Membranoproliferative glomerulonephritis following allogeneic hematopoietic stem cell transplantation

Nephrotic syndrome after allogeneic hematopoietic stem cell transplantation has been increasingly described as a manifestation of chronic graft-versus-host disease (GVHD); however, GVHD-associated membranoproliferative glomerulonephritis is extremely rare. A 44-year-old man developed nephrotic syndrome 24 months after HSCT for acute lymphoblastic leukemia. The renal biopsy showed type I membranoproliferative glomerulonephritis. Salivary gland biopsy demonstrated mild lymphocytic infiltration, indicating chronic GVHD. Improvement of the proteinuria and recovery of renal function were achieved within 11 months of treatment with oral prednisolone and azathioprine.     

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.     

Favorable long-term outcome of nephrotic syndrome after allogeneic hematopoietic stem cell transplantation

BACKGROUND: The development of nephrotic syndrome (NS) after allogeneic hematopoietic stem cell transplantation (HS-CT) is a rare complication with few long-term outcome data. PATIENTS: Clinical course and long-term outcome of three adult patients and one child with NS after HSCT (total number of transplants n = 533) are presented. RESULTS: The median age at onset of NS was 35 years (range 15 - 56), occurring at a median of 17 months (range 11 - 21) after HSCT. Discontinuation of cyclosporine A (CSA) prior to onset of NS was a consistent feature and occurred a median of 6 months (range 2 - 10 months) prior to the development of NS. The histopathological lesion was membranous nephropathy (n = 3) and membranoproliferative glomerulonephritis Type 1 (n = 1). History of acute or concomitant clinically apparent chronic graft versus host disease (GVHD) was present in all cases except the pediatric patient who had abundant DR-activated cytotoxic T cells without evidence of viral reactivation. Long-term immunosuppression for 11 - 36 months with steroids (n = 1), combined steroids and CSA (n = 2) or CSA alone in steroid-refractory NS (n = 1) resulted in sustained remission of the NS in all patients (12 months - 8 years off immunosuppression). CONCLUSION: NS after HSCT seems to be etiologically related to subclinical or overt chronic GVHD, which flares up after discontinuation of CSA. However, resumption of immunosuppression can reverse NS as well as GVHD and induce favorable sustained long-term remission.     

Lower limb pain following allogeneic hematopoietic stem cell transplantation in Japanese children

BackgroundPatients who undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT) can experience musculoskeletal pains in their lower limbs in the early and late post-transplantation period. This study investigated demographics and clinical characteristics of the lower limb pain (LLP) among Japanese survivors of pediatric allo-HSCT.MethodsA total of 143 consecutive Japanese patients who had undergone allo-HSCT less than 18 years of age in a single institute between 2005 and 2015 were reviewed. Patients referred for in-house orthopedic evaluation of their sustained LLPs that impaired ambulation were defined as LLP group. Illness/transplantation-related parameters were compared between LLP group and non-LLP group.ResultsNinety children with a mean age of 8.5 years at transplantation were enrolled. Their median follow-up period following transplantation was 6.3 years (range, 2.1–12.5). There were four patients in LLP group, whose etiologies were AVN of the femoral head and insufficiency fracture (ISF) of the tibia or the medial cuneiform bone. Cumulative dose of steroids that administered from six months before transplantation to six months after discharge from hospitalization for transplantation was significantly higher in LLP group than non-LLP group. Additionally, the two groups differed significantly in terms of hospitalization period after transplantation. LLP caused by AVN of the femoral head manifested between six months and two years, whereas that caused by ISF within the first six months after transplantation.ConclusionsThe incidence of sustained LLP that impairs ambulation following contemporary allo-HSCT is not common in Japanese pediatric survivors. The risk of developing musculoskeletal LLP may increase with a higher steroid dosage in the peri-transplant period. LLP caused by AVN of the femoral head is likely to manifest later than that caused by ISF.     

异基因造血干细胞移植后早期特发性肺炎综合征的危险因素及发病机制

目的 研究异基凶造血干细胞移植(allo-HSCT)术后早期特发性肺炎综合征(IPS)的独立危险因素及发病机制.方法 同顾件分析192例allo-HSCT受者的临床资料,观察术后急性移植物抗宿主病(aGVHD)和IPS的发牛情况及其临床表现,对患者年龄、性别、原发病、移植时疾病状态(高危组70例,疾病处于难治、未缓解状态;标危组122例,疾病处于缓解状态)、供者类型、HLA相合程度、移植类型、预处理方案、急性移植物抗宿主病(aGVHD)、aGVHD程度、aGVHD累及器官等11项临床因素进行单因素分析,将有统计学意义的因素进行Logistic多因素同归分析,筛选出发生IPS的独立危险因素,并结合文献,探讨其发病机制.结果 192例allo-HSCT受者中,有23例发生IPS,发生时间为术后76 d(32～120 d),其中20例经治疗无效死亡,发病至死亡的时间为9 d(3～92 d),其余3例治愈.23例IPS患者中,有19例发生过aGVHD,其中肠道aGVHD16例.单因素分析显示,高危组、非亲缘供者、HLA不合、发生aGVHD、Ⅲ～Ⅳ度aGVHD及肠道aGVHD等6个因素具有统计学意义;多凶素分析显示,非亲缘供者、Ⅲ～Ⅳ度aGVHD和肠道aGVHD等3个因素是发生IPS的独立危险因素.结论 非亲缘供者、Ⅲ～Ⅳ度aGVHD及肠道aGVHD是发生IPS的独立危险因素;IPS可能是由aGVHD引起的肺部病变.     

Risk factors and severe outcome in thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation

BACKGROUND: Thrombotic microangiopathy (TMA) has been described as severe complication after hematopoietic stem cell transplantation (HSCT). The principal aim of this study was to focus the incidence and the outcome of TMA in the era of more complex HSCTs. METHODS: We analyzed the role of some predicting factors for the incidence and the outcome of TMA after HSCT. We enrolled 539 consecutive patients (307 males, median age 31 years) undergoing HSCT from match or mismatch human leukocyte antigen family donor (314) or match/mismatch unrelated (195) and haploidentical donor (30) for malignant or nonmalignant diseases. TMA diagnosis was performed by homogeneous clinical and laboratory criteria. RESULTS: Sixty-four of 539 patients presented TMA (11,87%) and the five-year cumulative incidence of TMA was 14% (HR=0.13). Fifty nine of 64 patients were affected by malignant and 5/64 by non-malignant diseases. On multivariate analysis, TMA occurrence was influenced by graft versus host disease >grade II (P=0.0001), donor type (P=0.029), gender (P=0.0233), total body irradiation based conditioning regimen (P=0.0041). Three factors for TMA outcome proved to be statistically significant by multivariate analysis: age (P=0.009), donor type (P=0.0187) and TMA index (P=0.029). The TMA mortality rate was 50%. The outcome was influenced by defibrotide (P=0.02 in univariate analysis). CONCLUSIONS: The study underlines the possibility of finding out which patients are more prone to developing post-HSCT TMA, and identifies which risk factors are more frequently associated with a dismal outcome after TMA.     

ABO血型主要不合异基因造血干细胞移植后纯红细胞再生障碍的临床分析

目的探讨ABO血型主要不合者异基因造血干细胞移植（allo-HSCT）后并发纯红细胞再生障碍（PRCA）的危险因素、临床转归以及PRCA的治疗和预防。方法42例行allo-HSCT，其中供、受者AN）血型主要不合者33例，主次双向不合者9例，27例受者血型为O型。预处理后，13例行骨髓移植，25例行外周血干细胞移植，4例行脐血移植。6例移植前行供者型血浆置换。移植后采用环孢素A（CsA）及短程甲氨蝶呤（MTX）联用预防移植物抗宿主病（GVHD）。结果42例均获得供者细胞植入，11例移植后并发PRCA（26．2％），11例的血型均为O型，其供者9例为A型，2例为B型；移植前行供者型血浆置换的O型受者，移植后均未发生PRCA。并发PRCA的11例中，8例经红细胞输注后自然缓解，2例行供者型血浆置换，其凝集素滴度下降后缓解，1例予利妥昔单抗治疗后缓解。单因素分析表明，O型受者、A型供者以及A型供给O型者与PRCA的发生相关，多因素分析表明，A型供给0型者是发生PRCA的独立危险因素（RR为10．999，95％可信区间为1．975-61．258，P〈0．05）。结论A型供给O型者与PRCA的发生密切相关；移植前行供者型血浆置换可预防PRCA的发生；供者型血浆置换和利妥昔单抗可有效治疗PRCA。     

Effects of immunosuppressive agents on magnesium metabolism early after allogeneic hematopoietic stem cell transplantation

BACKGROUND: The calcineurin inhibitors, cyclosporine A (CSA) and tacrolimus, cause hypomagnesemia by suppressing reabsorption of magnesium (Mg) from renal tubules. To assess whether the effect on Mg metabolism after allogeneic hematopoietic stem cell transplantation (HSCT) differs among calcineurin inhibitors, we prospectively evaluated the Mg metabolism in recipients of allogeneic HSCT who received CSA or tacrolimus METHODS: Patients who underwent allogeneic HSCT were enrolled. CSA and tacrolimus were given by continuous infusion starting from day -1. Serum Mg and the total amount of urinary Mg excretion were measured once before starting of CSA or tacrolimus, and once weekly after HSCT for 4 weeks. Mg was supplemented with magnesium l-aspartate by continuous infusion to maintain the serum Mg level >1.4 mEq/L. RESULTS: Thirty-six patients were evaluated (12 in the CSA group, 24 in the tacrolimus group). The serum Mg level began to decrease in both groups at the first week after HSCT, and the mean serum Mg levels were significantly lower in the tacrolimus group than in the CSA group from the first to the third week. The total amount of urinary Mg excretion and Mg supplementation began to increase in both groups at the second week after HSCT, and the amounts in the tacrolimus group were significantly higher than those in the CSA group. CONCLUSIONS: Although both calcineurin inhibitors increased urinary Mg excretion and caused hypomagnesemia shortly after HSCT, the effect was more significant with tacrolimus than with CSA. This observation may explain the higher incidence of renal impairment and encephalopathy in patients receiving tacrolimus.     

大剂量化疗联合二次干细胞移植治疗急性白血病复发患者的护理

对5例急性白血病异基因造血干细胞移植后复发的患者给予大剂量化疗联合供者外周血干细胞输注治疗,同时加强心理护理,密切观察病情变化,加强化疗药物不良反应及移植后并发症的观察与护理。结果1例死于急性移植物抗宿主病合并感染,1例白血病髓外复发死亡,3例现分别存活195d、232d和375d。     

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。     

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.     

Immune reconstitution at 6 months following T-cell depleted hematopoietic stem cell transplantation is predictive for treatment outcome

BACKGROUND: Compared with allogeneic bone marrow, in cytokine mobilized blood stem cell grafts, the number of hematopoietic progenitors and lymphoid cells is higher. Consequently, we compared the immune reconstitution following these two transplant modalities in patients receiving T-cell depleted grafts for hematological malignancies and studied the impact of lymphocyte subset recovery on clinical outcome. METHODS: Conditioning for transplantation was radiation-based, while graft versus host disease prophylaxis was by ex vivo T-cell depletion with Campath-1 antibodies. Clinical parameters of patients receiving bone marrow or cytokine-mobilized progenitor cell transplants were reviewed with emphasis placed on defining infectious events and on the causes of treatment failure (relapse, graft failure, or any cause of death). The blood lymphoid subsets, as well as markers for memory and naive T cells, were sequentially studied by standard flow cytometry. Serum immunoglobulins (Ig) concentrations were also determined. RESULTS: The patient population included 15 females and 27 males with a median age of 32.5 (range 15-54) years. Source of human leukocyte antigen-identical sibling allogeneic grafts was bone marrow in 14 and peripheral blood (PBPC) in 28. The median follow-up was of 1,278 (range 47-2,466) days. Following hematopoietic recovery, within the first year, 28 patients were readmitted for pyrexial episodes, and four died of sepsis. In both groups, while the CD8+ subset recuperated rapidly, CD19 and CD4+ T cells remained significantly decreased even after 12 months, leading to persistently abnormal CD4:CD8 ratios. The median values of CD16+ and CD56+ (natural killer) cells remained normal throughout the study period. Despite the patients who were receiving PBPC grafts having significantly higher numbers of allogeneic mononuclear cells (x 10(8)/kg; median: 6.97; range 4.03-10.10 vs. 0.71; range 0.45-0.99; P<0.001) and colony-forming unit granulocyte-macrophages (CFU-GMs) (x 10(4)/kg; median: 27.75; range 0-196, 2 vs. 13.05; range 2.43-57; P<0.05), the recovery rate of B cells or T-cell subpopulations was similar to those receiving bone marrow transplantation (BMT). Double fluorescence studies showed that CD2/CD45RO and RA as well as CD4/CD45RO and RA remained subnormal even after 12 months follow-up. During the observation period, except for IgA, normal levels of immunoglobulins were detected. In all, 18 out of 42 patients failed therapy, and 14 patients died. Treatment failure occurred at a median of 270 (range 47-1,638) days and was significantly associated with low total lymphocyte count (P = 0.01), CD2 (P = 0.09), CD8 (P = 0.01), CD19 (P = 0.02), CD45RA (P = 0.05), and CD4/CD45RA (P = 0.01), when tested at 6 months from transplantation. CONCLUSIONS: After T-cell depleted allogeneic PBPC or BMT, no differences in the rate of immune recovery were detected. However, patients with specific subset abnormalities at 6 months from grafting had a significantly higher risk of treatment failure.     

Clinical features of late onset non-infectious pulmonary complications following pediatric allogeneic hematopoietic stem cell transplantation

Park M, Koh KN, Kim BE, Im HJ, Seo JJ. Clinical features of late onset non‐infectious pulmonary complications following pediatric allogeneic hematopoietic stem cell transplantation.
Clin Transplant 2011: 25: E168–E176. © 2010 John Wiley & Sons A/S. Abstract: Background: Late onset non‐infectious pulmonary complications (LONIPCs) are major causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo‐HSCT). We evaluated the incidence and the outcomes of LONIPCs in children who underwent allo‐HSCT. Methods: Data for 143 children who underwent allo‐HSCT at Asan Medical Center between April 2002 and April 2009 were reviewed, and the 127 who survived more than three months were enrolled. Results: Eleven (8.7%) developed LONIPCs at a median eight months (range 3–14 months) after allo‐HSCT, presenting with cough and dyspnea. Six had bronchiolitis obliterans and five had idiopathic pneumonia syndrome. FVC declined more significantly in LONIPC than in non‐LONIPC patients three months after HSCT. A significant risk factor for the development of LONIPCs was chronic graft‐versus‐host disease (GVHD) (p = 0.002). At a median follow‐up of 36 months, the three‐yr overall survival rate in LONIPC patients was significantly lower than that of non‐LONIPC patients (37.4% vs. 72.7%, p = 0.02). The major cause of death was respiratory failure. Conclusions: Along with chronic GVHD, deterioration of pulmonary function at three months after HSCT may help in the early identification of patients at risk of subsequent LONIPCs. Considering the poor prognosis of LONIPC, strategies should be aimed at their prevention.     

Blood eosinophilia as a marker of favorable outcome after allogeneic stem cell transplantation

Eosinophilia is observed in a variety of disorders including acute and chronic graft-versus-host disease (GVHD). The clinical records of 237 patients who underwent allogeneic stem cell transplantation (allo-SCT) were retrospectively reviewed. Eosinophilia, defined as a relative eosinophil count>4% within the first 100 days, was observed in 135 patients (57%). The incidence of grades II-IV acute GVHD was significantly higher in patients without eosinophilia than in those with eosinophilia (68% vs. 43%; P<0.001). The incidence of chronic GVHD was significantly higher in patients without eosinophilia than in those with eosinophilia (73% vs. 56%; P=0.011). Relapse rate was similar between patients with and without eosinophilia (33% vs. 27%; P=0.438). The probability of nonrelapse mortality was 10% in patients with eosinophilia, which was significantly lower than that in patients without eosinophilia (31%; P<0.001), and the overall survival (OS) at 3 years was 67% in patients with eosinophilia, which was significantly higher than that in patients without eosinophilia (51%; P=0.003). Multivariate analysis identified older age, high-risk disease, acute GVHD, sex disparity between patient and donor, and the absence of eosinophilia as significant factors for reduced OS. These data lead us to conclude that eosinophilia after allo-SCT may serve as a favorable prognostic marker.     

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     

异基因造血干细胞移植受者代谢综合征的发生情况

异基因造血干细胞移植（hematopoieticcelltransplantation,HCT）后代谢综合征的发生主要由预处理导致的神经激素系统紊乱、血管内皮损伤、移植物的免疫和炎症作用以及继发的移植物抗宿主病及其治疗等引起。对代谢综合征及其组分（糖尿病、高血压、血脂紊乱等）的筛查可以尽早地调整治疗策略,控制危险因素的发生,进而降低远期的心血管疾病的发生率和致死率。为此,美国的研究人员回顾性分析了86例异基因HCT受者代谢综合征的发生情况,并与代谢综合征在普通人群中的流行情况进行比较。     

The significance of cytomegalovirus viremia at day 100 or more following allogeneic hematopoietic stem cell transplantation

We conducted a single‐center retrospective review of patients who had received allogeneic hematopoietic stem cell transplantation (HSCT) between January 2003 and December 2007, to assess the incidence and risk factors for late CMV infection and evaluate its effects on outcomes. Twenty of 49 HSCT recipients (41%) developed CMV infection at day ≥100 after transplant. Univariable analysis showed that having a matched unrelated donor, having early CMV infection, having a diagnosis of lymphoma, and receipt of antithymocyte globulin were risks for developing late CMV. On multivariable analysis, the occurrence of CMV prior to day 100 and lymphoma conferred a significant risk for late CMV infection. Of the 20 patients with late CMV infection, two patients manifested CMV disease (10%). Despite the relatively low incidence of CMV disease, patients with late CMV infection had a 4.8‐fold increased risk of death compared to patients without late CMV. Identifying patients at increased risk for developing late CMV infection may be important for prompting more intensive monitoring of infection late after HSCT, particularly because this manifestation of CMV is associated with poorer outcomes.     

单倍体造血干细胞移植治疗急性淋巴细胞白血病植入失败的二次移植策略

目的  探讨急性T淋巴细胞白血病患者初次单倍体造血干细胞移植后植入失败并发生致命性并发症的二次移植策略。方法  1例男性患者诊断为急性T淋巴细胞白血病,2015年11月接受供者为其胞妹的首次单倍体造血干细胞移植后植入失败,并发生大肠杆菌败血症、血清病、肝静脉闭塞症和多器官功能衰竭。首次移植后32 d行供者为其父亲的挽救性二次单倍体造血干细胞移植,二次移植前未进行预处理化学药物治疗（化疗）,采用移植后环磷酰胺（PTCy）方案为基础的移植物抗宿主病（GVHD）预防方案。结果  造血干细胞移植术后12 d白细胞植入,术后67 d血小板植入。血清病、败血症及肝静脉闭塞症治愈,器官功能改善。但移植后第18个月,即2017年6月,患者死于白血病复发。结论  植入失败患者二次移植前不进行预处理化疗,采用PTCy预防GVHD有望获得成功植入。