Relapse remains a challenge after transplantation in pediatric patients with hematological malignancies. Myeloablative regimens used for disease control are associated with acute and long-term adverse effects. We used a CD45RA-depleted haploidentical graft for adoptive transfer of memory T cells combined with NK-cell addback and hypothesized that maximizing the graft-versus-leukemia (GVL) effect might allow for reduction in intensity of conditioning regimen. In this phase II clinical trial (NCT01807611), 72 patients with hematological malignancies (complete remission (CR)1: 25, ≥ CR2: 28, refractory disease: 19) received haploidentical CD34 + enriched and CD45RA-depleted hematopoietic progenitor cell grafts followed by NK-cell infusion. Conditioning included fludarabine, thiotepa, melphalan, cyclophosphamide, total lymphoid irradiation, and graft-versus-host disease (GVHD) prophylaxis consisted of a short-course sirolimus or mycophenolate mofetil without serotherapy. The 3-year overall survival (OS) and event-free-survival (EFS) for patients in CR1 were 92% (95% CI:72–98) and 88% (95% CI: 67–96); ≥ CR2 were 81% (95% CI: 61–92) and 68% (95% CI: 47–82) and refractory disease were 32% (95% CI: 11–54) and 20% (95% CI: 6–40). The 3-year EFS for all patients in morphological CR was 77% (95% CI: 64–87) with no difference amongst recipients with or without minimal residual disease (P = 0.2992). Immune reconstitution was rapid, with mean CD3 and CD4 T-cell counts of 410/μL and 140/μL at day + 30. Cumulative incidence of acute GVHD and chronic GVHD was 36% and 26% but most patients with acute GVHD recovered rapidly with therapy. Lower rates of grade III-IV acute GVHD were observed with NK-cell alloreactive donors (P = 0.004), and higher rates of moderate/severe chronic GVHD occurred with maternal donors (P = 0.035). The combination of a CD45RA-depleted graft and NK-cell addback led to robust immune reconstitution maximizing the GVL effect and allowed for use of a submyeloablative, TBI-free conditioning regimen that was associated with excellent EFS resulting in promising long-term outcomes in this high-risk population. The trial is registered at ClinicalTrials.gov (NCT01807611).

中文翻译：

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富含记忆 T 细胞的半相合移植与 NK 细胞加在一起可带来有希望的长期结果：一项 II 期试验


血液系统恶性肿瘤儿科患者移植后复发仍然是一个挑战。用于疾病控制的清髓性方案与急性和长期不良反应相关。我们使用 CD45RA 耗尽的半相合移植物进行记忆 T 细胞的过继转移，并结合 NK 细胞加旧，并假设最大化移植物抗白血病 （GVL） 效应可能允许降低预处理方案的强度。在这项 II 期临床试验 （NCT01807611） 中，72 名血液系统恶性肿瘤患者 （完全缓解 （CR）1：25，≥ CR2：28，难治性疾病：19）接受了半相合 CD34 + 富集和 CD45RA 耗尽的造血祖细胞移植物，然后进行 NK 细胞输注。预处理包括氟达拉滨、噻替哌、美法仑、环磷酰胺、全淋巴照射和移植物抗宿主病 （GVHD） 预防，包括短程西罗莫司或吗替麦考酚酯，无血清治疗。CR1 患者的 3 年总生存期 （OS） 和无事件生存期 （EFS） 分别为 92% （95% CI：72-98） 和 88% （95% CI： 67-96）;≥ CR2 分别为 81% （95% CI： 61-92） 和 68% （95% CI： 47-82），难治性疾病为 32% （95% CI： 11-54） 和 20% （95% CI： 6-40）。所有形态学 CR 患者的 3 年 EFS 为 77% （95% CI： 64-87），有或没有微小残留病的受者之间没有差异 （P = 0.2992）。免疫重建迅速，第 + 30 天的平均 CD3 和 CD4 T 细胞计数分别为 410/μL 和 140/μL。急性 GVHD 和慢性 GVHD 的累积发病率分别为 36% 和 26%，但大多数急性 GVHD 患者在治疗后恢复迅速。在 NK 细胞同种异体反应供体中观察到较低的 III-IV 级急性 GVHD 发生率 （P = 0.004），母体供体发生中/重度慢性 GVHD 的发生率较高 （P = 0.035）。CD45RA 耗尽的移植物和 NK 细胞反添加的结合导致强大的免疫重建，最大限度地提高 GVL 效果，并允许使用与出色的 EFS 相关的亚清髓性、无 TBI 的调节方案，从而在该高危人群中产生有希望的长期结果。该试用版在 ClinicalTrials.gov （NCT01807611） 注册。