Haploidentical allogeneic hematopoietic cell transplantation in adults using CD3/CD19 depletion and reduced intensity conditioning:: An update
Haploidentical allogeneic hematopoietic cell transplantation in adults using CD3/CD19 depletion and reduced intensity conditioning:: An update
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DOI：
10.1016/j.bcmd.2007.07.001
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发表时间：
2008-01-01
影响因子：
2.3
通讯作者：
Kanz, Lothar
中科院分区：
文献类型：
--
作者：
Bethge, Wolfgang A.;Faul, Christoph;Kanz, Lothar
在用CD 34选择的干细胞进行高剂量预处理后进行的单倍相合造血细胞移植（HHCT）由于高方案相关毒性、缓慢植入和延迟免疫重建而变得复杂，导致治疗相关死亡率（TRM）增加。在CliniMACS设备上使用降低强度预处理（RIC）和移植物CD 3/CD 19消耗以及抗CD 3和抗CD 19涂层微珠的新方案可能会使HHCT具有较低的毒性和更快的植入。去除CD 3/CD 19的移植物不仅含有CD 34+干细胞，而且含有CD 34阴性祖细胞、自然杀伤细胞、移植物促进细胞和树突状细胞。RIC采用氟达拉滨（150-200 mg/m2）、塞替派（10 mg/kg）、美法仑（120 mg/m2）和OKT-3（5 mg/天，第-5天至第+14天），无移植后免疫抑制。29例患者（中位年龄= 42（范围，21-59）岁）已移植与此方案。诊断为AML（n = 16），ALL（n = 7），NHL（n = 3），MM（n = 2）和CML（n = 1）。患者为难治性疾病或既往HCT后复发的“高危”患者。去除CD 3/CD 19的单倍体相合移植物中位CD 34+细胞/kg为7.6 × 10（6）（范围：3.4-17 × 10（6）），CD 3 + T细胞/kg为4.4 × 10（4）（范围：0.006-44 × 10（4）），CD 56+细胞/kg为7.2 × 10（7）（范围：0.02-37.3 × 10（7））。29例患者中有19例存在供受者KIR配体错配。该方案耐受性良好，最大急性毒性为2-3级粘膜炎。由于4例患者接受200 mg/m2氟达拉滨治疗时出现严重神经毒性，剂量降至150 mg/m2。植入迅速，所有患者中粒细胞>500/μ L的中位时间为12天（范围，10-21），血小板> 20，000/μ L的中位时间为11天（范围，7-38），完全供体嵌合体在2-4周后出现。II-IV度GVHD的发生率为48%，其中II度=10，III度=2和IV度=2。一名接受最高T细胞剂量的患者发生了致命的IV级GVHD。前100天的TRM为6/29（20%），死亡原因为特发性肺炎综合征（n = 1）、毛霉菌病（n = 1）、肺炎（n = 3）或GVHD（n = 1）。总生存率为9/29例患者（31%），死亡原因为感染（n = 7）、GVHD（n = 1）和复发（n = 12），中位随访时间为241天（范围，112-1271）。总之，该方案在缺乏合适供体的高风险患者中是有希望的，并且前瞻性I/II期研究正在进行中。(C)2007爱思唯尔公司All rights reserved.
Haploidentical hematopoietic cell transplantation (HHCT) after high dose conditioning with CD34-selected stem cells has been complicated by high regimen related toxicities, slow engraftment and delayed immune reconstitution leading to increased treatment related mortality (TRM). A new regimen using reduced intensity conditioning (RIC) and graft CD3/CD19 depletion with anti-CD3 and anti-CD19 coated microbeads on a CliniMACS device may allow HHCT with lower toxicity and faster engraftment. CD3/CD19 depleted grafts not only contain CD34+ stem cells but also CD34 negative progenitors, natural killer, graft facilitating and dendritic cells. RIC was performed with fludarabine (150-200 mg/m(2)), thiotepa (10 mg/kg), melphalan (120 mg/m(2)) and OKT-3 (5 mg/day, day -5 to +14) and no posttransplant immunosuppression. Twenty nine patients (median age = 42 (range, 21-59) years) have been transplanted with this regimen. Diagnosis were AML (n = 16), ALL (n = 7), NHL (n = 3), MM (n = 2) and CML (n = 1). Patients were "high risk" with refractory disease or relapse after preceding HCT. The CD3/CD19 depleted haploidentical grafts contained a median of 7.6 x 10(6) (range, 3.4-17 x 10(6)) CD34+ cells/kg, 4.4 x 10(4) (range, 0.006-44 x 10(4)) CD3+ T cells/kg and 7.2 x 10(7) (range, 0.02-37.3 x 10(7)) CD56+ cells/kg. Donor-recipient KIR-ligand-mismatch was found in 19 of 29 patients. The regimen was well tolerated with maximum acute toxicity being grade 2-3 mucositis. Because of severe neurotoxicity in 4 patients treated with 200 mg/m(2) fludarabine, the dose was reduced to 150 mg/m(2). Engraftment was rapid with a median time to >500 granulocytes/mu L of 12 (range, 10-21) days, >20,000 platelets/mu L of 11 (range, 7-38) days and full donor chimerism after 2-4 weeks in all patients. Incidence of grade II-IV degrees GVHD was 48% with grade II degrees=10, III degrees=2 and IV degrees=2. One patient, who received the highest T-cell dose, developed lethal grade IV GVHD. TRM in the first 100 days was 6/29 (20%) with deaths due to idiopathic pneumonia syndrome (n = 1), mucormycosis (n = 1), pneumonia (n = 3) or GVHD (n = 1). Overall survival is 9/29 patients (31%) with deaths due to infections (n = 7), GVHD (n = 1) and relapse (n = 12) with a median follow-up of 241 days (range, 112-1271). In conclusion, this regimen is promising in high risk patients lacking a suitable donor, and a prospective phase I/II study is ongoing. (C) 2007 Elsevier Inc. All rights reserved.