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采用减低剂量预处理及去除CD3/CD19的单倍体相合异基因造血细胞移植治疗成人患者:快速植入且毒性低。

Haploidentical allogeneic hematopoietic cell transplantation in adults with reduced-intensity conditioning and CD3/CD19 depletion: fast engraftment and low toxicity.

作者信息

Bethge Wolfgang A, Haegele Matthias, Faul Christoph, Lang Peter, Schumm Michael, Bornhauser Martin, Handgretinger Rupert, Kanz Lothar

机构信息

Medical Center, University of Tuebingen, Tuebingen, Germany.

出版信息

Exp Hematol. 2006 Dec;34(12):1746-52. doi: 10.1016/j.exphem.2006.08.009.

Abstract

OBJECTIVE

CD3/CD19 depletion may improve engraftment and immune reconstitution after haploidentical hematopoietic cell transplantation (HHCT) as grafts not only contain CD34+ stem cells but also CD34- progenitors and natural killer, dendritic, and facilitating cells.

PATIENTS AND METHODS

Ten consecutive patients received HHCT with CD3/CD19-depleted grafts. Reduced-intensity conditioning was performed with fludarabine (150-200 mg/m2), thiotepa (10 mg/kg), melphalan (120 mg/m2), and OKT-3 (5 mg/day, day -5 to +14) without additional posttransplant immunosuppression. Diagnoses were AML (n = 4), ALL (n = 3), NHL (n = 2), and multiple myeloma (n = 1). All patients were "high risk" with refractory disease or relapse after preceding HCT. The CD3/CD19-depleted haploidentical grafts contained a median of 7.8 x 10(6) (range, 5.2-17 x 10(6)) CD34+ cells/kg, 5.5 x 10(7) (range, 0.02-8.6 x 10(7)) CD56+ cells/kg, and 2.0 x 10(4) (range, 0.006-44 x 10(4)) CD3+ T cells/kg. Engraftment was rapid with median time to greater than 500 granulocytes/microL of 13 (range, 11-17) days, greater than 20,000 platelets/microL of 11 (range, 8-16) days, and full donor chimerism after 2 weeks in all patients. Six cases of grade II GVHD occurred. One patient, who received the highest T cell dose, developed lethal grade IV GVHD. Treatment-related mortality in the first 100 days was 3/10 (30%) with one death each due to idiopathic pneumonia syndrome, GVHD, and CMV disease. Two patients died after day 100, one due to relapse and one with systemic adenoviral infection. Overall survival is 5/10 patients (50%) with a median follow-up of 435 (range, 229-814) days.

CONCLUSION

This regimen is promising in high-risk patients lacking a suitable donor, and a prospective phase I/II study is ongoing.

摘要

目的

在单倍体相合造血细胞移植(HHCT)后,清除CD3/CD19可能会改善植入和免疫重建,因为移植物不仅含有CD34+干细胞,还含有CD34-祖细胞以及自然杀伤细胞、树突状细胞和辅助细胞。

患者和方法

连续10例患者接受了清除CD3/CD19的移植物的HHCT。采用氟达拉滨(150 - 200 mg/m2)、噻替派(10 mg/kg)、美法仑(120 mg/m2)和OKT - 3(5 mg/天,-5至+14天)进行减低强度预处理,且不进行额外的移植后免疫抑制。诊断包括急性髓系白血病(AML,n = 4)、急性淋巴细胞白血病(ALL,n = 3)、非霍奇金淋巴瘤(NHL,n = 2)和多发性骨髓瘤(n = 1)。所有患者均为“高危”患者,之前的造血细胞移植后疾病难治或复发。清除CD3/CD19的单倍体相合移植物中,CD34+细胞中位数为7.8×10⁶(范围5.2 - 17×10⁶)个/kg,CD56+细胞为5.5×10⁷(范围0.02 - 8.6×10⁷)个/kg,CD3+T细胞为2.0×10⁴(范围0.006 - 44×10⁴)个/kg。植入迅速,粒细胞计数大于500/μL的中位时间为13天(范围11 - 17天),血小板计数大于20000/μL的中位时间为11天(范围8 - 16天),所有患者在2周后均达到完全供者嵌合状态。发生了6例Ⅱ级移植物抗宿主病(GVHD)。1例接受最高T细胞剂量的患者发生了致死性Ⅳ级GVHD。前100天的治疗相关死亡率为3/10(30%),分别有1例死于特发性肺炎综合征、GVHD和巨细胞病毒(CMV)疾病。2例患者在100天后死亡,1例死于复发,1例死于全身性腺病毒感染。10例患者中有5例(50%)总体存活,中位随访时间为435天(范围229 - 814天)。

结论

该方案对于缺乏合适供者的高危患者很有前景,一项前瞻性Ⅰ/Ⅱ期研究正在进行中。

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