Bader P, Beck J, Frey A, Schlegel P G, Hebarth H, Handgretinger R, Einsele H, Niemeyer C, Benda N, Faul C, Kanz L, Niethammer D, Klingebiel T
Department of Pediatric Hematology/Oncology, University Children's Hospital, Tübingen, Germany.
Bone Marrow Transplant. 1998 Mar;21(5):487-95. doi: 10.1038/sj.bmt.1701119.
Within a prospective study we analyzed hematopoietic chimerism in serial peripheral blood samples taken from 55 patients with acute leukemias (ALL 21, AML 20, MDS 14) with a median age of 13.5 years at very short time intervals following allogeneic bone marrow transplantation (allo-BMT). The investigation was performed to determine the implications of mixed hematopoietic chimerism (MC) with regard to the clinical outcome in patients with acute leukemias after allo-BMT. Analysis of chimerism was performed by PCR of variable number of tandem repeat (VNTR) sequences with a maximum sensitivity of 0.8%. Thirteen male patients transplanted with the marrow of a female donor were also studied by amplification of a Y-chromosome-specific alphoid repeat (0.1-0.01% sensitivity). VNTR analysis in 55 patients revealed complete chimerism (CC) in 36 cases, MC in 18 follow-ups and autologous recovery in one patient. Quantitative analysis of MC identified 10/18 patients with increasing autologous patterns in whom 9/10 subsequently relapsed. The patient with autologous recovery relapsed as well. Eight of 18 patients with MC showed decreasing amounts of autologous DNA and became CC upon further follow-up. In contrast, only 7/36 patients with CC in the prior analysis of chimerism status relapsed. However, in 4/7 patients the interval between last CC confirmation and relapse was more than 4 months. In 2/7 patients autologous DNA was not detectable in peripheral blood but in bone marrow aspirates. One of these seven patients developed a fulminant relapse within 3 weeks. The probability of relapse-free survival for patients with CC is 0.67 (n = 36), for patients with decreasing MC 1.0 (n = 8) and for patients with increasing MC 0.1 (n = 10). In summary, the results demonstrate that serial and quantitative chimerism analysis at short time intervals by PCR provides a reliable and rapid screening method for the early detection of recurrence of underlying disease and is therefore a prognostic tool to identify patients at highest risk of relapse.
在一项前瞻性研究中，我们分析了55例急性白血病患者（21例急性淋巴细胞白血病、20例急性髓细胞白血病、14例骨髓增生异常综合征）在异基因骨髓移植（allo-BMT）后极短时间间隔内采集的系列外周血样本中的造血嵌合体情况。这些患者的中位年龄为13.5岁。进行这项研究是为了确定混合造血嵌合体（MC）对急性白血病患者allo-BMT后临床结局的影响。通过对可变数目串联重复序列（VNTR）进行聚合酶链反应（PCR）分析嵌合体，最大灵敏度为0.8%。对13例接受女性供体骨髓移植的男性患者，还通过扩增Y染色体特异性α卫星重复序列（灵敏度为0.1%-0.01%）进行了研究。对55例患者的VNTR分析显示，36例为完全嵌合体（CC），18次随访中有MC，1例患者出现自体恢复。对MC的定量分析发现，18例患者中有10例自体模式增加，其中10例中有9例随后复发。出现自体恢复的患者也复发了。18例有MC的患者中有8例自体DNA量减少，进一步随访后变为CC。相比之下，在之前嵌合体状态分析中CC的36例患者中只有7例复发。然而，在7例患者中的4例，最后一次CC确认与复发之间的间隔超过4个月。在7例患者中的2例，外周血中未检测到自体DNA，但在骨髓穿刺物中检测到。这7例患者中有1例在3周内发生暴发性复发。CC患者的无复发生存概率为0.67（n = 36），MC减少的患者为1.0（n = 8），MC增加的患者为0.1（n = 10）。总之，结果表明，通过PCR在短时间间隔内进行系列和定量嵌合体分析，为潜在疾病复发的早期检测提供了一种可靠且快速的筛查方法，因此是一种识别复发风险最高患者的预后工具。
