非亲缘供者异基因造血干细胞移植治疗恶性血液病15例

背景：异基因造血干细胞移植是治愈恶性血液病的主要方法,但中国多为单子女家庭,因此探索非亲缘供者异基因造血干细胞移植的治疗效果及并发症防治具有重要的意义。 目的：观察非亲缘供者异基因造血干细胞移植治疗15例恶性血液病的疗效和相关并发症。 方法：15例恶性血液病患者接受非血缘关系异基因造血干细胞移植治疗。所有患者均采用经典或改良的马利兰联合环磷酰胺预处理方案。4例采用环孢素A+短程甲氨蝶呤+麦考酚吗乙酯预防移植物抗宿主病,另11例患者同时加用抗胸腺细胞球蛋白。输注供者有核细胞中位数为6.3×108/kg,CD34+细胞中位数为3.1×106/kg。 结果与结论：除1例移植后早期死亡不能评估外,其余14例经检测均证实植活。发生急性移植物抗宿主病Ⅰ度5例,Ⅱ、Ⅲ、Ⅳ度各1例;慢性局限性移植物抗宿主病8例。发生肺部真菌感染5例,巨细胞病毒病毒血症3例,带状疱疹病毒感染2例,出血性膀胱炎6例。15例患者中目前无病存活10例,生存期为5个月~11年。结果提示非血缘关系异基因造血干细胞移植是安全且可行的,治疗恶性血液病疗效良好,降低移植相关并发症已成为非血缘关系异基因造血干细胞移植需解决的首要问题。     

白消安在非亲缘异基因造血干细胞移植预处理中的应用

背景：口服白消安剂型胃肠道吸收不稳定,影响异基因造血干细胞疗效且毒性增加。静脉剂型白消安在国内最近几年用于临床,但在非亲缘异基因移植预处理中应用的相关报道甚少。 目的：探讨静脉剂型白消安在非亲缘异基因造血干细胞移植预处理中应用的疗效并观察其毒副作用。 方法：14例非亲缘异基因干细胞移植采用静脉剂型白消安联合环磷酰胺预处理方案,18例亲缘异基因干细胞移植采用口服白消安联合环磷酰胺预处理方案,观察两组造血重建、植入率等疗效指标及胃肠道反应、口腔黏膜炎、出血性膀胱炎、肝功能损害、移植物抗宿主病等相关毒性指标。 结果与结论：两组患者植入率均为100%。静脉剂型组肝脏毒性、口腔黏膜炎发生率明显低于口服剂型组(14% vs. 67%,7% vs. 55%),差异均有显著性意义(P < 0.01),而胃肠道反应、出血性膀胱炎、造血重建、急性移植物抗宿主病、局限性移植物抗宿主病等方面差异均无显著性意义(P > 0.05)。结果可见静脉剂型白消安应用于非亲缘异基因造血干细胞移植预处理可获得满意疗效,且毒副反应少。     

HLA单倍体相合与全相合外周血造血干细胞移植后的急性移植物抗宿主病

背景：异基因外周血造血干细胞移植成为造血干细胞移植的主要方式,近年来HLA单倍体相合造血干细胞移植因供者来源广泛在临床应用较多,急性移植物抗宿主病仍是影响移植成功率的主要因素。 目的：观察亲缘HLA单倍体相合与全相合异基因外周血造血干细胞移植后急性移植物抗宿主病的发生特点,探讨降低急性移植物抗宿主病发生率的方法及单倍体造血干细胞移植应用于临床的意义。 方法：行异基因外周血造血干细胞移植的患者52例,其中HLA全相合组31例,单倍体组21例。HLA单倍体组采用改良马利兰/环磷酰胺+兔抗人胸腺T细胞免疫球蛋白预处理方案,HLA全相合组采用改良马利兰/环磷酰胺预处理方案。移植物抗宿主病的预防采用短程甲氨蝶呤+环孢素A+吗替麦考酚酯的方案。 结果与结论：52例患者均获得完全持久干细胞植入。其中,急性移植物抗宿主病发病率为48%(25/52),Ⅲ-Ⅳ度急性移植物抗宿主病发病率为23%(12/52);全相合组及单倍体组急性移植物抗宿主病累积发病率分别为39%(12/31)和62%(13/21)(P > 0.05);全相合组及单倍体组Ⅲ-Ⅳ度急性移植物抗宿主病累积发病率分别为10%(3/31)和43%(9/21)(P < 0.05);发生于移植后+30 d、+31 d-+60 d、+61 d-+100 d的急性移植物抗宿主病类型分布差异无显著性意义(P > 0.05);发生在移植后+30 d内的急性移植物抗宿主病发生率高于移植后   +31 d-+60 d和+61 d-+100 d;发生急性移植物抗宿主病组和无急性移植物抗宿主病组复发率、2年无病生存率差异无显著性意义(P > 0.05),全相合组与单倍体组相比复发率差异无显著性意义(P > 0.05),2年无病生存率前者高于后者(P < 0.05)。说明采用上述移植方案,单倍体组安全性与疗效接近全相合组;在缺乏HLA相合供者时,单倍体造血干细胞移植是治疗恶性血液病的重要方法。中国组织工程研究杂志出版内容重点：干细胞;骨髓干细胞;造血干细胞;脂肪干细胞;肿瘤干细胞;胚胎干细胞;脐带脐血干细胞;干细胞诱导;干细胞分化;组织工程全文链接：     

单倍型异基因造血干细胞移植治疗重型再生障碍性贫血:回顾性分析

背景:随着国内独生子女家庭的普及,全相合造血干细胞移植受干细胞来源限制,临床应用受到局限,因此单倍型造血干细胞移植越来受到亲睐。目的:回顾性对比分析单倍型异基因造血干细胞移植和全相合异基因造血干细胞移植治疗重型再生障碍性贫血的临床疗效及安全性。方法:选取解放军北京军区总医院血液科2013年1月至2015年1月接受单倍型异基因造血干细胞移植治疗的15例重型再生障碍性贫血患者(治疗组)病例资料,预处理方案为环磷酰胺、氟达拉滨、白舒非联合抗人淋巴细胞免疫球蛋白,供者接受粒细胞集落刺激因子动员,移植方式应用骨髓联合外周血干细胞移植。采用联合免疫抑制剂包括环孢素A、甲氨蝶呤、他克莫司等预防移植物抗宿主病。同时选择同期行全相合异基因造血干细胞移植治疗的15例重型再生障碍性贫血患者病例资料作为对照组,统计两组患者移植相关并发症及存活情况。结果与结论:随访至2015年7月,治疗组中位随访时间20.7个月(6-30个月),全部患者均获造血重建,4例发生移植物抗宿主病、5例合并肺部感染、3例合并败血症,因肺部感染死亡1例、败血症死亡1例、移植物抗宿主病死亡2例;对照组中位随访时间19.7个月(5-28个月),全部患者均获造血重建,3例发生移植物抗宿主病、4例合并肺部感染,因移植物抗宿主病死亡2例、肺部感染死亡1例,两组患者总生存率分别为73%和80%,差异无显著性意义(P=0.67)。结果表明单倍型移植治疗重型再生障碍性贫血安全有效,临床疗效与全相合造血干细胞移植相当。     

异基因造血干细胞移植治疗24例重型再生障碍性贫血北大核心

背景:重型再生障碍性贫血病情重、病死率高,需快速恢复造血功能,目前异基因造血干细胞移植为一线治疗方案,同胞全相合异基因造血干细胞移植为首选,单倍体相合造血干细胞移植作为替代治疗方案也取得了较好的效果。目的:探讨异基因造血干细胞移植(包括同胞全相合造血干细胞移植及单倍体相合造血干细胞移植)治疗重型再生障碍性贫血的临床疗效。方法:回顾性分析2015年4月至2021年7月于徐州市中心医院接受异基因造血干细胞移植治疗24例重型再生障碍性贫血患者的临床资料,其中接受同胞全相合造血干细胞移植8例,接受单倍体相合造血干细胞移植16例。24例重型再生障碍性贫血患者预处理方案为氟达拉滨、环磷酰胺、抗淋巴细胞球蛋白方案。同胞全相合造血干细胞移植采用环孢素联合短程甲氨蝶呤预防移植物抗宿主病,单倍体相合造血干细胞移植在此基础上增加吗替麦考酚酯。结果与结论:①24例重型再生障碍性贫血患者中有2例患者预处理期间死于严重感染,其余22例均达造血重建;中性粒细胞植入中位时间为12.5(10-18)d,血小板植入中位时间为14.5(10-26)d;②22例植入成功患者发生急性移植物抗宿主病8例(36%),Ⅲ/Ⅳ度急性移植物抗宿主病2例,慢性移植物抗宿主病累计发生4例(18%),Ⅲ/Ⅳ度慢性移植物抗宿主病1例;③18例患者存活,6例患者死亡,5年预计总生存率为74%;④结果表明,异基因造血干细胞移植为重型再生障碍性贫血的有效治疗手段,同胞全合供者作为首选,无同胞全相合供者时可选择单倍体相合供者作为替代。     

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。     

多种来源造血干细胞移植治疗重型再生障碍性贫血

背景：造血干细胞移植是年轻重型再生障碍性贫血患者首选方法,但在中国多数重型再生障碍性贫血患者无合适的供者,单倍体相合或非血缘造血干细胞移植国内外目前还处于探索阶段,联合间充质干细胞移植报道少见。 目的：观察不同干细胞来源造血干细胞移植治疗重型再生障碍性贫血的疗效。 方法：10例(3~52岁)重型再生障碍性贫血患者,分别接受了亲缘HLA相合(2例),单倍体相合(5例),非血缘(3例)的外周血和/或骨髓造血干细胞移植,其中5例患者同时联合了间充质干细胞共移植。预处理方案主要为环磷酰胺、氟达拉滨和抗人胸腺球蛋白,以霉酚酸酯、环孢素A加短疗程的甲氨蝶呤预防移植物抗宿主病,单倍体相合移植的患者在此基础上加马利兰和CD25单克隆抗体;同基因的例5患者预处理方案为抗人胸腺球蛋白+甲基泼尼龙。输注间充质干细胞的量为(0.27~1.85)×10⁶/kg。接受和未接受间充质干细胞组的患者回输的造血干细胞有核细胞分别为(7.4~17.38)×10⁸/kg和(6.09~13.68)×10⁸/kg。 结果与结论：除1例单倍体相合患者移植未成功,+36 d死于并发症外,余患者移植后染色体及DNA指纹检测等说明造血干细胞移植完全供者植入。移植后中性粒细胞达到0.5×10⁹ L^-1,血小板计数≥20×10⁹ L^-1中位时间分别为12 d和13 d;其中造血功能恢复快慢的趋势是同基因移植>外周血或/和骨髓+间充质干细胞移植>单纯外周血或/和骨髓干细胞移植,而亲缘HLA全相合的52岁患者造血恢复最慢。非血缘移植例1、6患者发生了Ⅰ度急性移植物抗宿主病,单倍体相合移植的例2和例10患者发生了Ⅱ度急性移植物抗宿主病后出现了局限性的慢性移植物抗宿主病,余下患者移植后生活质量良好,无慢性移植物抗宿主病;除未接受间充质干细胞的例3患者移植后出现严重感染外,其余患者移植后再未出现严重的感染和出血。结果提示造血干细胞是安全,高效治疗重型再生障碍性贫血的方法,联合应用间充质造血干细胞者患者造血恢复快,移植并发症少。     

异基因造血干细胞移植后膜性肾病1例

背景：移植物抗宿主病的诊断与膜性肾病发病关系密切。 目的：观察异基因造血干细胞移植后肾脏损害的临床特征,以期早期诊断移植物抗宿主病。 方法：回顾性分析1例急性白血病异基因造血干细胞移植后合并膜性肾病患者的临床表现及治疗转归。 结果与结论：患者临床表现为大量蛋白尿、高脂血症、低白蛋白血症等肾病综合征特征,同时眼干、口干等慢性移植物抗宿主病表现加重。肾脏病理诊断为膜性肾病。应用免疫抑制剂如泼尼松、他克莫司及雷公藤等治疗4个月后尿蛋白转阴,临床症状改善。随访3年病情无反复,生活质量好。提示异基因造血干细胞移植后肾脏损害是慢性移植物抗宿主病的一种特殊表现,加强免疫抑制治疗后转归良好,肾脏病理检查对诊断有重要意义。 关键词：膜性肾病;造血干细胞移植;移植物抗宿主病;肾活检;免疫抑制 doi:10.3969/j.issn.1673-8225.2012.06.022     

异基因造血干细胞移植后EB病毒再激活的危险因素分析

背景：异基因造血干细胞移植后EB病毒再激活可导致致死性的移植后淋巴细胞增殖性疾病及相关疾病,目前国内尚未建立完整的EB病毒再激活及其相关性疾病的诊疗体系。 目的：前瞻性研究异基因造血干细胞移植后患者EB病毒再激活的发生和相关危险因素。 方法：纳入129例接受异基因造血干细胞移植的患者,采用实时定量PCR方法定期测定外周血中EB病毒载量,Kaplan-Meier模型分析其再激活的发生率,Logistic回归分析模型分析其再激活的相关危险因素。 结果与结论：异基因造血干细胞移植后EB病毒再激活及其相关疾病发生率高,EB病毒再激活发生的危险因素有HLA配型不合、应用抗胸腺细胞球蛋白、Ⅲ~Ⅳ度急性移植物抗宿主病及年龄小于20岁。     

非血缘脐血移植治疗恶性血液病发生移植物抗宿主病与移植物抗白血病效应分离的机制

背景:国内外多项临床研究均表明非血缘脐血移植相对于外周血干细胞或骨髓移植,不仅具有较低的移植物抗宿主病发生率,并且疾病复发率也明显降低,具有较强的移植物抗白血病效应,是临床上分离移植物抗宿主病和移植物抗白血病效应的模型之一。非血缘脐血移植后免疫细胞如何分化,为何具有较强的移植物抗白血病效应,目前机制尚不清楚。目的:回顾性分析非血缘脐血移植患者长期临床随访资料,并探讨非血缘脐血移植后优势细胞亚群及分化、相关活化与抑制分子的表达情况,进一步探讨非血缘脐血移植后移植物抗宿主病与移植物抗白血病效应分离的机制。方法:2012-07-01/2017-06-31在中国科学技术大学附属第一医院(安徽省立医院)接受造血干细胞移植治疗的成人恶性血液病患者154例,其中非血缘脐血移植93例,同胞外周血干细胞移植61例。通过收取非血缘脐血移植和外周血干细胞移植患者的骨髓标本,重点对非血缘脐血移植患者T细胞相关免疫特征进行研究,探讨非血缘脐血移植临床移植物抗宿主病与移植物抗白血病效应的分离现象。结果与结论:(1)经过中位61个月(42-99个月)的长期随访,非血缘脐血移植组5年慢性移植物抗宿主病发生率、5年移植...     

The impact of human herpesvirus 6B reactivation on early complications following allogeneic hematopoietic stem cell transplantation.

Although human herpesvirus 6 (HHV-6) has been considered an important opportunistic and potentially fatal pathogen for allogeneic hematopoietic stem cell transplantation (HSCT), the clinical significance of HHV-6 reactivation remains controversial. In this study, we monitored HHV-6 DNAemia in 72 consecutive allogeneic HSCT recipients by real-time quantitative polymerase chain reaction. A total of 680 peripheral blood specimens were collected from the recipients before HSCT or at weekly intervals after HSCT. As the predominant variant, HHV-6B was detectable at least once in 47.2% (34/72) of HSCT recipients on the median day 21 (range, 7-84 days); HHV-6A reactivation occurred in only 1 recipient (1.4%). Detectable HHV-6B reactivation was associated with increased probability of skin rash by day 30 after HSCT (hazard ratio [HR], 3.68; 95% confidence interval [CI], 1.24-10.92; P = .019), cytomegalovirus (CMV) antigenemia (HR, 2.35; 95%CI, 1.32-4.19; P = .004), and hemorrhagic cystitis (HC) (HR, 2.59; 95%CI, 0.96-6.98; P = .061) by day 100 after HSCT. Neutrophil and platelet engraftment, mortality for 100 days after HSCT were not affected by HHV-6B reactivation. In conclusion, HHV-6 reactivation is a common event, and this study demonstrates a correlation between HHV-6B infection and CMV reactivation, early rash, and possibly increased incidence of HC after transplantation.     

BK Viremia Precedes Hemorrhagic Cystitis in Children Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

BK virus is associated with hemorrhagic cystitis after hematopoietic stem cell transplantation (HSCT), although evidence supporting a causal relationship remains limited. Although BK viruria is common after HSCT, BK viremia may better predict clinically significant cystitis, similar to its predictive value for nephropathy after kidney transplantation. We hypothesized that BK viremia would precede hemorrhagic cystitis in a cohort of 88 consecutive children prospectively enrolled to originally study thrombotic microangiopathy in the first 100 days after allogeneic HSCT. Cox regression models with time-varying covariates assessed the association between different BK viremia cutoffs and the development of hemorrhagic cystitis, defined as at least macroscopic hematuria. Subjects with a peak plasma BK viral load 1 to 9999 copies/mL had an adjusted hazard ratio of 4.2 (95% confidence interval (CI), 1.3 to 13.7) for the development of hemorrhagic cystitis. Those with peak BK viremia >100,000 copies/mL had an adjusted hazard ratio of 116.8 (95% CI, 12 to 1136) for cystitis. Other independent risk factors for hemorrhagic cystitis included age >7 years and HHV-6 viremia. Neither graft-versus-host disease nor achieving engraftment increased the risk for cystitis. If therapeutic strategies are found to be effective, these observations may support screening for BK viremia after HSCT, as currently recommended for other DNA viruses.     

Relationship of BK Polyoma Virus (BKV) in the Urine with Hemorrhagic Cystitis and Renal Function in Recipients of T Cell–Depleted Peripheral Blood and Cord Blood Stem Cell Transplantations

Hematopoietic stem cell transplant (HSCT) recipients are at significant risk for BK virus (BKV) reactivation, hemorrhagic cystitis (HC), and renal dysfunction. We prospectively monitored 98 patients who had received HSCT by serial BKV PCR in the urine through day (D) +100 to analyze the relationship between BK viruria and HC, serum creatinine (Cr), and creatinine clearance (CrCl) through D +180 or death. Patients, median age 52 years (range, 20 to 73), received T cell–depleted (50%) or cord blood allografts (21%). Median pre-HSCT BKV IgG titers were 1:10,240. Incremental increase in BKV IgG titers correlated with developing BK viruria ≥ 10⁷ copies/mL. By D +100, 53 (54%) patients had BK viruria. BKV load in the urine increased at engraftment and persisted throughout D +100. HC developed in 10 patients (10%); 7 of 10 with BK viruria. In competing risk analyses, BK viruria ≥ 10⁷ copies/mL, older age, cytomegalovirus reactivation, and foscarnet use were risk factors for HC. Cr and CrCl at 2, 3, and 6 months after HSCT were similar between patients with and without BK viruria.     

Hemorrhagic Cystitis in a Cohort of Pediatric Transplantations: Incidence,Treatment, Outcome,and Risk Factors

Hemorrhagic cystitis (HC) can be a severe complication in hematopoietic stem cell transplantation (HSCT). To identify risk factors and etiology and to improve treatment, a number of factors were analyzed retrospectively in a cohort of 74 consecutive pediatric HSCTs between 2007 and 2009 in a single institution. The 74 transplantations were done in 67 children. Potential risk factors for HC were age, gender, underlying disease, ablative conditioning, graft-versus-host disease prophylaxis, unrelated donor, stem cell source, conditioning regime, acute graft-versus-host disease and cytomegalovirus reactivation.Fourteen patients developed HC (19%). In all but 4 cases (71%), HC appeared after engraftment. Severity was assessed as grade 1 in 1, grade 2 in 8, and grade 3 in 5 cases. In 79% of the patients with HC, urine samples showed BK virus. This may provide guidance for future prevention policies. In 11 children, treatment included forced hydration, spasmolytics, and bladder irrigation. Three children required cystoscopy, intravesical therapy and/or antiviral therapy. Statistical analysis revealed age over six years to be a risk factor for the development of HC.We conclude that current conditioning regimens lead to a still considerable incidence of HC in pediatric HSCT, necessitating the evaluation of screening protocols and preventive measures.     

供受者感染乙肝病毒对造血干细胞移植后肝炎复发及愈后的影响

目的分析移植前供、受者感染乙肝病毒对造血干细胞移植后肝炎复发及愈后的影响。方法对上海第一人民医院2006年1～11月移植前供、受者感染乙肝病毒的23例恶性血液病患者,进行移植前后肝功能、乙肝免疫标记物、HBVDNA等检测,并结合临床综合分析。血清丙氨酸氨基转移酶（ALT）、γ谷氨酰转肽酶（GGT）采用速率法,血清总胆红素（TBIL）采用终点比色法检测;乙肝病毒血清标志物采用酶免疫测定（EIA）;HBVDNA测定采用聚合酶链反应（PCR）试剂盒。结果①9例HBV感染的自体移植患者移植后3例发生乙型肝炎,其中2例为移植前HBsAg阳性,乙肝发作时3例HBVDNA及肝功能指标均明显增高;②14例HBV感染的供、受者移植后5例患者发生乙型肝炎,HBVDNA及肝功能指标均明显增高;③移植前HBsAg或HBVDNA阳性移植后发生乙肝相关性肝损的几率显著高于阴性组（X^2分别为8.44、9.07,均大于X0.005^2,P〈0.005）;④移植前HBsAg或HBVDNA阳性对移植预后均无影响（X^2分别为2.58、0.24,均小于X0.05^2,P〉0.05）;⑤1例患者异体移植后41d,乙肝合并戊肝,发生急性黄疸性肝炎,第46天重症GVHD死亡。结论移植前HBsAg和HBVDNA阳性均是HBV感染和再激活的高危因素,移植要密切监测免疫标志物和HBVDNA。移植前HBsAg和HBVDNA阳性不影响患者的生存,要注意非常见肝炎的多重感染。     

单倍型异基因造血干细胞移植后发生巨细胞病毒感染的临床分析

目的 探讨单倍型异基因造血干细胞移植后发生巨细胞病毒(CMV)感染的临床特点及治疗.方法 对北京军区总医院血液科2011年1月-2013年1月采用单倍型异基因造血干细胞移植治疗的50例患者的临床资料进行回顾性研究,供者接受粒细胞集落刺激因子动员,采用骨髓加外周血干细胞联合移植,预处理方案以改良BUCY方案为主,移植后监测CMV-DNA,分析CMV感染的特点并探讨其治疗方法.结果 全部患者中男32例,女18例,年龄5-45岁,平均年龄23.8岁,其中共12例发生CMV血症,发生率为24％,首次检出CMV-DNA中位时间是移植后50天(36-72),CMV定量范围为2.4×103-6.2×106拷贝/mL,其中6例为CMV相关性出血性膀胱炎,2例为CMV相关性间质性肺炎,抗CMV治疗后全部患者CMV-DNA转阴.结论 单倍型异基因造血干细胞移植后巨细胞病毒感染发生率高,更昔洛韦、膦甲酸钠抗病毒治疗疗效可靠、不良反应少.     

Hemorrhagic cystitis following allogeneic hematopoietic cell transplantation

We conducted a retrospective study to investigate the incidence, risk factors, and clinical features of hemorrhagic cystitis (HC) following allogeneic hematopoietic cell transplantation (allo-HCT). Adult patients who developed HC after allo-HCT were identified from the HCT database of the Asan Medical Center and their medical records were reviewed. From December 1993 to August 2001, a total of 210 adult patients underwent allo-HCT. Fifty-one patients developed HC with a cumulative incidence of 25.7%. The median onset of HC was post-transplant day 24 (range, -2 to 474), and the median duration was 31 days (range, 8 to 369). Significant risk factors for HC by univariate analysis included diagnosis of chronic myelogenous leukemia (p=0.028), unrelated HCT (p=0.029), grade III-IV acute graft-versus-host disease (GVHD) (p<0.001), extensive chronic GVHD (p=0.001), and positive cytomegalovirus antigenemia between post transplant days 31 and 60 (p=0.031). Multivariate analysis showed that grade III-IV acute GVHD was the most important risk factor for the occurrence of HC after allo-HCT (odds ratio, 3.38; 95% CI, 1.36-8.39). Late-onset HC, which occurred beyond 3 weeks after allo-HCT, was more frequently associated with GVHD than early-onset HC (p=0.007). Our data suggest that a portion of late-onset HC might be a manifestation of GVHD.     

Incidence, clinical outcome, and management of virus-induced hemorrhagic cystitis in children and adolescents after allogeneic hematopoietic cell transplantation.

We analyzed the incidence, etiology, risk factors, and clinical management of hemorrhagic cystitis (HC) in 102 children who underwent allogeneic stem cell transplantation: 28 from matched siblings, 57 from unrelated donors, and 17 from mismatched relatives. Conditioning regimens consisted of high-dose chemotherapy (n=83) or total body irradiation (n=19). In all children, urine and plasma were prospectively screened for human polyomavirus (HPV; BK virus [BKV] and JC virus [JCV]) or adenovirus (AdV) DNA with a polymerase chain reaction-based assay. Viral DNA was detected in the urine of 56 children (54.9%): BKV in 48 (47%), JCV in 4 (3.9%), and AdV in 4 (3.9%). HC occurred in 26 children (25.5%), and viruria was detected in all of them: BKV in 21 (80.8%), AdV in 4 (14.4%), and JCV in 1 (3.8%). All patients with AdV viruria developed HC. The cumulative incidence of HC in patients with HPV viruria was 0.43. The only significant risk factor for HC in patients with HPV-positive urine was conditioning with high-dose chemotherapy. Twenty-two children were treated with cidofovir, with no significant toxicity. In all treated patients but 1, the clinical symptoms were moderate, and no HC-related death was observed. We conclude that virus-induced HC is a frequent complication after allogeneic hematopoietic cell transplantation. Treatment with cidofovir is feasible, and further studies are warranted to evaluate its activity in HC mediated by BKV or JCV.     

Adenovirus infection in hematopoietic stem cell transplantation: effect of ganciclovir and impact on survival.

Adenoviruses (ADV) are emerging as important causes of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). In mainly non-T-cell depleted HSCT recipients, we analyzed the incidence of ADV infection, risk factors for infection, the effect of ganciclovir administered for prevention of cytomegalovirus (CMV), and the impact of ADV infection on survival. The overall incidence of ADV, irrespective of the method of detection, was 8.5% (450/5233) and 12.3% (43/348) after the first or second allogeneic HSCT, and 6.3% (78/1219) and 6.5% (5/77) after the first or second autologous HSCT, respectively. The most frequent sites of infection and disease were stool and gastrointestinal tract, respectively. Statistically significant risk factors associated with ADV infections among allogeneic recipients included younger age, grade II to IV graft-versus-host disease, year of transplantation, and a second allogeneic HSCT. Furthermore, allogeneic patients seronegative for CMV at transplantation and seropositive allogeneic patients who did not receive ganciclovir, either at engraftment or as pre-emptive therapy on CMV reactivation, were at higher risk of developing ADV infections compared with seropositive patients who received ganciclovir (odds ratio=1.8, 95% confidence interval (CI) 1.2 to 2.8, P=.005 and odds ratio=3.4, 95% CI 2.1 to 5.55, P<.0001, respectively). The hazard of overall mortality was higher in patients who contracted ADV compared with those who did not (hazard ratio 1.5, 95% CI 1.3 to 1.7, P<.0001). This study shows that ADV infections are associated with poor transplantation outcome in T-cell repleted HSCT recipients. Ganciclovir, given for CMV prevention, may have a protective effect. Controlled treatment and prevention studies are warranted.     

Toll-like 4 receptor variant, Asp299Gly, and reduced risk of hemorrhagic cystitis after hematopoietic stem cell transplantation

Hemorrhagic cystitis (HC) is a major cause of morbidity after hematopoietic stem cell transplantation. Toll-like receptor 4 (TLR4) is a pattern recognition receptor of the innate immune system and induces inflammation. Individuals with the single nucleotide polymorphisms Thr399Ile (rs4986791) or Asp299Gly (rs4986790) of TLR4 show diminished inflammatory responsiveness to endotoxins. The genotype of TLR4 was determined in 166 children who underwent allogeneic hematopoietic stem cell transplantation and in their donors. Asp299Gly was present in 21 patients (13%) and 24 donors (14%). Thr399Ile was found in 22 patients (13%) and 25 donors (15%). The incidence of HC was significantly lower in patients with Asp299Gly (0% vs 23%; P = .009) and in patients who underwent transplantation from a donor with Asp299Gly (4% vs 23%; P = .05). The trend was the same for Thr399Ile-donor positive (8% vs 22%; P = .17), recipient positive (9% vs 22%; P = .25), donor or recipient positive (8% vs 23%; P = .04). Multivariate analysis revealed age, conditioning with busulfan, and absence of Asp299Gly as independent risk factors for HC. In conclusion, the TLR4 Asp299Gly variant seems to confer protection against hemorrhagic cystitis. This study provides the first indication that the innate immune system through TLR4 signaling pathway plays a role in the pathogenesis of HC after hematopoietic stem cell transplantation.