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Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is an under-recognized yet potentially devastating complication of hematopoietic stem cell transplantation (HSCT) which had increased awareness in recent years. This report summarizes the demographics and outcomes of pediatric TA-TMA in Hong Kong., Methods: All patients aged below 18 years who underwent HSCT in the Hong Kong Children's Hospital and were diagnosed to have TA-TMA during the 2-year period from April 1, 2019 to March 31, 2021 were included., Results: A total of 73 transplants (51 allogeneic and 22 autologous) in 63 patients had been performed. Six patients (four males and two females) developed TA-TMA at a median duration of 2.5 months post-HSCT. The incidence rate was 9.52%. Of the six TA-TMA patients, five underwent allogenic one underwent autologous HSCT, respectively. Three of them were histologically proven. All four patients with cyclosporine had stopped the drug once TA-TMA was suspected. Median six doses of eculizumab were administered to five out of six patients. Three patients died (two due to fungal infection and one due to acute-on-chronic renal failure) within 3 months upon diagnosis of TA-TMA. Among three survivors, two stabilized with mild stage 2 chronic kidney disease (CKD) while the other suffered from stage 5 end-stage CKD requiring lifelong dialysis., Conclusion: In conclusion, recognition and diagnosis of TA-TMA are challenging. Early recognition and prompt administration of complement blockage with eculizumab may be beneficial in selected cases. Further prospective research studies are recommended to improve the management and outcomes of TA-TMA., (© 2022 Wiley Periodicals LLC.)

Background: Hematopoietic stem cell transplantation, despite being a curative treatment for various pediatric disorders, is associated with significant acute and chronic complications., Methods: This retrospective review of 196 hematopoietic stem cell transplantation episodes (144 allogeneic, 52 autologous) performed in a tertiary pediatric unit focused on neurological symptoms and complications occurred from the start of conditioning to within 3 years of transplantation. Indications for transplantation included both benign and malignant diseases. For episodes involving allogeneic transplantation, 42% of donors were matched-unrelated, 19% were matched-sibling, and 12% were haploidentical.  RESULTS: Neurological complications developed in 17% of all hematopoietic stem cell transplantation episodes. Tumors of central nervous system and leukemia or lymphoma were two indications reported to have higher incidence of 42% and 21%, respectively. The occurrence of neurological complications was significantly associated with primary diagnosis (p = 0.01), central nervous system involvement by underlying disease (p = 0.001), and radiation-based conditioning (p = 0.018). Upon multivariate analysis, central nervous system involvement by underlying disease remained to be the only significant factor (p = 0.019), while radiation-based containing conditioning (p = 0.029) is revealed to be associated when considering allogeneic transplantation alone. Pre-transplant central nervous system-directed treatment, allogeneic versus autologous donor, stem cell source, donor type, busulfan use, and cyclosporin use were not significantly associated with neurological complications. Patients with neurological complications were also found to have an inferior 2-year overall survival (53.9% ± 8.8% versus 63.8% ± 4.2%; p = 0.016)., Conclusion: Neurological complications were common in pediatric hematopoietic stem cell transplantation and were associated with adverse outcome; non-radiation containing conditioning regimens might be beneficial in mitigating the risk of such complications., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Allogeneic hematopoietic stem cell transplantation is curative for transfusion-dependent thalassemia, but mixed chimerism (MC) may herald graft rejection. We report a child who failed bone marrow transplant (BMT) from matched unrelated donor (MUD) successfully salvaged with haploidentical peripheral blood stem cell transplant (PBSCT), but had MC in T-lymphocyte compartment despite near-complete donor chimerism in myeloid compartment. MC was successfully improved by repeated CD45RA-depleted donor lymphocyte infusion (DLI). A 2-year-old Chinese girl with beta-thalassemia major underwent 12/12-MUD BMT with HU/AZA/Cy/Flu/Bu/TT conditioning resulted in graft rejection. As donor refused second donation, rescue haploidentical PBSCT was performed with alemtuzumab/fludarabine/treosulfan conditioning. Harvest product was CD3/CD45RA depleted with extra products cryopreserved. Split cell chimerism performed 1-month after haplo-transplant showed 97% mother, 3% MUD, and 0% host for granulocytes but 38% mother, 62% MUD, and 0% host for CD3 + T cells. In view of low haploidentical donor chimerism in T-lymphocyte compartment, CD45RA-depleted DLI using cryopreserved product was performed on day + 38, after thymoglobulin 3 mg/kg given as T-cell depletion 3 days beforehand. T-cell chimerism improved to 51% mother and 49% MUD post-DLI. Second cryopreserved CD45RA-depleted DLI was given 17 days after the first DLI (day + 55), and 100% full chimerism of mother's T cells was gradually established without significant graft-versus-host disease (GVHD) or viral reactivation. To conclude, split lineage chimerism determination is beneficial to guide management strategy. For MC in T-cell compartment, CD45RA-depleted DLI is a potential alternative to unselected T cells as it carries lower risk of GVHD and infection., (© 2020 Wiley Periodicals LLC.)

Primary central nervous system (CNS) post-transplant lymphoproliferative disorder (PTLD) in childhood is rare. Twenty-five patients were retrieved from nine European Intergroup for Childhood Non-Hodgkin's Lymphoma and/or international Berlin-Frankfurt-Münster Study Group members. Types of allografts included kidney (n = 11), liver (n = 4), heart (n = 5), bowel (n = 1) and haematopoietic stem cells (n = 4). Eighteen were male, 16 ≥ 10 years old, 21 had monomorphic disease and 24 solid intracranial tumour masses. Four-year event-free and overall survival rates were 50% ± 10% and 74% ± 9% respectively. This report represents the largest paediatric series of CNS PTLD reported to date, showing favourable survival odds following systemic and intrathecal chemotherapy and rituximab administration., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Refractory or relapsed acute lymphoblastic leukemia (r/r ALL) represents the leading cause of cancer mortality in children. Clofarabine is effective in inducing remission thus enabling bridging to hematopoietic stem cell transplantation (HSCT). We report the results in treating Hong Kong Chinese pediatric patients with r/rALL by clofarabine/cyclophosphamide/etoposide (CLO-218) combination therapy. A retrospective review of patients treated between January 2009 and December 2014 in the two tertiary referral pediatric oncology units in Hong Kong. Thirteen patients were identified. All were Chinese and seven were male. Median age at clofarabine treatment was 8 years and the median duration of follow-up was 10 months. Nine patients had B-ALL and four had T-ALL. All were refractory to the preceding regimen(s). The median number of prior treatment regimens was 2; two patients had previous HSCT. Complete remission (CR) was achieved in five patients, Complete remission with incomplete counts (CRi) in two, PR in two, and non-remission (NR) in two. All four patients with T-ALL responded with three patients achieving CR. Eight out of nine patients who responded could be bridged to HSCT. Among those who were transplanted, four remained alive and in remission, three relapsed post-HSCT, and one died from transplant-related mortality. Treatment toxicities were common including febrile neutropenia in all subjects and culture-proven bacteremia in five patients. Hepatotoxicity was mild and reversible with no case of veno-occlusive disease. The clofarabine-based regimen is a promising strategy to induce disease remission in r/rALL and bridge to HSCT. Septic complications are, however, frequent necessitating prompt management with adequate supportive care in specialized centers.

Background: Hepatic veno-occlusive disease (VOD) is a severe complication after haematopoietic stem cell transplantation (HSCT). Different drugs with different mechanisms of action have been tried in HSCT recipients to prevent hepatic VOD. However, it is uncertain whether high-quality evidence exists to support any prophylactic therapy., Objectives: We aimed to determine the effects of various prophylactic therapies on the incidence of hepatic VOD, overall survival, mortality, quality of life (QOL), and the safety of these therapies in people undergoing HSCT., Search Methods: We searched the Cochrane Central Registe of Controlled Trials (CENTRAL), MEDLINE, EMBASE, conference proceedings of three international haematology-oncology societies and two trial registries in January 2015, together with reference checking, citation searching and contact with study authors to identify additional studies., Selection Criteria: We included randomised controlled trials (RCTs) comparing prophylactic therapies with placebo or no treatment, or comparing different therapies for hepatic VOD in people undergoing HSCT., Data Collection and Analysis: We used standard methodological procedures expected by Cochrane., Main Results: We included 14 RCTs. Four trials (612 participants) compared ursodeoxycholic acid with or without additional treatment versus placebo or no treatment or same additional treatment. Two trials (259 participants) compared heparin with no treatment. Two trials (106 participants) compared low molecular weight heparin (LMWH) with placebo or no treatment. One trial (360 participants) compared defibrotide with no treatment. One trial (34 participants) compared glutamine with placebo. Two trials (383 participants) compared fresh frozen plasma (FFP) with or without additional treatment versus no treatment or same additional treatment. One trial (30 participants) compared antithrombin III with heparin versus heparin. One trial compared heparin (47 participants) with LMWH (46 participants) and prostaglandin E1 (PGE1) (47 participants). No trial investigated the effects of danaparoid. The RCTs included participants of both genders with wide age range and disease spectrum undergoing autologous or allogeneic HSCT. Funding was provided by government sources (two studies), research fund (one study), pharmaceutical companies that manufactured defibrotide and ursodeoxycholic acid (two studies), or unclear source (nine studies). All RCTs had high risk of bias because of lack of blinding of participants and study personnel, or other risks of bias (mainly differences in baseline characteristics of comparison groups).Results showed that ursodeoxycholic acid may reduce the incidence of hepatic VOD (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.40 to 0.88; number needed to treat for an additional beneficial outcome (NNTB) 15, 95% CI 7 to 50, low quality of evidence), but there was no evidence of difference in overall survival (hazard ratio (HR) 0.83, 95% CI 0.59 to 1.18, low quality of evidence). It may reduce all-cause mortality (RR 0.70, 95% CI 0.50 to 0.99; NNTB 17, 95% CI 8 to 431, low quality of evidence) and mortality due to hepatic VOD (RR 0.27, 95% CI 0.09 to 0.87; NNTB 34, 95% CI 16 to 220, very low quality of evidence). There was no evidence of difference in the incidence of hepatic VOD between treatment and control groups for heparin (RR 0.47, 95% CI 0.18 to 1.26, very low quality of evidence), LMWH (RR 0.27, 95% CI 0.06 to 1.18, very low quality of evidence), defibrotide (RR 0.62, 95% CI 0.38 to 1.02, low quality of evidence), glutamine (no hepatic VOD in either group, very low quality of evidence), FFP (RR 0.66, 95% CI 0.20 to 2.17, very low quality of evidence), antithrombin III (RR 0.13, 95% CI 0.01 to 2.15, very low quality of evidence), between heparin and LMWH (RR 1.96, 95% CI 0.80 to 4.77, very low quality of evidence), between heparin and PGE1 (RR 1.20, 95% CI 0.58 to 2.50, very low quality of evidence), and between LMWH and PGE1 (RR 0.61, 95% CI 0.24 to 1.55, very low quality of evidence). There was no evidence of difference in survival between treatment and control groups for heparin (92.6% vs. 88.7%) and defibrotide (HR 1.04, 95% CI 0.54 to 2.02, low quality of evidence). There were no data on survival for trials of LMWH, glutamine, FFP, antithrombin III, between heparin and LMWH, between heparin and PGE1, and between LMWH and PGE1. There were no data on quality of life (QoL) for any trials. Eleven trials reported adverse events. There was no evidence of difference in the frequency of adverse events between treatment and control groups except for one trial showing that defibrotide resulted in more adverse events compared with no treatment (RR 18.79, 95% CI 1.10 to 320.45). These adverse events included coagulopathy, gastrointestinal disorders, haemorrhage and microangiopathy. The quality of evidence was low or very low due to bias of study design, and inconsistent and imprecise results., Authors' Conclusions: There is low or very low quality evidence that ursodeoxycholic acid may reduce the incidence of hepatic VOD, all-cause mortality and mortality due to VOD in HSCT recipients. However, the optimal regimen is not well-defined. There is insufficient evidence to support the use of heparin, LMWH, defibrotide, glutamine, FFP, antithrombin III, and PGE1. Further high-quality RCTs are needed.

Background: The immunosuppressed state in patients undergoing hematopoietic stem cell transplantation (HSCT) predisposes them to activation of latent viral infections such as herpesvirus types 6 and 7 (HHV6 and HHV7). We aimed to evaluate the incidence, manifestations, outcomes, and risk factors of HHV 6 and HHV 7 infections after pediatric hematopoietic stem cell transplantation., Material and Methods: We performed 106 HSCTs (86 allogeneic and 20 autologous) on 94 children (56 boys, median age 7.1 years) during 2006-2012. Patients suspected to have HHV6 or HHV7 infections were tested using polymerase chain reaction on serum and/or cerebrospinal fluid., Results: Among the 63 patients tested for HHV, 10 patients (15.9%) were infected (HHV-6 (n=6), HHV-7 (n=4)) at a median of 18 days post-HSCT (cumulative incidence 11.5% at 1 year). Manifestations included fever (90%), rash (70%), hepatitis (80%), pneumonitis (50%), central nervous system (CNS) manifestations (40%), and graft failure (10%). One patient had persistent CNS infection despite treatment with foscarnet, ganciclovir, and cidofovir. Seven patients cleared herpesvirus after a median of 22 days. Four patients died (relapse of malignancy [n=3], acute graft-versus-host disease [aGVHD] [n=1]). Herpesvirus infections were associated with adenovirus infection (p=0.001) and severe (grade III-IV) aGVHD (p=0.037)., Conclusions: We concluded that HHV6 and HHV7 infections are common after pediatric HSCT. Most infections were self-limited and could be associated with adenovirus infection and severe aGVHD. Further studies are needed to evaluate predictors of severe morbidity or mortality, and define optimal prophylaxis and treatment.

We retrospectively analysed the outcomes of 127 children with acquired severe aplastic anaemia (SAA) who had received haematopoietic stem cell transplantation (HSCT) between 2000 and 2011 in one of the 10 Asia Pacific institutions. Fifty-three were matched sibling donor (MSD) and 74 were alternative donor (AD), including 22 matched unrelated donor, 32 mismatched unrelated donor and 20 mismatched related donor. With a median follow up 45.5 months (13-139) and when compared to the MSD group, AD recipients had more grade II-IV acute graft-versus-host disease (aGVHD; 14.3% vs. 32.8%, P = 0.029), but similar grade III-IV aGVHD (10.2% vs. 12.5%, P = 0.774), graft failure (GF) (15.1% vs. 15.5%, P = 0.658) and 5-year overall survival (90.6% vs. 83.7%, P = 0.251). As a source of stem cell, peripheral blood stem cells (PBSC) resulted in less GF (18% vs. 9.1% P = 0.013), similar grade II-IV aGVHD (28.1% vs. 17.4%, P = 0.258), chronic GVHD (25.8% vs. 29.3%, P = 0.822) and similar outcomes (89.7% vs. 82.4%, P =0.665) when compared to bone marrow (BM). In univariate analysis, GF (P < 0.001) and grade II-IV aGVHD (P = 0.009) were predictors of poor survival. In multivariate analysis, only GF was associated with poor survival (P = 0.012). The outcome of AD and PBSC HSCT were comparable to that of MSD and BM HSCT in the Asia Pacific region., (© 2013 John Wiley & Sons Ltd.)

Norovirus infections are increasingly being recognized as important causes of diarrhea in hematopoietic stem cell transplantation (HSCT) recipients. This retrospective study aimed to evaluate the cumulative incidence, risk factors, and outcomes of norovirus infection in pediatric HSCT recipients. Among 55 patients age <21 years who underwent first HSCT between July 2007 and June 2011, 49 patients developed diarrhea and had stool tested for norovirus. Eight of these patients were found to be infected with norovirus. All were sporadic cases and manifested with nausea, vomiting, and diarrhea. The median age of these patients was 5.2 years (range, 0.5-18.5 years). Six were males. Seven patients underwent unrelated donor HSCT, and 1 patient underwent autologous cord blood HSCT. Two patients had norovirus infection before HSCT that persisted after transplantation. In the remaining 6 patients, norovirus developed at a median of 36.5 days posttransplantation (range, 5-517 days). The cumulative incidence of norovirus infection was 12.9% at 2 years posttransplantation. Risk factors for norovirus infection included the use of peripheral blood or cord blood as the stem cell source (P = .043) and administration of fludarabine (P = .002) and alemtuzumab (P = .011). The median time to viral clearance was 145 days (range, 13-263 days). Four-year survival was similar in norovirus-infected patients and noninfected patients (56.3% versus 58.3%)., (Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

aGVHD of the GI tract is common after allogeneic HSCT. Corticosteroids are the mainstay of treatment. Recent data suggest infliximab might be beneficial for steroid refractory aGVHD. We reviewed our experience in 10 pediatric patients who developed severe steroid refractory aGVHD (stage 3, n = 6; stage 4, n = 4), after an allogeneic matched unrelated HSCT for various hematological diseases (leukemia, n = 7; thalassemia, n = 3). The median age was 9.5 yr (range, 0.8-18.5 yr). All patients received 10 mg/kg infliximab weekly for 3-4 doses. Eight patients had CR and two had partial response. None of the patients developed therapy-related adverse effects. All patients developed infections subsequently, which may or may not be related to infliximab. Five patients developed chronic GVHD (cGVHD) (four severe, one mild). Six patients died at 66-1451 days post-transplant, from infection (n = 3), aGVHD (n = 1), lung cGVHD (n = 1), or idiopathic pneumonia (n = 1). Four patients were alive at 238-924 days post-transplant, all of whom had an increase in BMI by six months post-transplant. In conclusion, infliximab is well tolerated and appears effective in children with steroid refractory or dependent GI aGVHD. Infection is common and mortality remains high., (© 2012 John Wiley & Sons A/S.)

Autologous hematopoietic stem cell transplant (AHSCT) has been advocated as a form of salvage therapy for children with high-risk or relapsed brain tumors but only limited data are available currently. We report the outcomes of pediatric brain tumors treated with AHSCT in a quaternary referral center in Hong Kong over 10 years (June 1996-May 2006). Thirteen patients with medulloblastoma (n = 9), cerebral primitive neuroectodermal tumor (n = 1), ependymoma (n = 1), germ cell tumor (n = 1) and cerebellar rhabdoid (n = 1) were transplanted because of tumor residual (n = 1) or recurrence (n = 12). Uniform upfront treatment protocols were adopted according to specific tumor types. Prior to AHSCT, 8 patients (61.5%) achieved complete remission and 5 (38.5%) were in partial remission. Conditioning employed thiotepa 300 mg/m2, etoposide 250 mg/m2)and carboplatin 500 mg/m2 daily for 3 days. Toxicity included mucositis and neutropenic fever in all patients, grade 4 hepatic toxicity in 4 patients (including hepatic veno-occlusive disease in 2 patients) and grade 4 renal toxicity in 1 patient. The 5-year event-free survival was 53.9%. Five patients died of disease recurrence or progression 8-21 months after transplant with a median disease-free period of 8 months post-transplant. One died of transplant-related complications in the early post-transplant period. Seven survived for a median of 5.4 years (maximum follow-up of 9.8 years), with six having Lansky-Karnofsky performance score above 80. All survivors had complete remission before transplant though 2 had leptomeningeal spread. We conclude that AHSCT can achieve long-term survival in children with recurrent brain tumor. However, those with macroscopic residual tumor before transplant cannot be salvaged.

A retrospective cohort of 163 children with 171 hematopoietic stem cell transplantation (HSCT) performed during Mar. 1992-Dec. 2005 were analyzed to evaluate the incidence, risk factors, management, and outcome of hemorrhagic cystitis (HC). Fourteen patients (8.2%) developed HC (6 boys, median age 6.6 years) at 0-166 days after HSCT (median 25 days), and lasted for 3-96 days (median 26 days). Older age at transplant (median 11.0 vs. 6.4 years, P = 0.013), allogeneic transplant (OR = 4.4, P = 0.02), cyclophosphamide-containing conditioning (OR = 4.87, P = 0.008), moderate-to-severe acute graft-versus-host disease (GVHD) (OR = 3.56, P = 0.025) and hepatic GVHD (OR = 3.62, P = 0.017) were associated with higher risks of HC in univariate but not multivariate analyses. While estrogen was ineffective in most patients, intravesical formalin, which was used in five patients, was found to be a very effective yet safe treatment for intractable HC. Patients with HC had longer hospital stay (median 175 vs. 88 days, P = 0.004). HC resolved after treatments in all cases but eight of the 14 patients subsequently died of other complications of HSCT. In conclusion, HC is a serious complication of allogeneic HSCT. Treatment with intravesical formalin appears effective and safe and can be considered early in severe HC to reduce the risk of morbidity and mortality.

Abstract: Relapsed/refractory NB carries a bleak outcome, warranting novel treatment options. HaploHSCT induces a graft‐versus‐NB effect via natural killer cell alloreactivity. Review of patients with relapsed/refractory NB who underwent haploHSCT with ex vivo T‐cell depletion in our unit from 2013 through 2018. Ten patients were identified (male=5; median age at haploHSCT=6.45 y, range: 3.49‐11.02 y). Indications were relapsed in 7 and refractoriness in 3; disease status at haploHSCT was CR in 2, PR in 6, and PD in 2. All patients received peripheral blood stem cell grafts after ex vivo T‐cell depletion (CD3/CD19‐depletion=1; TCR‐αβ/CD19‐depletion=4; CD3/CD45RA‐depletion=4; and TCR‐αβ/CD45RA‐depletion=1). Conditioning regimens were fludarabine‐based. Neutrophils engrafted on median D + 10 (range: D + 9 to +13), and platelets engrafted (≥20 × 109/L) on median D + 8 (range: D + 5 to D + 14). Early T‐ and NK‐cell recovery were evident. Of the 10 patients, acute rejection developed in 1 (who died of PD despite rescue HSCT), and 1 died of sepsis before engraftment; 8 experienced full donor‐chimerism post‐HSCT. Among the 8, 6 experienced CR, 1 died of PD, and 1 died of pulmonary hypertensive crisis before evaluation. At publication, 4 were in remission (2.8, 7.4, 28.5, and 58.9 months). No significant GvHD occurred. HaploHSCT with selective ex vivo T‐cell depletion may be a safe and useful salvage strategy for relapsed/refractory NB. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite very poor survival, controversies remain in the treatment for refractory or relapsed non-Hodgkin lymphoma (r/r NHL) in children and adolescents. The current project identifies and reports international experience on re-induction treatment of r/r NHL, hematopoietic stem cell transplantation, risk factors associated with outcome, and suggests treatment recommendations. Despite poor survival, controversies remain in the treatment for refractory or relapsed pediatric non-Hodgkin lymphoma (r/r NHL). The current project aimed to collect international experience on the re-induction treatment of r/r NHL, hematopoietic stem cell transplantation (HSCT), risk factors associated with outcome, and to suggest treatment recommendations. Inclusion criteria were (i) refractory disease, disease progression or relapse of any NHL subtype except anaplastic large cell lymphoma, (ii) age < 18 years at initial diagnosis, (iii) diagnosis in/after January 2000. Data from 639 eligible patients were evaluable. The eight-year probability of overall survival was 34 ± 2% with highly significant differences according to NHL subtypes: 28 ± 3% for 254 Burkitt lymphoma/leukemia, 50 ± 6% for 98 diffuse large B-cell lymphomas, 57 ± 8% for 41 primary mediastinal large B-cell lymphomas, 27 ± 3% for 177 T-lymphoblastic lymphomas, 52 ± 10% for 34 precursor-B-cell lymphoblastic lymphomas and 30 ± 9% for 35 patients with rare NHL subtypes. Subtype-specific factors associated with survival and treatment recommendations are suggested. There were no survivors without HSCT, except in few very small subgroups. Conclusions: There is an urgent need to further improve survival in r/r NHL. The current study provides the largest real-world series, which underlines the role of HSCT and suggests treatment recommendations. [ABSTRACT FROM AUTHOR]