Adding 5-day decitabine to the conditioning regimen for haploidentical bone marrow transplantation in aplastic anaemia patients results in satisfactory clinical outcomes
Adding 5-day decitabine to the conditioning regimen for haploidentical bone marrow transplantation in aplastic anaemia patients results in satisfactory clinical outcomes
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在再生障碍性贫血患者半相合骨髓移植预处理方案中添加 5 天地西他滨可取得满意的临床结果
DOI：
10.1038/s41409-022-01729-z
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发表时间：
2022-06
期刊：
影响因子：
--
通讯作者：
Shengjin Fan
中科院分区：
文献类型：
--
作者：
Linqing Tang;Yiting Wu;Ruiqi Lei;Jie Liu;Dan Guo;Yanqiu Zhao;huibo Li;Shengjin Fan
来自匹配的同胞供体（MSD）的造血干细胞移植（HSCT）是年轻严重再生障碍性贫血（SAA）患者的一种可治愈的治疗方法，且长期总生存（OS）率在90%以上[1]。每年针对SAA的单倍体相合造血干细胞移植（HID-HSCT）的比例呈上升趋势[2]。但由于多个HLA位点不匹配以及移植前大量输血，II-IV级急性移植物抗宿主病（aGVHD）和慢性GVHD的发生率分别为26.6%和25.0%[3]，仍远高于MSD患者。人们对移植过程中免疫反应中表观遗传调控的认识不断增强[4]。最近，临床研究推荐在恶性血液病移植中添加地西他滨，因为它显示出令人满意的增强移植物抗白血病（GVL）效果并降低GVHD发生率[5]。迄今为止，尚无关于在 AA 患者移植预处理方案中添加地西他滨的有效性和安全性的研究。因此，我们在此研究了“北京方案”与5天地西他滨预备方案相结合的临床结果。我们对2015年6月至2019年12月期间的33例患者进行了回顾性研究，其中33例患者接受地西他滨联合Bu/Cy/ATG预处理方案。该研究得到了哈尔滨医科大学第一附属医院机构审查委员会的批准。 AA 的诊断和疾病严重程度的评估是根据以前的标准定义的[6]。所有捐赠者每天一次接受5-10 μg/kg重组人粒细胞集落刺激因子（rhG-CSF），连续3-5天，然后我们在第01天收获骨髓（BM）细胞，在第02天（必要时在第03天）收获外周血干细胞（PBSC）。在这项研究中，所有患者在移植前接受 5–15 mg/m2 地西他滨（第 9 至 5 天）。调理治疗包括以下内容： 0.8 mg/kg 静脉注射 (IV) Bu，每天四次，第 7 天和第 6 天； 50mg/kg IV Cy，每天一次，在第− 5、− 4、− 3 和− 2 天；和 2.5 mg/kg IV ATG（兔子，Genzyme Polyclonals SA S，法国），从第 5 天到第 1 天连续五天（或从第 5 天到第 2 天连续四天）每天一次。所有患者均接受环孢素 A (CsA)、吗替麦考酚酯 (MMF) 和短期甲氨蝶呤 (MTX) 作为 aGVHD 预防。根据患者病情和临床医生经验适当调整治疗方案。急性和慢性GVHD 根据国际标准进行分级[7, 8]。使用 Kaplan-Meier 方法分析总生存期 (OS) 和无失败生存期 (FFS) 的主要终点。移植物输注的参与者被纳入移植物失败（GF）、移植相关死亡率（TRM）和 GVHD 的累积发生率（CI）分析中。使用SPSS 26.0和R 3.2版进行统计分析。 2. 这项回顾性研究的更全面的细节之前已经描述过[9]。表 1 总结了研究患者 (n= 33) 的 HSCT 前后特征。该研究队列（19 名女性患者，57.6%）接受 HID-HSCT 的中位年龄为 9 岁（范围，6-13 岁）。其中 12 名患者 (36.4%) 符合极重度再生障碍性贫血 (VSAA) 的标准，其中中性粒细胞计数< 0.2×109。在接受 AA 诊断后的中位 3 个月（范围为 1-15 个月）内，患者接受中位单核细胞 (MNC) 浓度为 20.0×108/kg 的干细胞……
Haematopoietic stem cell transplantation (HSCT) from a matched sibling donor (MSD) is a curable treatment for younger severe aplastic anaemia (SAA) patients, and the long-term overall survival (OS) rate is above 90%[1]. The annual percentage of haploidentical haematopoietic stem cell transplantation (HID-HSCT) for SAA has shown an increasing trend [2]. However, owing to multiple mismatched HLA loci and heavy transfusions before transplantation, the rates of grades II–IV acute graft-versus-host disease (aGVHD) and chronic GVHD were 26.6% and 25.0%[3], respectively, which are still much higher than those of patients with a MSD. The awareness of epigenetic regulation in the immune response during transplantation is increasing [4]. Recently, clinical studies have recommended the addition of decitabine in transplantation for malignant haematological disease, as it has shown a satisfactory enhancement of the graftversus-leukaemia (GVL) effect and a reduction in the incidence of GVHD [5]. Until now, there has been no study about the efficacy and safety of adding decitabine to the conditioning regimen for transplantation with AA patients. Therefore, we herein investigated the clinical outcomes that combined the “Beijing protocol” with 5-day decitabine for preparative regimen. We conducted a retrospective study from June 2015 to December 2019, in which 33 patients received decitabine combined with Bu/Cy/ATG conditioning regimen. The study was approved by the Institutional Review Board of the First Affiliated Hospital of Harbin Medical University. The diagnosis of AA and assessment of disease severity were defined according to previous criteria [6]. All donors received 5–10 μg/kg recombinant human granulocyte colony-stimulating factor (rhG-CSF) once daily for 3–5 consecutive days, and then we harvested bone marrow (BM) cells on day 01 and peripheral blood stem cells (PBSCs) on day 02 (and day 03 if necessary). In this study, all patients received 5–15 mg/m2 decitabine (days− 9 to− 5) before transplantation. Conditioning therapy consisted of the following: 0.8 mg/kg intravenous (IV) Bu four times daily on days− 7 and− 6; 50mg/kg IV Cy once daily on days− 5,− 4,− 3, and− 2; and 2.5 mg/kg IV ATG (rabbit, Genzyme Polyclonals SA S, France) once daily for five consecutive days from days− 5 to− 1 (or four consecutive days from days− 5 to− 2). All patients received cyclosporin A (CsA), mycophenolate mofetil (MMF) and shortterm methotrexate (MTX) as aGVHD prophylaxis. The therapeutic schedule was adjusted appropriately according to patient’s condition and clinician’s experience. Acute and chronic GVHD were graded according to international criteria [7, 8]. The primary endpoints of overall survival (OS) and failure-free survival (FFS) were analysed using the Kaplan–Meier method. Participants with infused grafts were included in the cumulative incidence (CI) analysis of graft failure (GF), transplantation related mortality (TRM) and GVHD. Statistical analyses were conducted using SPSS 26.0 and R version 3.2. 2. More comprehensive details of this retrospective study have been previously describe [9]. Table 1 summarises the pre-and post-HSCT characteristics of the study patients (n= 33). The median age of this study cohort (19 female patients, 57.6%) receiving HID-HSCT was 9 years (range, 6–13 years). Twelve (36.4%) of these patients met the criteria for very severe aplastic anaemia (VSAA), in which the neutrophil count was< 0.2× 109. At a median of 3 months (range, 1–15 months) after receiving an AA diagnosis, the patients were infused with stem cells with a median mononuclear cell (MNC) concentration of 20.0× 108/kg …
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DOI：
10.1007/3-540-29623-9_6338
发表时间：
2009
期刊：
--
影响因子：
--
作者：
通讯作者：
--
影响因子：
6.5
作者：
Jing Chen;V. Lee;C. Luo;A. Chiang;S. Hongeng;P. Tan;A. Tan;Kleebsabai Sanpakit;Chun Fu Li
通讯作者：
Jing Chen;V. Lee;C. Luo;A. Chiang;S. Hongeng;P. Tan;A. Tan;Kleebsabai Sanpakit;Chun Fu Li
影响因子：
4.8
作者：
Xu, L. P.;Liu, K. Y.;Huang, X. J.
通讯作者：
Huang, X. J.
影响因子：
20.3
作者：
B. Camitta;E. Thomas;D. Nathan;G. Santos;E. Gordon-Smith;R. Gale;J. Rappeport;R. Storb
通讯作者：
B. Camitta;E. Thomas;D. Nathan;G. Santos;E. Gordon-Smith;R. Gale;J. Rappeport;R. Storb
影响因子：
4.3
作者：
Greinix, Hildegard T.;Loddenkemper, Christoph;Wolff, Daniel
通讯作者：
Wolff, Daniel