Hemophagocytic lymphohistiocytosis is a sign of poor outcome in pediatric Epstein‐Barr virus‐associated post‐transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation

EBV‐related PTLD developing after HSCT is a potentially life‐threatening disease. HLH is uncommon after allogeneic HSCT. Data on outcome of patients with PTLD and concomitant HLH after allogeneic HSCT are limited. In this retrospective study, we collected demographic, clinical, laboratory, and outcome data for 408 patients who underwent allogeneic HSCT from 2006 to 2015. Graft source included CB (n = 135; 33.1%), PBSCs (n = 34; 8.3%), and BM (n = 239; 58.6%). Eight out of 408 patients (2%) developed EBV‐PTLD with a median age at HSCT of 5.9 years (range: 2.3‐17.3). All eight patients received ATG as part of the conditioning regimen. Graft source was PBSC in three patients (37.5%), BM in four patients (50%), and CB in one patient (12.5%). Donors were matched unrelated in five patients (62.5%) and matched sibling in three patients (37.5%). Seven out of eight patients developed EBV‐PTLD within the first 100‐day post‐HSCT. Lymph node biopsy revealed early lesions in three patients, polymorphic in three patients, and monomorphic PTLD in two patients. Three patients (37.5%) died within 1 month of EBV‐PTLD diagnosis. All deceased patients developed HLH manifestations with two of them meeting HLH diagnostic criteria and one having an incomplete workup. PTLD after allogeneic HSCT with manifestations of HLH is associated with high mortality. Early identification and treatment of EBV‐PTLD seems imperative to control the disease, especially if signs of HLH are evolving.     

Haploidentical hematopoietic stem cell transplantation with post‐transplant high‐dose cyclophosphamide in high‐risk children: A single‐center study

Recently, haploidentical transplantations have been performed with unmanipulated BM or PBSC. This approach is becoming more widely adopted with the use of PTCY. However, there is limited evidence about this approach in children. We present 15 children who received 16 haploidentical HSCT with unmanipulated BM or PBSC using PTCY for GVHD prophylaxis. Post‐transplant CY(50 mg/kg IV) was given on the third and fifth day, and CsA or tacrolimus with MMF or MP was also used for GVHD prophylaxis. All patients engrafted at a median of 16 and 18 days for neutrophil and thrombocyte recovery, respectively. Grades II–III acute GVHD developed in seven patients, and mild chronic GVHD was found in two patients. Two patients died within the first 100 days due to sepsis (TRM 12.5%). Eleven patients are currently alive, with a median follow‐up of 12 months (range 6–22 months). The 12‐month OS and DFS were 75 ± 10.8% and 68.8 ± 11.6%, respectively. Our results with these high‐risk patients are encouraging for haploidentical HSCT in pediatric patients. Future studies should continue to assess haploidentical HSCT, including comparison of other modalities, in a primary pediatric population.     

The incidence of autoimmune hemolytic anemia in pediatric hematopoietic stem cell recipients post‐first and post‐second hematopoietic stem cell transplant

The reported incidence of post‐allogeneic HSCT AIHA was between 4.4% and 6% following a single transplant. Cord blood transplantation, T‐cell depletion, and chronic GvHD are significantly associated with post‐transplant AIHA. During an 11‐yr period, data for 500 pediatric HSCT recipients were eligible for evaluation of the incidence of AIHA post‐first and post‐second transplants. Demographic, transplant, and post‐transplant‐related variables were analyzed. Twelve of 500 (2.4%) recipients at a median of 273 days and seven of 72 (9.7%) recipients at a median of 157 days developed AIHA post‐first and post‐second HSCT, respectively. Post‐first HSCT, none of the MRD recipients developed AIHA (0/175 MRD vs. 12/325 other donors, p = 0.04). Four of 12 required a second HSCT to control the AIHA. After the second HSCT, MUD was significantly associated with the development of AIHA. No other variables were associated with the post‐second transplant AIHA. The incidence of AIHA post‐first and post‐second HSCT was less than the reported. The increased incidence of AIHA among recipients of second HSCT is most likely due to the profound immune dysregulation. A much larger, prospective study would be needed to evaluate the incidence, complications, and management of post‐transplant AIHA.     

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。     

Eltrombopag for secondary failure of platelet recovery post‐allogeneic hematopoietic stem cell transplant in children

Secondary failure of platelet engraftment occurs in 20% of patients undergoing allogeneic HSCT and is associated with poor outcome. Currently, there are no guidelines for treatment of late thrombocytopenia and platelet transfusion is the mainstay of treatment. Here, we describe the use of Eltrombopag to treat secondary failure of platelet recovery following HSCT in a child with severe aplastic anemia. Eltrombopag resulted in recovery of platelet count with no need for platelet transfusion support with no reported side effects. Eltrombopag may be used successfully in children with secondary failure of platelet recovery post‐HSCT for SAA.     

Neutrophil function in children following allogeneic hematopoietic stem cell transplant

HSCT is a lifesaving procedure for children with malignant and non‐malignant conditions. The conditioning regimen renders the patient severely immunocompromised and recovery starts with neutrophil (PMN) engraftment. We hypothesize that children demonstrate minimal PMN dysfunction at engraftment and beyond, which is influenced by the stem cell source and the conditioning regimen. Peripheral blood was serially collected from children at 1 to 12 months following allogeneic HSCT. PMN superoxide () production, degranulation (elastase), CD11b surface expression, and phagocytosis were assessed. Twenty‐five patients, mean age of 10.5 yr with 65% males, comprised the study and transplant types included: 14 unrelated cord blood stem cells (cords), seven matched related bone marrow donors, three matched unrelated bone marrow donors, and one peripheral blood progenitor cells. Engraftment occurred at 24 days. There were no significant differences between controls and patients in PMN production, phagocytosis, CD11b surface expression, and total PMN elastase. Elastase release was significantly decreased <6 months vs. controls (p < 0.05) and showed normalization by six months for cords only. The conditioning regimen did not affect PMN function. PMN function returns with engraftment, save elastase release, which occurs later related to the graft source utilized, and its clinical significance is unknown.     

Engraftment syndrome following allogeneic hematopoietic stem cell transplantation in children

Abstract:  ES is a complication that occurs immediately before or at the timing of neutrophil engraftment following autologous or allogeneic SCT. It is characterized by fever, skin rash, and non-cardiac pulmonary infiltrates. We evaluated the incidence, risk factors, and outcomes of ES following allogeneic SCT in children. Of 100 pediatric patients, 20 (20%) developed ES occurring at a median of 14 days (range 8–27 days) post-transplant. Patients presented with fever (100%), skin rash (100%), diffuse pulmonary infiltration (25%), and body weight gain (85%). On multivariate analysis, significant risk factors for ES included younger age (<8 yr old) and human leukocyte antigen disparity between donors and recipients. Univariate analysis showed that patients with ES had a higher incidence of developing chronic graft-versus-host disease and ES was not associated with other complications. Event-free survival did not significantly differ between patients with and without ES regardless of the presence of malignant or non-malignant diseases.     

Bullous pemphigoid after allogeneic hematopoietic stem cell transplantation

Bullous pemphigoid (BP) is an autoimmune skin disorder characterized by subepidermal blisters due to deposit of autoantibody against dermal basement membrane protein. It has been reported that BP can occur after allogeneic hematopoietic stem cell transplantation (HSCT). We describe a patient with BP having autoantibody against BP180 after unrelated‐donor HSCT against T lymphoblastic leukemia. The patient was treated with steroid leading to complete resolution of BP, but T lymphoblastic leukemia progressed rapidly after steroid hormone treatment. Given that immunosuppressant may reduce graft‐versus‐tumor effect, immunomodulatory agents such as nicotinamide and tetracycline, erythromycin, and immunoglobulin may be appropriate as soon as typical blister lesions are seen after HSCT.     

Toxic epidermal necrolysis in a child 6 months post‐hematopoietic stem cell transplantation

TEN is a rare and critical disease mostly caused by drugs. It is mediated by activated CD8+ T cells that cause keratinocyte apoptosis with the assistance of cytokines/chemokines. We herein report a pediatric case of TEN after allogeneic HSCT with precursor B‐cell acute lymphoblastic leukemia (pre‐B‐ALL) in second complete remission. Although we did not evaluate the T‐cell subpopulation in blood or skin lesion of the patient, an imbalanced immune reconstitution after HSCT might additively contribute to the development of TEN.     

Proven Epstein–Barr encephalitis with negative EBV‐DNA load in cerebrospinal fluid after allogeneic hematopoietic stem cell transplantation in a child with acute lymphoblastic leukemia

We report a case of EBV encephalitis in a seven‐yr‐old child with Ph+ ALL. Two months after an allogeneic HSCT from his HLA mismatched mother, the patient showed an altered sensorium, generalized seizures, and a left hemiparesis. Brain MRI demonstrated multiple lesions highly suggestive for viral encephalitis. Blood and CSF PCR analyses were negative for the most common viruses involved in immunocompromised patients including EBV. A cerebral biopsy was performed, which showed intense gliosis and perivascular lymphocytic cuffing. PCR analysis performed on brain tissue was positive only for the EBV genome, while extensive investigations for other viral infections were negative. The patient's neurological symptoms rapidly worsened and he died two months later. This case report suggests that in patients presenting neurological and radiological signs of encephalitis after an HSCT, an EBV involvement should be considered, even in the absence of CSF and blood PCR virus detection.     

Treatment and outcomes in classic Hodgkin lymphoma post‐transplant lymphoproliferative disorder in children

Classic Hodgkin lymphoma post‐transplant lymphoproliferative disorder (HL‐PTLD) has been rarely reported in children, with limited data available to guide treatment decisions. We report a retrospective review of five children diagnosed with classic HL‐PTLD following solid organ transplant between 2007 and 2013 at Stanford University. Patients were treated with Stanford V chemotherapy and involved field radiation therapy. With a median follow‐up of 7.2 years (range, 4.7–10.5 years) since diagnosis, all patients remain in remission from HL‐PTLD and free from graft failure. In this series, combined modality therapy with risk‐adapted chemotherapy and radiation therapy was a successful strategy for the treatment of classic HL‐PTLD.     

Severe lung injury and lung biopsy in children post‐hematopoietic stem cell transplantation: The differences between allogeneic and autologous transplantation

To review outcome of children post‐allogeneic (allo) and autologous (auto) SCT with severe lung injury who had lung biopsy and to determine whether the diagnoses provided by lung biopsy had an impact on outcome. Retrospective study was carried out from January 2000 to June 2010. Nine hundred and eighteen children (0–18 yr) received SCT (allo 476, auto 442), and 59 biopsies were performed in 48 patients. Most common result of lung biopsy was non‐infectious inflammation and recurrent disease in allo‐ and autorecipients, respectively. In a multivariate analysis, survival of allorecipients who had management change was inferior (p = 0.002; HR: 3.12). These patients were extremely sick, and management change was the last attempt to stabilize their respiratory status. There was a trend toward superior survival for children who had biopsy after 100 days following SCT (p = 0.09; HR: 0.55) and a trend toward inferior survival for those with proven infections within two wk of biopsy (p = 0.07; HR: 2.14). Only 31% of allorecipients and 25% of autorecipients survived. There were no biopsy‐related complications. Lung biopsy itself appears to be well tolerated, although requiring a biopsy seems to carry a poor prognosis; this seems to be due to different causes, auto (relapse), allo (non‐infectious inflammation).     

Multiple viral infections post‐hematopoietic stem cell transplantation are linked to the appearance of chronic GVHD among pediatric recipients of allogeneic grafts

Olkinuora HA, Taskinen MH, Saarinen‐Pihkala UM, Vettenranta KK. Multiple viral infections post‐hematopoietic stem cell transplantation are linked to the appearance of chronic GVHD among pediatric recipients of allogeneic grafts.
Pediatr Transplantation 2010:14:242–248. © 2009 John Wiley & Sons A/S. Abstract: Delayed immune reconstitution and the ensuing opportunistic infections among children following hematopoietic stem cell transplantation (HSCT) are associated with increased treatment‐related morbidity and mortality (TRM). We retrospectively evaluated the impact of viral infections on the posttransplant recovery of pediatric recipients of stem cell grafts as a reflection of their posttransplant immunoreconstitution in a single institution setting. The case histories of 124 children (during 1/1999‐9/2006) were reviewed for infectious episodes, and correlated with their respective clinical parameters. Patients with a high risk for CMV received prophylaxis, but failures in the prophylaxis were common (40%). 110/124 (89%) of these allogeneic patients had at least one viral reactivation/clinical infection posttransplant. In this group of pediatric patients chronic GVHD (P<0,001) and secondary graft failure were significantly (P=0,001) associated with early (during the first 100 days post HSCT), multiple (≥ 2) viral infections. Our data indicate that viruses are common pathogens among pediatric recipients of allogeneic stem cell grafts. In this group of patients multiple viral infections early on seem to reflect an even more severe degree of immunological derangement in the recipient and identify a group of patients with an increased risk of chronic GVHD and secondary graft failure.     

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.