背景:在患有血液系统恶性肿瘤的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治疗方案与急性和长期不良反应相关。我们使用CD45RA耗尽的单倍体移植物过继转移记忆T细胞并结合NK细胞回输,并假设最大化移植物抗白血病(GVL)效应可能会降低预处理方案的强度。
方法:在本II期临床试验(NCT01807611)中,72例血液恶性肿瘤患者(完全缓解(CR)1:25,≥CR2:28,难治性疾病:19)接受了富含CD34的单倍体和CD45RA的造血祖细胞移植物,然后进行NK细胞输注。调理包括氟达拉滨,Thiotepa,melphalan,环磷酰胺,总淋巴照射,移植物抗宿主病(GVHD)的预防包括短程西罗莫司或霉酚酸酯,无需血清疗法。
结果:CR1患者的3年总生存率(OS)和无事件生存率(EFS)分别为92%(95%CI:72-98)和88%(95%CI:67-96);≥CR2为81%(95%CI:61-92)和68%(95%CI:47-82),难治性疾病为32%(95%CI:54-6)。所有患者形态CR的3年EFS为77%(95%CI:64-87),在有或没有微小残留病的接受者之间没有差异(P=0.2992)。免疫重建很快,在第30天,平均CD3和CD4T细胞计数为410/μL和140/μL。急性GVHD和慢性GVHD的累积发生率分别为36%和26%,但大多数急性GVHD患者通过治疗迅速恢复。NK细胞同种反应性供体观察到III-IV级急性GVHD的发生率较低(P=0.004),母体供者的中度/重度慢性GVHD发生率更高(P=0.035)。
结论:CD45RA耗尽的移植物和NK细胞回补的组合导致了强大的免疫重建,最大限度地提高了GVL效应,并允许使用清髓性下,与优秀的EFS相关的无TBI预处理方案在该高危人群中产生有希望的长期结果。该试验在ClinicalTrials.gov(NCT01807611)注册。
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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).