荧光原位杂交法检测造血干细胞移植后骨髓嵌合状态和微量残留病灶

目的 探讨荧光原位杂交（FISH）法在异基因造血干细胞移植（allo-HSCT）后检测供、受者骨髓嵌合状态和微量残留病灶（MRD）的作用。方法 2001年2月至2005年6月对83例患者进行allo-HSCT。对供者为异性的64例受者实施骨髓细胞性染色体着丝粒探针FISH法检测，评价供、受者骨髓嵌合状态及其动态改变；对供、受者性别相同而有特殊染色体异常的19例受者，应用相应的基因探针（BCR／ABL、AMIL1／ETO和MLL）对骨髓细胞行FISH法检测，评价微量残留病灶的发生。结果 64例异性allo-HSCT的受者中，50例供、受者骨髓嵌合度在99％以上；7例早期嵌合度偏低（96．2％～98．7％），在随访过程中逐渐上升至99％以上，移植后均未复发原病；另外7例嵌合度在随访过程中呈进行性下降，其中3例微量残留病灶在10％以上，均同时出现血液学复发；4例患者微量残留病灶在2％～5％之间，其中2例经快速停用免疫抑制剂后出现严重的移植物抗宿主病（GVHD）；1例在免疫抑制剂快速减量后骨髓嵌合度逐步上升至99．9％，目前仍处于完全缓解（CR）状态中；1例持续处于CR状态。19例供、受者性别相同的allo-HSCT受者中，16例移植后未检测到原来的异常核型；1例检测到10％的微量残留病灶，经免疫抑制剂减量4个月后降为1％，移植后1年仍在完全缓解中；2例分别在移植后1个月和4个月时出现原来的染色体异常。复查骨髓为原病复发，再次化疗未缓解。结论 应用FISH法检测allo-HSCT后骨髓嵌合状态和微量残留病灶，对判断植入、复发和指导早期干预性免疫治疗有重要意义。     

Myeloablative allogeneic hematopoietic stem cell transplantation in elderly patients

This study aimed to evaluate the outcome following myeloablative allogeneic hematopoietic stem cell transplantation (SCT) among patients older than 50 yr of age. A total of 215 patients with a median age of 57 yr underwent allogeneic hematopoietic SCT for early (41%) or advanced (59%) hematologic malignancies. After a median follow-up of 36 months a 10-yr survival estimate of 56 +/- 6% could be assessed for patients in early disease stages while patients with advanced diseases showed a significantly decreased survival probability of 31 +/- 5% (p < 0.0002). Transplant related mortality (TRM) at day 100 and 365 post-transplant was 13% and 30% for early but increased to 21% and 49% for advanced disease stages. As major determinants of TRM advanced disease stage (p < 0.0001) and occurrence of grades II-IV graft-vs.-host disease (GVHD) (p < 0.0001) were identified. These results show that hematopoietic SCT following myeloablative conditioning is also applicable to elderly patients whereas disease stage and high-grade GVHD represent the essential prognostic factors for outcome.     

Telemetric monitoring of pulmonary function after allogeneic hematopoietic stem cell transplantation

BACKGROUND: Late-onset noninfectious pulmonary complications (LONIPC) are both frequent and severe after allogeneic hematopoietic stem cell transplantation (HSCT). The high mortality rate (40-80%) may be related to delayed diagnosis. We assessed the use of telemetric home surveillance of pulmonary function for early diagnosis of LONIPC in transplant recipients. METHODS: This prospective study monitored pulmonary function in 37 allogeneic HSCT recipients. About 3 months after HSCT, they received a portable spirometer that measured forced vital capacity, forced expiratory volume per second, and midexpiratory flow 25-75 (MEF25-75). Data were transmitted twice weekly by telephone. Conventional plethysmography confirmed any significant deterioration (>20%). RESULTS: Thirteen episodes of spirometric deterioration were detected by telemetry in 11 patients during a median 17-month (4-41) follow-up period after transplantation. In these cases, examinations including spirometry, high-resolution thoracic computed tomography and bronchoalveolar lavage diagnosed LONIPC in eight episodes in seven patients (cumulative incidence 23.4%, SE 0.08, at month 24 after transplant): bronchiolitis obliterans (BO, n=3), interstitial pneumonia (IP, n=4), or both BO and IP (n=1). Five episodes improved and three were stabilized with increased immunosuppressive therapy. At the last follow-up, of the seven patients with LONIPC, one successfully stopped immunosuppressive therapy, two were receiving low-dose mycophenolate mofetil, and four were receiving low-dose corticosteroid therapy. There were no cases of respiratory failure and no patient died from LONIPC. CONCLUSION: Telemetric home monitoring of pulmonary function is a useful procedure for early diagnosis of LONIPC before clinical pulmonary symptoms and may improve outcome after allogeneic HSCT.     

Costs of allogeneic hematopoietic stem cell transplantation

BACKGROUND: This study aims to determine the total costs after allogeneic hematopoietic stem cell transplantation (ASCT) and factors associated with increases or decreases in costs. METHODS: We collected all in- and outpatient costs during 5 years in 93 patients who had undergone ASCT in 1998 and 1999 at our unit. The inpatient costs included all those related to a patient from the first day of admission until discharge and then all costs of readmission in the Stockholm area. RESULTS: The total median cost of five posttransplant years was 139,414 (52,095-345,640) euros (euros) or 167,296 US dollars (the rate of 1 euro is approximately 1.2 US dollars). The costs were highest during the first year-median inpatient and outpatient costs 100,650 euros and 13,066 euros, respectively. The total costs during the first year were higher in patients with acute graft-versus-host disease grades III-IV (relative hazards [RH] 1.35, P = 0.003), bacteremia (RH 1.33, P = 0.005), veno-occlusive disease of the liver (RH 1.32, P = 0.005), prophylaxis with granulocyte colony-stimulating factor (G-CSF; RH 1.31, P = 0.01), acute leukemia (RH 1.32, P = 0.008), and treatment in hospital instead of at home (RH 1.20, P < 0.07). During the early transplant period, a second transplantation (RH 1.28, P = 0.014) and hemorrhagic cystitis (HC; RH 1.24, P = 0.03) were also associated with higher costs. The total 5-year cost declined with longer survival rates (r = 0.4028, P < 0.001) and reduced intensity conditioning (RH 0.79, P=0.024). CONCLUSION: Higher costs of ASCT were associated with retransplantation, acute leukemia, G-CSF prophylaxis, hospital care, myeloablative conditioning, and major transplant-related complications.     

异基因造血干细胞移植患儿营养状况的纵向调查

目的了解异基因造血干细胞移植患儿营养状况的变化。方法分别于移植前、移植后30d、60d、100d对89例异基因造血干细胞移植患儿进行身高、体质量、体质指数(BMI)、三头肌皮褶厚度(TSF)、中上臂围(MUAC)、腰围(WC)等人体学测量,同时测量脂肪组织(FM)、体脂百分比(%BF)、去脂组织(FFM)及去脂组织百分比(%FFM)等人体成分,并进行生化指标白蛋白(ALB)、前白蛋白(PreALB)测量,比较异基因造血干细胞移植患儿营养状况的改变。结果人体学测量结果显示,在移植后100d内患儿体质量、BMI、TSF均呈现先降后升趋势,在移植后30d降至最低点,然后逐渐上升(P0.05,P0.01),WC在移植后100d内持续升高(P0.01);人体成分测量结果显示,%BF、FM在移植后60d内明显升高(均P0.05),%FFM在移植后60d内显著降低(P0.01);生化测量结果显示,ALB呈先升后降再上升的趋势,PreALB在移植后60d内显著上升(P0.01)。结论在异基因造血干细胞移植后30d内,多数人体学及人体成分测量指标下降;而在移植后60d则存在FFM丢失和FM不断蓄积的现象。不建议将ALB和PreALB作为评价造血干细胞移植患儿营养状况的可靠指标。     

异基因造血干细胞移植后慢性移植物抗宿主病的临床分析

目的：探讨异基因造血干细胞移植（allo-HSCT）后慢性移植物抗宿主病（cGVHD）的临床特点、相关危险因素及治疗效果。方法：回顾性分析69例allo-HSCT患者的临床资料。根据供、受者的关系以及配型情况，将患者分为三组：A组为亲缘全相合异基因骨髓移植，22例；B组为亲缘全相合异基因外周血干细胞移植，37例；C组为非血缘移植和不全相合移植，10例。术前均采用化疗预处理，术后采用短程甲氨蝶呤联合环孢素A（CsA）预防移植物抗宿主病（GVHD）。局限性cGVHD患者多采用单一免疫抑制剂（CsA或糖皮质激素）治疗，病情进展者采用标准方案（CsA联合糖皮质激素）治疗；广泛性cGVHD患者则需用标准方案治疗（一线治疗方案）。一线治疗无效、病情进展者，对一线治疗依赖不能停药，或停药后病情反复者，需用他克莫司、霉酚酸酯及硫唑嘌呤治疗（二线治疗方案）。结果：移植后随访6～120个月，中位时间为43个月，39例诊断为cGVHD，其中局限性cGVHD13例（33．3％，13／39），广泛性cGVHD26例（66．7％，26／39），7例死于cGVHD或与之相关的并发症。B组cGVHD发生率较A组显著升高（P〈0．05），B组和C组的广泛性cGVHD发生率显著高于A组（P〈O．05）。外周血干细胞移植和病程中发生2～4度急性GVHD是cGVHD发生的主要危险因素。局限性cGVHD患者采用一线方案治疗的有效率显著高于广泛性cGVHD患者（P〈0．05），标准危险度cGVHD者的治疗有效率显著优于高危险度cGVHD者（P〈0．05）。结论：eGVHD是allo-HSCT后常见并发症和致死原因；广泛性cGVHD多发生于异基因外周血干细胞移植、HLA配型不全相合移植和非血缘移植，且临床治疗效果不佳。     

非亲缘异基因造血干细胞移植治疗白血病患者疗效观察

目的探讨非亲缘异基因造血干细胞移植(URD-HSCT)治疗白血病的效果。方法 10例白血病患者(急性髓细胞白血病第1次缓解期3例,急性淋巴细胞白血病第1次缓解期3例、第2次缓解期1例,慢性髓细胞白血病慢性期3例)接受URD-HSCT治疗。所有患者均采用经典的或改良的白消安联合环磷酰胺预处理方案。4例采用环孢素+短程甲氨蝶呤+吗替麦考酚酯预防移植物抗宿主病(GVHD),另6例患者加用抗胸腺细胞免疫球蛋白。输注供者有核细胞中位数为5.6×108/kg,CD34+细胞中位数为3.3×106/kg。结果除1例在移植后早期死亡不能评估外,其余9例均证实植活。发生急性GVHDⅠ度3例和Ⅱ度、Ⅲ度、Ⅳ度各1例,局限性慢性GVHD7例;发生真菌感染4例、CMV血症3例、出血性膀胱炎3例。10例患者目前无病存活7例,生存期为3个月～10年。结论 URD-HSCT安全而耐受性好,移植相关并发症仍是影响URD-HSCT效果的主要问题。     

Biological advances in acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation is a potentially curative therapy for many malignant and non-malignant hematological diseases. Unfortunately, na?ve donor T cells that are critical for the success of this effective therapy also cause its most severe toxicity--graft-versus-host disease (GVHD). Recent experimental observations have brought into focus a critical role for additional cell populations in the pathogenesis and modulation of GVHD. A better understanding of the complex interactions involving these cellular subsets and the inflammatory cascades is likely to be critical in the pathophysiology of GVHD. This review will primarily focus on the immunobiology of experimental acute GVHD with an emphasis on the recent observations on the novel role of innate and adaptive cellular subsets in the activation, effector phases, and target organ specificity of acute GVHD.     

The relationship between body mass index and outcomes in leukemic patients undergoing allogeneic hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) is being used increasingly in an attempt to cure many hematological disorders. Obesity has become a world wide phenomenon and is a known risk factor for numerous medical conditions, but its role in transplant outcomes remained controversial. Total of 192 patients with acute leukemia who underwent sibling HLA matched HSCT were analyzed to find the effect of pre-transplant body mass index (BMI) on transplant outcomes such as time to engraftment, infections, graft vs. host disease (GvHD), and overall survival (OS) for the period of three yr (April 2006-March 2009). There was a significant correlation between higher pre-transplant BMI and shorter engraftment time (p = 0.010); but no relation between BMI and GvHD, infection, and OS was found. The results of this study showed that patients with higher BMI may have a shorter engraftment time; but lower, although not significant, survival rate compared to non-obese patients.     

异基因造血干细胞移植患者术后并发脑脓肿的护理

对1例骨髓增生异常综合征患者行异基因造血干细胞移植,术后并发脑脓肿。对患者加强护理,即密切监测患者病情,及时发现症状并采取对应的护理措施,包括颅内压增高的护理、肢体运动障碍的护理、发热(抗感染)的护理、心理护理、预防出血的护理、并发症的观察。结果患者移植成功,脑脓肿得到有效控制,顺利出院。提出避免引起颅内压增高的因素、控制感染、预防出血、促进造血重建,为患者制订个体化的康复计划,可使脑脓肿得到控制,促进康复。     

Monitoring of minimal residual disease by quantitative WT1 gene expression following reduced intensity conditioning allogeneic stem cell transplantation in acute myeloid leukemia

Candoni A, Toffoletti E, Gallina R, Simeone E, Chiozzotto M, Volpetti S, Fanin R. Monitoring of minimal residual disease by quantitative WT1 gene expression following reduced intensity conditioning allogeneic stem cell transplantation in acute myeloid leukemia.
Clin Transplant 2011: 25: 308–316. © 2010 John Wiley & Sons A/S. Abstract: WT1 is well‐known to be a panleukemic marker that is expressed in 90% of acute myeloid leukemias (AML). Quantification of WT gene expression in bone marrow (BM) samples may be useful as a marker of minimal residual disease (MRD) during and after treatment for early prediction of relapse. We evaluated the validity of this AML‐MRD marker after reduced intensity conditioning (RIC) allogeneic stem cell transplantation (SCT). The quantitative assessment of WT1 expression by real‐time quantitative PCR (RQ‐PCR) was measured in 25 patients (pts) with AML at diagnosis, at the time of RIC‐SCT and after transplant at precise time points. All pts showed high WT1 levels at diagnosis with a mean of 4895 (SD 4462) and a median of 3679 (range 454–16 853) copies WT1/10⁴ ABL. At transplant, 18/25 pts (72%) were in complete cytologic remission (CcR) and 7/25 (28%) had refractory AML. At the pre‐SCT evaluation, BM samples from pts transplanted in CcR showed significantly lower WT1 expression levels compared to the samples from pts with refractory AML (p = 0.002). Median follow‐up after RIC‐SCT was 18 months (range 2–54). On 18 pts transplanted in CcR, those (17/18) who maintained CcR after RIC‐SCT displayed a WT1 copy number persistently low during all the follow‐up period. In patients who received RIC‐SCT with active disease obtaining a sustained CcR after transplant (3/25), WT1 levels decreased to normal range in the first two months after RIC‐SCT and remained low through the entire study period. All pts who relapsed after RIC‐SCT (4/25) had a high WT1 copy number before the cytologic relapse. In 50% of these cases, an increase in WT1 expression was documented before molecular chimerism decreasing. With this experience, taking into account the limited number of pts, we confirmed a concordance between WT1 expression levels (measured by RQ‐PCR at precise and sequential time points) and status of AML before and after RIC‐SCT and we found a concordance between WT1 expression levels and hematopoietic chimerism status. Our data suggest that, in the RIC‐SCT setting, the sequential and quantitative analysis of WT1 may be useful as a leukemia marker for monitoring MRD and as a predictor of overt AML cytologic relapse.     

Comparative outcomes of reduced intensity and myeloablative allogeneic hematopoietic stem cell transplantation in patients under 50 with hematologic malignancies

We have conducted a direct comparison of the outcomes of reduced intensity and myeloablative conditioning in younger adults with hematological malignancies<50 yr. One hundred and five patients received transplants from human leukocyte antigen (HLA)-matched donors, via either reduced intensity (n=35) or myeloablative conditioning (n=70). The median ages of the reduced intensity and myeloablative groups were 36 and 33 yr (p=0.014). Neutrophil engraftment (i.e. time to absolute neutrophil count>0.5x10(9)/L) occurred more rapidly in the reduced intensity group (median: 10 d; range: 0-21 d) than in the myeloablative group (median: 18 d; range: 11-38 d; p<0.0001). The incidence of grades 2-4 acute graft-vs.-host disease were similar between the reduced intensity and myeloablative groups, at 17% vs. 24% respectively (p=0.40). The cumulative incidence of day 100 non-relapse mortality was 18% in the reduced intensity group, and 21% in the myeloablative group (p=0.88). The overall two-yr survival rates were 43% in the reduced intensity group, and 35% in the myeloablative group (p=0.72). In conclusion, reduced intensity transplantation yielded outcomes comparable with those of myeloablative transplantation in patients under 50 with hematological malignancies.     

造血重建对异基因造血干细胞移植患者早期生活质量的影响

目的探讨造血重建对异基因造血干细胞移植(HSCT)患者早期生活质量的影响,为针对性干预提供参考。方法将122例患者以出净化病房时血小板是否重建分为造血重建组(88例)和造血延迟组(34例),采用癌症治疗功能评价系统-骨髓移植生命质量测评量表(FACT-BMT)测评患者在入净化病房前、移植后1、3、6个月生活质量。结果 122例患者不同时间点生活质量得分差异有统计学意义,其中移植后1个月得分最低,6个月时得到显著改善(P<0.05,P<0.01);造血重建组前3个时间点生活质量得分显著高于造血延迟组(均P<0.05)。多元回归分析结果显示早期造血重建与否是HSCT患者生活质量的主要影响因素,其次为移植物抗缩主病及性别(均P<0.05)。结论早期造血重建可作为HSCT患者术后生活质量的预测因素,护理人员应特别注重对造血延迟患者的针对性护理,以助HSCT患者在术后早期获得较好的生活质量。     

自体造血干细胞移植后序贯异基因造血干细胞移植治疗浆母细胞淋巴瘤一例

正浆母细胞淋巴瘤(plasmablastic lymphoma,PBL)是一种罕见的非霍奇金淋巴瘤,来源于B细胞,侵袭性高、预后差,具有独特的临床特征。宁波市第一医院血液科采用自体造血干细胞移植(autologous hematopoietic stem cell transplantation,auto-HSCT)后序贯异基因造血干细胞移植(allogeneic     

Fatal varicella zoster virus encephalitis in two patients following allogeneic hematopoietic stem cell transplantation

BACKGROUND: Reduced cellular immunocompetence following allogeneic hematopoietic stem cell transplantation (aHSCT) increases susceptibility to viral infections. Varicella zoster virus (VZV) reactivation in this setting most commonly manifests as dermatomal herpes zoster but in some cases life-threatening VZV encephalitis occurs. STUDY DESIGN/RESULTS: We describe the cases of two patients who presented with shingles 3 and 18 months, respectively, after HLA-matched peripheral blood stem cell transplantation (PBSCT). Unfortunately, in the further clinical course both patients developed fatal VZV encephalitis, despite initial high-dose intravenous therapy with acyclovir and in one case with additional VZV-immunoglobulin. CONCLUSION: These two cases suggest that rapid intervention with systemic treatment is warranted and raise the question whether initial combination therapy with intravenous acyclovir and foscarnet, VZV vaccination or long-term low-dose acyclovir are needed to improve treatment and clinical outcome in immunocompromised patients, having undergone allogeneic HSCT.     

原发性淀粉样变性患者行自体外周血干细胞移植术后护理

对13例原发性淀粉样变性患者行自体外周血干细胞移植.结果患者均获得外周血重建,完全缓解5例,部分缓解3例,疾病稳定3例,进展2例.提出术后做好口腔黏膜炎及胃肠道反应的护理,观察并及时处理术后出血,加强心律失常的监护及时调节容量平衡,有助于提高移植成功率.     

Increased incidence of cytomegalovirus retinitis after allogeneic hematopoietic stem cell transplantation

Six cases of cytomegalovirus retinitis (CMVR) after allogeneic hematopoietic stem cell transplantation were diagnosed between 2002 and 2005 in our center, whereas only one case was diagnosed between 1985 and 2001. Cumulative incidence reaches 2.2%, whereas this complication has been rarely described after hematopoietic stem cell transplantation. We aimed to describe clinical and biologic features of CMVR and search for risk factors associated with CMVR. CMVR was diagnosed on specific funduscopic examination in all patients either on visual symptoms (n=3) or on systematic ophthalmologic examination (n=3). CMVR occurred in the context of unrelated transplantation in patients with profound immune defect and multiple episodes of cytomegalovirus (CMV) reactivation. The combination of a CMV-seropositive recipient and CMV-seronegative donor was the leading risk factor.