Straathof Karin C, Rao Kanchan, Eyrich Matthias, Hale Geoff, Bird Prudence, Berrie Eleanor, Brown Lucinda, Adams Stuart, Schlegel Paul G, Goulden Nicholas, Gaspar H Bobby, Gennery Andrew R, Landais Paul, Davies E G, Brenner Malcolm K, Veys Paul A, Amrolia Persis Jal
Great Ormond Street Children's Hospital, London, UK.
Lancet. 2009 Sep 12;374(9693):912-20. doi: 10.1016/S0140-6736(09)60945-4. Epub 2009 Sep 2.
Stem-cell transplantation can cure primary immunodeficiencies. However, in patients with pre-existing organ toxicity, patients younger than 1 year, and those with DNA or telomere repair disorders, chemotherapy-based conditioning is poorly tolerated and results in major morbidity and mortality. We tested a novel antibody-based minimal-intensity conditioning (MIC) regimen to assess whether this approach allowed curative donor stem-cell engraftment without non-haemopoietic toxicity.
16 high-risk patients underwent stem-cell transplantation for primary immunodeficiencies with an MIC regimen consisting of two rat anti-CD45 monoclonal antibodies YTH 24.5 and YTH 54.12 for myelosuppression, and alemtuzumab (anti-CD52) and fludarabine, and low dose cyclophosphamide for immunosuppression. Donors were matched siblings (n=5), and matched (9) and mismatched (2) unrelated donors.
Antibody-based conditioning was well tolerated, with only two cases of grade 3 and no grade 4 toxicity. Rates of clinically significant acute (n=6, 36%) and chronic graft-versus-host disease (GVHD) (n=5, 31%) were acceptable. 15 of 16 patients (94%) engrafted, of whom 11 (69%) achieved full or high-level mixed chimerism in both lymphoid and myeloid lineages, and three achieved engraftment in the T-lymphoid lineage only. One patient needed retransplantation. At a median of 40 months post-transplant, 13 of 16 patients (81%) in this high-risk cohort were alive and cured from their underlying disease.
Monoclonal antibody-based conditioning seems well tolerated and can achieve curative engraftment even in patients with severe organ toxicity or DNA repair defects, or both. This novel approach represents a shift from the paradigm that intensive chemotherapy or radiotherapy, or both, is needed for donor stem-cell engraftment. This antibody-based conditioning regimen may reduce toxicity and late effects and enable SCT in virtually any primary immunodeficiency patient with a matched donor.
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干细胞移植可治愈原发性免疫缺陷病。然而，对于已有器官毒性的患者、1岁以下的患儿以及存在DNA或端粒修复障碍的患者，基于化疗的预处理耐受性较差，会导致严重的发病率和死亡率。我们测试了一种新型的基于抗体的低强度预处理（MIC）方案，以评估这种方法能否在不产生非造血毒性的情况下实现供体干细胞的治愈性植入。
16例高危患者接受了针对原发性免疫缺陷病的干细胞移植，采用的MIC方案包括两种用于骨髓抑制的大鼠抗CD45单克隆抗体YTH 24.5和YTH 54.12，以及用于免疫抑制的阿仑单抗（抗CD52）、氟达拉滨和低剂量环磷酰胺。供体为匹配的同胞（n = 5）、匹配的（9例）和不匹配的（2例）无关供体。
基于抗体的预处理耐受性良好，仅2例出现3级毒性，无4级毒性。具有临床意义的急性移植物抗宿主病（GVHD）（n = 6，36%）和慢性GVHD（n = 5，31%）的发生率均可接受。16例患者中有15例（94%）实现植入，其中11例（69%）在淋巴系和髓系均达到完全或高水平混合嵌合，3例仅在T淋巴细胞系实现植入。1例患者需要再次移植。在移植后中位40个月时，该高危队列中的16例患者中有13例（81%）存活且潜在疾病治愈。
基于单克隆抗体的预处理似乎耐受性良好，即使在存在严重器官毒性或DNA修复缺陷或两者兼有的患者中也能实现治愈性植入。这种新方法代表了从供体干细胞植入需要强化化疗或放疗或两者兼有的模式的转变。这种基于抗体的预处理方案可能会降低毒性和远期效应，并使几乎任何有匹配供体的原发性免疫缺陷病患者都能接受干细胞移植。
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