Awasthi Rakesh, Grupp Stephan A, Waldron Edward R, Yanik Gregory A, Tam Constantine S, Rives Susana, McGuirk Joseph P, Pulsipher Michael A, Jaeger Ulrich, Myers Gary D, Borchmann Peter, Schuster Stephen J, Stefanski Heather E, Bishop Michael R, Chakraborty Abhijit, Masood Aisha, Baruchel André, Waller Edmund K
BioMedical Research, Novartis Pharmaceuticals Corporation, East Hanover, NJ.
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Blood Adv. 2025 Sep 9;9(17):4405-4414. doi: 10.1182/bloodadvances.2024014995.
Tisagenlecleucel is a CD19-directed autologous chimeric antigen receptor (CAR) T-cell therapy. Quantitative polymerase chain reaction assays are highly sensitive in defining in vivo kinetics by measuring CAR transgene in peripheral blood. This study aimed to identify clinically meaningful CAR T-cell blood levels that correlated with response/relapse. In pediatric/young adult patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL), maximum CAR T-cell blood levels were higher in patients with ongoing complete remission and in patients with CD19- relapse relative to those with CD19+ relapse. In adult patients with R/R diffuse large B-cell lymphoma (DLBCL), no apparent association between in vivo kinetics and response was noted, with a wide range of transgene levels at relapse. In B-ALL, patients with B-cell aplasia sustained >6 months had higher CAR T-cell expansion relative to those with early B-cell recovery (BCR) (<6 months after infusion); however, a definitive cutoff for BCR-associated expansion level could not be identified. In most patients with B-ALL, BCR >6 months maintained favorable responses. However, early BCR could not be confirmed as a potential indicator of relapse due to high censoring from transplant, following presumed risk of relapse. However, allografting in these patients may potentially mitigate the poor prognosis related to early BCR. In DLBCL, BCR was not associated with relapse. These findings suggest that blood CAR transgene levels may be associated with long-term responses; however, they lack robust predictive potential for relapses. As reported earlier, next-generation sequencing for minimal residual disease appears to be a reliable biomarker predictive of relapse for B-ALL.
替沙格赛定是一种靶向CD19的自体嵌合抗原受体（CAR）T细胞疗法。定量聚合酶链反应检测通过测量外周血中的CAR转基因，在定义体内动力学方面具有高度敏感性。本研究旨在确定与反应/复发相关的具有临床意义的CAR T细胞血液水平。在复发/难治性（R/R）B细胞急性淋巴细胞白血病（B-ALL）的儿科/年轻成人患者中，持续完全缓解的患者和CD19复发的患者相对于CD19+复发的患者，最大CAR T细胞血液水平更高。在R/R弥漫性大B细胞淋巴瘤（DLBCL）的成人患者中，未观察到体内动力学与反应之间的明显关联，复发时转基因水平范围广泛。在B-ALL中，B细胞发育不全持续>6个月的患者相对于早期B细胞恢复（BCR）（输注后<6个月）的患者，CAR T细胞扩增更高；然而，无法确定与BCR相关的扩增水平的明确临界值。在大多数B-ALL患者中，BCR>6个月维持了良好的反应。然而，由于移植后的高审查率以及假定的复发风险，早期BCR不能被确认为复发的潜在指标。然而，这些患者的同种异体移植可能会减轻与早期BCR相关的不良预后。在DLBCL中，BCR与复发无关。这些发现表明，血液CAR转基因水平可能与长期反应相关；然而，它们缺乏对复发的强大预测潜力。如先前报道，微小残留病的下一代测序似乎是B-ALL复发的可靠预测生物标志物。
