Haploidentical stem cell transplantation for acute leukemia
Haploidentical stem cell transplantation for acute leukemia
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DOI：
10.1007/bf03165238
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发表时间：
2002-08-01
影响因子：
2.1
通讯作者：
Martelli, MF
中科院分区：
文献类型：
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作者：
Aversa, F;Terenzi, A;Martelli, MF
预约：自1993年3月以来; 133例高危急性白血病患者（66例AML，67例ALL）接受了大剂量的T细胞去除造血干细胞。1993年至1995年的预处理方案包括TBI，塞替派，ATG和CY的36名患者接受了由凝集素分离的骨髓和PBPC组成的接种物。1995年后，为了最小化预处理的血液学外毒性并消除GvHD，我们在预处理中用氟达拉滨代替CY，并使用CellPro（n=44例患者）或自1999年1月起使用CliniMacs（n=53例患者）通过CD 34（+）细胞的阳性选择来耗尽PBPC的T细胞。1999年1月对方案进行的后续修改是暂停移植后G-CSF。进行中的工作：我们在这里报告的结果，在过去的53例急性白血病患者，所有这些移植根据我们的修改方案。年龄范围为9至62岁，33例AML患者的中位年龄为38岁，20例ALL患者的中位年龄为23岁。所有患者均处于高风险状态，因为25例患者在移植时实际上处于复发状态，16例患者处于第二次或更晚的CR状态，甚至12例CR 1患者也处于高风险状态，因为预后不良。总计52/53例患者（98%）植入。即使在45至62岁的14名患者中，基于TBI-氟达拉滨的预处理也耐受良好。无肝脏静脉闭塞性疾病，严重粘膜炎的发生率低。即使没有给予移植后免疫抑制剂治疗，也只有4例发生大于或等于II级的急性GvHD，只有1例进展为慢性GvHD。总体而言，16例患者（30%）死于非白血病原因。复发主要发生在移植时已经复发的患者中（12/25）。到目前为止，在移植时处于CR的28例患者中只有3例复发。正如我们的研究小组已经表明的那样，在没有GvHD的情况下，供体与受体NK细胞同种异体反应性发挥了特异性移植物与AML的作用。事实上，白血病复发在其供体为NK同种异体反应性的AML受者中得到很大程度的控制，16例中仅2例复发。迄今为止，移植时达到任何CR的18例AML患者中有13例（72%）和10例ALL患者中有5例（50%）无病生存，而移植时复发的15例患者中有4例（16%）生存。在18例AML患者和10例ALL患者中，CR移植患者的无事件生存率分别为60%和38%。在16例AML患者中，其移植包括供体与受体NK细胞同种异体反应性的EFS概率显著优于那些移植没有的患者（70% vs 7%）。总之，根据我们目前的研究结果，全单倍型错配移植的最合适的候选者应该是在疾病的早期，建议选择NK同种异体反应性供体。
Premise: Since March 1993; 133 patients with high-risk acute leukemia (66 AML, 67 ALL) have received a megadose of T-cell depleted hematopoietic stem cells. The 1993-95 conditioning protocol included TBI, thiotepa, ATG and CY for 36 patients who received an inoculum made up of lectin-separated bone marrow and PBPCs. After 1995, to minimise the extra-hematological toxicity of the conditioning and eliminate GvHD, we substituted fludarabine for CY in the conditioning and PBPCs were depleted of T-cells by a positive selection of the CD34(+) cells, using CellPro (n=44 patients) or, since January 1999, CliniMacs (n=53 patients). A later modification to the protocol in January 1999 was the suspension of post transplant G-CSF. Work in Progress: We report here the results in the last 53 acute leukemia patients all of whom were transplanted under our modified protocol. Ages ranged from 9 to 62 years with a median of 38 years for the 33 patients with AML and 23 for the 20 with ALL. All were at high risk because 25 were actually in relapse at transplant, 16 were in second or later CR and even the 12 patients in CR1 were at high risk because of the unfavourable prognostic features. Overall 52/53 patients (98%) engrafted. The TBI-Fludarabine-based conditioning was well tolerated even in the 14 patients between 45 and 62 years of age. There was no veno-occlusive disease of the liver and the incidence of severe mucositis was low. Even though no post-transplant immunosuppressive therapy was given acute GvHD grade greater than or equal to II occurred in only 4 cases and only one progressed to chronic GvHD. Overall, 16 patients (30%) have died of non-leukemic causes. Relapses occurred mainly in patients who were already in relapse at transplant (12/25). Only 3 of the 28 who were in any CR at transplant have so far relapsed. As our group has already shown, donor-vs-recipient NK cell alloreactivity exerts a specific graft-vs-AML effect in the absence of GvHD. In fact, leukemia relapse was largely controlled in AML recipients whose donor was NK alloreactive, with only 2 out of 16 relapsing. To date, 13 of 18 AML (72%) and 5 of 10 ALL (50%) who were in any CR at transplant, survive disease-free while 4 of the 15 patients (16%) in relapse at transplant survive. The probability of event-free survival for patients transplanted in CR is 60% in the 18 AML patients and 38% in the 10 ALL. The probability of EFS was significantly better in the 16 AML patients whose transplant included donor vs recipient NK cell alloreactivity than in those whose transplant did not (70% vs 7%). In conclusion, given our current results, the most suitable candidate for the full haplotype mismatched transplant should be in early stage disease and selection of an NK alloreactive donor is recommended.