Division of Hematology/Oncology, University of Washington, Seattle Children's Hospital, Seattle, WA.
Division of Oncology, Cell Therapy and Transplant Section, Children's Hospital of Philadelphia, Philadelphia, PA.
Blood Adv. 2023 Feb 28;7(4):575-585. doi: 10.1182/bloodadvances.2022007423.
Relapse following chimeric antigen receptor (CAR) T-cell therapy directed against CD19 for relapsed/refractory B-acute lymphoblastic leukemia (r/r B-ALL) remains a significant challenge. Three main patterns of relapse predominate: CD19 positive (CD19pos) relapse, CD19 negative (CD19neg) relapse, and lineage switch (LS). Development and validation of risk factors that predict relapse phenotype could help define potential pre- or post-CAR T-cell infusion interventions aimed at decreasing relapse. Our group sought to extensively characterize preinfusion risk factors associated with the development of each relapse pattern via a multicenter, retrospective review of children and young adults with r/r B-ALL treated with a murine-based CD19-CAR construct. Of 420 patients treated with CAR, 166 (39.5%) relapsed, including 83 (50%) CD19pos, 68 (41%) CD19neg, and 12 (7.2%) LS relapses. A greater cumulative number of prior complete remissions was associated with CD19pos relapses, whereas high preinfusion disease burden, prior blinatumomab nonresponse, older age, and 4-1BB CAR construct were associated with CD19neg relapses. The presence of a KMT2A rearrangement was the only preinfusion risk factor associated with LS. The median overall survival following a post-CAR relapse was 11.9 months (95% CI, 9-17) and was particularly dismal in patients experiencing an LS, with no long-term survivors following this pattern of relapse. Given the poor outcomes for those with post-CAR relapse, study of relapse prevention strategies, such as consolidative hematopoietic stem cell transplantation, is critical and warrants further investigation on prospective clinical trials.
嵌合抗原受体（CAR）T 细胞疗法针对复发/难治性 B 急性淋巴细胞白血病（r/r B-ALL）中的 CD19 治疗后复发仍然是一个重大挑战。主要有三种复发模式：CD19 阳性（CD19pos）复发、CD19 阴性（CD19neg）复发和谱系转换（LS）。开发和验证可预测复发表型的风险因素，有助于确定旨在降低复发风险的潜在 CAR T 细胞输注前或后干预措施。我们的团队通过对接受基于鼠的 CD19-CAR 构建体治疗的 r/r B-ALL 儿童和年轻成人进行的多中心回顾性研究，广泛分析了与每种复发模式发展相关的输注前风险因素。在接受 CAR 治疗的 420 例患者中，有 166 例（39.5%）复发，包括 83 例（50%）CD19pos、68 例（41%）CD19neg 和 12 例（7.2%）LS 复发。更多的完全缓解累积次数与 CD19pos 复发相关，而较高的输注前疾病负担、先前的blinatumomab 无反应、年龄较大和 4-1BB CAR 构建体与 CD19neg 复发相关。KMT2A 重排是唯一与 LS 相关的输注前风险因素。CAR 后复发后的中位总生存期为 11.9 个月（95%CI，9-17），在经历 LS 的患者中尤其不佳，在这种复发模式下没有长期幸存者。鉴于 CAR 后复发患者的预后较差，研究复发预防策略，如巩固性造血干细胞移植，至关重要，值得在前瞻性临床试验中进一步研究。
