Publications by authors named "Paul G Schlegel"

59 Publications

Prostaglandin E in a TLR3- and 7/8-agonist-based DC maturation cocktail generates mature, cytokine-producing, migratory DCs but impairs antigen cross-presentation to CD8 T cells.

Cancer Immunol Immunother 2020 Jun 25;69(6):1029-1042. Epub 2020 Feb 25.

Laboratory for Stem Cell Processing and Cellular TherapyUniversity Medical Center, Children's Hospital, Würzburg, Germany.

Mature dendritic cells (DCs) represent cellular adjuvants for optimal antigen presentation in cancer vaccines. Recently, a combination of prostaglandin E (PGE) with Toll-like receptor agonists (TLR-P) was proposed as a new standard to generate superior cytokine-producing DCs with high migratory capacity. Here, we compare TLR-P DCs with conventional DCs matured only with the proinflammatory cytokines TNFα and IL-1ß (CDCs), focussing on the interaction of resulting DCs with CD8 T-cells. TLR-P matured DCs showed elevated expression of activation markers such as CD80 and CD83 compared to CDCs, together with a significantly higher migration capacity. Secretion of IL-6, IL-8, IL-10, and IL-12 was highest after 16 h in TLR-P DCs, and only TLR-P DCs secreted active IL-12p70. TLR-P DCs as well as CDCs successfully primed multifunctional CD8 T-cells from naïve precursors specific for the peptide antigens Melan-A, NLGN4X, and PTP with comparable priming efficacy and T-cell receptor avidity. CD8 T-cells primed by TLR-P DCs showed significantly elevated expression of the integrin VLA-4 and a trend for higher T-cell numbers after expansion. In contrast, TLR-P DCs displayed a substantially reduced capability to cross-present CMVpp65 protein antigen to pp65-specific T cells, an effect that was dose-dependent on PGE during DC maturation and reproducible with several responder T-cell lines. In conclusion, TLR-P matured DCs might be optimal presenters of antigens not requiring processing such as short peptides. However, PGE seems less favorable for maturation of DCs intended to process and cross-present more complex vaccine antigens such as lysates, proteins or long peptides.
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http://dx.doi.org/10.1007/s00262-019-02470-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223547PMC
June 2020

Viral reactivations following hematopoietic stem cell transplantation in pediatric patients - A single center 11-year analysis.

PLoS One 2020 4;15(2):e0228451. Epub 2020 Feb 4.

Department of Oncology, Hematology and Stem Cell Transplantation, University Children's Hospital Würzburg, Würzburg, Germany.

Viral reactivation occurs frequently in the context of immunodeficiency and immunosuppression after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and can cause severe complications. The aim of this single-center retrospective analysis was to characterize viral infections in the first year after HSCT, to investigate risk factors and to study the impact of viral infections on transplantation outcome. This will facilitate the identification of at-risk patients and the development of new preventive strategies. 107 pediatric allo-HSCT from January 2005 through December 2015 were analyzed for infections with Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus 6 (HHV-6), adenovirus (ADV), herpes simplex virus (HSV) and varicella zoster virus (VZV). Viral infections were detected after 68.2% of transplantations. The viruses most commonly encountered were HHV-6 (36/107) and EBV (30/107). Severe viral disease was rare (7/107) and none of the patients died as result of viral reactivation. Important risk factors for viral infections were higher age at HSCT, donor type and occurrence of acute graft-versus-host disease (aGvHD). Especially for EBV, transplant from an unrelated donor and in-vivo T-cell depletion (TCD) had a significant effect on infection rates, whereas for CMV the strongest effect was seen by donor and recipient serostatus with recipient seropositivity most predictive for reactivation. The occurrence of severe aGvHD was associated with EBV and ADV infections. For HSV, the recipient serostatus was identified as prognostic factor for HSV infections, while we found higher age at time of HSCT as risk factor for VZV infections. The overall survival of patients with or without viral infections did not differ significantly. Interestingly, when looking at the 85 patients in our cohort who had received an HSCT for a malignant disease, a tendency towards lower relapse rates was seen in patients affected by viral infections (HR 0.51, 95% CI 0.25 - 1.06, p = 0.072). Viral reactivations are common after pediatric allo-HSCT, though severe complications were rare in our collective. Determining risk factors for viral reactivations may help to identify patients in need of intensified monitoring and to individualize preventive strategies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228451PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6999888PMC
April 2020

Treatment of children under 4 years of age with medulloblastoma and ependymoma in the HIT2000/HIT-REZ 2005 trials: Neuropsychological outcome 5 years after treatment.

PLoS One 2020 23;15(1):e0227693. Epub 2020 Jan 23.

Department of Paediatric Haematology and Oncology, University Medical Centre, Hamburg-Eppendorf, Hamburg, Germany.

Young children with brain tumours are at high risk of developing treatment-related sequelae. We aimed to assess neuropsychological outcomes 5 years after treatment. This cross-sectional study included children under 4 years of age with medulloblastoma (MB) or ependymoma (EP) enrolled in the German brain tumour trials HIT2000 and HIT-REZ2005. Testing was performed using the validated Wuerzburg Intelligence Diagnostics (WUEP-D), which includes Kaufman-Assessment-Battery, Coloured Progressive Matrices, Visual-Motor Integration, finger tapping "Speed", and the Continuous Performance Test. Of 104 patients in 47 centres, 72 were eligible for analyses. We assessed whether IQ was impacted by disease extent, disease location, patient age, gender, age at surgery, and treatment (chemotherapy with our without craniospinal irradiation [CSI] or local radiotherapy [LRT]). Median age at surgery was 2.3 years. Testing was performed at a median of 4.9 years after surgery. Patients with infratentorial EPs (treated with LRT) scored highest in fluid intelligence (CPM 100.9±16.9, mean±SD); second best scores were achieved by patients with MB without metastasis treated with chemotherapy alone (CPM 93.9±13.2), followed by patients with supratentorial EPs treated with LRT. In contrast, lowest scores were achieved by patients that received chemotherapy and CSI, which included children with metastasised MB and those with relapsed MB M0 (CPM 71.7±8.0 and 73.2±21.8, respectively). Fine motor skills were reduced in all groups. Multivariable analysis revealed that type of treatment had an impact on IQ, but essentially not age at surgery, time since surgery or gender. Our results confirm previous reports on the detrimental effects of CSI in a larger cohort of children. Comparable IQ scores in children with MB treated only with chemotherapy and in children with EP suggest that this treatment strategy represents an attractive option for children who have a high chance to avoid application of CSI. Longitudinal follow-up examinations are warranted to assess long-term neuropsychological outcomes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227693PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977734PMC
April 2020

Hematopoietic stem cell transplantation for children with acute myeloid leukemia-results of the AML SCT-BFM 2007 trial.

Leukemia 2020 02 2;34(2):613-624. Epub 2019 Oct 2.

Department of Pediatrics, Division of Pediatric Hematology and Oncology, University of Düsseldorf, Düsseldorf, Germany.

AML SCT-BFM 2007 was the first hematopoietic stem cell transplantation (HCT) trial in Germany to comply with the European Clinical Trials Directive, and aimed to standardize pediatric HCT for acute myeloid leukemia (AML) across centers in Germany, Austria, and the Czech Republic. Children with high-risk features and a good early response achieving a complete first remission (CR-1) and those in CR-2 after a first relapse were stratified to receive HCT from a matched donor after myeloablative conditioning consisting of busulfan, cyclophosphamide, and melphalan. Four-year EFS and OS were 61 and 70%. Cumulative incidence of relapse (CIR) was 22%. TRM was 15% and correlated with age reaching 9% (SE 3%) in children younger than 12 years and 31% (SE 9%) in older children and adolescents. Children with poorly responding primary disease or relapse were allocated to receive early HCT after a cytoreductive regimen with fludarabine, amsacrine, and cytarabine, followed by reduced intensity conditioning and prophylactic donor lymphocyte infusions. Four-year EFS and OS were 49 and 53%. CIR was 38% and TRM 11%. For patients with primary poor response disease, early use of RIC HCT followed by prophylactic DLI can induce long-term remissions in more than 50% (EFS 46% (SE 9%)).
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http://dx.doi.org/10.1038/s41375-019-0584-8DOI Listing
February 2020

Re-expression of CD14 in Response to a Combined IL-10/TLR Stimulus Defines Monocyte-Derived Cells With an Immunoregulatory Phenotype.

Front Immunol 2019 28;10:1484. Epub 2019 Jun 28.

Department of Hematology, Oncology and Stem Cell Transplantation, University Children's Hospital, University of Würzburg, Würzburg, Germany.

Interleukin 10 is a central regulator of the antigen-presenting function of myeloid cells. It exerts immunomodulatory effects and induces a regulatory phenotype in monocyte-derived cells . We analyzed phenotype and function of monocytic cells in relation to the cytokine milieu and the timing of TLR-based activation. In GM-CSF/IL-4 cultured human monocytic cells, we identified two, mutually exclusive cell populations arising from undifferentiated cells: CD83 fully activated dendritic cells and CD14 macrophage like cells. Re-expression of CD14 occurs primarily after a sequential trigger with a TLR signal following IL-10 preincubation. This cell population with re-expressed CD14 greatly differs in phenotype and function from the CD83 cells. Detailed analysis of individual subpopulations reveals that exogenous IL-10 is critical for inducing the shift toward the CD14+ population, but does not affect individual changes in marker expression or cell function in most cases. Thus, plasticity of CD14 expression, defining a subset of immunoregulatory cells, is highly relevant for the composition of cellular products (such as DC vaccines) as it affects the function of the total product.
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http://dx.doi.org/10.3389/fimmu.2019.01484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611188PMC
October 2020

Gonadal Function after Busulfan Compared with Treosulfan in Children and Adolescents Undergoing Allogeneic Hematopoietic Stem Cell Transplant.

Biol Blood Marrow Transplant 2019 09 11;25(9):1786-1791. Epub 2019 May 11.

Goethe-Universität, Universitätsklinikum Frankfurt, Frankfurt, Germany.

Gonadal impairment is an important late effect with a significant impact on quality of life of transplanted patients. The aim of this study was to compare gonadal function after busulfan (Bu) or treosulfan (Treo) conditioning regimens in pre- and postpubertal children. This retrospective, multicenter study included children transplanted in pediatric European Society for Blood and Marrow Transplantation (EBMT) centers between 1992 and 2012 who did not receive gonadotoxic chemoradiotherapy before the transplant. We evaluated 137 patients transplanted in 25 pediatric EBMT centers. Median age at transplant was 11.04 years (range, 5 to 18); 89 patients were boys and 48 girls. Eighty-nine patients were prepubertal at transplant and 48 postpubertal. One hundred eighteen children received Bu and 19 Treo. A higher proportion of girls treated with Treo in the prepubertal stage reached spontaneous puberty compared with those treated with Bu (P = .02). Spontaneous menarche was more frequent after Treo than after Bu (P < .001). Postpubertal boys and girls treated with Treo had significantly lower luteinizing hormone levels (P = .03 and P = .04, respectively) compared with the Bu group. Frequency of gonadal damage associated with Treo was significantly lower than that observed after Bu. These results need to be confirmed in a larger population.
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http://dx.doi.org/10.1016/j.bbmt.2019.05.005DOI Listing
September 2019

Differences of Immune Reconstitution of Dendritic Cells in Pediatric GvHD Patients After Allogenic Stem Cell Transplantation.

J Pediatr Hematol Oncol 2019 03;41(2):e101-e107

Department of Pediatric Hematology and Oncology, University Hospital Würzburg, Germany.

Background: Hematopoietic stem cell transplantation (HSCT) is a life-saving procedure for children with a variety of (non) malignant conditions. GvHD is a severe complication with high morbidity and mortality. The pathogenesis remains unclear. We studied dendritic cell (DC) reconstitution to detect potential differences, which may improve our knowledge in the development of chronic GvHD (cGvHD).

Procedure: We examined immune reconstitution (T, B, and NK cells and dendritic cells) at defined time points in a pediatric cohort who underwent 61 allogeneic HSCTs.

Results: Regarding DC reconstitution we found a fast reconstitution of the DC compartment negatively correlated with age. After HSCT, both myeloid DC (mDC) and plasmacytoid DC (pDC) counts recover to pre-HSCT levels within 2 months. Higher CCR7 positive cell counts were found in patients receiving TBI during engraftment and during the whole posttransplant period we found a correlation with an improved outcome. In cGVHD patients decreased total DC counts and increased pDCs were found after day+100. No relevant correlation was achieved regarding to HLA-matching, stem cell manipulation of the graft as well as HSCT-indication compared with different DC counts.

Discussion: Pathogenesis of cGvHD remains complex. Our data suggest an influence of dendritic cells, which may contribute to the clinical picture and should be further investigated in future studies.
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http://dx.doi.org/10.1097/MPH.0000000000001342DOI Listing
March 2019

Comparison of Immune Reconstitution After Allogeneic Versus Autologous Stem Cell Transplantation in 182 Pediatric Recipients.

J Pediatr Hematol Oncol 2019 07;41(5):e302-e307

Department of Pediatric Hematology and Oncology, University Hospital Würzburg, Würzburg.

Hematopoietic stem cell transplantation (HSCT) is a life-saving procedure for children with a variety of malignant and nonmalignant conditions. However, even if immune reconstitution after HSCT has been studied extensively, until now, data on the comparison of immune reconstitution after autologous versus allogeneic HSCT are scarce, but might provide important clinical implications. We examined immune reconstitution (T cells, B cells, and NK cells) at defined timepoints in 147 children who received 182 HSCTs. Differences in the time course of immune reconstitution were analyzed in autologous versus allogeneic HSCT. We identified a quicker immune reconstitution in the T-cell compartment, especially in the CD4 and naive subset after autologous HSCT, whereas recipients of allogeneic transplants showed a higher TCRgd proportion. B-cell reconstitution showed a delayed immune reconstitution after allogeneic HSCT in the first 2 years after HSCT. However, a reconstitution of all lymphocyte subsets after HSCT could be achieved in all patients. Children undergoing an HSCT show a different pattern of immune reconstitution in the allogeneic and autologous setting. This might influence the outcome and should affect the clinical handling of infectious prophylaxis and revaccinations.
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http://dx.doi.org/10.1097/MPH.0000000000001340DOI Listing
July 2019

High-grade glioma associated immunosuppression does not prevent immune responses induced by therapeutic vaccines in combination with T depletion.

Cancer Immunol Immunother 2018 Oct 27;67(10):1545-1558. Epub 2018 Jul 27.

Department of Pediatric Oncology, University Children's Hospital Würzburg, Josef-Schneider-Strasse 2, 97080, Würzburg, Germany.

High-grade gliomas (HGG) exert systemic immunosuppression, which is of particular importance as immunotherapeutic strategies such as therapeutic vaccines are increasingly used to treat HGGs. In a first cohort of 61 HGG patients we evaluated a panel of 30 hematological and 34 plasma biomarkers. Then, we investigated in a second cohort of 11 relapsed HGG patients receiving immunomodulation with metronomic cyclophosphamide upfront to a DC-based vaccine whether immune abnormalities persisted and whether they hampered induction of IFNγ T-cell responses. HGG patients from the first cohort showed increased numbers of leukocytes, neutrophils and MDSCs and in parallel reduced numbers of CD4/CD8 T-cells, plasmacytoid and conventional DC2s. MDSCs and T-cell alterations were more profound in WHO IV° glioma patients. Moreover, levels of MDSCs and epidermal growth factor were negatively associated with survival. Serum levels of IL-2, IL-4, IL-5 and IL-10 were altered in HGG patients, however, without any impact on clinical outcome. In the immunotherapy cohort, 6-month overall survival was 100%. Metronomic cyclophosphamide led to > 40% reduction of regulatory T cells (T). In parallel to T-depletion, MDSCs and DC subsets became indistinguishable from healthy controls, whereas T-lymphopenia persisted. Despite low T-cells, IFNγ-responses could be induced in 9/10 analyzed cases. Importantly, frequency of CD8VLA-4 T-cells with CNS-homing properties, but not of CD4 VLA-4 T-cells, increased during vaccination. Our study identifies several features of systemic immunosuppression in HGGs. Metronomic cyclophosphamide in combination with an active immunization alleviates the latter and the combined treatment allows induction of a high rate of anti-glioma immune responses.
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http://dx.doi.org/10.1007/s00262-018-2214-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182405PMC
October 2018

Low incidence of symptomatic osteonecrosis after allogeneic HSCT in children with high-risk or relapsed ALL - results of the ALL-SCT 2003 trial.

Br J Haematol 2018 10 20;183(1):104-109. Epub 2018 Jul 20.

Department of Paediatrics, Medical University of Vienna, Children's Cancer Research Institute (CCRI), St. Anna Kinderkrebsforschung, Vienna, Austria.

Osteonecrosis (ON) was prospectively assessed in 557 children and adolescents in the Berlin-Frankfurt-Münster Stem Cell Transplantation in children with acute lymphoblastic leukaemia 2003 trial. Median age at haematopoietic stem cell transplantation (HSCT) was 10·3 years (range 0·5-26). Cumulative incidence of symptomatic ON (sON) was 9% at 5 years (standard deviation 1%), median time from HSCT to diagnosis of sON was 12·4 months (range 1-126). Multivariate analysis identified age at HSCT [10-15 years vs. <10 years: hazard ratio (HR) 3·73, P = 0·009; >15 years vs. <10 years: HR 5·46, P = 0·001], diagnosis of sON prior to HSCT and chronic graft-versus-host disease (yes versus no: HR 2·696, P = 0·015) as significant independent risk factors for the development of sON.
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http://dx.doi.org/10.1111/bjh.15511DOI Listing
October 2018

Spontaneous reversion of a lineage switch following an initial blinatumomab-induced ALL-to-AML switch in -rearranged infant ALL.

Blood Adv 2018 06;2(12):1382-1385

Pediatric Hematology, Oncology and Stem Cell Transplantation, Children's Hospital, University of Würzburg, Würzburg, Germany; and.

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http://dx.doi.org/10.1182/bloodadvances.2018018093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020817PMC
June 2018

IL12-mediated sensitizing of T-cell receptor-dependent and -independent tumor cell killing.

Oncoimmunology 2016 Jul 19;5(7):e1188245. Epub 2016 May 19.

Children's Hospital, Pediatric Hematology, Oncology and Stem Cell Transplantation, University of Würzburg, Würzburg, Germany; Clinical Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.

Interleukin 12 (IL12) is a key inflammatory cytokine critically influencing Th1/Tc1-T-cell responses at the time of initial antigen encounter. Therefore, it may be exploited for cancer immunotherapy. Here, we investigated how IL12, and other inflammatory cytokines, shape effector functions of human T-cells. Using a defined culture system, we followed the gradual differentiation and function of antigen-specific CD8(+) T cells from their initial activation as naïve T cells through their expansion phase as early memory cells to full differentiation as clonally expanded effector T cells. The addition of IL12 8 days after the initial priming event initiated two mechanistically separate events: First, IL12 sensitized the T-cell receptor (TCR) for antigen-specific activation, leading to an approximately 10-fold increase in peptide sensitivity and, in consequence, enhanced tumor cell killing. Secondly, IL12 enabled TCR/HLA-independent activation and cytotoxicity: this "non-specific" effect was mediated by the NK cell receptor DNAM1 (CD226) and dependent on ligand expression of the target cells. This IL12 regulated, DNAM1-mediated killing is dependent on src-kinases as well as on PTPRC (CD45) activity. Thus, besides enhancing TCR-mediated activation, we here identified for the first time a second IL12 mediated mechanism leading to activation of a receptor-dependent killing pathway via DNAM1.
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http://dx.doi.org/10.1080/2162402X.2016.1188245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006926PMC
July 2016

Immunotherapy in atypical teratoid-rhabdoid tumors: Data from a survey of the HGG-Immuno Group.

Cytotherapy 2016 09 12;18(9):1178-86. Epub 2016 Jul 12.

Stem Cell Laboratory, University Children's Hospital Würzburg, University of Würzburg, Germany. Electronic address:

Background Aims: Atypical rhabdoid/teratoid tumors (AT/RT) are the most common brain tumors in infants and associated with a dismal prognosis. Although intensification of first-line therapy has resulted in improvement of overall survival, novel treatment strategies are needed. Because immunotherapy has resulted in remarkable results in several adult tumor entities, incorporation of immunotherapy into AT/RT treatment offers a novel alternative.

Methods: We retrospectively analyzed data from 7 AT/RT patients from five countries treated within the HGG-Immuno Consortium. Two patients were ≤1 year and 4 patients were ≤2 years of age at diagnosis. All received immunotherapy with autologous, tumor-lysate-loaded dendritic cells (DCs) on a compassionate use basis using a schedule of three to four weekly DC vaccinations with up to 2 × 10(7) DCs per vaccine, followed by three lysate boosts each 1 month apart.

Results: Monocyte collections (median age at apheresis 31.5, range 20-143 months) and vaccinations were uneventful without any severe adverse event related to the vaccine, demonstrating feasibility and safety in this very young age group. Two children received immunotherapy during their primary and the remaining five during second- or third-line therapy. Three of seven patients survived long term with a follow-up of 143, 138 and 46 months, with at least two of them harboring somatic mutations. One long-term survivor was vaccinated during primary treatment and the other two after first or second relapse/progression. Two analyzed patients showed positive CD8(+) T-cell responses after vaccination.

Discussion: Our data demonstrate that anti-tumor immunotherapy with autologous DCs is feasible and safe in young children with ATRTs and that this approach warrants further investigation in controlled clinical trials.
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http://dx.doi.org/10.1016/j.jcyt.2016.06.004DOI Listing
September 2016

MB3W1 is an orthotopic xenograft model for anaplastic medulloblastoma displaying cancer stem cell- and Group 3-properties.

BMC Cancer 2016 Feb 17;16:115. Epub 2016 Feb 17.

University Children's Hospital, Pediatric Oncology, Hematology and Stem Cell Transplantation, University of Würzburg, Würzburg, Germany.

Background: Medulloblastoma is the most common malignant brain tumor in children and can be divided in different molecular subgroups. Patients whose tumor is classified as a Group 3 tumor have a dismal prognosis. However only very few tumor models are available for this subgroup.

Methods: We established a robust orthotopic xenograft model with a cell line derived from the malignant pleural effusions of a child suffering from a Group 3 medulloblastoma.

Results: Besides classical characteristics of this tumor subgroup, the cells display cancer stem cell characteristics including neurosphere formation, multilineage differentiation, CD133/CD15 expression, high ALDH-activity and high tumorigenicity in immunocompromised mice with xenografts exactly recapitulating the original tumor architecture.

Conclusions: This model using unmanipulated, human medulloblastoma cells will enable translational research, specifically focused on Group 3 medulloblastoma.
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http://dx.doi.org/10.1186/s12885-016-2170-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4756501PMC
February 2016

Fulminant skin GvHD with a cytokine pattern resemblant of cytokine release syndrome successfully treated with multimodal immunosuppression including tocilizumab.

Pediatr Blood Cancer 2015 Nov 7;62(11):2033-5. Epub 2015 Jul 7.

University Hospital of Würzburg, Children's Hospital, Pediatric Stem Cell Transplantation, Josef-Schneider-Strasse 2, 97080, Würzburg, Germany.

Acute Graft-versus-Host-Disease (GvHD) is a potentially life-threatening complication after allogeneic stem cell transplantation. If not treated early and adequately, the complex immunological mechanisms may lead to a self-perpetuating cycle of alloreactivity, which is then associated with a high mortality. Here we assessed the cytokine profile on a daily basis in a patient with grade 4 skin GvHD, demonstrating a signature resembling cytokine-release-syndrome. After multimodal immunosuppressive intervention, including treatment with the IL6 receptor-blocking antibody tocilizumab, the severe clinical symptoms unexpectedly resolved within 48 hr.
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http://dx.doi.org/10.1002/pbc.25595DOI Listing
November 2015

Haematopoietic stem cell transplantation for refractory Langerhans cell histiocytosis: outcome by intensity of conditioning.

Br J Haematol 2015 Jun 27;169(5):711-8. Epub 2015 Mar 27.

CIBMTR® (Center for International Blood and Marrow Transplant Research), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.

Patients with Langerhans cell histiocytosis (LCH) refractory to conventional chemotherapy have a poor outcome. There are currently two promising treatment strategies for high-risk patients: the first involves the combination of 2-chlorodeoxyadenosine and cytarabine; the other approach is allogeneic haematopoietic stem cell transplantation (HSCT). Here we evaluated 87 patients with high-risk LCH who were transplanted between 1990 and 2013. Prior to the year 2000, most patients underwent HSCT following myeloablative conditioning (MAC): only 5 of 20 patients (25%) survived with a high rate (55%) of transplant-related mortality (TRM). After the year 2000 an increasing number of patients underwent HSCT with reduced intensity conditioning (RIC): 49/67 (73%) patients survived, however, the improved survival was not overtly achieved by the introduction of RIC regimens with similar 3-year probability of survival after MAC (77%) and RIC transplantation (71%). There was no significant difference in TRM by conditioning regimen intensity but relapse rates were higher after RIC compared to MAC regimens (28% vs. 8%, P = 0·02), although most patients relapsing after RIC transplantation could be salvaged with further chemotherapy. HSCT may be a curative approach in 3 out of 4 patients with high risk LCH refractory to chemotherapy: the optimal choice of HSCT conditioning remains uncertain.
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http://dx.doi.org/10.1111/bjh.13347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433436PMC
June 2015

Human Parthenogenetic Embryonic Stem Cell-Derived Neural Stem Cells Express HLA-G and Show Unique Resistance to NK Cell-Mediated Killing.

Mol Med 2015 Mar 23;21:185-96. Epub 2015 Mar 23.

Institute for Medical Radiology and Cell Research (MSZ) in the Center for Experimental Molecular Medicine (ZEMM), University of Würzburg, Würzburg, Germany.

Parent-of-origin imprints have been implicated in the regulation of neural differentiation and brain development. Previously we have shown that, despite the lack of a paternal genome, human parthenogenetic (PG) embryonic stem cells (hESCs) can form proliferating neural stem cells (NSCs) that are capable of differentiation into physiologically functional neurons while maintaining allele-specific expression of imprinted genes. Since biparental ("normal") hESC-derived NSCs (N NSCs) are targeted by immune cells, we characterized the immunogenicity of PG NSCs. Flow cytometry and immunocytochemistry revealed that both N NSCs and PG NSCs exhibited surface expression of human leukocyte antigen (HLA) class I but not HLA-DR molecules. Functional analyses using an in vitro mixed lymphocyte reaction assay resulted in less proliferation of peripheral blood mononuclear cells (PBMC) with PG compared with N NSCs. In addition, natural killer (NK) cells cytolyzed PG less than N NSCs. At a molecular level, expression analyses of immune regulatory factors revealed higher HLA-G levels in PG compared with N NSCs. In line with this finding, MIR152, which represses HLA-G expression, is less transcribed in PG compared with N cells. Blockage of HLA-G receptors ILT2 and KIR2DL4 on natural killer cell leukemia (NKL) cells increased cytolysis of PG NSCs. Together this indicates that PG NSCs have unique immunological properties due to elevated HLA-G expression.
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http://dx.doi.org/10.2119/molmed.2014.00188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503648PMC
March 2015

Immunotherapy with the trifunctional anti-CD20 x anti-CD3 antibody FBTA05 (Lymphomun) in paediatric high-risk patients with recurrent CD20-positive B cell malignancies.

Br J Haematol 2015 Apr 11;169(1):90-102. Epub 2014 Dec 11.

Department of Paediatric Oncology, Haematology and Immunology, University of Duesseldorf, Duesseldorf, Germany.

Children with B cell malignancies refractory to standard therapy are known to have a poor prognosis and very limited treatment options. Here, we report on the treatment and follow-up of ten patients diagnosed with relapsed or refractory mature B-cell Non Hodgkin Lymphoma (B-NHL), Burkitt leukaemia (B-AL) or pre B-acute lymphoblastic leukaemia (pre B-ALL). All children were treated with FBTA05 (now designated Lymphomun), an anti-CD3 x anti-CD20 trifunctional bispecific antibody (trAb) in compassionate use. Within individual treatment schedules, Lymphomun was applied (a) after allogeneic stem cell transplantation (allo-SCT, n = 6) to induce sustained long-term remission, or (b) stand alone prior to subsequent chemotherapy to eradicate residual disease before allo-SCT (n = 4). Nine of ten children displayed a clinical response: three stable diseases (SD), one partial remission (PR) and five induced or sustained complete remissions (CR). Five of these nine responders died during follow-up. The other patients still maintain CR with a current overall survival of 874-1424 days (median: 1150 days). In conclusion, despite the dismal clinical prognosis of children refractory to standard therapy, immunotherapy with Lymphomun resulted in a favourable clinical outcome in this cohort of refractory paediatric patients.
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http://dx.doi.org/10.1111/bjh.13242DOI Listing
April 2015

Thrombosis as a complication of central venous access in pediatric patients with malignancies: a 5-year single-center experience.

BMC Hematol 2014 1;14(1):18. Epub 2014 Oct 1.

Department of Pediatric Hematology/Oncology and Stem Cell Transplantation, University Children's Hospital, D31, Josef-Schneider-Straße 2, D-97080 Würzburg, Germany.

Background: Reliable central venous access (CVC) is essential for hematology-oncology patients since frequent puncture of peripheral veins-e.g., for chemotherapy, antibiotic administration, repeated blood sampling, and monitoring-can cause unacceptable pain and psychological trauma, as well as severe side effects in cases of extravasation of chemotherapy drugs. However, CVC lines still carry major risk factors, including thrombosis, infection (e.g., entry site, tunnel, and luminal infections), and catheter dislocation, leakage, or breakage.

Methods: Here we performed a retrospective database analysis to determine the incidence of CVC-associated thrombosis in a single-center cohort of 448 pediatric oncologic patients, and to analyze whether any subgroup of patients was at increased risk and thus might benefit from prophylactic anticoagulation.

Results: Of the 448 patients, 269 consecutive patients received a CVC, and 55 of these 269 patients (20%) also had a thrombosis. Of these 55 patients, 43 had at least one CVC-associated thrombosis (total number of CVC-associated thrombosis: n = 52). Among all patients, the median duration of CVC exposure was 464 days. Regarding exposure time, no significant difference was found between patients with and without CVC-associated thrombosis. Subclavia catheters and advanced tumor stages seem to be the main risk factors for the development of CVC-associated thrombosis, whereas pharmacologic prophylaxis did not seem to have a relevant impact on the rate of thrombosis.

Conclusions: We conclude that pediatric surgeons and oncologists should pay close attention to ensuring optimal and accurate CVC placement, as this appears the most effective tool to minimize CVC-associated complications.
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http://dx.doi.org/10.1186/2052-1839-14-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4195887PMC
October 2014

Development and validation of a fully GMP-compliant production process of autologous, tumor-lysate-pulsed dendritic cells.

Cytotherapy 2014 Jul 13;16(7):946-64. Epub 2014 May 13.

Laboratory of Pediatric Immunology, Department of Microbiology and Immunology, KU Leuven, Belgium (on behalf of the HGG-Immuno Network).

Background And Aims: One of the major challenges of dendritic cell (DC) vaccination is the establishment of harmonized DC production protocols. Here, we report the transfer and validation of a successfully used open DC manufacturing method into a closed system, good manufacturing practice (GMP)-compatible protocol.

Methods: All production steps (lysate generation, monocyte selection, DC culture and cryopreservation) were standardized and validated.

Results: Tumor lysate was characterized by histology, mechanically homogenized and avitalized. This preparation yielded a median of 58 ± 21 μg protein per milligram of tumor tissue. Avitality was determined by trypan blue staining and confirmed in an adenosine triphosphate release assay. Patient monocytes were isolated by elutriation or CD14 selection, which yielded equivalent results. DCs were subsequently differentiated in Teflon bags for an optimum of 7 days in CellGro medium supplemented with interleukin (IL)-4 and granulocyte macrophage colony stimulating factor and then matured for 48 h in tumor necrosis factor-α and IL-1ß after pulsing with tumor lysate. This protocol resulted in robust and reproducible upregulation of DC maturation markers such as cluster of differentiation (CD)80, CD83, CD86, human leukocyte antigen-DR and DC-SIGN. Functionality of these DCs was shown by directed migration toward C-C motif chemokine ligand 19/21, positive T-cell stimulatory capacity and the ability to prime antigen-specific T cells from naive CD8(+) T cells. Phenotype stability, vitality and functionality of DCs after cryopreservation, thawing and washing showed no significant loss of function. Comparison of clinical data from 146 patients having received vaccinations with plate-adherence versus GMP-grade DCs showed no inferiority of the latter.

Conclusions: Our robust, validated and approved protocol for DC manufacturing forms the basis for a harmonized procedure to produce cancer vaccines, which paves the way for larger multi-center clinical trials.
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http://dx.doi.org/10.1016/j.jcyt.2014.02.017DOI Listing
July 2014

Dendritic cell vaccination in pediatric gliomas: lessons learnt and future perspectives.

Front Pediatr 2013 Jun 10;1:12. Epub 2013 Jun 10.

Department of Pediatric Oncology, University Children's Hospital, University of Würzburg Würzburg, Germany.

Immunotherapy of malignant gliomas with autologous dendritic cells (DCs) in addition to surgery and radiochemotherapy has been a focus of intense research during the past decade. Since both children and adults are affected by this highly aggressive brain tumor, 10-15% of the several hundred vaccinated patients represent children, making pediatric glioma patients the largest uniform pediatric vaccination cohort so far. In general, DC vaccination in malignant gliomas has been shown to be safe and several studies with a non-vaccinated control group could clearly demonstrate a survival benefit for the vaccinated patients. Interestingly, children and adolescents below 21 years of age seem to benefit even more than adult patients. This review summarizes the findings of the 25 clinical trials published so far and gives a perspective how DC vaccination could be implemented as part of multimodal therapeutic strategies in the near future.
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http://dx.doi.org/10.3389/fped.2013.00012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3860891PMC
June 2013

Reduced-intensity conditioning and HLA-matched haemopoietic stem-cell transplantation in patients with chronic granulomatous disease: a prospective multicentre study.

Lancet 2014 Feb 23;383(9915):436-48. Epub 2013 Oct 23.

Division of Experimental Cancer Medicine, KFC, Novum, Laboratory Medicine, Karolinska University Hospital-Huddinge Stockholm, Sweden; Karolinska Institute, Stockholm, Sweden.

Background: In chronic granulomatous disease allogeneic haemopoietic stem-cell transplantation (HSCT) in adolescents and young adults and patients with high-risk disease is complicated by graft-failure, graft-versus-host disease (GVHD), and transplant-related mortality. We examined the effect of a reduced-intensity conditioning regimen designed to enhance myeloid engraftment and reduce organ toxicity in these patients.

Methods: This prospective study was done at 16 centres in ten countries worldwide. Patients aged 0-40 years with chronic granulomatous disease were assessed and enrolled at the discretion of individual centres. Reduced-intensity conditioning consisted of high-dose fludarabine (30 mg/m(2) [infants <9 kg 1·2 mg/kg]; one dose per day on days -8 to -3), serotherapy (anti-thymocyte globulin [10 mg/kg, one dose per day on days -4 to -1; or thymoglobuline 2·5 mg/kg, one dose per day on days -5 to -3]; or low-dose alemtuzumab [<1 mg/kg on days -8 to -6]), and low-dose (50-72% of myeloablative dose) or targeted busulfan administration (recommended cumulative area under the curve: 45-65 mg/L × h). Busulfan was administered mainly intravenously and exceptionally orally from days -5 to -3. Intravenous busulfan was dosed according to weight-based recommendations and was administered in most centres (ten) twice daily over 4 h. Unmanipulated bone marrow or peripheral blood stem cells from HLA-matched related-donors or HLA-9/10 or HLA-10/10 matched unrelated-donors were infused. The primary endpoints were overall survival and event-free survival (EFS), probabilities of overall survival and EFS at 2 years, incidence of acute and chronic GVHD, achievement of at least 90% myeloid donor chimerism, and incidence of graft failure after at least 6 months of follow-up.

Findings: 56 patients (median age 12·7 years; IQR 6·8-17·3) with chronic granulomatous disease were enrolled from June 15, 2003, to Dec 15, 2012. 42 patients (75%) had high-risk features (ie, intractable infections and autoinflammation), 25 (45%) were adolescents and young adults (age 14-39 years). 21 HLA-matched related-donor and 35 HLA-matched unrelated-donor transplants were done. Median time to engraftment was 19 days (IQR 16-22) for neutrophils and 21 days (IQR 16-25) for platelets. At median follow-up of 21 months (IQR 13-35) overall survival was 93% (52 of 56) and EFS was 89% (50 of 56). The 2-year probability of overall survival was 96% (95% CI 86·46-99·09) and of EFS was 91% (79·78-96·17). Graft-failure occurred in 5% (three of 56) of patients. The cumulative incidence of acute GVHD of grade III-IV was 4% (two of 56) and of chronic graft-versus-host disease was 7% (four of 56). Stable (≥90%) myeloid donor chimerism was documented in 52 (93%) surviving patients.

Interpretation: This reduced-intensity conditioning regimen is safe and efficacious in high-risk patients with chronic granulomatous disease.

Funding: None.
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http://dx.doi.org/10.1016/S0140-6736(13)62069-3DOI Listing
February 2014

Src-kinase inhibitors sensitize human cells of myeloid origin to Toll-like-receptor-induced interleukin 12 synthesis.

Blood 2013 Aug 8;122(7):1203-13. Epub 2013 Jul 8.

Children's Hospital, Pediatric Hematology, Oncology and Stem Cell Transplantation, University of Würzburg, Würzburg, Germany.

Src-kinase inhibitors hold great potential as targeted therapy against malignant cells. However, such inhibitors may also affect nonmalignant cells and cause pronounced off-target effects. We investigated the role of the dual kinase inhibitor dasatinib on human myeloid cells. Dasatinib is clinically used for the treatment of bcr/abl⁺ leukemias because it blocks the mutated tyrosine kinase abl. To understand its effect on the development of antigen-specific T-cell responses, we assessed antigen-specific priming of human, naïve T cells. In surprising contrast to the direct inhibition of T-cell activation by dasatinib, pretreatment of maturing dendritic cells (DCs) with dasatinib strongly enhanced their stimulatory activity. This effect strictly depended on the activating DC stimulus and led to enhanced interleukin 12 (IL-12) production and T-cell responses of higher functional avidity. Src-kinase inhibitors, and not conventional tyrosine kinase inhibitors, increased IL-12 production in several cell types of myeloid origin, such as monocytes and classical or nonclassical DCs. Interestingly, only human cells, but not mouse or macaques DCs, were affected. These data highlight the potential immunostimulatory capacity of a group of novel drugs, src-kinase inhibitors, thereby opening new opportunities for chemoimmunotherapy. These data also provide evidence for a regulatory role of src kinases in the activation of myeloid cells.
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http://dx.doi.org/10.1182/blood-2013-03-488072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744989PMC
August 2013

Impaired B-cell reconstitution in children after chemotherapy for standard or medium risk acute precursor B-lymphoblastic leukemia.

Leuk Lymphoma 2014 Apr 25;55(4):870-5. Epub 2013 Jul 25.

Department of Pediatric Haematology, Hemostaseology, Oncology and Stem Cell Transplantation.

Chemotherapy for childhood acute lymphoblastic leukemia (ALL) is a highly effective treatment, but at the same time causes significant suppression of the patient's immunity. Immune reconstitution was studied in a homogeneous cohort of 48 children with standard or medium risk ALL treated according to the ALL-Berlin-Frankfurt-Münster (BFM) protocol. Whereas the T-cell compartment was only moderately affected and recovered to normal levels quickly after treatment cessation, B-cells were significantly reduced during and after therapy. In particular, the naive B-cell compartment declined. Even 5 years after the end of therapy, B-cell distribution was disturbed and patients showed an ongoing reconstitution. Thus, even standard regimens for chemotherapy cause severe B-cell depletion that resolves only gradually.
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http://dx.doi.org/10.3109/10428194.2013.816423DOI Listing
April 2014

Highlights of the third International Conference on Immunotherapy in Pediatric Oncology.

Pediatr Hematol Oncol 2013 Aug 12;30(5):349-66. Epub 2013 Jun 12.

Department for Stem Cell Transplantation and Immunology, J.W. Goethe-University Hospital, University Hospital for Children and Adolescents, Frankfurt/Main, Germany.

The third International Conference on Immunotherapy in Pediatric Oncology was held in Frankfurt/Main, Germany, October 1-2, 2012. Major topics of the conference included (i) cellular therapies using antigen-specific and gene-modified T cells for targeting leukemia and pediatric solid tumors; (ii) overcoming hurdles and barriers with regard to immunogenicity, immune escape, and the role of tumor microenvironment; (iii) vaccine strategies and antigen presentation; (iv) haploidentical transplantation and innate immunity; (v) the role of immune cells in allogeneic transplantation; and (vi) current antibody/immunoconjugate approaches for the treatment of pediatric malignancies. During the past decade, major advances have been made in improving the efficacy of these modalities and regulatory hurdles have been taken. Nevertheless, there is still a long way to go to fully exploit the potential of immunotherapeutic strategies to improve the cure of children and adolescents with malignancies. This and future meetings will support new collaborations and insights for further translational and clinical immunotherapy studies.
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http://dx.doi.org/10.3109/08880018.2013.802106DOI Listing
August 2013

A diagnostic window for the treatment of acute graft-versus-host disease prior to visible clinical symptoms in a murine model.

BMC Med 2013 May 21;11:134. Epub 2013 May 21.

Department of Medicine II, Würzburg University Clinics, Zinklesweg 10, Würzburg, D-97078, Germany.

Background: Acute graft-versus-host disease (aGVHD) poses a major limitation for broader therapeutic application of allogeneic hematopoietic cell transplantation (allo-HCT). Early diagnosis of aGVHD remains difficult and is based on clinical symptoms and histopathological evaluation of tissue biopsies. Thus, current aGVHD diagnosis is limited to patients with established disease manifestation. Therefore, for improved disease prevention it is important to develop predictive assays to identify patients at risk of developing aGVHD. Here we address whether insights into the timing of the aGVHD initiation and effector phases could allow for the detection of migrating alloreactive T cells before clinical aGVHD onset to permit for efficient therapeutic intervention.

Methods: Murine major histocompatibility complex (MHC) mismatched and minor histocompatibility antigen (miHAg) mismatched allo-HCT models were employed to assess the spatiotemporal distribution of donor T cells with flow cytometry and in vivo bioluminescence imaging (BLI). Daily flow cytometry analysis of peripheral blood mononuclear cells allowed us to identify migrating alloreactive T cells based on homing receptor expression profiles.

Results: We identified a time period of 2 weeks of massive alloreactive donor T cell migration in the blood after miHAg mismatch allo-HCT before clinical aGVHD symptoms appeared. Alloreactive T cells upregulated α4β7 integrin and P-selectin ligand during this migration phase. Consequently, targeted preemptive treatment with rapamycin, starting at the earliest detection time of alloreactive donor T cells in the peripheral blood, prevented lethal aGVHD.

Conclusions: Based on this data we propose a critical time frame prior to the onset of aGVHD symptoms to identify alloreactive T cells in the peripheral blood for timely and effective therapeutic intervention.
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http://dx.doi.org/10.1186/1741-7015-11-134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3665617PMC
May 2013

Lower TGFß serum levels and higher frequency of IFNγ-producing T cells during early immune reconstitution in surviving children after allogeneic stem cell transplantation.

Pediatr Blood Cancer 2013 Jan 23;60(1):121-8. Epub 2012 May 23.

Pediatric Stem Cell Transplant Unit, University Children's Hospital, Germany.

Background: Allogeneic hematopoietic stem cell transplantation (SCT) is increasingly used as a salvage therapy for patients with high-risk malignancies as well as life-threatening non-malignant diseases. However, only limited data about the association between outcome and functional parameters of recovering lymphocytes are available so far.

Procedures: In this prospective study of 19 pediatric SCT recipients, we serially evaluated immune parameters quantitatively and qualitatively before and throughout allogeneic SCT. These data were analyzed with respect to survival.

Results: Age, gender, GvHD, and type of graft were not different between surviving and non-surviving patients. Notably, in our cohort there was no case of transplant-related or infectious mortality. However, with the exception of two patients with advanced MDS, all patients not in complete remission (CR) relapsed in addition to three patients in higher CR (n = 7). All seven patients relapsing after allogeneic SCT later succumbed to their disease recurrence. Uni- and multivariate analysis showed that relapsing patients had higher TGFß serum levels as well as lower percentages of IFNγ-producing T cells before and early after transplantation. Furthermore, relapsing patients had a further decline in their thymic function between day 60 and 120 whereas non-relapsing patients already showed increasing TREC values during this time interval.

Conclusions: Collectively, patients who later relapse show a different pattern of immune reconstitution before and at early time points post-transplantation.
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http://dx.doi.org/10.1002/pbc.24208DOI Listing
January 2013

Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial.

Lancet 2012 Apr 23;379(9823):1301-9. Epub 2012 Feb 23.

University of Regensburg, Regensburg, Germany.

Background: Hepatic veno-occlusive disease is a leading cause of morbidity and mortality after haemopoietic stem-cell transplantation (HSCT). We aimed to assess whether defibrotide can reduce the incidence of veno-occlusive disease in this setting.

Methods: In our phase 3 open-label, randomised controlled trial, we enrolled patients at 28 European university hospitals or academic medical centres. Eligible patients were younger than 18 years, had undergone myeloablative conditioning before allogeneic or autologous HSCT, and had one or more risk factor for veno-occlusive disease based on modified Seattle criteria. We centrally assigned eligible participants on the basis of a computer-generated randomisation sequence (1:1), stratified by centre and presence of osteopetrosis, to receive intravenous defibrotide prophylaxis (treatment group) or not (control group). The primary endpoint was incidence of veno-occlusive disease by 30 days after HSCT, adjudicated by a masked, independent review committee, in eligible patients who consented to randomisation (intention-to-treat population), and was assessed with a competing risk approach. Patients in either group who developed veno-occlusive disease received defibrotide for treatment. We assessed adverse events to 180 days after HSCT in all patients who received allocated prophylaxis. This trial is registered with ClinicalTrials.gov, number NCT00272948.

Findings: Between Jan 25, 2006, and Jan 29, 2009, we enrolled 356 eligible patients to the intention-to-treat population. 22 (12%) of 180 patients randomly allocated to the defibrotide group had veno-occlusive disease by 30 days after HSCT compared with 35 (20%) of 176 controls (risk difference -7·7%, 95% CI -15·3 to -0·1; Z test for competing risk analysis p=0·0488; log-rank test p=0·0507). 154 (87%) of 177 patients in the defibrotide group had adverse events by day 180 compared with 155 (88%) of 176 controls.

Interpretation: Defibrotide prophylaxis seems to reduce incidence of veno-occlusive disease and is well tolerated. Thus, such prophylaxis could present a useful clinical option for this serious complication of HSCT.

Funding: Gentium SpA, European Group for Blood and Marrow Transplantation.
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http://dx.doi.org/10.1016/S0140-6736(11)61938-7DOI Listing
April 2012