成人急性淋巴细胞白血病造血干细胞移植治疗的选择

急性淋巴细胞性白血病(ALL)虽然在接受诱导化疗后大多数患者可以达到完全缓解,但是较高的复发率是影响ALL预后的关键.异基因造血干细胞移植(BMT)已成为治疗ALL的有效方法,对减少复发、提高长期生存至关重要.在移植供者的选择上,HLA相合的亲缘供者是首选,HLA相合的无关供者造血干细胞移植与相合同胞供者造血干细胞移植疗效相似,也有部分研究中心的报告表明无关供者造血干细胞移植效果优于亲缘供者.HLA半相合的亲缘供者造血干细胞移植也是可行的选择.Ph染色体+是ALL患者明确的不良预后因素,造血干细胞移植可以改善Ph+ALL患者的预后,与伊马替尼等酪氨酸激酶抑制剂的联合应用可使治疗效果得到显著的提高.     

成人急性淋巴细胞白血病造血干细胞移植治疗的选择

急性淋巴细胞性白血病(ALL)虽然在接受诱导化疗后大多数患者可以达到完全缓解,但是较高的复发率是影响ALL预后的关键.异基因造血干细胞移植(BMT)已成为治疗ALL的有效方法,对减少复发、提高长期生存至关重要.在移植供者的选择上,HLA相合的亲缘供者是首选,HLA相合的无关供者造血干细胞移植与相合同胞供者造血干细胞移植疗效相似,也有部分研究中心的报告表明无关供者造血干细胞移植效果优于亲缘供者.HLA半相合的亲缘供者造血干细胞移植也是可行的选择.Ph染色体+是ALL患者明确的不良预后因素,造血干细胞移植可以改善Ph+ALL患者的预后,与伊马替尼等酪氨酸激酶抑制剂的联合应用可使治疗效果得到显著的提高.     

成人急性淋巴细胞白血病造血干细胞移植治疗的选择

急性淋巴细胞性白血病(ALL)虽然在接受诱导化疗后大多数患者可以达到完全缓解,但是较高的复发率是影响ALL预后的关键.异基因造血干细胞移植(BMT)已成为治疗ALL的有效方法,对减少复发、提高长期生存至关重要.在移植供者的选择上,HLA相合的亲缘供者是首选,HLA相合的无关供者造血干细胞移植与相合同胞供者造血干细胞移植疗效相似,也有部分研究中心的报告表明无关供者造血干细胞移植效果优于亲缘供者.HLA半相合的亲缘供者造血干细胞移植也是可行的选择.Ph染色体+是ALL患者明确的不良预后因素,造血干细胞移植可以改善Ph+ALL患者的预后,与伊马替尼等酪氨酸激酶抑制剂的联合应用可使治疗效果得到显著的提高.     

成人急性淋巴细胞白血病造血干细胞移植治疗的选择

急性淋巴细胞性白血病(ALL)虽然在接受诱导化疗后大多数患者可以达到完全缓解,但是较高的复发率是影响ALL预后的关键.异基因造血干细胞移植(BMT)已成为治疗ALL的有效方法,对减少复发、提高长期生存至关重要.在移植供者的选择上,HLA相合的亲缘供者是首选,HLA相合的无关供者造血干细胞移植与相合同胞供者造血干细胞移植疗效相似,也有部分研究中心的报告表明无关供者造血干细胞移植效果优于亲缘供者.HLA半相合的亲缘供者造血干细胞移植也是可行的选择.Ph染色体+是ALL患者明确的不良预后因素,造血干细胞移植可以改善Ph+ALL患者的预后,与伊马替尼等酪氨酸激酶抑制剂的联合应用可使治疗效果得到显著的提高.     

成人急性淋巴细胞白血病造血干细胞移植治疗的选择

急性淋巴细胞性白血病(ALL)虽然在接受诱导化疗后大多数患者可以达到完全缓解,但是较高的复发率是影响ALL预后的关键.异基因造血干细胞移植(BMT)已成为治疗ALL的有效方法,对减少复发、提高长期生存至关重要.在移植供者的选择上,HLA相合的亲缘供者是首选,HLA相合的无关供者造血干细胞移植与相合同胞供者造血干细胞移植疗效相似,也有部分研究中心的报告表明无关供者造血干细胞移植效果优于亲缘供者.HLA半相合的亲缘供者造血干细胞移植也是可行的选择.Ph染色体+是ALL患者明确的不良预后因素,造血干细胞移植可以改善Ph+ALL患者的预后,与伊马替尼等酪氨酸激酶抑制剂的联合应用可使治疗效果得到显著的提高.     

成人急性淋巴细胞白血病造血干细胞移植治疗的选择

急性淋巴细胞性白血病(ALL)虽然在接受诱导化疗后大多数患者可以达到完全缓解,但是较高的复发率是影响ALL预后的关键.异基因造血干细胞移植(BMT)已成为治疗ALL的有效方法,对减少复发、提高长期生存至关重要.在移植供者的选择上,HLA相合的亲缘供者是首选,HLA相合的无关供者造血干细胞移植与相合同胞供者造血干细胞移植疗效相似,也有部分研究中心的报告表明无关供者造血干细胞移植效果优于亲缘供者.HLA半相合的亲缘供者造血干细胞移植也是可行的选择.Ph染色体+是ALL患者明确的不良预后因素,造血干细胞移植可以改善Ph+ALL患者的预后,与伊马替尼等酪氨酸激酶抑制剂的联合应用可使治疗效果得到显著的提高.     

成人急性淋巴细胞白血病造血干细胞移植治疗的选择

急性淋巴细胞性白血病(ALL)虽然在接受诱导化疗后大多数患者可以达到完全缓解,但是较高的复发率是影响ALL预后的关键.异基因造血干细胞移植(BMT)已成为治疗ALL的有效方法,对减少复发、提高长期生存至关重要.在移植供者的选择上,HLA相合的亲缘供者是首选,HLA相合的无关供者造血干细胞移植与相合同胞供者造血干细胞移植疗效相似,也有部分研究中心的报告表明无关供者造血干细胞移植效果优于亲缘供者.HLA半相合的亲缘供者造血干细胞移植也是可行的选择.Ph染色体+是ALL患者明确的不良预后因素,造血干细胞移植可以改善Ph+ALL患者的预后,与伊马替尼等酪氨酸激酶抑制剂的联合应用可使治疗效果得到显著的提高.     

成人急性淋巴细胞白血病造血干细胞移植治疗的选择

急性淋巴细胞性白血病(ALL)虽然在接受诱导化疗后大多数患者可以达到完全缓解,但是较高的复发率是影响ALL预后的关键.异基因造血干细胞移植(BMT)已成为治疗ALL的有效方法,对减少复发、提高长期生存至关重要.在移植供者的选择上,HLA相合的亲缘供者是首选,HLA相合的无关供者造血干细胞移植与相合同胞供者造血干细胞移植疗效相似,也有部分研究中心的报告表明无关供者造血干细胞移植效果优于亲缘供者.HLA半相合的亲缘供者造血干细胞移植也是可行的选择.Ph染色体+是ALL患者明确的不良预后因素,造血干细胞移植可以改善Ph+ALL患者的预后,与伊马替尼等酪氨酸激酶抑制剂的联合应用可使治疗效果得到显著的提高.     

成人急性淋巴细胞白血病造血干细胞移植治疗的选择

急性淋巴细胞性白血病(ALL)虽然在接受诱导化疗后大多数患者可以达到完全缓解,但是较高的复发率是影响ALL预后的关键.异基因造血干细胞移植(BMT)已成为治疗ALL的有效方法,对减少复发、提高长期生存至关重要.在移植供者的选择上,HLA相合的亲缘供者是首选,HLA相合的无关供者造血干细胞移植与相合同胞供者造血干细胞移植疗效相似,也有部分研究中心的报告表明无关供者造血干细胞移植效果优于亲缘供者.HLA半相合的亲缘供者造血干细胞移植也是可行的选择.Ph染色体+是ALL患者明确的不良预后因素,造血干细胞移植可以改善Ph+ALL患者的预后,与伊马替尼等酪氨酸激酶抑制剂的联合应用可使治疗效果得到显著的提高.     

成人急性淋巴细胞白血病造血干细胞移植治疗的选择

急性淋巴细胞性白血病(ALL)虽然在接受诱导化疗后大多数患者可以达到完全缓解,但是较高的复发率是影响ALL预后的关键.异基因造血干细胞移植(BMT)已成为治疗ALL的有效方法,对减少复发、提高长期生存至关重要.在移植供者的选择上,HLA相合的亲缘供者是首选,HLA相合的无关供者造血干细胞移植与相合同胞供者造血干细胞移植疗效相似,也有部分研究中心的报告表明无关供者造血干细胞移植效果优于亲缘供者.HLA半相合的亲缘供者造血干细胞移植也是可行的选择.Ph染色体+是ALL患者明确的不良预后因素,造血干细胞移植可以改善Ph+ALL患者的预后,与伊马替尼等酪氨酸激酶抑制剂的联合应用可使治疗效果得到显著的提高.     

Is leukemic transformation of donor cells possible?

AIM: To genotype tumor cells in the recurrence of leukemia after allogenic transplantation of bone marrow (TBM). MATERIAL AND METHODS: Standard cytogenetics and fluorescent hybridization in situ (FISH) with a probe to the centrometic sites of X/Y chromosomes were used in examination of 2 patients with acute promyelocytic and acute non-differentiated leukemia after allogenic TBM from donors of the opposite gender. Bone marrow was studied 1, 2, 3, 6, 9, 12, 15, 17, 18 months after the transplantation. RESULTS: One of the patient in leukemia recurrence there were 72% cells with one X chromosome with unknown origin. 28% donor cells were with genotype XX. The primary archival cytological sample of the recipient's bone marrow 68% cells did not contain Y chromosome. Thus, the clone with Y loss is the recipient's clone and leukemia after transplantation developed from the recipient's cells. The other patient had only 8% dividing cells with her karyotype XX with translocation t(10;11) while 92% metaphases were donor's ones; the interphase cells ratio was 75% of host cells and 25% donor cells. This confirms leukemia origin from the recipient's cells. CONCLUSION: High sensitive quantitative method FISH indicates a true correlation between the host and donor cells and is a method of choice for genotyping leukemic cells in recurrence after transplantation of bone marrow. While standard caryotyping depends on mytotic activity of donor and host cell populations, use of only one cytogenetic test for determination of leukemia origin after TBM may provoke diagnostic errors.     

单倍体相合骨髓移植白血病患者造血重建的临床研究

为研究未去除T细胞的单倍体骨髓移植后造血重建的特点 ,对 15例HLA 2 - 3个位点不匹配骨髓移植亲属供者使用G CSF 3- 4 μg/ (kg·d) ,连续 7天后采髓。预处理方案采用大剂量阿糖胞苷联合环磷酰胺和全身照射。应用环孢菌素A和氨甲喋呤、抗胸腺细胞球蛋白及霉酚酸酯 (MMF)预防移植物抗宿主病。移植后观察血像、骨髓像、行染色体分析及HLA位点鉴定。移植后分别于 3,6和 12个月及 2年追踪鉴定植入状态。结果发现 ,15例患者全部移植物植入 ,移植后中性粒细胞 >0 .5× 10 9/L和血小板 >2 0× 10 9/L的时间分别为 18(13- 2 3)天及 2 2 (16- 32 )天。骨髓像显示各系造血均恢复。 7例应用染色体检查 ,8例应用HLA位点 ,4例应用血型 ,1例应用DNA指纹检测 ,植入鉴定结果除 1例复发患者于移植后 2个月骨髓复发植入鉴定为供、受者嵌合外 ,其他患者均呈持续全部稳定植入。移植后发生I度急性GVHD 8例 ,II-IV度GVHD 5例 ,可评价的慢性GVHD共 8例。结论 :供者应用G CSF后采髓 ,加大预处理剂量 ,联合应用作用机理不同的多种免疫抑制剂进行HLA单倍体的骨髓移植 ,可跨越人类HLA多样性屏障。     

Transfusion of donor peripheral blood buffy coat cells as effective treatment for relapsed acute leukemia after transplantation of allogeneic bone marrow or peripheral blood stem cells from the same donor

BACKGROUND: The transfusion of same-donor peripheral blood buffy coat (PBBC) cells to chronic myelocytic leukemia patients in relapse after bone marrow transplantation has been increasingly used as an effective antileukemic therapy. A graft-versus-leukemia effect mediated by immunocompetent donor T cells underlies its success. In acute leukemia, however, the effect of this adoptive cellular immunotherapy has not been established, and the results are generally poor. STUDY DESIGN AND METHODS: Five patients, three with acute lymphoblastic leukemia and two with acute myelocytic leukemia, who relapsed within 6 months after allogeneic marrow transplantation were enrolled in a nonrandomized pilot study to receive donor PBBC cell transfusions either before or after undergoing cytoreductive chemotherapy. ABO genotyping and polymerase chain reaction amplification of human tetrameric short tandem repeats DNA typing were used to test for marrow chimerism. RESULTS: Two acute lymphoblastic leukemia patients-both of whom underwent chemotherapy before PBBC cell transfusions, experienced a complete remission, and developed acute and then chronic, extensive graft-versus-host disease-have been leukemia-free for 9 and 7 months, respectively. Repeated molecular studies of their marrow as early as 2 weeks to 8 months after treatment confirmed that the marrow was of donor origin. The other three patients, who chose not to undergo chemotherapy before PBBC cell transfusions, failed to achieve remission and died 14, 16, and 30 days, respectively, after leukemia relapse. CONCLUSION: Adoptive cellular immunotherapy may be effective for acute lymphoblastic leukemia patients in relapse after bone marrow transplantation if chemotherapy is administered before PBBC cell transfusions are initiated.     

Generation of leukemia-reactive cytotoxic T lymphocyte clones from the HLA-identical bone marrow donor of a patient with leukemia.

Allogeneic bone marrow transplantation (BMT) has been associated with a graft-vs.-leukemia (GVL) reactivity. Since T cell depletion of the bone marrow graft has decreased the risk of graft-vs.-host disease (GVHD), but has been associated with higher rates of leukemia relapse, GVL reactivity is probably caused by donor-derived T lymphocytes. Previously, we demonstrated that minor histocompatibility (mH) antigen-specific cytotoxic T lymphocyte (CTL) clones, generated from patients after BMT, are capable of major histocompatibility complex-(MHC) restricted lysis of (clonogenic) myeloid leukemic cells. Here, we investigated whether donor-derived leukemia-specific CTL clones can be generated in vitro, before BMT, using irradiated leukemic cells from a patient with acute myeloid leukemia as stimulator cells, and peripheral blood or bone marrow from the HLA genotypically identical sibling donor as responder cells. Several CTL lines were generated that showed specific lysis (> 50%) of the recipient leukemic cells in a 51Cr-release assay. Two of these CTL lines were cloned by limiting dilution in the presence of the irradiated recipient cells. Multiple leukemia-reactive, HLA class I and II-restricted clones with various specificities could be established. These alloreactive, antileukemic CTL clones may cause GVL reactivity after BMT, and may be used as adjuvant immunotherapy in the treatment of leukemia.     

G-CSF动员供者外周血单个核细胞输注治疗异基因造血干细胞移植后复发白血病的临床研究

目的观察重组人粒细胞集落刺激因子(G-CSF)动员的供者外周血单个核细胞输注治疗异基因造血干细胞移植后,白血病复发的有效性及安全性。方法对2009年7月至2011年2月该科20例异基因造血干细胞移植后复发的白血病患者,予以输注G-CSF动员后供者外周血单个核细胞。其中5例急性淋巴细胞白血病-CR2,8例急性髓系白血病-CR2,2例急性髓系白血病-CR3,3例急性混合细胞白血病,2例加速期慢性髓系白血病。在异基因造血干细胞移植后,半年内,20例患者均复发,予G-CSF动员后,供者外周血单个核细胞输注,每次输注细胞量按1×105/kg、2×105/kg、4×105/kg逐级增加,每次输注间隔4周。结果 12例患者再次完全缓解,8例患者未缓解。输注后,3例患者发生了Ⅰ~Ⅱ度急性移植物抗宿主病,12例患者发生了慢性移植物抗宿主病,5例未发生并发症,未观察到输注相关的全血细胞减少。结论 G-CSF动员供者外周血单个核细胞输注治疗异基因造血干细胞移植后,白血病复发有较好的疗效,不良反应小,值得临床进一步推广。     

异基因造血干细胞移植后白血病复发伴活动性移植物抗宿主病患者的临床研究

目的 探讨异基因造血干细胞移植(allo-HSCT)后白血病复发伴活动性移植物抗宿主病(GVHD)患者GVHD与GVL效应的分离.方法 分析11例接受allo-HSCT后在白血病复发时存在活动性GVHD的患者其原发病、疾病状态、复发时GVHD类型、供者淋巴细胞输注(DLI)疗效及转归等对GVL效应的影响.结果 11例患者包括急性淋巴细胞白血病5例,急性髓系白血病6例,其中5例曾行预防性DLI,复发时伴有活动性DLI后GVHD,包括2例Ⅱ度急性GVHD(aGVHD),1例原局限型慢性GVHD(cGVHD)加重+新发Ⅱ度aGVHD,2例广泛型cGVHD;这5例患者复发后,2例行化疗+治疗性DLI,DLI后在广泛型cGVHD反复加重情况下,1例达完全缓解(CR)后再次复发,1例未达CR.另6例患者复发前未行预防性DLI,白血病复发时亦均存在活动性GVHD,包括3例广泛型cGVHD、1例Ⅰ度aGVHD及2例Ⅲ～Ⅳ度aGVHD,复发后行化疗+治疗性DLI,之后2例达CR后再次复发,4例未达CR.结论 allo-HSCT后活动性GVHD不一定伴随可抑制白血病复发的有效GVL效应.     

Clinical study on the relapsd leukemia patients with graft versus host disease after allogeneic hematopoietic stem cell transplantation

OBJECTIVE: To explore the dissociation of graft-versus-leukemia (GVL) effects from graft-versus-host disease (GVHD) in the patients who experienced GVHD during leukemia relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: The primary disease, disease status, GVHD, response to donor lymphocyte infusion (DLI) and prognosis were analysed in 11 leukemia patients who relapsed with GVHD after allo-HSCT. RESULTS: Of the 11 relapsed, 5 were acute lymphoblastic leukemia and 6 acute myeloid leukemia. Five received DLI before relapse and all developed post-DLI GVHD, including 2 grade II acute GVHD (aGVHD), 1 limited chronic GVHD (cGVHD) plus grade II aGVHD, and 2 extensive cGVHD. After relapse of the 5 patients, 2 received Chemo-DLI, one achieved CR with extensive cGVHD and then relapsed again, the other didn't achieved CR. The other 6 patients didn't received DLI before relapse and also developed post-HSCT GVHD while relapsing, including 3 extensive cGVHD, 1 grade I aGVHD and 2 grade II-IV aGVHD. After relapse, these 6 patients received Chemo-DLI, 2 achieved CR and then relapsed again, 4 didn't achieved CR. CONCLUSION: The elicited GVHD after allo-HSCT may not accompany effective GVL effects inhibiting leukemic relapse.     

同一供者外周血单个核细胞输注治疗单倍相合骨髓移植后白血病复发

本研究探讨同一供者外周血单个核细胞输注（DMNCI）治疗单倍相合骨髓移植后白血病复发的疗效和安全性。3例单倍相合骨髓移植后白血病复发患者接受G-CSF动员的DMNCI治疗,其中例1和例2骨髓移植前分别为ph＋急性淋巴细胞性白血病伴中枢神经系统侵犯部分缓解及慢性粒细胞性白血病急性变部分缓解,在骨髓移植后这两例均血液学复发,各接受单次DMNCI,单个核细胞剂量分别为8.25×10^8/kg和5.24×10^8/kg;CD3^＋细胞剂量分别为1.87×10^8/kg和1.14×10^8/kg。第3例骨髓移植前为CML急性变,治疗后并达缓解。移植后分子水平复发,接受逐渐提高单次细胞数量的分次输注,首次DMNCI剂量为2.0×10^7/kg,CD3^＋细胞剂量为1.1×10^7/kg。同时观察3例患者输注后白血病缓解情况及并发症。结果显示,3例患者均出现不同疗效,2例血液学复发患者骨髓均暂时缓解,但分别于DMNCI后41、48天死于严重移植物抗宿主病（GVHD）、复发及衰竭。分子水平复发患者分次接受DMNCI,输注2次后达分子水平缓解,STR-PCR测定证实为供者基因型。3例均发生急性GVHD,2例接受单次剂量输注者发生Ⅳ度以上GVHD,1例接受分次输注患者发生Ⅰ度GVHD。3例均未发生明显骨髓抑制,分子水平缓解者随访半年无病生存。结论：DMNCI可能具有抗白血病作用,可用于单倍相合骨髓移植后白血病复发的治疗,对分子水平复发者的疗效较对血液学复发者好;输注MNC为×10^8/kg后GVHD严重。DMNCI起始剂量×10^7/kg并逐渐提高单次剂量的分次输注方法更为安全。     

Transfusion of donor buffy coat cells in the treatment of persistent or recurrent malignancy after allogeneic bone marrow transplantation

BACKGROUND: Patients who experience relapse after allogeneic bone marrow transplantation have a poor prognosis. However, preclinical and clinical data have strongly suggested the existence of an immune- mediated anti-tumor effect of allogeneic bone marrow transplantation. This effect, termed graft-versus-leukemia, may be harnessed purposefully in patients with posttransplant relapses by the administration of immune cells obtained by leukapheresis of the original bone marrow donor. STUDY DESIGN AND METHODS: Thirteen patients with persistent or recurrent hematologic malignancy after HLA-matched sibling-donor allogeneic bone marrow transplantation were treated with transfusion of buffy coat cells collected from the original bone marrow donors. Mononuclear cell dose ranged from 1.18 to 4.28 × 10(8) per kg. Alpha-interferon (1.5-3 × 10(6) U/m2 3-5x/week) was given to seven patients. Patients were observed for the development of graft-versus- host disease and disease response. RESULTS: Three of five patients with chronic myelogenous leukemia had complete remissions. One of five patients with active acute leukemia attained complete remission. A sixth acute leukemia patient treated with buffy coat transfusion after the induction of remission with chemotherapy relapsed 12 months later. One patient with myeloma had a complete but transient response. A patient with Hodgkin's disease did not respond. Four patients remain in remission 4, 16, 17, and 29 months after attaining complete remission. Graft-versus-host disease occurred in eight patients, including all of those with a complete response. One patient developed transient pancytopenia. CONCLUSION: The transfusion of donor buffy coat cells has significant anti-tumor activity in patients with relapsed hematologic malignancy after allogeneic bone marrow transplantation. This effect is strongly associated with graft-versus-host disease.     

急性髓性白血病完全缓解患者残留白血病细胞检测研究

本研究的目的是观察急性髓性白血病患者完全缓解后血液和骨髓中微小残留病变变化情况 ,并探讨微小残留病变在监测急性髓性白血病复发中的应用价值。用流式细胞术检测 3 3例化疗达完全缓解的急性髓性白血病患者血液和骨髓中残留白血病细胞 (residualleukemiccells,RLC)。结果显示 :急性髓性白血病完全缓解组和正常对照组外周血RLC分别为 ( 4 .75 18± 4 .15 3 7) %和 ( 0 .4 83 5± 0 .2 0 0 5 ) % ,二者比较有统计学差异 (P <0 .0 0 1) ;完全缓解组骨髓和正常对照组骨髓RLC分别为 ( 17.90 82± 2 0 .4 819) %和 ( 0 .72 85± 0 .2 2 0 9) % ,二者比较有统计学差异 ( P <0 .0 0 1) ;持续缓解组与复发组外周血RLC分别为 ( 2 .2 3 3± 1.5 92 3 ) %和 ( 10 .2 3 69± 9.4 714 ) % ;持续缓解组与复发组骨髓RLC分别为 ( 4 .779± 3 .0 3 3 6) %和 ( 3 8.0 685± 19.4 2 95 ) %。二组比较有统计学差异 (P <0 0 0 1)。结论 :应用流式细胞术检测残留白血病细胞对及时预测复发有重要意义 ,有利于在复发早期进行治疗。