Nonmyeloablative preparative regimens: how relevant for acute myelogenous leukemia?
Nonmyeloablative preparative regimens: how relevant for acute myelogenous leukemia?
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DOI：
10.1038/sj.leu.2402034
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发表时间：
2001-04-01
期刊：
影响因子：
11.4
通讯作者：
Storb, R
中科院分区：
文献类型：
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作者：
Storb, R
在骨髓移植的主要组织相容性相同的情况下，必须克服两个障碍。一种是排斥屏障，或宿主抗移植物反应;另一种是移植物抗宿主反应。这两个过程都是由T淋巴细胞介导的，这表明在控制移植物抗宿主反应中有效的药物也可能能够调节宿主抗移植物反应，从而使旨在骨髓消融的移植前高剂量治疗最小化。动物模型已经证明了全身照射（TBI）和植入的剂量-反应关系。在犬中，920 cGy的单次剂量（对应于1500 cGy分次TBI）导致几乎所有动物的植入。当剂量减少50%时，大多数动物排斥移植物。使用该剂量，泼尼松的添加没有增强植入，但是给予5周的环孢霉素导致所有动物的植入。当放射剂量进一步降低至200 cGy时，环孢素仅允许植入3-4个月，之后移植物被排斥。甲氨蝶呤和环孢霉素的组合导致2/5的动物中的植入，但其余的被排斥。新的免疫抑制剂，霉酚酸酯（MMF），阻断从头嘌呤合成，被证明是协同与环孢素。使用4周的MMF和5周的环孢素，11/12只动物成功建立了长期植入。1观察2年后，混合供者嵌合状态得以维持。当TBI的剂量进一步降低到100 cGy时，没有发生长期植入，这表明宿主和移植物之间存在微妙的平衡。为了阐明TBI是否对创造骨髓空间很重要，我们用450 cGy照射从颈部到上腹部的中央淋巴结链，然后给予MMF和环孢素。2血液学毒性轻微，血小板最低值为100000/l，粒细胞最低值为3000-5000/l。在移植后6周，供体细胞存在于未照射的骨髓空间中，这表明辐射不是创造空间所必需的。1年后，将供体淋巴细胞输注给动物，在9周内，受体细胞通过PCR消失，表明完全同种异体移植。因此，在没有全身细胞毒性治疗的情况下建立了同种异体移植物。临床试验使用200 cGy的全身辐射和HLA相同的同种异体干细胞沿着霉酚酸酯和环孢霉素，最初导致混合嵌合体。完全嵌合体发生在发生移植物抗宿主病的患者中。这些患者中的许多人的疾病得到缓解。在那些没有发生急性移植的病人中-
In the major histocompatibility identical setting of a marrow transplant, two barriers must be overcome. One is the rejection barrier, or host-versus-graft reaction; the other is the graftversus-host reaction. Both processes are mediated by T lymphocytes, suggesting that agents which were effective in controlling graft-versus-host reactions might also be able to modulate hostversus-graft reactions, thereby allowing minimization of the pretransplant high-dose therapy aimed at myeloablation. Animal models have demonstrated a dose–response relationship with respect to total body irradiation (TBI) and engraftment. In dogs, a single dose of 920 cGy, corresponding to 1500 cGy fractionated TBI, results in engraftment in virtually all of the animals. When the dose is decreased by 50%, the majority of animals reject their grafts. Using this dose, the addition of prednisone did not enhance engraftment, but cyclosporine given for 5 weeks led to engraftment in all of the animals. When the radiation dose was decreased further to 200cGy, cyclosporine only allowed engraftment for 3–4 months, after which the grafts were rejected. The combination of methotrexate and cyclosporine resulted in engraftment in 2/5 animals, but the rest rejected. The novel immunosuppressant, mycophenolate mofetil (MMF), which blocks de novo purine synthesis, was shown to be synergistic with cyclosporine. Using 4 weeks of MMF and 5 weeks of cyclosporine, 11/12 animals successfully established long-term engraftment. 1 After 2 years of observation, mixed donor chimerism was maintained. When the dose of TBI was further decreased to 100 cGy, long-term engraftment did not occur, suggesting a delicate balance between the host and the graft. To elucidate whether TBI is important for creating marrow space, we irradiated the central lymph node chain from the neck down to the upper abdomen with 450 cGy and then administered MMF and cyclosporine. 2 The hematologic toxicity was mild, with a platelet nadir of 100 000/l and granulocyte nadir of 3000–5000/l. At 6 weeks post transplant, donor cells were present in nonirradiated marrow spaces, suggesting that radiation is not necessary to create space. After 1 year, donor lymphocyte infusions were given to the animals and, within 9 weeks, recipient cells disappeared by PCR, indicating complete allograft. Therefore, an allograft had been established without systemic cytotoxic therapy. Clinical trials using 200 cGy of total body radiation and HLA-identical allogeneic stem cells along with MMF and cyclosporine have resulted in mixed chimerism initially. Complete chimerism occurs in patients who develop graft-versushost disease. Many of these patients had remissions of their disease. In those patients who did not develop an acute graft-