自体造血干细胞移植联合异体细胞因子诱导的杀伤细胞及白细胞介素2治疗高危急性髓系白血病2例*

背景：自体造血干细胞移植治疗高危急性髓系白血病的复发率极高,如何降低移植后复发率至今仍是难点。 目的：观察自体造血干细胞移植联合异体细胞因子活化杀伤(CIK)细胞及白细胞介素2治疗高危急性髓系白血病的临床效果。 方法：2例高危急性髓系白血病患者,经诱导化疗及巩固强化治疗后,在第1次缓解期行自体造血干细胞移植, 移植后1个月给予三四疗程异体CIK细胞输注,每隔半年1个疗程,每疗程分5次输注异体CIK细胞,每隔1日输注1次。每次输注CIK细胞前半小时内给予皮下注射白细胞介素2,第1次输注后隔日皮下注射白细胞介素2,半年后减为隔2日1次,1年后减为隔3日1次,1年半后减为1次/周,维持半年后结束,预防白血病复发。 结果与结论：2例患者自体造血干细胞移植后输注异体CIK细胞及皮下注射白细胞介素2无发热、寒战、皮疹等不良反应,无骨髓抑制及移植物抗宿主反应,治疗安全。2例患者持续缓解时间分别为20个月及2年,目前仍无复发。首次得出对于无合适供者的高危急性髓系白血病患者,在缓解后可行自体造血干细胞移植联合异体CIK细胞及白细胞介素2治疗,有机会获得长期无病生存。       

预处理不含抗胸腺细胞球蛋白非血缘脐血移植治疗急性髓系白血病和急性淋巴细胞白血病306例随访评价

背景:脐血造血干细胞移植作为急性白血病的根治手段,应用越来越广泛,但是其在不同白血病的治疗效果尚无对比,通过分疾病的疗效对比,可指导不同患者进行移植方式的选择。目的:对比分析脐血造血干细胞移植治疗急性髓系白血病和急性淋巴细胞白血病的疗效差异。方法:回顾性分析接受非血缘脐血造血干细胞移植治疗的306例急性白血病患者的临床资料,其中急性淋巴细胞白血病194例,急性髓系白血病112例。所有患者均接受不含抗胸腺细胞球蛋白的清髓性预处理方案,预防移植物抗宿主病为环孢素联合吗替麦考酚酯。结果与结论:①除了急性淋巴细胞白血病移植后的复发率比急性髓系白血病略高以外,两组患者在接受非血缘脐血移植术后的疗效基本一致;②在青少年和年轻成人组(年龄15-39岁),急性髓细胞白血病的中性粒细胞和血小板植入速率均快于急性淋巴白血病白血病,其中CD34+细胞数和预处理方案是针对中性粒细胞植入的独立影响因素,而CD34+细胞数同时也是针对血小板植入的独立影响因素,在该年龄组,急性淋巴细胞白血病患者移植后的复发率依然高于急性髓系白血病,其中慢性移植物抗宿主病是独立影响因素;③移植后免疫重建检测提示,脐血移植后4个月时急性髓系白血病患者的脐血CD8+T细胞重建要优于急性淋巴细胞白血病患者;④上述数据说明,预处理不含抗胸腺细胞球蛋白的非血缘脐血移植对于急性淋巴细胞白血病和急性髓系白血病均有良好的疗效。中国科学技术大学附属第一医院(安徽省立医院)血液科具有干细胞移植资质。     

异基因外周血造血干细胞移植治疗白血病*

背景：异基因外周血造血干细胞移植是治疗白血病的有效手段。 目的：比较血缘与非血缘供者异基因外周血造血干细胞移植治疗白血病的造血重建、免疫重建、感染、移植物抗宿主病及疗效。 方法：选择接受异基因外周血造血干细胞移植治疗的白血病患者45例,其中30例患者接受血缘供者造血干细胞移植(血缘组),15例患者接受非血缘供者造血干细胞移植(非血缘组)。 结果与结论：①造血重建：血缘组白细胞和血小板重建时间均快于非血缘组(P < 0.05)。在移植后30~40 d植活证据指标测定提示异体造血干细胞在受者体内完全植活。②T细胞重建：两组移植后各时间点T细胞重建差异无显著性意义。③感染发生率：两组移植后早期感染发生率,急、慢性移植物抗宿主病发生率差异无显著性意义(P > 0.05)。④白血病复发：两组移植后复发率差异无显著性意义(P > 0.05)。⑤无病生存：两组移植后2年无病生存率差异无显著性意义(P > 0.05)。表明血缘供者异基因外周血造血干细胞移植后的造血重建较非血缘供者迅速,但两者间移植后T细胞重建、感染发生率、移植物抗宿主病及无病生存并无差异。      

父母供子女单倍型造血干细胞移植治疗恶性血液病

背景：单倍型造血干细胞移植是治疗恶性血液病的一种有效方法,合适的供者及快速查找到合适的供者有助于提高移植的成功率。 目的：比较父母供子女单倍型造血干细胞移植治疗恶性血液病的临床疗效。 方法：对郑州大学第一附属医院92例恶性血液病患者行父母为供者的单倍型造血干细胞移植治疗,分为父供子移植、父供女移植、母供子移植、母供女移植4组,对比4组患者移植物抗宿主病的发生率、复发率、2年无病生存率及总生存率等。 结果与结论：92例患者均完全植入并获得造血重建,4组急性移植物抗宿主病发生率、慢性移植物抗宿主病发生率和复发率差异无显著性意义(P > 0.05)。但4组Ⅲ、Ⅳ度急性移植物抗宿主病发生率、2年无病生存率、2年总生存率差异有显著性意义(P < 0.05)。其中父供子移植组、母供女移植组的Ⅲ、Ⅳ度急性移植物抗宿主病发生率低于父供女移植组和母供子移植组;同时父供子移植组和母供女移植组的2年无病生存率、2年总生存率高于父供女移植组和母供子移植组。可见父母供子女单倍型造血干细胞移植是安全可行的,供受者性别相同比供受者性别不同的疗效好。     

异基因外周血干细胞移植后的心膈角髓肉瘤

背景：异基因造血干细胞移植是治愈白血病的主要方法,但经过异基因造血干细胞移植的患者仍面临着复发的风险,髓肉瘤为一种罕见的髓外复发方式,且临床疗效差,因此了解髓肉瘤的特点及治疗方法十分必要。 目的：分析异基因外周血干细胞移植后髓肉瘤的临床特点及治疗方法。 方法：异基因外周血干细胞移植后并发心膈角髓肉瘤患者1例,先后予手术切除肿块、化疗、放疗等联合方法治疗,观察临床疗效及相关并发症和生存情况。 结果与结论：患者在2个疗程的化疗过程中出现了败血症、真菌性肺炎及感染性休克等并发症,之后接受了纵隔放疗,髓肉瘤未再复发。无病生存25个月后出现中枢神经系统白血病。造血干细胞移植后髓肉瘤罕见且临床表现多变,主要依靠病理组织学和免疫组化检查确诊。可采用手术、化疗、放疗、二次移植和分子靶向治疗等方法,但个体化的治疗方案仍需进一步探讨。     

清肿瘤性异基因造血干细胞移植

标准的清髓性异基因造血干细胞移植(allo-HSCT)对于需代替治疗的造血与免疫系统的非恶性疾病,应当是合理或足够的;然而,对于恶性血液病患者,清除患者骨髓造血组织,成功重建异体正常造血与免疫系统,并不一定能完全治愈恶性血液病,因为白血病(干)细胞并非只限骨髓中存在,它可浸润骨髓之外的其他任何组织。临床实践证实,allo-HSCT后仍然有30%左右的患者疾病复发,特别是具有高危因素或难治复发患者复发率可高达40%～70%以上。这些复发的白血病细胞几乎全系源自患者移植前本身的白血病细胞,其中半数患者以髓外部位复发开始,有证据提示,清髓性移植并没有完全杀灭患者体内的白血病细胞,特别是那些对化放疗不敏感或栖居在髓外"庇护所"中的白血病干细胞,最终导致疾病复发。因此笔者提出并建立了一个清肿瘤性异体造血干细胞移植(TAHSCT)的概念,在临床上对其进行了初步的探讨。其内容贯穿于移植技术全过程的各个环节,但主要为应用个体化清肿瘤性预处理方案和加强移植后免疫治疗。     

HLA相合同胞异基因外周血造血干细胞移植治疗急性白血病

背景：HLA相合同胞间异基因外周血造血干细胞移植是治疗急性白血病的一种有效方法。 目的：评价HLA相合异基因外周血造血干细胞移植治疗急性白血病的临床疗效及并发症。 方法：25例急性白血病患者接受HLA相合同胞的异基因外周血造血干细胞移植,其中急性髓系白血病20例,急性淋巴细胞白血病5例。预处理方案为BU+CY方案或CY+TBI方案,移植物抗宿主病预防采用环孢素A+吗替麦考酚酯+短程甲氨蝶呤。 结果：最短随访2个月,最长随访80个月。患者均获造血重建,中性粒细胞≥0.5×10⁹ L^-1的时间为10~18 d,血小板≥20× 10⁹ L^-1的时间为10~37 d。主要并发症：感染败血症12例,巨细胞病毒感染9例,带状疱疹病毒感染3例,发生急性移植物抗宿主病10例,慢性移植物抗宿主病11例,出血性膀胱炎4例。至随访结束,17例无病生存,8例死亡。提示HLA相合同胞异基因外周血造血干细胞移植是治疗急性白血病安全有效的方法。     

急性淋巴细胞白血病应用同胞全相合造血干细胞移植治疗的价值研究

目的:分析同胞全相合造血干细胞移植治疗急性淋巴细胞白血病的临床疗效.方法:选取我院2017年7月至2019年12月收治的82例急性淋巴细胞白血病患者,根据移植类型分为同胞全相合造血干细胞移植研究组和单倍体造血干细胞移植对照组,均41例,对比造血功能重建、并发症、预后情况等.结果:研究组中性粒细胞植入时间短于对照组,并发症低于对照组,总体生存率高于对照组,均有统计学差异(P<0.05).结论:同胞全相合造血干细胞移植是治疗急性淋巴细胞白血病的有效手段,可加速中性粒细胞植入,提高预后生存率.     

单倍体相合异基因造血干细胞移植治疗白血病

背景：对于无HLA全相合同胞供者的患者,采用单倍体相合造血干细胞移植面临移植物抗宿主病重、移植相关死亡率高的风险,但通过不同的移植模式,将有可能获取相近的疗效。 目的：观察亲缘HLA单倍体相合异基因造血干细胞移植治疗白血病的疗效,并与亲缘HLA全相合异基因造血干细胞移植相比较。 方法：45例白血病患者分为2组。单倍体组移植方式为外周血或联合骨髓干细胞移植,预处理方案为改良白消安与环磷酰胺或加抗胸腺细胞球蛋白,移植物抗宿主病的预防采用环孢素A+甲氨蝶呤+霉酚酸脂;全相合组移植方式为外周血干细胞移植,预处理方案为BuCY,移植物抗宿主病的预防采用环孢素A+甲氨蝶呤。 结果与结论：两组均获得造血重建时间差异无显著性意义。单倍体及全相合组急性移植物抗宿主病的累积发病率分别为73%对52%(P > 0.05);慢性移植物抗宿主病的累积发病率分别为56%对45%(P > 0.05);移植相关死亡率分别为36%对17%(P > 0.05);单倍体组无复发,全相合组复发2例;两组的预计3年累积无病生存率分别为61%对60%(P > 0.05)。结果提示,亲缘单倍体异基因造血干细胞移植的总体疗效与亲缘全相合异基因造血干细胞移植相似,但中重度急性移植物抗宿主病的发生率较后者为高。     

地西他滨联合造血干细胞移植治疗骨髓增生异常综合征转化急性白血病

背景：由骨髓增生异常综合征转化的急性白血病为难治白血病,临床疗效差,缓解率低,生存期短,因此探索新的有效治疗方法极为重要。 目的：观察地西他滨联合造血干细胞移植治疗骨髓增生异常综合征转化急性白血病的临床疗效及并发症。 方法：骨髓增生异常综合征转化的急性髓细胞白血病患者1例,先后予2个疗程地西他滨及异基因造血干细胞移植,观察临床疗效、地西他滨的毒副作用及移植相关并发症。 结果与结论：经2个疗程地西他滨治疗后,达到完全缓解,主要不良反应为骨髓抑制并发感染,该患者再接受异基因造血干细胞移植后获得无病生存213 d,移植过程中出现急性移植物抗宿主病及肺部感染。结果提示地西他滨联合造血干细胞移植治疗骨髓增生异常综合征转化急性白血病获得良好效果,毒副作用及相关并发症可控制,为临床上骨髓增生异常综合征转化急性白血病的治疗提供了新方法。     

Autologous stem cell transplantation for acute myeloid leukemia in first remission.

We studied the feasibility, toxicity, and efficacy of a 2-step approach to autologous stem cell transplantation for patients with acute myeloid leukemia in first remission. Step 1 consisted of consolidation chemotherapy including cytarabine 2000 mg/m2 twice daily for 4 days concurrent with etoposide 40 mg/kg by continuous infusion over 4 days. During the recovery from this chemotherapy, peripheral blood stem cells were collected under granulocyte colony-stimulating factor stimulation. Step 2, autologous stem cell transplantation, involved the preparative regimen of busulfan 16 mg/kg followed by etoposide 60 mg/kg and reinfusion of unpurged peripheral blood stem cells. A total of 128 patients were treated. During step 1, there was 1 treatment-related death. A median CD34+ cell dose of 14 (x10(6)/kg) was collected in 3 aphereses. Ten patients suffered relapse before transplantation, and 117 patients (91%) proceeded to transplantation. During step 2, there were 2 treatment-related deaths, and 35 patients subsequently suffered relapse. With median follow-up of 30 months, 5-year disease-free survival for all patients entered in the study is projected to be 55%. By cytogenetic risk group, 5-year disease-free survival is 73% for favorable-risk patients, 51% for intermediate-risk patients, and 0% for poor-risk patients. We conclude that this 2-step approach to autologous transplantation produces excellent stem cell yields and allows a high percentage of patients to receive the intended therapy. Preliminary efficacy analysis is very encouraging, with outcomes that appear superior to those of conventional chemotherapy.     

New strategies in the treatment of acute myelogenous leukemia: mobilization and transplantation of autologous peripheral blood stem cells in adult patients

During the last decade high-dose Ara-C (HIDAC; single doses of 3 g/m(2)) and autologous stem cell transplantation have been increasingly used as postremission therapy in adult acute myelogenous leukemia (AML). Controlled clinical trials have demonstrated a long-term disease-free survival of 40%-50% for patients treated with at least two courses of HIDAC. Other studies have demonstrated that postremission autologous bone marrow transplantation results in a disease-free survival equal to or better than conventional chemotherapy. However, autotransplantation with mobilized peripheral blood stem cells (PBSC) would now be preferred instead of autologous bone marrow, due to the shorter hematopoietic reconstitution period. The results reviewed in the present article suggest that HIDAC and autologous PBSC transplantation can be combined in the postremission treatment of adult AML, and this combination therapy may also reduce minimal residual disease and the risk of posttransplant relapse. From the available studies it cannot be concluded whether graft purging further reduces the relapse risk. However, the possible advantage of combination therapy with repeated courses of HIDAC and autologous PBSC transplantation needs to be demonstrated in prospective clinical trials before it can be recommended as a part of the routine treatment in AML.     

The problem of thrombocytopenia after hematopoietic stem cell transplantation

Thrombocytopenia after hematopoietic stem cell transplantation (HSCT) is associated with an increased risk of bleeding and utilization of significant resources. This review presents an analysis of risk factors associated with delayed platelet engraftment. The retrospective analysis included 1,468 recipients of autologous or allogeneic transplants treated between January 1, 1990 and July 1, 1995. Risk factors associated with delayed platelet engraftment after autologous HSCT included use of marrow rather than peripheral blood as the source of stem cells, being transplanted for acute myeloid leukemia rather than other diseases, positive patient serology for cytomegalovirus and the presence of infection post-transplant before engraftment. Risk factors associated with delayed platelet engraftment after allogeneic marrow transplantation included unrelated as opposed to related donor transplants, being transplanted for diseases other than chronic myelogenous leukemia, increased age, onset of acute graft-versus-host disease (AGVHD), male gender, the administration of methotrexate for GVHD prophylaxis and the presence of infection before engraftment. Delayed platelet recovery is associated with decreased survival after both autologous and allogeneic transplants. Management of delayed platelet recovery by transfusion of blood products requires significant medical resources and is of some risk to the patients. Further development of new strategies may safely reduce the need for blood products. These include peripheral blood stem cell transplants (allogeneic and autologous), new algorithms for administering routine platelet transfusions and investigative biological agents for stimulating megakaryocytopoiesis. Further studies may elucidate the cause of increased platelet consumption associated with infection and GVHD.     

Long-term outcome of autologous transplantation of peripheral blood progenitor cells as postremission management of patients > or =60 years with acute myelogenous leukemia.

The optimal postremission treatment for elderly patients with acute myelogenous leukemia (AML) is presently unknown, but recent studies report the feasibility of autologous stem cell transplantation in this population. To better understand the long-term outcome of autologous transplantation in AML patients > or =60 years of age, we evaluated high-dose chemoradiotherapy preparative conditioning followed by transplantation of peripheral blood progenitor cells procured after a single cycle of cytarabine-based consolidation chemotherapy as postremission therapy in 27 patients aged 60 to 71 years (median age, 65 years) with newly diagnosed AML in first complete remission (CR). The median follow-up from CR for all patients was 13.6 months (range, 6.0-123.1 months). The median follow-up from remission for surviving patients was 81 months (range, 41.4-123.1 months). Seven patients are alive in continuous CR, 19 died from relapse, and 1 died as a result of treatment-related infection. Leukemia-free survival and overall survival are 10.3 and 13.4 months, respectively. Actuarial leukemia-free and overall survival at 3 years are 25% +/- 9% and 28% +/- 9%, respectively. Our results demonstrate that autologous transplantation of peripheral blood progenitor cells is well tolerated and feasible for patients > or =60 years of age with AML in first CR. Future investigation should focus on a randomized study evaluating a larger group of elderly patients in first CR comparing autologous stem cell transplantation with conventional cytarabine-based consolidation chemotherapy to identify the optimal postremission therapy.     

Use of fluorescence in situ hybridization to detect minimal residual disease in hematopoietic stem cell assays from peripheral blood stem cells of 2 patients with trisomy 8 acute myeloid leukemia

Fluorescence in situ hybridization (FISH) was used to analyze peripheral blood stem cells (PBSC) and stem cell assays (SCA) derived from them in 2 patients with acute myeloid leukemia (AML) with trisomy 8 as the sole chromosome abnormality prior to undergoing autologous stem cell transplantation. In both cases, the demonstration of cells containing trisomy 8 in the stem cell product led to significant changes in the patients' treatment. In the initial PBSC collections from each patient, trisomy 8 was found in aspirated granulocyte-monocyte (GM) colonies or aspirated GM clusters but not entire cell populations of SCA dish or uncultured PBSC (one patient). FISH analyses for specific cytogenetic abnormalities in hematopoietic stem cell cultures may be a more useful means of assessing the quality of the stem cell product in patients being considered for autologous stem cell transplantation.     

单倍体相合造血干细胞移植治疗高危白血病

背景：异基因造血干细胞移植是治疗高危白血病的主要方法,单倍体相合的造血干细胞移植扩展了移植的应用范围。 目的：观察“改良Bu/Cy+ATG”为预处理方案的单倍体相合造血干细胞移植治疗高危白血病的疗效。 方法：对19例高危白血病患者,均采用“改良Bu/Cy+ATG”预处理方案,采用外周血造血干细胞移植5例,外周血+骨髓造血干细胞移植14例。应用甲氨蝶呤,环孢素A,吗替麦考酚酯预防移植物抗宿主病。 结果与结论：①短期疗效：中性粒细胞恢复的中位时间为12(8~20) d;血小板恢复的中位时间为13(10~31) d;移植后100 d内,移植相关死亡率为(15.8±8.4)%。②移植物抗宿主病发生情况：Ⅰ~Ⅳ度急性移植物抗宿主病总发生率(63.1±11.1)%,慢性移植物抗宿主病发生率(54.54±15.0)%。③远期疗效：2年无病生存率为(28.2±15.5)%,2年总体生存率为(46.9±16.5)%。结果提示,高危白血病无人类白细胞抗原相合血缘供者及无人类白细胞抗原相合非血缘供者,而又急需进行挽救性移植时,“改良Bu/Cy+ATG”为预处理方案的单倍体相合造血干细胞移植是一种可行的选择。     

异基因骨髓联合外周干细胞移植术治疗白血病12例

目的探讨异基因骨髓联合外周干细胞移植术在白血病治疗中的应用，评价其疗效和安全性。方法12例白血病患者接受异基因骨髓联合外周干细胞移植，其中急性白血病8例，慢性白血病4例，供者均为同胞HIA配型全相合，预处理方案采用“改良BU／CY2”，分两天采集外周干细胞及骨髓不做任何处理输注。移植后观察预处理毒副作用、移植相关并发症、植入情况、生存情况，并与同期白血病患者（单用化疗治疗）生存情况对比。最长随访时间25月。结果12例患者中1例早期死于肝静脉阻塞综合征，11例植入顺利并存活至今，生存率明显高于化疗组。1例发生Ⅰ度aGVHD，2例发生局限性cGVHD，发生时间分别为＋150d、＋130d发生肝静脉阻塞综合征1例，发生时间为＋10d。毒副作用主要为恶心、呕吐、肝肾功能损伤。结论异基因骨髓联合外周干细胞移植术安全有效、并发症少，值得推广。     

流式细胞仪检测急性婴幼儿白血病干细胞

背景：有关儿童急性髓细胞性白血病干细胞含量的测定及急性髓细胞性白血病患儿缓解后白血病干细胞含量与急性白血病微小残留病之间关系的研究国内外未见报道。 目的：通过测定急性髓细胞性白血病干细胞或急性髓细胞性白血病干细胞-IPIC在儿童急性白血病患儿骨髓单个核细胞中的含量,研究急性髓细胞性白血病患儿缓解后白血病干细胞含量与急性白血病微小残留病水平之间的关联。 方法：收集白血病患儿113例次。采用骨髓单个核细胞分离及单细胞悬液制成单细胞悬液,进行单个核细胞染色、急性髓细胞性白血病干细胞分析及根据初诊免疫表型获得白血病相关表型,并采用该白血病相关免疫表型进行单抗组合和流式细胞术测定分析。 结果与结论：①初诊急性髓细胞性白血病组骨髓单个核细胞中急性髓细胞性白血病干细胞含量明显高于初诊急性淋巴细胞性白血病组和非肿瘤对照组(P均< 0.017),初诊急性淋巴细胞性白血病组骨髓单个核细胞中急性髓细胞性白血病干细胞-IPIC含量显著高于非肿瘤对照组(P < 0.017)。②对33例次缓解急性髓细胞性白血病患儿急性髓细胞性白血病干细胞和急性白血病微小残留病相关性分析发现,两者存在显著负相关性。结果提示,①急性髓细胞性白血病干细胞-IPIC也存在于初诊急性淋巴细胞性白血病患儿骨髓细胞中,且当急性淋巴细胞性白血病获完全缓解时急性髓细胞性白血病干细胞-IPIC含量却没有下降,但非肿瘤对照组标本中急性髓细胞性白血病干细胞-IPIC的含量极微。②急性髓细胞性白血病患儿缓解后骨髓中急性髓细胞性白血病干细胞含量和急性白血病微小残留病水平之间存在着明显的负相关。     

Transplantation of haploidentically mismatched stem cells for the treatment of malignant diseases

Hematopoietic stem cell transplantation (HSCT) from HLA haploidentical mismatched donors has recently been developed for patients with high-risk acute leukemia who do not have a matched donor. After a high intensity conditioning regimen the HLA barrier is overcome by infusing a graft containing a megadose of T cell-depleted progenitor cells. Nowadays, for graft processing automated peripheral blood CD34⁺ cell immunoselection is time and labor saving and ensures a high CD34⁺ cell recovery rate. Besides providing 4.5 log T cell depletion of the graft, it guarantees a 3.5 log B cell depletion, which helps prevent EBV-related lymphoproliferative disorders. Excellent engraftment rates are associated with a very low incidence of graft-versus-host disease and regimen-related mortality even in patients who are over 40 years old. Overall, event-free survival and transplant-related mortality compare favorably with reports from unrelated matched transplants. Donor natural killer cell alloreactivity also plays a role in improving outcome in patients with acute myeloid leukemia. These results show the haploidentical transplant to be a viable, alternative source of stem cells for adults with acute leukemia at high-risk of relapse who do not have matched donors, and encourage extending it to patients with an indication to transplant.