Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases
Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases
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DOI：
10.1182/blood.v91.3.756.756_756_763
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发表时间：
1998-02-01
期刊：
影响因子：
20.3
通讯作者：
Or, R
中科院分区：
文献类型：
--
作者：
Slavin, S;Nagler, A;Or, R
与危险的即时和晚期并发症相关的清髓调理被认为是准备同种异体血液或骨髓移植（同种异体 BMT）以治疗恶性血液疾病和遗传性疾病的强制性第一步。免疫介导的移植物抗白血病 (GVL) 效应构成了同种异体 BMT 的主要益处。因此，我们在同种异体 BMT 之前引入了相对非清髓性条件的使用，旨在建立供体免疫造血细胞植入的宿主抗移植物耐受性，从而诱导 GVL 效应以取代残留的恶性或遗传异常的宿主细胞。我们对 26 名具有异基因 BMT 标准适应症的患者进行的初步数据，包括急性白血病 (n = 10)；慢性白血病 (n = 8)、非霍奇金淋巴瘤 (n = 2)、骨髓增生异常综合征 (n = 1)、多发性骨髓瘤 (n = 1) 和遗传性疾病 (n = 4) 表明，包括氟达拉滨、抗 T 淋巴细胞球蛋白和低剂量白消安 (8 mg/kg) 在内的非清髓性调理具有极好的耐受性， 没有严重的手术相关毒性。粒细胞集落刺激因子动员血液干细胞移植与标准剂量的环孢菌素 A 作为唯一的抗移植物抗宿主病 (GVHD) 预防导致稳定的部分 (n = 9) 或完全 (n = 17) 嵌合。 9 名患者的绝对中性粒细胞计数 (ANC) 未降至 0.1 x 10(9)/L 以下，而 2 名从未经历过 ANC 的患者在 0 至 35（中位数 12）天内达到了 20 x 10(9)/L。 14 名患者完全没有经历 GVHD；严重GVHD（3级和4级）是4名患者的单一主要并发症和死亡原因，发生在早期停用环孢素A后。2/3的病例通过同种异体细胞治疗逆转了复发，目前通过细胞遗传学分析和聚合酶链反应没有残留宿主DNA（男性）。迄今为止，观察期超过 1 年（中位 8 个月），26 名接受同种异体非清髓性干细胞移植治疗的患者中有 22 名患者（85%）存活，21 名患者（81%）无病。 14 个月无病生存的精算概率为 77.5%（95% 置信区间，53% 至 90%）。通过同种异体非清髓性干细胞移植成功根除恶性和遗传异常的宿主造血细胞，代表了一种潜在的新方法，可以更安全地治疗多种具有异基因 BMT 适应症的临床综合征。短暂的混合嵌合现象可以保护宿主免受严重急性GVHD的影响，可以通过逐步增加供体淋巴细胞输注成功逆转同种异体后BMT，从而消除宿主来源的恶性或遗传异常祖细胞。 (C) 1998 年，美国血液学会。
Myeloablative conditioning associated with hazardous immediate and late complications is considered as a mandatory first step in preparation for allogeneic blood or marrow transplantation (allogeneic BMT) for the treatment of malignant hematologic disorders and genetic diseases. Immune-mediated graft-versus-leukemia (GVL) effects constitute the major benefit of allogeneic BMT. Therefore, we have introduced the use of relatively nonmyeloablative conditioning before allogeneic BMT aiming for establishing host-versus-graft tolerance for engraftment of donor immunohematopoietic cells for induction of GVL effects to displace residual malignant or genetically abnormal host cells. Our preliminary data in 26 patients with standard indications for allegeneic BMT, including acute leukemia (n = 10); chronic leukemia (n = 8), non-Hodgkin's lymphoma (n = 2), myelodysplastic syndrome (n = 1), multiple myeloma (n = 1), and genetic diseases (n = 4) suggest that nonmyeloablative conditioning including fludarabine, anti-T-lymphocyte globulin, and low-dose busulfan (8 mg/kg) is extremely well tolerated, with no severe procedure-related toxicity. Granulocyte colony-stimulating factor mobilized blood stem cell transplantation with standard dose of cyclosporin A as the sole anti-graft-versus-host disease (GVHD) prophylaxis resulted in stable partial (n = 9) or complete (n = 17) chimerism. In 9 patients absolute neutrophil count (ANC) did not decrease to below 0.1 x 10(9)/L whereas 2 patients never experienced ANC 20 x 10(9)/L were achieved within 0 to 35 (median 12) days. Fourteen patients experienced no GVHD at all; severe GVHD (grades 3 and 4) was the single major complication and the cause of death in 4 patients, occurring after early discontinuation of cyclosporine A. Relapse was reversed by allogeneic cell therapy in 2/3 cases, currently with no residual host DNA (male) by cytogenetic analysis and polymerase chain reaction. To date, with an observation period extending over 1 year (median 8 months), 22 of 26 patients (85%) treated by allogeneic nonmyeloablative stem cell transplantation are alive, and 21 (81%) are disease-free. The actuarial probability of disease-free survival at 14 months is 77.5% (95% confidence interval, 53% to 90%). Successful eradication of malignant and genetically abnormal host hematopoietic cells by allogeneic nonmyeloablative stem cell transplantation represents a potential new approach for safer treatment of a large variety of clinical syndromes with an indication for allegeneic BMT. Transient mixed chimerism which may protect the host from severe acute GVHD may be successfully reversed postallogeneic BMT with graded increments of donor lymphocyte infusions, thus resulting in eradication of malignant or genetically abnormal progenitor cells of host origin. (C) 1998 by The American Society of Hematology.