Detectable minimal residual disease before allogeneic hematopoietic stem cell transplantation predicts extremely poor prognosis in children with acute lymphoblastic leukemia

BACKGROUND: The level of minimal residual disease (MRD) prior to allogeneic hematopoietic stem cell transplantation (HSCT) has been shown to be an independent prognostic factor for outcome of pediatric patients with high-risk acute lymphoblastic leukemia (ALL). Retrospective studies which used (semi-) quantitation of clone-specific immunoglobulin/T-cell receptor (Ig/TCR) rearrangements have documented the feasibility and practicality of this technique. This approach has also been disputed due to the occurrence of clonal evolution and generally high MRD levels prior to HSCT. PROCEDURE: In our prospective study, MRD before and after HSCT was monitored using quantitative real-time PCR in a cohort of 36 children with ALL consecutively transplanted in our center between VIII/2000 and VII/2004. RESULTS: In 25 of 36 patients, MRD level prior HSCT was assessed. Seventeen patients were classified as MRD-negative and eight were MRD-positive up to 9 x 10(-2). In MRD-positive subgroup, seven events (six relapses) occurred post-transplant in striking contrast to only one relapse in MRD-negative subgroup (event-free survival (EFS) log-rank P < 0.0001). MRD proved to be the only significant prognostic factor in a multivariate analysis (P < 0.0001). Adoptive immunotherapy including donor lymphocyte infusions in patients with adverse dynamics of MRD after HSCT had only limited and/or temporary effect. Clonal evolution did not present a problem precluding MRD monitoring in any of patients suffering a post-transplant relapse. CONCLUSIONS: We show that MRD quantitation using clonal Ig/TCR rearrangements successfully assesses the risk in pediatric ALL patients undergoing allogeneic HSCT. As our ability to treat detectable MRD levels after HSCT is very limited, alternative strategies for MRD-positive patients prior HSCT are necessary.     

Iron overload in survivors of childhood leukemia after allogeneic hematopoietic stem cell transplantation

Abstract:  Iron overload has not been studied extensively and prospectively in pediatric survivors of allogeneic hematopoietic stem cell transplantation (HSCT); therefore, we conducted a prospective long-term study of 133 survivors of childhood leukemia to assess the incidence of and risk factors for iron overload and to investigate its association with organ dysfunction. One yr after HSCT, the mean serum ferritin level was 1158 ng/mL (range, 22–3264 ng/mL), with 124 patients (93.2%) having a serum ferritin level that exceeded the upper limit of the normal range (110 ng/mL). Thereafter, the serum ferritin level declined over time. There was a positive correlation between the level of serum ferritin and that of total bilirubin (r   =   0.21, p < 0.001) and glutamate pyruvate transaminase (r   =   0.17, p < 0.001). A high concentration of serum ferritin was associated with low cardiac fractional shortening (r   = −0.15, p  =  0.047). In addition, patients with hypothyroidism and GH deficiency had a higher level of serum ferritin than those without (p < 0.02). We conclude that iron overload is common after HSCT and is associated with hepatic, cardiac, and endocrine dysfunction.     

Outcome of hematopoietic stem cell transplantation of children with very high risk acute lymphoblastic leukemia in first complete remission

Schechter T, Ishaqi KM, Rojas M, Irina Z, Doyle JJ, Gassas A. Outcome of hematopoietic stem cell transplantation of children with very high risk acute lymphoblastic leukemia in first complete remission.
Pediatr Transplantation 2010:14: 377–382. © 2009 John Wiley & Sons A/S. Abstract: Approximately 10% of children with ALL present at diagnosis with VHR for relapse if treated with chemotherapy alone. They may benefit from allogeneic HSCT in CR1. We have reviewed the outcome of this population in our institution. Forty‐three patients (median age: 8.9 yr) with VHR ALL in CR1 underwent HSCT from October 1994 to April 2006. VHR features included Philadelphia chromosome (n = 17), induction failure (n = 9), hypodiploidy (n = 6), MLL gene rearrangement (n = 5), and others (n = 6). All patients received TBI (1200 cGy) with either CY and/or etoposide. Stem cell source was unrelated (n = 24) and related (n = 19). Incidence of grade III‐IV acute GVHD and chronic extensive GVHD were 25% and 16%, respectively. Twelve patients relapsed (eight received related HSCT). Eleven patients died due to transplant‐related mortality (eight received unrelated HSCT). For a median follow up of 39 months (range 11–110), the event free survival and OS were 0.49 (95% CI: 0.31–0.67) and 0.53 (CI: 0.44–0.71), respectively. Outcomes of children with VHR ALL receiving HSCT in CR1 remain unsatisfactory. Relapse, mainly after related HSCT, and TRM, mainly after unrelated HSCT, continue to be major problems.     

儿童异基因造血干细胞移植后急性肾损伤临床分析

目的分析儿童异基因造血干细胞移植(allo-HSCT)后急性肾损伤(AKI)的临床特征及危险因素。方法回顾性分析2016年8月至2020年3月于武汉儿童医院血液肿瘤科接受allo-HSCT患儿的临床资料,对比移植预处理开始前及移植后100天血肌酐(Cr)、肌酐清除率(Ccr),以及移植后1年的生存情况;采用logistic回归分析影响AKI发生的危险因素。结果共147例allo-HSCT患儿纳入研究,其中男85例、女62例,接受移植时中位年龄5.5岁(0.7个月～16岁)。其中101例(68.7%)患儿发生AKI,中位时间为移植后24.0(-5.0～91.0)d。二元logistic回归分析显示,移植后急性移植物抗宿主病(aGVHD)、肝窦间隙阻塞综合征(SOS)是AKI发生的独立危险因素(P<0.05)。按pRIFLE诊断标准将发生AKI的101例患儿分为风险期组54例、肾损伤期组31例以及肾衰竭期组16例。不同分期之间患儿Cr以及Ccr差异均有统计学意义(P<0.05),肾衰竭期组Cr较高,Ccr较低。allo-HSCT后随访1年,18例患儿死亡,其中AKI患儿死亡16...     

异基因造血干细胞移植并发致死性间质性肺炎

目的探讨小儿异基因造血于细胞移植并发间质性肺炎（IP）的发病病因、临床特点、危险因素及防治措施。方法根据尸解病理检查及聚合酶键反应技术对病毒病原学检测结果，结合临床移植资料综合分析。结果14例移植患儿中并发IP3例（3／14），分别死于十19天、＋76天、＋150天;3例IP中2例移植前后外周血及尸解肺组织直到CMV包涵体;4例3～4应急性GVHD患儿中3例并发IP，10例0～2度急性GVHD无1例并发IP。结论IP是移植早期死亡的重要原因之一，巨细胞病毒感染是IP的主要病原，GVHD严重程度与移植后并发IP密切相关.     

造血干细胞移植治疗儿童白血病若干问题

该文涉及各类儿童造血干细胞移植(HSCT),如骨髓移植(BMT)、外周血造血干细胞移植(PBSCT)和脐血移植(UCBT)治疗白血病的优缺点及HSCT在儿童白血病治疗中的地位。绝大多数儿童白血病可通过正规联合化疗根治,仅少数(约20%)高危、难治及复发的白血病是异基因HSCT的适应证,无适合的同胞供体时,可选择HLA全相合非血缘相关BMT或PBSCT,UD-UCBT更适合于儿童患者。     

Haploidentical hematopoietic stem cell transplantation for paediatric high‐risk T‐cell acute lymphoblastic leukaemia

Paediatric HR T‐cell ALL demonstrates dismal prognosis with chemotherapy, and poor outcomes could be improved with allo‐SCT. HID‐SCT is an almost immediately available choice; however, few studies have focused on the outcomes of HID‐SCT for paediatric HR T‐ALL. Forty‐eight consecutive HR T‐ALL children who underwent HID‐SCT were included. Survival outcomes and factors predictive of outcomes were retrospectively analysed. Of the 48 patients, 35 were in CR1, 10 in CR2, and three in relapse. The cumulative incidence of grade 3/4 aGVHD was 10.4% and that of extensive cGVHD was 28.4%. The CIR at three yr was 30.8% and that of NRM at three yr was 14.7%. At a median follow‐up of 20.0 (range 2.5–124.2) months, the three‐yr LFS was 54.4%. Children who received transplants during CR1 had a better LFS (65.7% vs. 26.0%, p = 0.008) and a lower relapse rate (19.8% vs. 56.7%, p = 0.014) compared to those during non‐CR1. HID‐SCT is feasible for HR T‐ALL children, and survival outcomes are better when performed in CR1 compared to non‐CR1. Prospective clinical trials would be needed to confirm that.     

异基因造血干细胞移植治疗儿童急性髓系白血病临床研究

目的评估应用异基因造血干细胞移植(allo-HSCT)治疗儿童急性髓系白血病(AML)的临床疗效及相关影响因素。方法回顾分析2002年1月至2017年11月49例确诊中、高危及复发AML行allo-HSCT患儿的临床资料,分析危险度分级、HLA分型、移植前状态、移植方式、干细胞来源及急慢性移植物抗宿主病(GVHD)等对allo-HSCT治疗效果的影响。结果 49例患儿中男35例、女14例,中位年龄9岁。三年总体存活率(OS)为(59.2±7.3)%,无白血病存活率(LFS)为(50.9±7.4)%。其中第1次缓解状态移植、非血缘移植、外周血干细胞移植、中危组移植的三年LFS分别为69.8%、69. 2%、73. 7%、65. 8%。19例死亡,分别为复发13例、严重感染5例、多器官衰竭1例。COX回归模型结果显示,急性GVHD是影响移植OS的独立危险因素(RR=3. 16,95%CI:1. 23～8. 09,P=0. 017),移植前状态为部分缓解及未缓解是影响移植LFS的独立危险因素(RR=4.76,95%CI:1.52～14.94,P=0.008;RR=5.28,95%CI:1.68～16.58,P=0.004)。结论移植前状态及急性GVHD是影响Allo-HSCT治疗儿童AML疗效的关键因素;白血病复发及感染是导致死亡的主要原因。     

Surveillance cultures in pediatric allogeneic hematopoietic stem cell transplantation

The value of surveillance cultures in predicting systemic infections and in guiding antimicrobial treatment is controversial. We investigated 57 pediatric allo‐SCTs between 2007 and 2009. ALL (34), AML (5), and severe aplastic anemia (4) were the largest patient groups. Conditioning was TBI‐based in 87% and 54% developed GVHD (21% grade III‐IV). Of the 2594 weekly colonization samples, 24% were positive (fecal bacteria 86%, fecal fungi 16%, Clostridium difficile 16%; throat bacteria 17% and throat fungi 4%). Enterobacteria and enterococci were the most common fecal findings, staphylococci and streptococci in the throat. Of the bacterial stool samples pretransplant, 74% (mostly enterococci) were resistant to our first‐line antibiotics (ceftazidime and cloxacillin). Candida species accounted for the majority of the fungal findings: 62% of the fecal and 78% in the throat. A total of 170 clinical infection episodes were recorded, and in 12 of these, the bacterial blood culture was positive. In 4/12 cases, the pathogen was detected in surveillance culture previously, leading to sensitivity and specificity of 33.3 and 47.4%, respectively. Positive predictive value of bacterial surveillance cultures was 0.9%. The antimicrobial treatment was changed in only five cases based on the surveillance culture results. Weekly surveillance cultures seldom provided clinical benefit and were not cost‐effective.     

Pharmacokinetics of high-dose etoposide administered in combination with fractionated total-body irradiation as conditioning for allogeneic hematopoietic stem cell transplantation in children with acute lymphoblastic leukemia

Etoposide (VP-16) is one of the most widely used antitumor agents in pediatric oncology as well as chemotherapeutic agents used in conditioning regimen prior to allo-HSCT for childhood ALL. This study included 21 children with ALL who underwent allo-HSCT after conditioning with FTBI and high-dose of VP-16 (60 mg/kg) given intravenously as single four-h infusion on day -3 (n=2) or day -4 (n=19) prior to allo-HSCT. Blood samples were collected at defined time intervals until 120 h elapsed from the end of infusion. VP-16 plasma concentrations were determined using validated HPLC method. Three-compartment model was assumed for assessing PK parameters of VP-16. The median value of VP-16 C(max) measured at the end of infusion was 188.0 μg/mL (range 148.0-407.0 μg/mL). Out of 21 studied children, VP-16 was still detectable in 17 patients 72 h (median concentration 0.31 μg/mL) and in eight patients 96 h (median concentration 0.31 μg/mL) after the end of infusion. VP-16 concentration 96 h after the end of infusion was positively correlated with VP-16 AUC and negatively correlated with VP-16 CL normalized to body weight.     

Secondary pulmonary alveolar proteinosis after unrelated cord blood hematopoietic cell transplantation

PAP is a rare alveolointerstitial lung disorder characterized histologically by the intra-alveolar accumulation of eosinophilic and PAS-positive material. We observed two cases of PAP after unrelated CB hematopoietic progenitor cell transplantation in children with ALL. No antagonist activity toward GM-CSF was identified in the patient tested. The putative multifactorial PAP etiology is discussed. This potentially curable condition should be considered in a CB allograft recipient with alveolointerstial lung disorder.     

异基因造血干细胞移植治疗儿童再生障碍性贫血临床分析

目的探讨异基因造血干细胞移植在儿童再生障碍性贫血治疗中的作用。方法10例再障患儿中,5例行HLA相合同胞供者异基因外周造血干细胞移植,3例行无关供者异基因外周造血干细胞移植,1例行无关供者骨髓移植,1例行脐血移植。结果1例接受脐血移植者未植活,其余9例均植入。中位植入时间14d（8～24d）,中性粒细胞〉0.5×10^9/L中位时间12d（8～19d）,血小板〉20×10^9/L中位时间17d（9～40d）。2例发生排斥,1例接受了第二次移植,1例移植后3个月血象开始自行恢复。结论如有HLA相合的同胞供者,异基因造血干细胞移植可作为儿童再障的一线治疗;临床重症感染无法控制的患儿,并非移植绝对反指征,相反可通过移植后的造血重建控制感染。     

Multiple extramedullary relapses without bone marrow involvement after second allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia

EMR without BM involvement after allogeneic HSCT is extremely rare, especially in children; only a few cases have been reported. A two-yr-old boy was diagnosed with AML (M4) and underwent allogeneic HSCT in first complete remission with BM from HLA-matched unrelated donor without GVHD. Four yr later, he had a BM relapse and after induction and consolidation chemotherapy, he received a second HSCT from an unrelated donor using peripheral blood stem cells. His second post-transplant course was complicated by extensive chronic GVHD involving the skin, oral cavity, and lungs, which was treated with tacrolimus and corticosteroid. Two yr later, he noticed a mild swelling in the right cheek area. The BM showed a complete remission marrow and a soft tissue biopsy was compatible with granulocytic sarcoma. PET-CT showed multifocal bone involvements. He received chemotherapy, and the chloromas decreased in size. We report a case of diffuse EMR of AML without BM involvement after a second allogeneic HSCT.     

Visual perceptual skills and visual motor integration in children and adolescents after allogeneic hematopoietic stem cell transplantation

The aim of the study was to study visual acuity, visual perceptual, and VMI skills in patients after HSCT in childhood. Tests of visual perceptual skills, VMI, and visual acuity were performed in 102 children/adolescents (age range 4.3‐20.9 years). Mean time from HSCT to testing was 6.0 years (0.9‐17.5 years). Visual acuity was median 1.0 decimal (range 0.16‐1.6). Visual perceptual skills (memory, form constancy, visual sequential memory) and VMI were low compared to age‐equivalent normative data with, respectively, 36%, 45%, 60%, and 46% of all patients performing below the 25 percentile. All patients performed significantly lower than the 50 percentile in the reference material in visual sequential memory, P < .001 (boys P < .001 and girls P < .05). All patients also performed significantly lower than the 50 percentile in VMI (P < .01) (boys P < .05). Pretransplant conditioning regimen did not affect outcome if the results were corrected for age at HSCT. Visual perceptual skill problems and VMI problems frequently occur in patients after HSCT in childhood. Age at HSCT and original diagnosis influence the outcome. Neuropsychological assessment including visual perception is recommended in children after HSCT.     

儿童异基因造血干细胞移植后淋巴细胞增殖性疾病的临床研究

目的探讨儿童异基因造血干细胞移植（allo-HSCT）后淋巴细胞增殖性疾病（PTLD）的诊治及预后。方法回顾性分析4例allo-HSCT后EBV相关性PTLD（EBV．PTLD）患儿的临床资料。其中,急性淋巴细胞白血病（高危）（ALL—HR）2例,重型再生障碍性贫血（SAA）2例。异基因外周血造血干细胞移植（allo-PBSCT）3例,异基因脐血造血干细胞移植（allo-UCBSCT）1例。结果4例患儿分别于allo．HSCT后第53、101、22、42d发生PTLD。临床表现为发热、鼻塞、扁桃体肿大、淋巴结肿大和肝脾肿大,移植前均EBNA-1-IgG（＋）、VCA．IgG（＋）;移植后EBV．DNA1．69×10^4～8．62×10^8 copies／mL。经淋巴结病理活检确诊为EBV-PTLD,其中1例为T细胞来源,3例为B细胞来源。例1予减停免疫抑制剂、使用利妥昔单抗、联合COP方案化疗及供者淋巴细胞输注（DU）治疗,PTLD反复且发生严重皮肤GVHD、肺部感染,移植后第193d死亡。余3例予减停免疫抑制剂及利妥昔单抗治疗,临床表现消失且EBV．DNA转阴,分别随访17、12、7个月均无病存活。结论动态监测EBV—DNA对PTLD早期发现具有重要意义。减停免疫抑制剂联合利妥昔单抗治疗EBV-PTLD疗效明显。化疗可导致严重感染,DLI治疗存在严重GVHD危险,不宜作为一线治疗。     

异基因造血干细胞移植治疗儿童慢性粒细胞性白血病的疗效分析

目的：研究异基因造血干细胞移植（allogeneic hematopoietic stem cell transplantation, allo-HSCT）治疗儿童慢性粒细胞性白血病（chronic myelogenous leukemia, CML）的治疗效果,寻找可能的影响因素,以期改善患者预后。方法：对接受allo-HSCT治疗的20例儿童CML患者,分别从年龄、性别、诊断至移植间隔时间、供受体HLA配型相合情况、移植时患儿疾病状态以及急慢性移植物抗宿主病（gost-v-host disease, GVHD）等多种因素进行疗效分析。结果：截止至随访日期,20例患者中,13例无病存活,7例死亡,其中4例死于急性重度GVHD,2例死于慢性GVHD及其并发症,1例死于移植后复发,3年总无病生存率为（64.6±1.1%）。单因素分析显示年龄是影响儿童CML治疗预后最重要的因素之一（P0.05）。多因素logistic回归分析也进一步证明仅年龄是影响预后的因素（P<0.01）。各种严重急慢性 GVHD是引起患者死亡最重要的原因。选择10位点全相合的供体进行移植治疗预后好。结论：allo-HSCT能有效治疗儿童CML,对于年龄≥10岁的CML患儿宜早期行allo-HSCT移植治疗,且尽可能选择10位点全相合的供体进行移植,积极防治GVHD,改善CML患儿移植治疗后的转归。     

Prophylactic treatment for hypertension and seizure in a case of allogeneic hematopoietic stem cell transplantation after posterior reversible encephalopathy syndrome

Fukuyama T, Tanaka M, Nakazawa Y, Motoki N, Inaba Y, Higuchi T, Koike K. Prophylactic treatment for hypertension and seizure in a case of allogeneic hematopoietic stem cell transplantation after posterior reversible encephalopathy syndrome. Pediatr Transplantation 2011: 15: E169–E173. © 2010 John Wiley & Sons A/S. Abstract: A six‐yr‐old boy developed PRES after induction chemotherapy for the relapse of acute lymphoblastic leukemia. Two months after PRES, he underwent BMT from an unrelated HLA‐mismatched donor. There were many risk factors for PRES in the BMT including the long‐term use of FK506 and methylprednisolone, grade III graft‐versus‐host disease, thrombotic microangiopathy, and sepsis. Prophylactic treatment for hypertension with nicardipine in conjunction with close monitoring of the magnesium level and the use of valproic acid might be an effective management approach to prevent post‐transplant PRES.