeurotoxicity\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24 (7.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16 (5.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (2.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHematological toxicity\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e153 (49.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e52 (16.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e101 (32.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHepatotoxicity\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e49 (16.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e43 (14.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (2.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePyrexia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e142 (46.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e138 (45.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (1.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eIn the MRD\u0026thinsp;+\u0026thinsp;group, among 93 cases, 91 were evaluated for MRD after blinatumomab, with an MRD clearance rate of 98.9% (n\u0026thinsp;=\u0026thinsp;90). The patient who did not achieve MRD negativity proceeded to allo-HSCT. Of the 90 patients who achieved MRD negativity, three relapsed, ranging from 5.5 to 11.2 months after blinatumomab, and two died. Of the two patients who were not evaluated, one discontinued blinatumomab on day 4 due to severe neurological events.\u003c/p\u003e\n\u003cp\u003eIn the MRD- group, 20 patients were MRD positive when evaluated by qPCR, and 29 were MRD positive by NGS. After blinatumomab treatment, 60.0% (n\u0026thinsp;=\u0026thinsp;12) and 65.5% (n\u0026thinsp;=\u0026thinsp;19) of patients turned qPCR-MRD or NGS-MRD negative, respectively. One patient whose qPCR-MRD turned negative relapsed 1.5 months later. No case relapsed among patients who achieved NGS-MRD negativity. However, two patients with persistent NGS-MRD relapsed at 1.2 and 2.8 months after the treatment of blinatumomab, respectively.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eOutcome analysis\u003c/h3\u003e\n\u003cp\u003eThe median follow-up duration for all patients was 16.1 months (range: 0.1 to 33.7 months). Patients in the MRD\u0026thinsp;+\u0026thinsp;and MRD- groups had significantly better outcomes than those in the NCR group, with 30-month OS rates of 91.6% (95% CI: 0.857\u0026ndash;0.979), 95.3% (95% CI: 0.915\u0026ndash;0.993), and 77.6% (95% CI: 0.674\u0026ndash;0.894), respectively (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and 30-month RFS rates of 90.7% (95% CI: 0.847\u0026ndash;0.972), 93.3% (95% CI: 0.890\u0026ndash;0.979), and 64.4% (95% CI: 0.495\u0026ndash;0.837), respectively (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The OS and RFS were similar between the MRD- and MRD\u0026thinsp;+\u0026thinsp;groups (P\u0026thinsp;=\u0026thinsp;0.246 and P\u0026thinsp;=\u0026thinsp;0.461) (Fig.\u0026nbsp;2).\u003c/p\u003e\n\u003cp\u003eIn the subgroup analysis of the NCR group, the OS at 30 months for the CR/CRh/CRi patients was higher than for those who only reached PR or non-remission (NR) were 87.0% (95% CI: 0.765\u0026ndash;0.988) and 50.0% (95% CI: 0.296\u0026ndash;0.844), respectively (P\u0026thinsp;=\u0026thinsp;0.001), and the 30-month RFS for the CR/CRh/CRi group was higher than that of the NR/PR group as well, with rates of 78.5% (95% CI: 0.669\u0026ndash;0.922) and 33.3% (95% CI: 0.128\u0026ndash;0.867), respectively (P\u0026thinsp;=\u0026thinsp;0.008, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eFurthermore, We also compared the RFS of patients who achieved MRD negativity in the NCR group and the MRD\u0026thinsp;+\u0026thinsp;group. There was no statistically significant difference in OS between the patients who achieved MFC-MRD negativity in the NCR group and those in the MRD\u0026thinsp;+\u0026thinsp;group, with 30-month OS rates of 85.7% (95% CI: 0.745\u0026ndash;0.987) and 93.2% (95% CI: 0.881\u0026ndash;0.986), respectively (P\u0026thinsp;=\u0026thinsp;0.270). However, the relapse rate in the NCR group was higher than that in the MRD\u0026thinsp;+\u0026thinsp;group, with 30-month RFS rates of 76.4% (95% CI: 0.638\u0026ndash;0.914) and 92.1% (95% CI: 0.866\u0026ndash;0.979), respectively (P\u0026thinsp;=\u0026thinsp;0.015) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eAdverse events\u003c/h3\u003e\n\u003cp\u003eA total of 262 patients (85.3%) experienced at least one drug-related adverse event (AE), with 126 patients (41.0%) experiencing grade\u0026thinsp;\u0026ge;\u0026thinsp;3 toxicities. Only one patient developed grade 5 CRS with IL-6 levels\u0026thinsp;\u0026gt;\u0026thinsp;5000 pg/mL and died of multiple organ failure (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The main adverse events were hematological toxicity and pyrexia, observed in 49.8% and 46.3% of patients, respectively. The most common grade\u0026thinsp;\u0026ge;\u0026thinsp;3 adverse event was hematological toxicity (32.9%). Most CRS and neurotoxicity events were grade 1 or 2, observed in 74 (24.1%) and 16 (5.2%) cases, respectively. Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 CRS was observed in 11 patients (3.6%) and grade\u0026thinsp;\u0026ge;\u0026thinsp;3 neurotoxicity in 8 patients (2.6%).\u003c/p\u003e\n\u003cp\u003eIn this study, a total of 36 patients (11.7%) temporarily discontinued treatment with blinatumomab due to AEs, and six patients (2.0%) permanently discontinued treatment. Among those who temporarily discontinued, four patients interrupted their dosage due to hepatotoxicity with elevated alanine aminotransferase levels, and six due to CRS. Additionally, five patients temporarily discontinued treatment for neurotoxicity, and seven for fever. Nine patients temporarily discontinued treatment due to multiple AEs (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e). As for permanent discontinuation, three patients stopped blinatumomab due to neurological events, with two of them experiencing seizures. One patient had to discontinue treatment due to grade\u0026thinsp;\u0026ge;\u0026thinsp;3 neutropenia complicated by infection. Two patients each had to discontinue blinatumomab due to CRS and acute pancreatitis (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eIn the subgroup analysis, 96.7% of patients in the NCR group experienced adverse events, which was higher than the 83.9% in the MRD\u0026thinsp;+\u0026thinsp;group (P\u0026thinsp;=\u0026thinsp;0.012) and 81.7% in the MRD- group (P\u0026thinsp;=\u0026thinsp;0.004). Additionally, the incidence of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs in the NCR, MRD+, and MRD- groups was 62.3%, 34.4%, and 36.6%, respectively (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), indicating that patients in the NCR group experienced more severe AEs. Regarding specific AEs, patients in the NCR group exhibited significantly higher rates of hematological toxicity, CRS, pyrexia, infections, and hepatotoxicity compared to the other two groups, with the exception of neurotoxicity (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eDespite the high cure rate of pediatric patients with B-ALL, the prognosis for patients with R/R B-ALL or persistent MRD positivity remains poor. Numerous prospective studies and retrospective real-world data have confirmed the efficacy and relative safety of blinatumomab in treating R/R B-ALL and inducing MRD negativity.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan additionalcitationids=\"CR13 CR14 CR15\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] This retrospective analysis is the largest multicenter real-world study in children to date, providing valuable insights into the real-world application of blinatumomab in the treatment of pediatric B-ALL in China.\u003c/p\u003e \u003cp\u003eIn our study, the application of blinatumomab therapy achieved a high CR rate of 72.1% in patients with bone marrow blasts\u0026thinsp;\u0026ge;\u0026thinsp;5% at the initiation of treatment, with 90.9% of these responders also achieving MRD negativity, which is comparable to or higher than multiple previous pediatric studies.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] This inspiring result indicates that blinatumomab is effective in inducing remission for relapsed/refractory or high-risk patients. Similarly, for patients with persistent MRD, blinatumomab has demonstrated excellent efficacy, with 98.9% of patients in the MRD\u0026thinsp;+\u0026thinsp;group achieving MFC-MRD negativity after one cycle of treatment, consistent with other pediatric studies.[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eWe divided the patients into three groups based on leukemia burden before the application of blinatumomab and found that patients in the NCR group with higher leukemia burden had a lower probability of achieving MRD negativity, with a rate of 65.6% (n\u0026thinsp;=\u0026thinsp;40/61). In contrast, the MRD\u0026thinsp;+\u0026thinsp;group with lower leukemia burden achieved a 96.8% MRD negativity rate. A similar result was found in the study by Locatelli and colleagues, where 79% of patients with \u0026ge;\u0026thinsp;5% blasts at baseline achieved MRD response, compared to 92% of patients with \u0026lt;\u0026thinsp;5% blasts during the first two cycles of blinatumomab.[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] Several other trials also demonstrated that a low leukemia burden improved survival and response to blinatumomab.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] The improved MRD response to blinatumomab is associated with a low baseline leukemia burden, which may be explained by the function and number of T cells. When the leukemia burden is high, T cells may be more prone to exhaustion. Therefore, patients receiving blinatumomab at a relatively low leukemia burden may benefit more. Consequently, some studies are evaluating the role of blinatumomab in children with chemotherapy-sensitive leukemia, including newly diagnosed or low-risk first-relapse B-ALL. This is also why blinatumomab is currently used for first-line treatment of patients with MRD positivity or even MRD negativity.\u003c/p\u003e \u003cp\u003eAdditionally, we found that achieving MRD negativity after blinatumomab treatment is related to prognosis. However, although achieving negative MRD, patients from NCR group still presented higher relapse rate than those from MRD\u0026thinsp;+\u0026thinsp;group, with 17.5% (7/40) of patients experiencing relapse later on, indicating that patients with low MRD burden were more likely to benefit from blinatumomab treatment.\u003c/p\u003e \u003cp\u003eApart from MFC-MRD, we also monitored MRD in some patients in the MRD- group using PCR or NGS, and the MRD response for these two methods was not as high as that for MFC. This may explain the relapse in patients achieving MFC-MRD negativity after blinatumomab application and why patients with MFC-MRD negativity still benefit from blinatumomab. Current studies have shown that undetectable NGS-MRD indicates a better prognosis than undetectable MFC-MRD in B-ALL.[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] The study by Min'er Gu and colleagues demonstrated that blinatumomab could further eradicate MRD after patients achieve MFC-MRD undetectable in B-ALL patients.[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] As MFC is not a very precise method for monitoring deep MRD, using other deeper MRD monitoring methods like PCR or NGS to guide blinatumomab application and subsequent treatment choices could lead to more accurate clinical decision-making.\u003c/p\u003e \u003cp\u003eToxicity was noted in our study, with 85.3% of patients experiencing at least one adverse event (AE), and 41% experiencing grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs, consistent with previous studies.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] The most common AEs were pyrexia and cytopenia, while the most feared adverse events, such as CRS and neurotoxicity, occurred at a low rate, particularly grade\u0026thinsp;\u0026ge;\u0026thinsp;3 (3.6% and 2.6%, respectively), consistent with data from other studies, confirming the relative safety of blinatumomab.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] However, in the study by Beneduce and colleagues[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], a significant number of neurological events were observed, while the rates of CRS and hematological toxicity were lower. This might be attributed to the higher number of patients with \u0026lt;\u0026thinsp;5% blasts recruited in their cohort, supporting the hypothesis that a low leukemic burden is associated with an off-target effect of blinatumomab due to non-specific T cell activation.[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] Furthermore, we conducted a subgroup analysis and found that AEs, except for neurotoxicity, were significantly higher in the NCR group than in the other two groups, similar to the previous study, further supporting the hypothesis.\u003c/p\u003e \u003cp\u003eAs a retrospective study, it is subject to inherent biases and limitations in data collection and reporting that may affect the validity of the findings. Additionally, as a multicenter retrospective study, physicians from different centers may be more flexible in the use of blinatumomab, potentially lacking a unified standard in terms of treatment options and duration. Although long-term follow-up was performed, the duration of follow-up may not be sufficient to capture all long-term effects and outcomes.\u003c/p\u003e \u003cp\u003eIn conclusion, this study investigates the impact of leukemia burden on the efficacy and toxicity of blinatumomab in pediatric B-ALL in a real-world setting in China. All patients treated with blinatumomab achieved a high rate of CR and MRD response. Patients with a lower leukemia burden before the administration of blinatumomab tend to have better OS and RFS, with fewer AEs, especially severe toxicities. However, regardless of the leukemia burden before treatment with blinatumomab, achieving MRD negativity after treatment indicates a favorable OS. Furthermore, the use of blinatumomab may lead to deeper remission. Employing more sensitive detection methods, such as PCR or NGS, to monitor MRD can better guide treatment.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6947%;\"\u003e\n \u003cp\u003eB-ALL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85.3053%;\"\u003e\n \u003cp\u003eB-cell acute lymphoblastic leukemia\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6947%;\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85.3053%;\"\u003e\n \u003cp\u003eOverall survival\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6947%;\"\u003e\n \u003cp\u003eHSCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85.3053%;\"\u003e\n \u003cp\u003eHematopoietic stem cell transplantation\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6947%;\"\u003e\n \u003cp\u003eMRD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85.3053%;\"\u003e\n \u003cp\u003eMinimal residual disease \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6947%;\"\u003e\n \u003cp\u003eRFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85.3053%;\"\u003e\n \u003cp\u003eRelapse-free survival\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6947%;\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85.3053%;\"\u003e\n \u003cp\u003eComplete remission\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6947%;\"\u003e\n \u003cp\u003eMFC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85.3053%;\"\u003e\n \u003cp\u003eMultiparametric flow cytometry\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6947%;\"\u003e\n \u003cp\u003eqPCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85.3053%;\"\u003e\n \u003cp\u003eQuantitative polymerase chain reaction\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6947%;\"\u003e\n \u003cp\u003eNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85.3053%;\"\u003e\n \u003cp\u003eNext-generation sequencing\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6947%;\"\u003e\n \u003cp\u003eAEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85.3053%;\"\u003e\n \u003cp\u003eAdverse events\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6947%;\"\u003e\n \u003cp\u003eNCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85.3053%;\"\u003e\n \u003cp\u003eNon-complete remission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14.6947%;\"\u003e\n \u003cp\u003eCNSL:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85.3053%;\"\u003e\n \u003cp\u003eCentral nervous system leukemia\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor information:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWeiling Yan\u003csup\u003e1#\u003c/sup\u003e, Shaoyan Hu\u003csup\u003e2#\u003c/sup\u003e, Wenjin Gao\u003csup\u003e3#\u003c/sup\u003e, Lihua Yang\u003csup\u003e4\u003c/sup\u003e, Yan Gu\u003csup\u003e5\u003c/sup\u003e, Yufeng Liu\u003csup\u003e6\u003c/sup\u003e, Yunyan He\u003csup\u003e7\u003c/sup\u003e, Dunhua Zhou\u003csup\u003e8\u003c/sup\u003e, Wenting Hu\u003csup\u003e9\u003c/sup\u003e, Xue Tang\u003csup\u003e10\u003c/sup\u003e, Ming Sun\u003csup\u003e11\u003c/sup\u003e, Lili Song\u003csup\u003e12\u003c/sup\u003e, Wenyu Yang\u003csup\u003e13\u003c/sup\u003e, Yalan You\u003csup\u003e14\u003c/sup\u003e, Yongmin Tang\u003csup\u003e1\u003c/sup\u003e*, Xiaojun Xu\u003csup\u003e1\u003c/sup\u003e*\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eDepartment of Hematology \u0026amp; Oncology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e2\u003c/sup\u003eDepartment of Hematology, Children's Hospital of Soochow University, Suzhou, Jiangsu, China\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e3\u003c/sup\u003eDepartment of Hematology \u0026amp; Oncology, Xi'an Children's Hospital, Xi'an, Shaanxi, China\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e4\u003c/sup\u003eDepartment of Pediatric Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e5\u003c/sup\u003eDepartment of Pediatric Hematology, The First Affiliated Hospital of Shandong First Medical University \u0026amp; Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e6\u003c/sup\u003eDepartment of Pediatric Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e7\u003c/sup\u003eDepartment of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e8\u003c/sup\u003eDepartment of Pediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e9\u003c/sup\u003eDepartment of Hematology \u0026amp; Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e10\u003c/sup\u003eDepartment of Hematology, Shenzhen Children's Hospital, Shenzhen, Guangdong, China\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e11\u003c/sup\u003eDepartment of Hematology, Wuhan Children's Hospital, Wuhan, Hubei, China\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e12\u003c/sup\u003eDepartment of Hematology, Henan (Zhengzhou) Children's Hospital, Zhengzhou, Henan, China\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e13\u003c/sup\u003eState Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology \u0026amp; Blood Diseases Hospital, Chinese Academy of Medical Sciences \u0026amp; Peking Union Medical College, Tianjin, China\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e14\u003c/sup\u003eDepartment of Hematology and Oncology, Children's Medical Center, Hunan Provincial People's Hospital（The First Affifiliated Hospital of Hunan Normal University）,Changsha, China\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e#\u003c/sup\u003eThese authors contributed equally to this work and share first authorship\u003c/p\u003e\n\u003cp\u003e*\u003cstrong\u003eCorresponding author\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYongmin Tang, Department of Hematology \u0026amp; Oncology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.\u003c/p\u003e\n\u003cp\u003eE-mail: [email protected]\u003c/p\u003e\n\u003cp\u003eXiaojun Xu, Department of Hematology \u0026amp; Oncology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.\u003c/p\u003e\n\u003cp\u003eE-mail: [email protected]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthical approval\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective study was approved by the Ethics Committee of the Children's Hospital, Zhejiang University School of Medicine (2023-IRB-0115-P-01).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eData availability statement\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCompeting Interests\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthor contributions\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXiaojun Xu and Yongmin Tang designed the study. Weiling Yan analyzed the data and wrote the manuscript. All authors collaborated in data interpretation, revised the manuscript and gave the final approval before manuscript submission.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHunger SP, Mullighan CG. Acute lymphoblastic leukemia in children. N Engl J Med. 2015;373(16):1541\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInaba H, Mullighan CG. Pediatric acute lymphoblastic leukemia. Haematologica. 2020;105(11):2524\u0026ndash;39.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHunger SP, Raetz EA. How i treat relapsed acute lymphoblastic leukemia in the pediatric population. Blood. 2020;136(16):1803\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBhojwani D, Pui CH. Relapsed childhood acute lymphoblastic leukaemia. Lancet Oncol. 2013;14(6):e205\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePui CH, Pei D, Raimondi SC, Coustan-Smith E, Jeha S, Cheng C, et al. Clinical impact of minimal residual disease in children with different subtypes of acute lymphoblastic leukemia treated with response-adapted therapy. Leukemia. 2017;31(2):333\u0026ndash;39.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evon Stackelberg A, Locatelli F, Zugmaier G, Handgretinger R, Trippett TM, Rizzari C, et al. Phase i/phase ii study of blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. J Clin Oncol. 2016;34(36):4381\u0026ndash;89.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLocatelli F, Zugmaier G, Rizzari C, Morris JD, Gruhn B, Klingebiel T, et al. Effect of blinatumomab vs chemotherapy on event-free survival among children with high-risk first-relapse b-cell acute lymphoblastic leukemia: a randomized clinical trial. JAMA. 2021;325(9):843\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrown PA, Ji L, Xu X, Devidas M, Hogan LE, Borowitz MJ, et al. Effect of postreinduction therapy consolidation with blinatumomab vs chemotherapy on disease-free survival in children, adolescents, and young adults with first relapse of b-cell acute lymphoblastic leukemia: a randomized clinical trial. JAMA. 2021;325(9):833\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeneduce G, De Matteo A, Stellato P, Testi AM, Bertorello N, Colombini A et al. Blinatumomab in children and adolescents with relapsed/refractory b cell precursor acute lymphoblastic leukemia: a real-life multicenter retrospective study in seven aieop (associazione italiana di ematologia e oncologia pediatrica) centers. Cancers (Basel). 2022;14(2).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLocatelli F, Maschan A, Boissel N, Strocchio L, Alam N, Pezzani I, et al. Pediatric patients with acute lymphoblastic leukemia treated with blinatumomab in a real-world setting: results from the neuf study. Pediatr Blood Cancer. 2022;69(4):e29562.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu Y, Li Y, Fan J, Qi P, Lin W, Yang J, et al. Blinatumomab for treating pediatric b-lineage acute lymphoblastic leukemia: a retrospective real-world study. Front Pediatr. 2022;10:1034373.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJabbour EJ, Short NJ, Jain N, Jammal N, Jorgensen J, Wang S, et al. Blinatumomab is associated with favorable outcomes in patients with b-cell lineage acute lymphoblastic leukemia and positive measurable residual disease at a threshold of 10(-4) and higher. Am J Hematol. 2022;97(9):1135\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLocatelli F, Zugmaier G, Mergen N, Bader P, Jeha S, Schlegel PG, et al. Blinatumomab in pediatric relapsed/refractory b-cell acute lymphoblastic leukemia: rialto expanded access study final analysis. Blood Adv. 2022;6(3):1004\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGore L, Locatelli F, Zugmaier G, Handgretinger R, O'Brien MM, Bader P, et al. Survival after blinatumomab treatment in pediatric patients with relapsed/refractory b-cell precursor acute lymphoblastic leukemia. Blood Cancer J. 2018;8(9):80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLocatelli F, Zugmaier G, Rizzari C, Morris JD, Gruhn B, Klingebiel T, et al. Improved survival and mrd remission with blinatumomab vs. Chemotherapy in children with first high-risk relapse b-all. Leukemia. 2023;37(1):222\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLocatelli F, Eckert C, Hrusak O, Buldini B, Sartor M, Zugmaier G, et al. Blinatumomab overcomes poor prognostic impact of measurable residual disease in pediatric high-risk first relapse b-cell precursor acute lymphoblastic leukemia. Pediatr Blood Cancer. 2022;69(8):e29715.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLocatelli F, Zugmaier G, Mergen N, Bader P, Jeha S, Schlegel PG, et al. Blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia: results of the rialto trial, an expanded access study. Blood Cancer J. 2020;10(7):77.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGokbuget N, Dombret H, Bonifacio M, Reichle A, Graux C, Faul C, et al. Blinatumomab for minimal residual disease in adults with b-cell precursor acute lymphoblastic leukemia. Blood. 2018;131(14):1522\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShort NJ, Kantarjian H, Ravandi F, Konopleva M, Jain N, Kanagal-Shamanna R, et al. High-sensitivity next-generation sequencing mrd assessment in all identifies patients at very low risk of relapse. Blood Adv. 2022;6(13):4006\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePulsipher MA, Carlson C, Langholz B, Wall DA, Schultz KR, Bunin N, et al. Igh-v(d)j ngs-mrd measurement pre- and early post-allotransplant defines very low- and very high-risk all patients. Blood. 2015;125(22):3501\u0026ndash;08.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGu M, Xia Y, Zhang J, Tang Y, Xu W, Song H, et al. The effectiveness of blinatumomab in clearing measurable residual disease in pediatric b-cell acute lymphoblastic leukemia patients detected by next-generation sequencing. Cancer Med. 2023;12(24):21978\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQueudeville M, Ebinger M. Blinatumomab in pediatric acute lymphoblastic leukemia-from salvage to first line therapy (a systematic review). J Clin Med. 2021;10(12).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKlinger M, Zugmaier G, Nagele V, Goebeler ME, Brandl C, Stelljes M, et al. Adhesion of t cells to endothelial cells facilitates blinatumomab-associated neurologic adverse events. Cancer Res. 2020;80(1):91\u0026ndash;101.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"acute lymphoblastic leukemia, pediatric, blinatumomab, real-world study","lastPublishedDoi":"10.21203/rs.3.rs-5197329/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5197329/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e Blinatumomab has demonstrated its efficacy and safety in pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL). The objective of this analysis was to describe the responses and toxicities of blinatumomab in pediatric patients with different leukemic burdens in the bone marrow.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e We enrolled patients aged 0-18 years who were diagnosed with CD19-positive B-ALL and treated with blinatumomab between January 2021 and May 2023 from 14 centers in China.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e A total of 307 patients were enrolled in this analysis. The complete remission (CR) rate was 72.1% among 61 patients with ≥5% blasts(non-complete remission, NCR group), of whom 90.9% achieved minimal residual disease (MRD) negativity. Among 93 patients with \u0026lt;5% blasts but multiparametric flow cytometry MRD (MFC-MRD) positive(MRD+ group), 96.8% achieved MRD negativity. Of the 153 MFC-MRD negative patients(MRD- group), 60.0% and 65.5% turned quantitative polymerase chain reaction MRD (qPCR-MRD) or next-generation sequencing MRD (NGS-MRD) negative, respectively. Additionally, Patients in the MRD+ and MRD- groups had significantly better outcomes than those in the NCR group, with 30-month OS rates of 91.6% (95% CI: 0.857-0.979), 95.3% (95% CI: 0.915-0.993), and 77.6% (95% CI: 0.674-0.894), respectively (P\u0026lt;0.001), and 30-month RFS rates of 90.7% (95% CI: 0.847-0.972), 93.3% (95% CI: 0.890-0.979), and 64.4% (95% CI: 0.495-0.837), respectively (P\u0026lt;0.001). There was no statistically significant difference in OS between the patients who achieved MFC-MRD negativity in the NCR group and those in the MRD+ group, with 30-month OS rates of 85.7% (95% CI: 0.745-0.987) and 93.2% (95% CI: 0.881-0.986), respectively (P=0.270). In this study, 41% of patients experienced grade ≥3 adverse events (AEs), with hematological toxicity being the most common (32.9%). The severe adverse events, such as cytokine release syndrome (CRS) and neurotoxicity, occurred at a low rate, particularly grade ≥3, at 3.6% and 2.6%, respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e Overall, these results indicate that blinatumomab is effective and well-tolerated. Patients with a lower leukemia burden before blinatumomab administration tend to have better overall survival and relapse-free survival with fewer AEs.\u003c/p\u003e","manuscriptTitle":"Leukemia burden impacts the efficacy and toxicity of blinatumomab in pediatric B-cell acute lymphoblastic leukemia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-11 09:58:01","doi":"10.21203/rs.3.rs-5197329/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"16d17578-d0ac-49c5-a688-dbf2308fdbf0","owner":[],"postedDate":"November 11th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-04-11T08:23:58+00:00","versionOfRecord":[],"versionCreatedAt":"2024-11-11 09:58:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5197329","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5197329","identity":"rs-5197329","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}