Division of Allergy & Immunology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
Transplant Cell Ther. 2021 Feb;27(2):169.e1-169.e9. doi: 10.1016/j.jtct.2020.10.006. Epub 2020 Dec 10.
TCRαβ/CD19-depleted HCT has been used with excellent outcomes in pediatric patients with hematologic malignancies, and several studies have demonstrated rapid immune reconstitution in the nonmalignant setting. However, immune recovery following TCRαβ/CD19-depleted hematopoietic cell transplantation (HCT) for malignancy remains incompletely elucidated. Furthermore, the majority of studies to date have used haploidentical and matched unrelated donors. Here we report results of immune reconstitution following TCRαβ/CD19-depleted HCT for hematologic malignancy in 51 pediatric patients with hematologic malignancies, the majority of whom received grafts from unrelated donors. Grafts were from matched unrelated (n = 20), mismatched unrelated (n = 20), and haploidentical (n = 11) donors. The median CD34 cell dose was 10.2 × 10/kg (range, 4.54 to 20 × 10/kg), and the median TCRαβ cell dose was 2.53 × 10/kg (range, 0 to 44.9 × 10/kg). Conditioning was myeloablative with either busulfan or total body irradiation, cyclophosphamide, and thiotepa. Thirty-three patients also received rabbit antithymocyte globulin. No prophylactic post-transplantation immune suppression was routinely given. Forty-three patients received rituximab on day +1 for recipient positive Epstein-Barr virus serology. Forty-nine patients (96%) engrafted with a median time to neutrophil recovery of 13 days (range, 8 to 30 days). Thirty-seven patients (73%) are alive at a median follow-up of 25 months (range, 6 to 50 months). Nine patients (18%) developed grade II-IV acute graft-versus-host disease (GVHD), and 5 patients (11%) developed extensive chronic GVHD. Twenty-six patients (51%) experienced viral reactivation. T cell reconstitution was rapid with significant numbers of CD3, CD4, and CD8 T cells present on first assessment at 4 months post-HCT, and significant numbers of naïve CD4 T cells were present by 8 months post-HCT. Chronic GVHD was associated with delayed T cell recovery; however, T cell reconstitution was not affected by underlying diagnosis, donor source, TCRαβ T cell dose, conditioning regimen, or use of antithymocyte globulin. B cell recovery mirrored T cell recovery, and i.v. Ig was discontinued at a median of 8 months (range, 4 to 22 months) post-HCT in patients alive and relapse-free at last follow-up. Immune reconstitution is rapid following TCRαβ/CD19-depleted HCT in pediatric patients with hematologic malignancies. Donor graft source, haploidentical or unrelated, did not affect immune reconstitution. Viral reactivation is common in the first 100 days post-HCT, indicating that improved T cell defense is needed in the early post-HCT period.
TCRαβ/CD19 耗竭的造血干细胞移植（HCT）已在儿科血液恶性肿瘤患者中取得了极好的结果，多项研究表明，在非恶性肿瘤患者中可快速重建免疫功能。然而，TCRαβ/CD19 耗竭的造血细胞移植（HCT）治疗恶性肿瘤后的免疫恢复情况仍不完全明确。此外，迄今为止，大多数研究都使用了单倍体相合和非血缘相关供者。在此，我们报告了 51 例血液恶性肿瘤患儿接受 TCRαβ/CD19 耗竭的 HCT 后免疫重建的结果，其中大多数患儿接受了非血缘相关供者的移植物。移植物来自匹配的非血缘（n=20）、不匹配的非血缘（n=20）和单倍体相合（n=11）供者。中位 CD34 细胞剂量为 10.2×10/kg（范围，4.54 至 20×10/kg），中位 TCRαβ 细胞剂量为 2.53×10/kg（范围，0 至 44.9×10/kg）。预处理采用全身照射、环磷酰胺和噻替哌联合或不联合白消安的清髓性方案。33 例患者还在第+1 天接受了兔抗胸腺细胞球蛋白。常规不给予移植后预防免疫抑制。43 例患者因受者 EBV 血清学阳性而在第+1 天接受利妥昔单抗治疗。49 例患者（96%）植入，中性粒细胞恢复的中位时间为 13 天（范围，8 至 30 天）。37 例患者（73%）在中位随访 25 个月（范围，6 至 50 个月）时仍存活。9 例（18%）患者发生 2 至 4 级急性移植物抗宿主病（GVHD），5 例（11%）患者发生广泛慢性 GVHD。26 例（51%）患者发生病毒再激活。HCT 后 4 个月首次评估时 T 细胞迅速重建，出现大量 CD3、CD4 和 CD8 T 细胞，HCT 后 8 个月时出现大量幼稚 CD4 T 细胞。慢性 GVHD 与 T 细胞恢复延迟相关，但 T 细胞重建不受基础诊断、供者来源、TCRαβ T 细胞剂量、预处理方案或使用抗胸腺细胞球蛋白的影响。B 细胞恢复与 T 细胞恢复相似，在最后一次随访时无疾病复发且存活的患者中，静脉注射免疫球蛋白在 HCT 后中位 8 个月（范围，4 至 22 个月）时停止。在儿科血液恶性肿瘤患者中，TCRαβ/CD19 耗竭的 HCT 后免疫重建迅速。供者移植物来源（单倍体相合或非血缘相关）不影响免疫重建。HCT 后 100 天内病毒再激活很常见，表明在 HCT 早期需要改善 T 细胞防御。
