Table 1_Blinatumomab demonstrates MRD eradication in MRD-positive/chemotherapy-delayed pediatric B-ALL and high response in relapsed/refractory cases: a multicenter cohort study.docx

BackgroundBlinatumomab, a bispecific T-cell engager targeting CD3+ and CD19+, promotes T cell–mediated cytotoxicity against B-cell precursor acute lymphoblastic leukemia (B-ALL). While its efficacy is established in relapsed/refractory (R/R) disease, its role as preemptive therapy for minimal residual disease (MRD)–positive patients or those experiencing chemotherapy delays remains undefined. Predictors of treatment failure also require further investigation.
MethodsIn this multicenter retrospective study, 105 patients who received blinatumomab were enrolled. Of these, 30 had R/R ALL, 21 were in complete remission (CR) with MRD positivity (CR-MRDpos), and 54 experienced chemotherapy delays. Eight patients received blinatumomab directly as reinduction therapy and 22 patients received burden-reduction chemotherapy prior to blinatumomab. In total, 11 children were in R/R status and 40 were in CR-MRDpos before treatment. Patients were subsequently bridged to stem cell transplantation, chimeric antigen receptor T-cell therapy (CAR-T), or protocol continuation. Treatment response was analyzed across CR-MRDpos, R/R, and CR with MRD negativity (CR-MRDneg). Immune reconstitution profiles (T-cell subsets, cytokine dynamics), cytogenetic markers, and clinical outcomes were assessed to identify predictors of treatment resistance.
ResultsThe CR rate was 81.8% in R/R and 82.5% in CR-MRDpos patients (P = 1.000). Of 74 courses with CR-MRDneg, 73 remained MRD-negative during treatment. Univariate analysis revealed poor cytogenetics (P = 0.0001), CD19+ B-cell loss (P = 0.046), and BCR-ABL1 positivity (P = 0.002) as predictors of poor response. Cox regression analysis identified high MRD (P = 0.014), BCR/ABL1 (P = 0.065), and poor cytogenetics (P = 0.025) as independent risk factors. Blinatumomab significantly increased CD3+ T cells [0.96 (0.03–3.79) to 1.13 (0.26–7.74) ×109/L, P = 0.016], along with CD4+ [0.35 (0.01–1.39) to 0.47 (0.07–2.94) ×109/L] and CD8+ T cells [0.41 (0.01–2.39) to 0.56 (0.07–6.07) ×109/L] (P = 0.005 and P = 0.006, respectively).The 1-year event-free survival for CR-MRDneg, CR-MRDpos, and R/R patients was 97.8% ± 2.2%, 86.7% ± 6.2%, and 73.3% ± 8.1%, respectively (P = 0.001), while overall survival was 97.8% ± 2.2%, 100%, and 93.3% ± 4.6% (P = 0.029).
ConclusionsBlinatumomab effectively clears MRD as preemptive therapy and serves as a bridging strategy during chemotherapy delays in pediatric B-ALL, while maintaining high response rates in R/R cases.

背景 博纳吐单抗（blinatumomab）是一种靶向CD3+和CD19+的双特异性T细胞衔接器，可介导T细胞对B细胞前体急性淋巴细胞白血病（B-cell precursor acute lymphoblastic leukemia, B-ALL）的细胞毒性作用。尽管其在复发/难治性（relapsed/refractory, R/R）疾病中的疗效已得到证实，但其作为微小残留病（minimal residual disease, MRD）阳性患者或出现化疗延迟患者的抢先治疗的作用仍不明确。治疗失败的预测因素也有待进一步研究。
方法 本项多中心回顾性研究共纳入105例接受博纳吐单抗治疗的患者。其中，30例为复发/难治性急性淋巴细胞白血病（R/R ALL）患者，21例为完全缓解（complete remission, CR）伴MRD阳性（CR-MRDpos）患者，54例出现化疗延迟。8例患者直接将博纳吐单抗作为再诱导治疗方案，22例患者在接受博纳吐单抗治疗前先行负荷降低化疗。共有11例患者治疗前处于R/R状态，40例处于CR-MRDpos状态。后续患者均过渡至造血干细胞移植、嵌合抗原受体T细胞疗法（chimeric antigen receptor T-cell therapy, CAR-T）或方案维持治疗。针对CR-MRDpos、R/R以及完全缓解伴MRD阴性（CR-MRDneg）患者，我们对其治疗应答情况进行了分析。同时评估了免疫重建特征（T细胞亚群、细胞因子动态变化）、细胞遗传学标志物及临床结局，以明确治疗耐药的预测因素。
结果 R/R患者的完全缓解率为81.8%，CR-MRDpos患者为82.5%（P = 1.000）。在74例达到CR-MRDneg的疗程中，73例患者治疗期间仍维持MRD阴性。单因素分析显示，不良细胞遗传学（P = 0.0001）、CD19+ B细胞缺失（P = 0.046）以及BCR-ABL1阳性（P = 0.002）为应答不佳的预测因素。Cox回归分析显示，高MRD水平（P = 0.014）、BCR/ABL1阳性（P = 0.065）以及不良细胞遗传学（P = 0.025）为独立危险因素。博纳吐单抗可显著升高CD3+ T细胞水平[0.96（0.03–3.79）×10^9/L升至1.13（0.26–7.74）×10^9/L，P = 0.016]，同时CD4+ T细胞[0.35（0.01–1.39）×10^9/L升至0.47（0.07–2.94）×10^9/L]与CD8+ T细胞[0.41（0.01–2.39）×10^9/L升至0.56（0.07–6.07）×10^9/L]水平亦显著升高（分别对应P = 0.005与P = 0.006）。CR-MRDneg、CR-MRDpos及R/R患者的1年无事件生存率分别为97.8% ± 2.2%、86.7% ± 6.2%与73.3% ± 8.1%（P = 0.001），总生存率分别为97.8% ± 2.2%、100%与93.3% ± 4.6%（P = 0.029）。
结论 博纳吐单抗作为抢先治疗可有效清除MRD，在儿童B-ALL患者出现化疗延迟时可作为桥接治疗策略，同时在R/R病例中可维持较高的应答率。