移植物抗宿主病对26例血液肿瘤患者异基因造血干细胞移植后长期生存的影响

背景与目的:移植物抗宿主病(graft-versus-hostdisease,GVHD)是异基因造血干细胞移植的一个主要并发症,亦是影响移植结果的重要因素。一些研究显示,不管是急性GVHD或慢性GVHD,都伴随有较强的移植物抗白血病(graft-versus-leukemia,GVL)作用,这种正向效应与降低异基因造血干细胞移植后白血病复发率及延长受者无病生存密切相关。本研究探讨GVHD的发生及其对异基因造血干细胞移植结果的影响。方法:回顾分析1995年3月至2005年10月26例血液肿瘤患者接受异基因造血干细胞移植术后GVHD的发生、肿瘤复发及生存情况,分析GVHD与血液肿瘤复发率、生存率的关系。结果:异基因造血干细胞移植后中位随访时间为20个月(2～127个月),20例患者术后发生GVHD(76.9%),其中1例受者复发(1/20),6例未出现GVHD的受者3例复发(3/6),两组复发率比较差异有显著性(P<0.05);移植后无病生存16例,死亡10例,Kaplan-Meier生存曲线示3年无病生存率为60%;发生GVHD的受者其无病生存率(15/20)较无GVHD受者(1/6)高(log-rank=7.30,P<0.05),发生GVHD时移植患者发生死亡的风险明显下降(RR值为0.20,P<0.05)。20例发生GVHD的受者,经治疗17例达完全缓解(completeresponse,CR),3例未达CR。17例CR受者中,无病生存15例;而未达CR的3例受者则无一例生存,两组生存率比较差异有显著性(P<0.05)。结论:GVHD是影响异基因造血干细胞移植结果的重要因素。GVHD治疗效果与移植受者无病生存密切相关,早期识别急性GVHD并予及时处理是治疗成功的关键。     

The Highest Leukaemia-Free Survival After Allogeneic Bone Marrow Transplantation is Seen in Patients with Grade I Acute Graft-Versus-Host Disease

The purpose of the present study was to evaluate the relation between the grade of acute graft-versus-host disease (GVHD) and several outcome parameters. Special attention was given to leukaemia-free survival (LFS). The study included 2,122 patients with acute leukaemia in first remission and 780 patients with chronic myeloid leukaemia (CML) in the first chronic phase, who were receiving first transplants from HLA-identical donors. Transplant-related mortality (TRM) was the same in patients with or without grade I acute GVHD, but was increased in patients with grades II, III and IV acute GVHD. In patients with grades 0, I, II, III and IV acute GVHD, the five-year probability of TRM overall was 20 1%, 19 2%, 30 2%, 61 4% and 90 3%, respectively. The incidence of relapse in patients with grades I-IV was lower than in patients without acute GVHD. The five-year relapse probability according to GVHD grade (0-IV), was 28 2%, 22 2%, 22 2%, 17 5% and 20 2%. The five-year LFS in all patients with leukaemia, according to grade of acute GVHD, was 57 2%, 63 2%, 55 3%, 32 4% and 8 3%. In multivariate analysis, adjustments for age, sex, diagnosis, interval from diagnosis to transplantation, T-cell depletion and year of transplantation were considered. Patients with grade I acute GVHD had the highest LFS (relative risk 0.84, p = 0.04 compared with those without acute GVHD).     

Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning.

PURPOSE: We have used a nonmyeloablative conditioning regimen consisting of total-body irradiation (2 Gy) with or without fludarabine (30 mg/m(2)/d for 3 days) for related and unrelated hematopoietic cell transplantation (HCT) in patients with hematologic malignancies who were not candidates for conventional HCT because of age, medical comorbidities, or preceding high-dose HCT. This approach relied on graft-versus-tumor (GVT) effects for control of malignancy. PATIENTS AND METHODS: We analyzed GVT effects in 322 patients given grafts from HLA-matched related (n = 192) or unrelated donors (n = 130). RESULTS: Of the 221 patients with measurable disease at HCT, 126 (57%) achieved complete (n = 98) or partial (n = 28) remissions. In multivariate analysis, there was a higher probability trend of achieving complete remissions in patients with chronic extensive graft-versus-host disease (GVHD; P = .07). One hundred eight patients (34%) relapsed or progressed. In multivariate analysis, achievement of full donor chimerism was associated with a decreased risk of relapse or progression (P = .002). Grade 2 to 4 acute GVHD had no significant impact on the risk of relapse or progression but was associated with increased risk of nonrelapse mortality and decreased probability of progression-free survival (PFS). Conversely, extensive chronic GVHD was associated with decreased risk of relapse or progression (P = .006) and increased probability of PFS (P = .003). CONCLUSION: New approaches aimed at reducing the incidence of grade 2 to 4 acute GVHD might improve survival after allogeneic HCT after nonmyeloablative conditioning.     

Induction of graft-versus-leukemia to prevent relapse after partially lymphocyte-depleted allogeneic bone marrow transplantation by pre-emptive donor leukocyte infusions.

In this prospective study we analyzed pre-emptive donor leukocyte infusions (DLI) in 82 consecutive patients transplanted with partially T cell-depleted grafts for acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, refractory anemia with excess of blasts, refractory anemia with excess of blasts in transformation and multiple myeloma. Donors were HLA-identical siblings. Patients without significant acute (>grade 1) and/or chronic GVHD were scheduled to be treated with DLI (35 patients) and 31 actually received DLI. Patients who developed acute GVHD >grade 1 and/or chronic GVHD were not scheduled to receive DLI and served as a comparison group (47 patients). The median interval between BMT and DLI was 22 weeks. The first six patients received 0.7 x 10(8) CD3+ cells/kg body weight (b.w.). Five out of these six patients developed acute GVHD (grade 1: n = 2, grade 3: n = 2 and grade 4: n= 1) which was more frequent and more severe than we had anticipated. In the next 25 patients the number of T lymphocytes was diminished to 0.1 x 10(8) CD3+ cells/kg b.w. which resulted in less frequent and less severe GVHD. Eight patients in this group developed acute GVHD (grade 1: n = 4, grade 2: n = 4) and three patients had limited chronic GVHD. Patients in the DLI group needed more time to establish complete donor chimerism confirmed by a higher number of mixed chimeras at 6 months after BMT. The projected 3-year probability of disease-free survival was 77% for the 35 patients intended to treat with DLI and 45% for the patients of the comparison group (P = 0.024). Relapse rate at 36 months after transplantation was 18% in the patients who were intended to treat with DLI and 44% in the comparison group (P = 0.026). We conclude that pre-emptive DLI is feasible and generates favorable relapse rates in patients who are at high risk for relapse. Furthermore, the incidence and severity of GVHD disease after DLI is dependent on the number of CD3+ cells infused.     

OMISSION OF DAY ＋11 METHOTREXATE DOES NOT APPEAR TO INFLUENCE INCIDENCE AND SEVERITY OF GRAFT-VERSUSHOST DISEASE AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION

Objective: To explore the influence of omission of the day 11 dose of methotrexate (MIX) on the incidence and severity of graft-versus-host disease(GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: From April 1997 to October 2002, 80 leukemia patients (46 men and 34 women aged from 12 to 56 years with a median age of 35) underwent allo-HSCT at our BMT unit. Among them, 58 patients received grafts from HLA-identical siblings, 8 from HLA one major antigen mismatched siblings and 14 from HLA-matched unrelated donors.All patients received a modified cyclosporine and short-course MTX regimen for GVHD prophylaxis,which included MTX 15 mg on day 1, and 10 mg on days 3 and 6 (MTX day 11 dose omitted) and cyclosporine given daily. Results: The overall incidence of grade Ⅰ-Ⅳ acute GVHD was 57.5% (46/80 patients), with grade Ⅱ-Ⅳ acute GVHD in 28 patients(35%) and grade Ⅲ-Ⅳ acute GVHD in 7 patients(8.8%). Among 58 patients receiving grafts from HLA-identical siblings, 24 patients developed grade Ⅰ-Ⅳ acute GVHD (41.4%), with grade Ⅱ-Ⅳ acute GVHD in 13 patients (22.4%) and grade Ⅲ-Ⅳ acute GVHD in 4 patients (6.9%). 21 out of 22 patients receiving grafts from HLA one major antigen mismatched siblings and HLA-matched unrelated donors developed grade Ⅰ-Ⅳ acute GVHD (95.5%),with grade Ⅱ-Ⅳ acute GVHD in 14 patients (63.6%)and grade Ⅲ-Ⅳ acute GVHD in 3 patients (13.6%).Chronic GVHD occurred in 38 out of 56 evaluable patients (67.9%), with extensive form in 15 patients(26.8%) and limited form in 23 patients (41.1%). With a median follow-up of 960 days (range 180-1980 days), the probability of leukemia-free survival at 3 years was 61.3% for all patients. Conclusion: Our results suggest that the day 11 MTX can be omitted without a major deleterious effect on the incidence and severity of graft-versus-host disease after HLA-identical sibling transplantation as well as HLA one major antigen mismatched sibling and HLA-matched unrelated donor transplantation.     

Allogeneic stem-cell transplantation with fludarabine and 2-Gy TBI-based conditioning regimen for chronic hematological malignancy: a study of 25 consecutive patients and a literature review

We analyzed the outcome of 25 consecutive patients with chronic hematological malignancy who underwent allogeneic stem-cell transplantation conditioned with fludarabine (30 mg/m2/day, thrice) and total body irradiation (2 Gy). All patients received peripheral blood stem cells from an HLA-identical sibling donor. With a median follow-up of 769 days (range, 244 - 1231), the estimated 2-year overall survival (OS), event-free survival (EFS), transplantation-related mortality and relapse rates were 53%, 45%, 27%, and 39%, respectively. All patients had initial engraftment. Acute Grade II - IV graft-versus-host disease (GVHD) was recorded in 14 patients (56%), including 7 (28%) with Grade III - IV GVHD. Sixteen of the 23 patients (70%) who survived more than 100 days developed chronic GVHD. OS and EFS were adversely influenced by acute Grade III - IV GVHD (p < 0.001 and p = 0.033, respectively), but chronic GVHD seemed to favorably influence these two parameters (p = 0.03 and p < 0.001, respectively). Patients with full-donor chimerism at day 30 had lower relapse rates, as did those who received high-dose allogeneic CD8+ lymphocytes with their graft (p = 0.026). Collectively, these results provide a framework for refining nonmyeloablative conditioning, to improve outcome with an acceptable risk of GVHD.     

Reduced intensity allogeneic hematopoietic stem cell transplantation for MDS using tacrolimus/sirolimus-based GVHD prophylaxis

We report a consecutive series of 59 patients with MDS who underwent reduced-intensity hematopoietic stem cell transplantation (RI-HSCT) with fludarabine/melphalan conditioning and tacrolimus/sirolimus-based GVHD prophylaxis. Two-year OS, EFS, and relapse incidences were 75.1%, 65.2%, and 20.9%, respectively. The cumulative incidence of non-relapse mortality at 100 days, 1 year, and 2 years was 3.4%, 8.5%, and 10.5%, respectively. The incidence of grade II-IV acute GVHD was 35.4%; grade III-IV was 18.6%. Forty of 55 evaluable patients developed chronic GVHD; of these 35 were extensive grade. This RI-HSCT protocol produces encouraging outcomes in MDS patients, and tacrolimus/sirolimus-based GVHD prophylaxis may contribute to that promising result.     

Combination of low-dose mycophenolate mofetil with cyclosporine and methotrexate as GVHD prophylaxis in unrelated donor allogeneic stem cell transplantation

We report the results of HLA-matched unrelated donor allogeneic stem cell transplantation with new GVHD prophylaxis regimen consisted of cyclosporine, methotrexate and low-dose mycophenolate mofetil in 139 patients with hematologic malignancies. The incidence of grades II–IV and III–IV acute GVHD were 43.0% and 17.3%, respectively. The incidence of chronic GVHD was 42.1%, with 16.5% extensive grade. The cumulative incidence of transplant-related mortality at 100 days and 3 years were 7.9% and 29.7%, respectively. Three-year overall survival, disease-free survival and relapse incidence were 58.7%, 55.3% and 19.6%, respectively. These results suggest the new regime may be effective for the prophylaxis of acute and chronic GVHD in unrelated donor transplantation.     

含氟达拉滨的预处理行异基因造血干细胞移植治疗恶性血液病的远期疗效

目的：观察含氟达拉滨的预处理方案进行异基因造血干细胞移植治疗恶性血液病的长期疗效。方法：选取2003年2 月至2004年12月间厦门大学附属中山医院收治的15例恶性血液病患者,其中急性髓性白血病3 例,急性淋巴细胞白血病5 例,慢性粒细胞白血病6 例,骨髓增生异常综合症（RAEB）1 例。供受者HLA 配型同胞全相合6 例,同胞或亲缘不相合8 例,非亲缘全相合1 例。预处理方案采用氟达拉滨（Flu 30mg/m2·d,共5d）、马利兰（BU4mg/kg·d,共2～3d）、环磷酰胺（CTX 50mg/kg·d,共2d）,其中8 例加用阿糖胞苷（Ara-c 1.0～2.0g/m2·d,共2d）,9 例HLA 不全相合及非血缘移植者加用兔抗胸腺细胞球蛋白（ATG 3.0～5.0mg/kg·d,共3d）。 预防移植物抗宿主病（GVHD）均采用骁悉（MMF）+ 环孢素（CsA）+ 短程甲氨喋呤（MTX）方案。利用SPSS11.5 统计软件及Kaplan-Meier 方法进行生存分析。结果：15例患者移植后均获得快速完全的植入,无严重的预处理相关毒性。46.7% 发生急性GVHD ,85.7% 发生慢性GVHD ;带状疱疹7.1% 。5 年总生存率为53.5% ,其中移植时处于第一次完全缓解（CR1）和慢性期患者11例,5 年生存率为72.7% ,复发率9.1% ,移植时处于第二次完全缓解（CR2）、复发、加速期及急变期的患者4 例,2 年生存率为0,复发率75,两者有统计学差异（P=0.000 3 和P<0.05）,主要死亡原因为疾病复发和GVHD 。结论：对于移植时处于CR1 和慢性期患者,采用含Flu并适当减低放化疗剂量的预处理方案是有效的移植预处理方案,毒副作用较少,未增加机会性感染,复发率较低;预处理中加入Flu对GVHD 发生率无明显影响。     

Long‐term follow‐up of haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for the treatment of leukemia

BACKGROUND:

Many patients who require allogeneic hematopoietic stem cell transplantation (allo‐HSCT) lack a human leukocyte antigen (HLA)‐matched donor. Recently, a new strategy was developed for HLA‐mismatched/haploidentical transplantation from family donors without in vitro T cell depletion (TCD).

METHODS:

Over the past 9 years, 756 patients underwent haploidentical transplantation using a protocol developed by the authors, which combines granulocyte‐colony stimulating factor–primed bone marrow (G‐BM) and peripheral blood stem cells without in vitro TCD. The long‐term outcome with this treatment modality was reported, and a risk‐factor analysis was provided.

RESULTS:

Of these patients, 752 (99%) achieved sustained, full donor chimerism. The incidence of grades 2 through 4 acute graft‐versus‐host disease (GVHD) was 43%, and the 2‐year cumulative incidence of total chronic GVHD was 53%. The 3‐year cumulative incidence of nonrelapse mortality was 18%. The 2‐year cumulative incidences of relapse were 15% and 26% in the standard‐risk and high‐risk groups, respectively. Of the 756 patients, 480 survived throughout the follow‐up period of 1154 days (range: 335‐3511 days) with the 3‐year leukemia‐free survival rates of 68% and 49% in the standard‐risk and high‐risk groups, respectively. Lower leukemia‐free survival was associated with high‐risk disease status (P = .001), chronic myelogenous leukemia disease type (P = .004), neutrophil engraftment beyond 13 days after transplant (P = .012), and the occurrence of grades 2 through 4 acute GVHD (P = .019).

CONCLUSIONS:

The results from the authors' 9‐year experience showed that G‐BM combined with peripheral blood stem cells from haploidentical donors, without in vitro TCD, is a reliable source of stem cells for transplantation by using the protocol developed by the authors. Cancer 2013. © 2012 American Cancer Society.     

Allogeneic bone marrow transplantation

The probability of long term survival for allogeneic graft patients was 63% for ALL, 60% for ANL and 47% for CML in the 1st remission or 1st chronic phase of each leukemia. The major causes of death were interstitial pneumonia, relapse of leukemia and infections. On relationship of GVHD and the long term survival, the probability of 5 years survival was 38%, 47% and 25% in grade 0, I and II-IV of acute GVHD respectively. The difference might be due to that of relapse rate of leukemia. And the relationship between the relapse rate and GVHD, the patients with both of acute and chronic GVHD showed the lowest relapse rate 15.9%, the patients without GVHD showed the highest relapse rate 37.8% and the patients with either of GVHD showed the rate of between those of two groups. This may suggest that GVHD both acute and chronic might have an ability that can suppress the relapse of leukemia, i.e. GVL reaction. Interstitial pneumonia occurred in 32% of allograft patients and was often lethal complication (53%). Among many of prophylaxis tested, the followings were effective, a lower dose rate of total body irradiation, the selection of CMV-seronegative platelets donor, and the prophylactic administration of anti-CMV high titer globulin. Colony stimulating factor of human urine was also effective for shortening the granulopenic period after transplantation to prevent severe infections.     

同胞间脐血移植治疗小儿急性淋巴细胞性白血病的时机选择与随访(附3例分析)

目的:同胞脐血具有组织相容性高,易获得HLA配型一致而不易被排斥的特点,本文报道同胞间脐血移植治疗3例小儿急性淋巴细胞性白血病的疗效并进行随访。方法:对3例急性淋巴细胞性白血病(2例高白细胞性高危CR1,1例标危并发中枢神经系统白血病CR2),进行了同胞间脐血移植,HLA高分辨2例全相合,1例5个位点相合。预处理选用白消安/环磷酰胺为主方案。于0d回输脐血,MNC数量为2.65×107/kg,2.23×107/kg,2.18×107/kg;CD34+细胞数量为1.92×107/kg,1.39×105/kg。预防移植物抗宿主病采用环孢霉素A、甲基泼尼松龙和甲氨蝶呤的方案。结果:中性粒细胞绝对值(ANC)≥0.5×109/L的天数分别是+13d、+24d、+20d,PLT≥20×109/L的时间为+19d、+46d、+21d,移植证据均为供者型。3例出现Ⅰ-Ⅱ度GVHD,均控制。随访中发生Ⅱ度慢性GVHD 1例,现长期存活2例,生活良好。结论:同胞间脐血移植是儿童高危白血病有效的治疗手段,急、慢性GVHD发生率较低,存在移植物抗白血病作用,更为安全可靠。     

Possible clinical benefits of the use of peripheral blood stem cells over bone marrow in the allogeneic transplantation setting for the treatment of childhood leukemia

BACKGROUND: The benefits of allogeneic peripheral blood stem/progenitor cell transplantation (PBSCT) over bone marrow transplantation (BMT), if any, have not been seriously evaluated in a pediatric population. We report here our experience with this procedure and demonstrate rapid engraftment to reduce procedure-related complications and enhanced allogeneic immune reaction to reduce leukemic relapse. METHODS: The feasibility of PBSCT was reviewed retrospectively. Four patients (2 AML and 2 ALL, aged 8-18 years) underwent allogeneic PBSCT for relapsed leukemia after primary allogeneic BMT (n = 2), for active hepatosplenic fungal abscess (n = 1) or for refractory relapse with conventional chemotherapy (n = 1). Four healthy donors (aged 10-49 years) received granulocyte colony-stimulating factor (G-CSF) 10 microg/kg/day by subcutaneous injection for 5 days. An individualized cytoreductive regimen was used before transplantation. RESULTS: No significant toxicities were observed in normal donors on G-CSF treatment or at collection of PBSC. After PBSCT, no significant acute toxicities were observed and the median duration to an absolute granulocyte count of 0.5 x 10(9)/l and a platelet count of 20 x 10(9)/l was 16 and 21 days, respectively. Although none of our patients developed acute graft-versus-host disease (GVHD), two developed chronic GVHD involving the liver and skin. Among those who developed chronic GVHD, one died of recurrent disease and another died of pneumonia 235 days after PBSCT. The two remaining patients have been alive without evidence of disease with follow-ups of 193 and 123 days, respectively. CONCLUSIONS: Allogeneic PBSCT can be a safe procedure in a pediatric population with fewer acute complications, although the potential risk of G-CSF treatment in normal donors should be seriously weighed against the existing risks of marrow aspiration under general anesthesia. The risk of chronic GVHD may need to be balanced against a possible graft-versus-leukemia benefit in patients at higher risk of leukemic relapse.     

异基因造血干细胞移植治疗急性T 淋巴细胞白血病和淋巴瘤：附50例临床报告

目的 探讨异基因造血干细胞移植（allogeneic hematopoietic stem cell transplantation,allo-HSCT）治疗急性T淋巴细胞白血病（T cell acute lymphoblastic leukemia,T-ALL）和急性T淋巴母细胞淋巴瘤（T cell acute lymphoblastic lymphoma, T-LBL）的疗效及预后。方法 回顾性分析2014—2019年于航天中心医院接受allo-HSCT的50例T-ALL/LBL患者的临床资料,分析其临床疗效、并发症及预后。结果 50例患者中男性41例,女性9例,中位年龄20.5岁（范围：9.0~63.0岁）;单倍体移植44例,脐血移植 2例,同胞全合移植 4例;T-ALL 40例,T-LBL 10例;移植前处于完全缓解（CR）状态16例,处于未完全缓解（非CR）状态34例。移植后,中位随访20个月（范围：1~84个月）,存活23例,死亡27例;移植后24个月的总生存率和无复发生存率分别为50.0%和44.0%,36个月的总生存率和无复发生存率分别为45.5%和40.0%。随访期间,共有20例患者复发,复发率为40.0%（20/50）。移植前获CR、无髓外病变、无中枢神经系统受累的患者预后较好,而移植前有无基因突变、不同预处理方案、有无急性/慢性GVHD患者的总生存期及无复发生存期组间比较差异无统计学意义（均P>0.05）。结论 在这项小样本、无对照的临床研究中,T-ALL/LBL患者在缓解期行allo-HSCT可能较挽救性移植的生存预后有所改善,其中复发为移植失败的主要原因。     

NIH-defined graft-versus-host disease and evidence for a potent graft-versus-leukemia effect in patients with acute lymphoblastic leukemia

BackgroundThe prognostic value of the NIH consensus criteria for graft-versus-host disease (GVHD) is not well defined yet.Patients and methodsWe analyzed NIH-defined GVHD in 147 acute lymphoblastic leukemia (ALL) patients.ResultsThe cumulative incidence of classic acute GVHD (aGVHD), late aGVHD and chronic GVHD (cGVHD) was 63%, 12% and 41%, respectively. cGVHD was subclassified as classic versus overlap syndrome in 40% versus 60% of cases. In multivariate Cox regression analysis with GVHD as time-dependent covariate, classic aGVHD grade III/IV had a negative impact on overall survival (OS) due to higher non-relapse mortality. cGVHD of any grade was associated with superior OS, which was due to lower relapse incidence. Classic cGVHD versus overlap syndrome had no differential impact. In 44 patients without GVHD after transplant who received donor lymphocyte infusions (DLI), the cumulative incidence of classic aGVHD, late aGVHD or cGVHD was 60%, 5% and 57%. Occurrence of cGVHD after DLI was associated with improved OS due to lower relapse incidence.ConclusionsThe NIH consensus criteria for GVHD clearly define prognostic subgroups in patients transplanted for ALL. The improved OS in patients developing cGVHD after transplant or DLI gives clear evidence for a potent graft-versus-leukemia effect in this indication.     

同胞间脐血移植治疗小儿急性淋巴细胞性白血病的时机选择与随访（附3例分析）

目的：同胞脐血具有组织相容性高,易获得HLA配型一致而不易被排斥的特点,本文报道同胞间脐血移植治疗3例小儿急性淋巴细胞性白血病的疗效并进行随访。方法：对3例急性淋巴细胞性白血病（2例高白细胞性高危CR1,1例标危并发中枢神经系统白血病CR2）,进行了同胞间脐血移植,HLA高分辨2例全相合,1例5个位点相合。预处理选用白消安/环磷酰胺为主方案。于0d回输脐血,MNC数量为2.65×107/kg,2.23×107/kg,2.18×107/kg;CD34＋细胞数量为1.92×107/kg,1.39×105/kg。预防移植物抗宿主病采用环孢霉素A、甲基泼尼松龙和甲氨蝶呤的方案。结果：中性粒细胞绝对值（ANC）≥0.5×109/L的天数分别是＋13d、＋24d、＋20d,PLT≥20×109/L的时间为＋19d、＋46d、＋21d,移植证据均为供者型。3例出现Ⅰ-Ⅱ度GVHD,均控制。随访中发生Ⅱ度慢性GVHD 1例,现长期存活2例,生活良好。结论：同胞间脐血移植是儿童高危白血病有效的治疗手段,急、慢性GVHD发生率较低,存在移植物抗白血病作用,更为安全可靠。     

Hematopoietic Stem Cell Transplantation for Patients with Chronic Myeloid Leukemia

OBJECTIVE To evaluate the effects of autologous and allogeneic hematopoietic stem cell transplantation (HSCT) for patients with chronic myeloid leukemia(CML).METHODS Fifty-seven patients with CML were treated by HSCT, including 8 cases treated with autologous transplantation purged in vivo and in vitro of minimal residual disease (MRD), 39 cases with related donor allogeneic HSCT (allo-HSCT) and 10 cases with unrelated donor alIo-HSCT. The conditioning regimen was a TBI (total-body irradiation) CY (cyclophosphamide, CTX) protocol in 32 patients, a modified BuCY (hydroxyurea, busulfan, Ara-C, CTX) protocal in 24 patients, and a MACC ( Melphalan, Ara-C, CTX and chlorethyl cyclohexyl nitrosourea ) protocol in one patient. Cyclosporine (CsA) and methotrexate (MTX) were used in patients with related-donor allo-HSCT, and CsA and MTX were added to mycophenolate mofetil (MMF) and antithymocyte globulin (ATG) in unrelated donor allo-HSCT for graft versus host disease (GVHD) prophylaxis. Otherwise, CsA was only used for GVHD prophylaxis in patients with accelerated phase (AP) and blast crisis (BC). The Kaplan-Meier survival analysis model was used to estimate the overall survival (OS) and the disease-free survival (DSF) at 5 years after transplantation.RESULTS Eight patients with autologous transplantation, except for 1 case who died of transplantation-related complications, obtained cytogenetic part or complete remission (CR) within 3 months after transplantation. One patient, who was in BC and obtained CR in hematology before transplantation, had been in molecular CR for 92 months after autologous transplantation. Among the 49 patients treated with alIo-HSCT, all obtained CR, except for one patient who died of hepatic veno-occlusive disease (VOD) and one who had not obtained CR. The incidence of infection and VOD was 33.3% and 7.0%, respectively, during transplantation. After transplantation the incidence of hemorrhagic cystitis (HC) and cytomegalovirus (CMV) interstitial pneumonia (IP) was 22.8% and 8.8%, respectively. VOD, HC and CMV IP did not occur in patients with autologous transplantation. The incidence of acute GVHD and the frequency of chronic GVHD was 41.0% and 48.6%, respectively, in patients with related and unrelated transplantation. The rate of relapse in patients with autologous and allogeneic transplantation was 57.1% and 12.8%, respectively. The DFS at 5 years after transplantation was 25.0% and 61.7%, respectively, in patients with autologous and related donor transplantation. The DFS at 5 years was 70.7% and 34.1%, respectively, in patients with CP (chronic phase) or AP and BC before transplantation.CONCLUSION AIIo-HSCT may have a higher clinical cure rate for CML patients with CP. The CsA MTX MMF ATG protocol is more effective for acute GVHD prophylaxis and can decrease the incidence and degree of GVHD in patients with unrelated donor transplantation, Autologous transplantation with purged bone marrow can prolong the survival time of CML patients and some may be cured with transplants of this type.     

Long-term follow-up of relapsed acute leukemia treated with immunotherapy after allogeneic transplantation: the inseparability of graft-versus-host disease and graft-versus-leukemia, and the problem of extramedullary relapse

Long-term outcome of 23 acute myeloid (AML, n=16) or lymphoblastic (ALL, n=7) leukemia patients who had received immunotherapy for treatment of persistent or recurrent disease 1.5-26 (median 4) months after allogeneic transplantation was studied to determine eventual survival. Immune manipulation comprised donor leukocyte infusion (n=18), interferon-alpha2b and/or interleukin-2 (n=15), and cyclosporine withdrawal (n=11) in various combinations. Graft-versus-host disease (GVHD) developed in 12 patients. Thirteen of 20 evaluable patients responded; 6 relapsing again. Eight patients died of toxicity, and 10 of progressive disease at 3-206 weeks (median 11). Five patients (3 AML, 2 ALL) are alive in remission with GVHD 2-46 months (median 23) after immunotherapy with Karnofsky scores of 70-100% (median 80). The overall survival of the whole group is 1-206 weeks (median 12), with an actuarial survival of 22% at 2 years. The development of GVHD was associated with superior survival in multivariate analysis (P=.007). Seven patients received immunosuppression because of the severity of GVHD (grade III/IV acute or extensive chronic): 3 died of GVHD, 3 improved but relapsed concomitantly, and 1 is alive in remission with extensive chronic GVHD. Four episodes of extramedullary relapse (granulocytic sarcomas) were seen in 3 patients with AML whose marrow remained in remission. We conclude that GVHD appears to be inseparable from graft-versus-leukemia in relapsed acute leukemia patients undergoing immunotherapy with a high proportion of patients dying due to toxicity or progressive disease, and isolated extramedullary relapse seems to be unusually common.     

Treatment of aplastic anemia

Survival of patients with aplastic anemia after immunosuppressive therapy with ATG/ALG ranges from 35% to 60%. However, long-term follow-up on these patients has indicated a high frequency of hematologic complications, including PNH, myelodysplasia, ANL, and recurrent aplasia. In contrast to immunosuppressive therapy, allogeneic marrow transplantation results in cure of aplasia. Problems initially limiting the success of HLA-matched allogeneic marrow transplants included graft rejection and complications associated with acute and chronic GVHD. Infusion of donor buffy coat cells along with marrow or alternatively more intensive immunosuppressive regimens containing irradiation have substantially decreased the risk of rejection. However, buffy coat infusion increases the incidence of chronic GVHD and irradiation treatment adds to toxicity of the conditioning regimen as well as producing long-term complications. The incidence and severity of acute GVHD have been significantly decreased by the use of MTX/CSP as GVHD prophylaxis; however, this regimen has had no impact on the incidence of chronic GVHD. Long-term survival in multiply transfused patients after HLA-identical marrow transplantation is on the order of 60% to 70%; survival in untransfused patients approximates 80%. Patients less than age 18 transplanted on protocols currently active in Seattle have greater than 90% survival. Further increases in survival must come from improvement in preventing and treating chronic GVHD. Patients diagnosed with aplastic anemia should have rapid HLA typing performed to identify possible marrow donors. Transfusions from prospective marrow donors should be avoided and the patient referred to a major treatment center. We continue to recommend allogeneic marrow transplantation for patients with severe aplastic anemia who are less than 40 years old and who have HLA-identical related donors. Immunosuppressive therapy should be tried first in patients without HLA-matched donors and for patients over the age of 40. HLA-mismatched marrow transplantation and use of unrelated marrow donors for severe aplastic anemia remain areas of active research.     

白血病患者造血干细胞移植前单次全身照射的预后分析

目的 回顾性分析单次全身照射(SFTBI)后行造血干细胞移植的白血病患者的预后及相关因素.方法 2008 年9月前7年半余共102例患者行SFrBI后移植.比较不同病理类型、移植方式及不同TBI参数组间生存率、复发率及间质性肺炎(IP)发生率差异,分析生存率、复发率和IP发生率的相关因素.结果 随访15～1482 d(中位值406 d).随访率为95.1%,随访满1、3年者分别为86、55例.1、3年生存率分别为59.0%、44.0%,单因素分析3年生存率有差异因素包括移植前有无复发(20%:55%,χ2=6.33,P=0.012)、移植方式(异基因比自体基因移植,39%:68%,χ2=8.06,P=0.005)、急性移植物抗宿主病(aGVHD)级别(≥3级比0～2级,0%:54%,χ2=7.52,P=0.006)、移植后有无复发(19%:58%,χ2=10.13,P=0.001)、有无IP(23%:58%,χ2=8.35,P=0.004).Cox模型多因素分析对生存有影响因素只有≥3级aGVHD(χ2=12.74,P=0.000).1、3年复发率分别为30.0%、50.0%,移植前已有过复发比无复发的复发率明显升高(47%:16%,χ2=7.32,P=0.007),Cox模型多因素分析显示移植前已有过复发对术后复发有影响(χ2=9.39,P=0.020).IP发生率为35.0%,全身剂量均匀度>3%和≤3%的分别为27%和4%(χ2=5.21,P=0.023),急性腮腺炎有和无的分别为34%和3%(χ2=14.15,P=0.000),异基因移植和自体移植的分别为31%和8%(χ2=7.70,P=0.006).Logistic多因素分析显示移植方式、急性腮腺炎及全身剂量均匀度对IP发生有影响(χ2=10.08、10.08、7.69,P=0.002、0.002、0.010).结论 ≥3级aGVHD患者3年生存率明显下降,全身剂量均匀性对IP发生有重要意义,异基因移植者更易发生IP,急性腮腺炎与IP明显相关,可能对预测IP发生有一定价值.