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Overall survival of patients with Nijmegen breakage syndrome depending on the time when they were treated due to malignancies: before and after 2000 year.

The dynamics of primary cancer incidence among patients with NBS described using the three-stage joint-point model.

Overall survival of patients with Nijmegen breakage syndrome after cancer diagnosis. Patients who underwent HSCT were marked with an asterix.

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Clathrin-mediated endocytosis (CME) is critical for internalisation of molecules across cell membranes. The FCH domain only 1 (FCHO1) protein is key molecule involved in the early stages of CME formation. The consequences of mutations in FCHO1 in humans were unknown. We identify ten unrelated patients with variable T and B cell lymphopenia, who are homozygous for six distinct mutations in FCHO1. We demonstrate that these mutations either lead to mislocalisation of the protein or prevent its interaction with binding partners. Live-cell imaging of cells expressing mutant variants of FCHO1 provide evidence of impaired formation of clathrin coated pits (CCP). Patient T cells are unresponsive to T cell receptor (TCR) triggering. Internalisation of the TCR receptor is severely perturbed in FCHO1-deficient Jurkat T cells but can be rescued by expression of wild-type FCHO1. Thus, we discovered a previously unrecognised critical role of FCHO1 and CME during T-cell development and function in humans. FCH domain only 1 (FCHO1) is a key molecule involved in clathrin-mediated endocytosis (CME). Here, the authors report homozygous FCHO1 mutations in individuals with variable T and B cell lymphopenia, which are associated with loss-of-function of FCHO1 and impaired formation of clathrin-coated pits in T cells.

Purpose: Nijmegen breakage syndrome (NBS) is a DNA repair disorder with a high predisposition to hematologic malignancies. Experimental Design: We describe the natural history of NBS, including cancer incidence, risk of death, and the potential effectiveness of hematopoietic stem cell transplantation (HSCT) in preventing both pathologies: malignancy and immunodeficiency. Results: Among 241 patients with NBS enrolled in the study from 11 countries, 151 (63.0%) patients were diagnosed with cancer. Incidence rates for primary and secondary cancer, tumor characteristics, and risk factors affecting overall survival (OS) were estimated. The cumulative cancer incidence was 40.21% ± 3.5% and 77.78% ± 3.4% at 10 years and 20 years of follow-up, respectively. Most of the tumors n = 95 (62.9%) were non-Hodgkin lymphomas. Overall, 20 (13.2%) secondary malignancies occurred at a median age of 18 (interquartile range, 13.7–21.5) years. The probability of 20-year overall survival (OS) for the whole cohort was 44.6% ± 4.5%. Patients who developed cancer had a shorter 20-year OS than those without malignancy (29.6% vs. 86.2%; P < 10−5). A total of 49 patients with NBS underwent HSCT, including 14 patients transplanted before malignancy. Patients with NBS with diagnosed cancer who received HSCT had higher 20-year OS than those who did not (42.7% vs. 30.3%; P = 0.038, respectively). In the group of patients who underwent preemptive transplantation, only 1 patient developed cancer, which is 6.7 times lower as compared with nontransplanted patients [incidence rate ratio 0.149 (95% confidence interval, 0.138–0.162); P < 0.0001]. Conclusions: There is a beneficial effect of HSCT on the long-term survival of patients with NBS transplanted in their first complete remission of cancer.

Chronic granulomatous disease (CGD) is a primary immunodeficiency resulting in life-threatening infections and inflammatory complications. Allogeneic hematopoietic cell transplantation (allo-HCT) can cure the disease, but the indication to transplant remains controversial. We performed a retrospective multicenter study of 712 patients with CGD who underwent allo-HCT transplantation from March 1993 through December 2018. We studied 635 children (aged 1 antigen mismatch. Choice of conditioning regimen did not influence OS or EFS. In summary, we report an excellent outcome after allo-HCT in CGD, with low incidence of graft failure and mortality in all ages. Older patients and recipients of 1-antigen-mismatched grafts had a less favorable outcome. Transplantation should be strongly considered at a younger age and particularly in the presence of a well-matched donor.

BACKGROUND Reduced toxicity conditioning for hematopoietic stem cell transplantation of patients with hemophagocyticlymphohistiocytosis (HLH) results in favorable survival, however at the expense of relevant rates of mixed chimerism. Factors predisposing to mixed chimerism remain to be determined. PROCEDURE Patients with primary HLH transplanted 2009-2016 after treosulfan- or melphalan-based conditioning regimens were analyzed in a retrospective multicenter study for survival, engraftment, chimerism, and adverse events. Mixed chimerism was considered substantial if

Treosulfan-based conditioning prior to allogeneic transplantation has been shown to have myeloablative, immunosuppressive, and antineoplastic effects associated with reduced non-relapse mortality (NRM) in adults. Therefore, we prospectively evaluated the safety and efficacy of treosulfan-based conditioning in children with hematological malignancies in this phase II trial. Overall, 65 children with acute lymphoblastic leukemia (35.4%), acute myeloid leukemia (44.6%), myelodysplastic syndrome (15.4%), or juvenile myelomonocytic leukemia (4.6%) received treosulfan intravenously at a dose of 10 mg/m2/day (7.7%), 12 g/m2/day (35.4%), or 14 g/m2/day (56.9%) according to their individual body surface area in combination with fludarabine and thiotepa. The incidence of complete donor chimerism at day +28 was 98.4% with no primary and only one secondary graft failure. At 36 months, NRM was only 3.1%, while relapse incidence was 21.7%, and overall survival was 83.0%. The cumulative incidence of acute graft-vs.-host disease was 45.3% for grades I–IV and 26.6% for grades II–IV. At 36 months, 25.8% overall and 19.4% moderate/severe chronic graft-vs.-host disease were reported. These data confirm the safe and effective use of treosulfan-based conditioning in pediatric patients with hematological malignancies. Therefore, treosulfan/fludarabine/thiotepa can be recommended for myeloablative conditioning in children with hematological malignancies.

We used hybrid capture-targeted next-generation sequencing of circulating cell-free DNA (ccfDNA) of pediatric Hodgkin lymphoma (PHL) patients to determine pathogenic mechanisms and assess the clinical utility of this method. Hodgkin-Reed/Sternberg (HRS) cell-derived single nucleotide variants, insertions/deletions, translocations and VH-DH-JH rearrangements were detected in pretherapy ccfDNA of 72 of 96 patients. Number of variants per patient ranged from 1 to 21 with allele frequencies from 0.6 to 42%. Nine translocation breakpoints were detected. Genes involved in JAK/STAT, NFkB and PI3K signaling and antigen presentation were most frequently affected. SOCS1 variants, mainly deletions, were found in most circulating tumor (ct) DNAs, and seven of the nine translocation breakpoints involved SOCS1. Analysis of VH-DH-JH rearrangements revealed an origin of PHL HRS cells from partially selected germinal center B cells. Amounts of pretherapy ctDNA were correlated with metabolic tumor volumes. Furthermore, in all ccfDNA samples of 43 patients with early response assessment quantitative qPET 3, indicative of a favorable clinical course, ctDNA was not detectable. In contrast, in five of six patients with qPET 3, indicative of an unfavorable clinical course, ctDNA remained detectable. ccfDNA analysis of PHL is thus a suitable approach to determine pathogenic mechanisms and monitor therapy response.

Reticular dysgenesis (RD) is a rare congenital disorder defined clinically by the combination of severe combined immunodeficiency (SCID), agranulocytosis, and sensorineural deafness. Mutations in the gene encoding adenylate kinase 2 were identified to cause the disorder. Hematopoietic stem cell transplantation (HSCT) is the only option to cure this otherwise fatal disease. Retrospective data on clinical presentation, genetics, and outcome of HSCT were collected from centers in Europe, Asia, and North America for a total of 32 patients born between 1982 and 2011. Age at presentation was

Background Survival after Allo-HSCT for severe idiopathic aplastic anemia (SAA) has improved over past 20 years, approaching 75% at 5 years. However, beyond survival, a SAA-adapted composite endpoint GVHD and relapse free survival (GRFS) may more accurately assess patient outcomes, becoming a meaningful study endpoint. We analyzed GRFS aiming to identify risk factors and specific causes of GRFS failure. Methods This retrospective analysis from the SAAWP Data Quality Initiative (DQI registry database) program of EBMT included patients with: diagnosis of idiopathic SAA; first Allo-HSCT from 2005 to 2016; and matched related (MRD) or unrelated donor (UD) (no cord blood). Relevant events for Kaplan-Meier calculation of GRFS were: relapse (including primary and secondary graft failure); grade 3-4 acute GVHD; extensive chronic GVHD; and death. In addition, we used a competing-risk model to analyze cumulative incidences of specific causes of GRFS failure. Results We analyzed 580 patients (385 adults and 195 younger than 18 years), with a median age of 23 years ( 6 months) and previous treatment before Allo-HSCT showed that age (HR=1.02, [1.01-1.03], p Among the 209 patients who underwent upfront Allo-HSCT from a MRD, 5-year GRFS was 77% (71-84). In multivariate analysis, time from diagnosis to Allo-HSCT (HR=2.64, [1.38-5.03], p=0.003) and age (HR=1.03, [1.00-1.05], p=0.039) independently influenced GRFS. When investigating the causes of GRFS failure in this subset of patients who underwent upfront MRD Allo-HSCT, time from diagnosis to Allo-HSCT was the only remaining factors significantly associated with the risk of death without prior failure (HR=0.29, [0.10-0.84], p=0.022). No factor was found specifically associated with any other causes of GRFS failure. Conclusions We observed 5-year GRFS of 69%, meaning that most of patients who underwent Allo-HSCT for idiopathic SAA are cured without experiencing severe forms of acute and chronic GVHD. In the context of upfront MRD Allo-HSCT, GRFS was even more promising (77%). In this particular setting, time from diagnosis to Allo-HSCT was the most important factor influencing GRFS, suggesting the need to proceed to Allo-HSCT as quick as possible when a MRD is available. Disclosures Ganser: Novartis: Consultancy; Celgene: Consultancy. Risitano:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau. Peffault De Latour:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Apellis: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Adenovirus (HAdV) infections confer a high risk of morbidity and mortality for immunocompromised patients after stem cell transplantation (SCT). Treatment with standard antiviral drugs is of limited efficacy and associated with a high rate of adverse effects. HAdV-specific T cells are crucial for sustained viral elimination and the efficacy of adoptive T-cell therapy with donor-derived HAdV-specific T cells has been reported by several investigators. Here, we report our experience with the transfer of HAdV-specific T cells specific for penton, which was recently identified as an immunodominant target of T cells, and hexon in a 14-year-old boy after T-cell-depleted haploidentical SCT for myelodysplastic syndrome (MDS). He developed severe HAdV-associated enteritis complicated by acute graft-versus-host disease (GvHD). The patient received ten infusions of allogeneic HAdV-specific T cells manufactured from the haploidentical stem cell donor using the CliniMacs Interferon-γ (IFN-γ) cytokine capture and immunomagnetic selection. Initially, T cells were generated against the immunodominant target hexon and in subsequent transfers dual antigen-specific T cells against hexon and penton were applied. T-cell transfers were scheduled individually tailored to current immunosuppressive treatment. Each transfer was followed by reduction of HAdV load in peripheral blood and clinical improvement. Importantly, T-cell responses to both penton and hexon pools emerged in patient blood after repetitive transfers. Unfortunately, the patient experienced bacterial sepsis, and in this context, severe GvHD requiring intensive immunosuppression followed by secondary progression of HAdV infection. The patient succumbed to multiorgan failure 283 days after SCT. This case demonstrates the feasibility of HAdV-specific T-cell transfer even in the presence of immunosuppressive treatment. Targeting of multiple immunodominant viral proteins may prove valuable in patients with complicated HAdV infections.

Background GATA2 deficiency is an inherited immunodeficiency and predisposition syndrome with a high risk of developing myelodysplastic syndrome (MDS) early in life. Allogeneic hematopoietic stem cell transplantation (HSCT) is presently the only curative therapy for affected patients (pts), but to date there has been no larger study examining in detail outcomes after HSCT for GATA2-related pediatric MDS. Here we report the results of an analysis of pts with a germline GATA2 mutation undergoing HSCT for a diagnosis of MDS enrolled in the registry of the European Working Group of MDS in Childhood (EWOG-MDS). Patients and transplantation procedure Of the 87 pts with GATA2 deficiency registered before the age of 18 years, 66 underwent HSCT between 01/1997 and 11/2018. One pt had to be excluded from the analysis due to lack of data. The 65 remaining pts (34 males/31 females) were transplanted at a median age of 13.5 (4.6-19.9) years. Twenty-seven pts were transplanted for refractory cytopenia of childhood (RCC), while 38 pts had advanced disease. The highest bone marrow (BM) blast percentage prior to HSCT was 5-19% (n=23), 20-29% (n= 9) or >30% blasts (n=5); in one pt with myelofibrotic MDS a blast count was not attainable. Karyotypes included monosomy 7 (n=44), der (1;7) (n=4), trisomy 8 (n=4), random aberration (n=1) or a normal karyotype (n=12). Five of the 38 pts with an increased blast percentage had received intensive AML-type therapy prior to HSCT. Pts were grafted from a matched sibling donor (MSD; n=17), unrelated donor (UD; n=40) or a mismatched family donor (MMFD; n=8). The stem cell source was BM (n=37), peripheral blood (n=27) or cord blood (n=1). Pts were prepared with a busulfan-based (n=35), treosulfan-based (n=21), total body irradiation-based (n=5) or an alternative conditioning regimen (n=4). Results At 5 years the probability of overall survival (pOS) and disease-free survival (DFS) was 0.74 [0.62-0.86] and 0.69 [0.57-0.81], respectively, non-relapse mortality was 0.15 [0.08-0.27] and the cumulative incidence of relapse was 0.16 [0.09-0.29]. All pts engrafted initially. The cumulative incidence of acute graft versus host disease (GVHD) grade II-IV and III-IV was 0.34 [0.24-0.48] and 0.12 [0.06-0.24], respectively, and of overall and extensive chronic GVHD 0.25 [0.16-0.39] and 0.08 [0.03-0.20]. The most common post-transplant infections were viral (39 of the 43 pts with infections) with one pt each with EBV-related post-transplant lymphoproliferative disease and primary CMV disease. There were no mycobacterial infections. The most common non-infectious complications were hepatobiliary (13 pts, including 3 with veno-occlusive disease) and pulmonary (10 pts, 5 of whom had been prepared with a busulfan-based conditioning regimen). Pts with >20% BM blasts showed a trend towards a poorer DFS (0.52 [0.24-0.80]) compared to pts with 5-19% blasts (0.72 [0.53-0.91]) or pts with RCC (0.80 [0.64-0.96]; p=0.15). Examining the influence of karyotype in pts with RCC, there were a total of 2 relapses and 3 deaths (1 after relapse) among the 12 pts with monosomy 7, while there was one event among the 15 RCC pts with a normal karyotype (n=10, 1 death), trisomy 8 (n=3), der (1;7) (n=1) or random aberration (n=1). Limiting the analysis to 9/10 or 10/10 HLA matched-donors, DFS was comparable for pts transplanted from an UD (0.73 [0.55-0.91]) versus a MSD (0.82 [0.64-1.00]). Of the 8 pts transplanted from a MMFD, one patient died after secondary graft failure. No major difference in outcome was seen according to age at HSCT, gender, time from diagnosis to HSCT or stem cell source. Of the five pts who had received AML-type therapy prior to HSCT, three died of a transplant-related cause or relapse. Conclusions and perspectives In summary, HSCT resulted in a pOS of 0.74 in this cohort of children and adolescents with GATA2 deficiency and MDS. Pts with increased blasts had a tendency towards poorer outcomes. The high risk of developing advanced MDS and the better outcome in early stages of the disease indicates that HSCT should be performed early in the clinical course of children diagnosed with GATA2 deficiency and MDS. Of note, there was no indication of excessive toxicity, disease-associated comorbidities or an increased risk of GVHD. The HSCT outcomes of children and adolescents with MDS and GATA2 deficiency are similar to what has been previously published for pts transplanted for MDS in the absence of GATA2 germline disease. Disclosures Bader: Amgen (Brasil), Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy; Medac: Patents & Royalties, Research Funding; Riemser, Neovii: Research Funding. Locatelli:Miltenyi: Honoraria; bluebird bio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees. Niemeyer:Celgene: Consultancy.

Background HD is a B-lineage lymphoma characterized, depending on subtype, by a prominent inflammatory infiltrate and fibrosis. Clinically, inflammatory symptoms like fever, weight loss and night sweats (B-symptoms) and increased blood biomarkers of inflammation, including ESR and CRP, are characteristic of more advanced disease. The clinical trial EURONET-PHL-C2 (Second International Inter-Group Study for Classical Hodgkin's Lymphoma in Children and Adolescents) is a randomized, prospective trial that compares chemo- and radiotherapy treatment concepts of different intensities in patients with intermediate and advanced HD. Patients are stratified by risk into 3 therapy groups (TL-1 to TL-3). An ESR> 30mm/h had been a risk factor for relapse in previous studies and leads to upstaging from the lowest (TL-1, Ann Arbor stage I and IIa without additional risk factors) to the intermediate risk group TL-2 in the current study. This addon pilot study tested urine proteomic patterns from pediatric patients with HD at diagnosis and compared them to the patterns of normal children. The questions were: Is there a HD-specific pattern, a pattern that identifies high risk or a pattern that correlates with inflammatory markers? Patients and methods Capillary electrophoresis coupled to mass spectrometry (CE-MS) was used to compare the peptide profiles in the mass range of 0.8 to 20 kDa of urine samples (N=34) from 16 children with pediatric Hodgkin lymphoma (PHL) as case and 32 age-matched children with no evidence of a disease (N=28) or with urinary tract infection (N=4) as control groups. Marker selection was based on a two-step strategy. First, a group-wise comparison of rank sum differences was performed on a set of 2418 annotated peptides with distribution frequencies above 30% in at least one of the groups with subsequent adjustment for multiple testing by the method of Bonferroni. In the second step marker candidates were further restricted to those demonstrating a significant positive or negative Spearman rho correlation coefficient (≥0.34 or ≤-0.34) to the Ann-Arbor classification criteria. From the resulting peptides a multivariate peptide marker classifier was established by support vector machine modeling and applied to an independent confirmation set of PHL (N=16, 31 urine samples) and control (N=18, 18 urine samples) patients to determine classification accuracy in receiver operating characteristics (ROC) analysis. Peptides included in the PHL classifier were resolved in their amino acid sequence by tandem mass spectrometry to identify the proteins from which the peptide markers are derived. Results The established multivariate peptide marker model consisting of 40 naturally occurring urinary peptides enabled absolute differentiation between PHL patients and children without signs of disease or urinary tract infection in independent validation as revealed by an area under the ROC curve value of 1.0 (95% confidence interval: 0.93 to 1.00, p Conclusions and perspective We were able to identify a proteomic pattern characteristic for HD, markers for relapse risk group or HD-associated inflammation were not yet identified. Disclosures Metzger: Mosaiques Diagnostics: Employment.

Mutations in the ataxia telangiectasia mutated (ATM) gene cause chromosomal instability leading to ataxia telangiectasia (AT). The AT phenotype classically combines cerebellar ataxia, vermal atrophy, athetosis, ocular motor abnormalities, physical and mental retardation, hypogonadism, and telangiectasia predominantly of the face and eyes. Affected persons commonly suffer from hypogammaglobulinemia and functional T-cell defects and have an increased risk of developing acute leukemias and lymphomas. As a consequence, life expectancy is decreased due to recurrent infections and malignancies.1, 2

Clathrin-mediated endocytosis (CME) is critical for internalisation of molecules across cell membranes. The FCH domain only 1 (FCHO1) protein is key molecule involved in the early stages of CME formation. The consequences of mutations in FCHO1 in humans were unknown. We identify ten unrelated patients with variable T and B cell lymphopenia, who are homozygous for six distinct mutations in FCHO1. We demonstrate that these mutations either lead to mislocalisation of the protein or prevent its interaction with binding partners. Live-cell imaging of cells expressing mutant variants of FCHO1 provide evidence of impaired formation of clathrin coated pits (CCP). Patient T cells are unresponsive to T cell receptor (TCR) triggering. Internalisation of the TCR receptor is severely perturbed in FCHO1-deficient Jurkat T cells but can be rescued by expression of wild-type FCHO1. Thus, we discovered a previously unrecognised critical role of FCHO1 and CME during T-cell development and function in humans., FCH domain only 1 (FCHO1) is a key molecule involved in clathrin-mediated endocytosis (CME). Here, the authors report homozygous FCHO1 mutations in individuals with variable T and B cell lymphopenia, which are associated with loss-of-function of FCHO1 and impaired formation of clathrin-coated pits in T cells.

(1) Background: Refractory acute graft-versus-host disease (R-aGvHD) remains a leading cause of death after allogeneic stem cell transplantation. Survival rates of 15% after four years are currently achieved, deaths are only in part due to aGvHD itself, but mostly due to adverse effects of R-aGvHD treatment with immunosuppressive agents as these predispose patients to opportunistic infections and loss of graft-versus-leukemia surveillance resulting in relapse. Mesenchymal stromal cells (MSC) from different tissues and those generated by various protocols have been proposed as a remedy for R-aGvHD but the enthusiasm raised by initial reports has not been ubiquitously reproduced. (2) Methods: We previously reported on a unique MSC product, which was generated from pooled bone marrow mononuclear cells of multiple third-party donors. The products showed dose-to-dose equipotency and greater immunosuppressive capacity than individually expanded MSCs from the same donors. This product, MSC-FFM, has entered clinical routine in Germany where it is licensed with a national hospital exemption authorization. We previously reported satisfying initial clinical outcomes, which we are now updating. The data were collected in our post-approval pharmacovigilance program, i.e., this is not a clinical study and the data is high-level and non-monitored. (3) Results: Follow-up for 92 recipients of MSC-FFM was reported, 88 with GvHD &ge, &deg, III, one-third only steroid-refractory and two-thirds therapy resistant (refractory to steroids plus &ge, 2 additional lines of treatment). A median of three doses of MSC-FFM was administered without apparent toxicity. Overall response rates were 82% and 81% at the first and last evaluation, respectively. At six months, the estimated overall survival was 64%, while the cumulative incidence of death from underlying disease was 3%. (4) Conclusions: MSC-FFM promises to be a safe and efficient treatment for severe R-aGvHD.

Introduction: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disease characterized by impairment of the phagocyte NADPH-oxidase complex, resulting in deficient microbial killing and life-threatening bacterial and fungal infections. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative approach, but it can be complicated by graft failure, graft versus-host disease (GvHD) and transplant-related mortality (TRM). In order to define prognostic risk factors in this setting, the IEWP of the EBMT performed a large retrospective registry study on 600 pediatric and adult patients with CGD undergoing allo-HSCT. Patients and Methods: We analyzed the outcome of patients with CGD who received allo-HSCT in EBMT centers between 1993 and 2017. The main end-points of the study were overall survival (OS) and event-free survival (EFS; events were death and primary or secondary engraftment failure) according to patient's age, donor type, stem cell source and conditioning regimen. One patient died before allo-HSCT and was excluded from analysis. Results: We studied 536 children (aged < 18 years) and 63 adults (aged ≥ 18 years) affected by CGD. The median follow-up was 45.37 months (IQR 15.8-81.8). Genetic results were available for 307 patients: inheritance was X-linked (75%) or autosomal recessive (25%). Median age at transplant was 7.2 years (range: 0.12-48.56). Conditioning regimen was Busulfan/Fludarabine (n=244; 41%), Busulfan/Cyclophosphamide (n=104; 17%), Treosulfan/Fludarabine (n=76; 13%), Treosulfan/Fludarabine/Thiotepa (n=52; 9%) or other drug combinations (n=123; 20%). Donors were human leukocyte antigen (HLA) matched related (MFD, 10/10; n=211, 40%), matched unrelated (MUD, 10/10 or 6/6 in UCB; n=201; 38%), mismatched related (MMFD, ≥ 9/10; n= 27; 5%) or mismatched unrelated (MMUD, ≥ 9/10 or 5/6 in UCB; n= 83; 16%). Stem cell source was bone marrow (BM; n=408; 69%), peripheral blood (PB; n=153; 26%) or umbilical cord blood (UCB; n=27; 5%). Donor engraftment occurred in 516 evaluable patients (88%), while primary or secondary engraftment failure occurred in 68 patients (12%). Seventy-nine patients (13%) died after allo-HSCT. The 2 year Kaplan-Meier estimate of OS and EFS were 87.1% (95% CI, 84.2-89.9) and 77.8% (95% CI, 74.2-81.4), respectively (Fig A). The 2-year cumulative incidence of grade II-IV acute GvHD, chronic GvHD and extensive chronic GvHD was 18.6% (95%, 15.1-22.2), 16.2 % (95%, 18.8-19.7) and 5.5% (95%, 3.4-7.7), respectively. A univariate cox model with spline term demonstrated that older age at transplant was associated with an increased risk of death (p=0.002). Children undergoing allo-HSCT had a superior 2y OS (88.1%; 95% CI 85.2-91.0), compared to adults (78.2%; 95% CI, 67.7-88.7), p=0.03 (Fig B). Patients undergoing allo-HSCT from a MFD had a superior EFS (86.5%; 95% CI 81.5-91.4) compared to MUD (73.3%; 95% CI 66.7-79.9), MMUD (78.2%; 95% CI 69-87.5) and MMFD (59.7; 95% CI 40.4-79.1), p< 0.001 (Fig C). Patients receiving BM grafts had superior 2y EFS (81.0%; 95% CI 76.9-85.1) compared to PB (72.5%; 95% CI 64.7-80.4) and UCB (66.7%; 95% CI 48.9-84.4), p=0.04. The pattern of disease inheritance and the choice of conditioning regimen didn't have an impact on outcome (Fig D). Fifty-three patients with graft failure underwent a second allo-HSCT and the 2y OS in this group was 82.1% (95% CI, 71.5-92.7). Year of transplantation didn't have an influence on outcome. Conclusion: This is the largest study describing the outcome of allo-HSCT in children and adults affected by CGD. We demonstrate an excellent outcome, with a low incidence of graft failure, TRM and GvHD. Older patients with CGD have reduced survival after allo-HSCT, indicating that transplant should be considered at a younger age. The use of a MMFD is associated with poorer outcome; indication to transplant in this setting should be carefully evaluated by the treating physicians. Disclosures Chiesa: Bluebird Bio: Consultancy; Gilead: Consultancy. Kalwak:medac: Other: travel grants; Sanofi: Other: travel grants. Sykora:Aventis-Behring: Research Funding; medac: Research Funding. Locatelli:Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; bluebird bio: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wynn:Orchard SAB: Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Equity Ownership; Chimerix: Research Funding; Genzyme: Honoraria; Bluebird Bio: Consultancy; Orchard Therapeutics: Consultancy; Chimerix: Consultancy. Zecca:Chimerix: Honoraria. Veys:Pfizer: Honoraria; Servier: Research Funding; Novartis: Honoraria. Slatter:Medac: Other: Travel assistance.

A total of 156 patients (age range 1.3-18.0 years, median 13.2 years; 91 (58.3%) male) with newly diagnosed CML (N = 146 chronic phase (CML-CP), N = 3 accelerated phase (CML-AP), N = 7 blastic phase (CML-BP)) received imatinib up-front (300, 400, 500 mg/m 2 , respectively) within a prospective phase III trial. Therapy response, progression-free survival, causes of treatment failure, and side effects were analyzed in 148 children and adolescents with complete data. Event-free survival rate by 18 months for patients in CML-CP (median follow-up time 25 months, range: 1-120) was 97% (95% CI, 94.2-99.9%). According to the 2006 ELN-criteria complete hematologic response by month 3, complete cytogenetic response (CCyR) by month 12, and major molecular response (MMR) by month 18 were achieved in 98, 63, and 59% of the patients, respectively. By month 36, 86% of the patients achieved CCyR and 74% achieved MMR. Thirty-eight patients (27%) experienced imatinib failure because of unsatisfactory response or intolerance (N = 9). In all, 28/148 patients (19%) underwent stem cell transplantation (SCT). In the SCT sub-cohort 2/23 patients diagnosed in CML-CP, 0/1 in CML-AP, and 2/4 in CML-BP, respectively, died of relapse (N = 3) or SCT-related complications (N = 2). This large pediatric trial extends and confirms data from smaller series that first-line imatinib in children is highly effective.

The inability to generate mesenchymal stromal cells (MSCs) of consistent potency likely is responsible for inconsistent clinical outcomes of patients with aGvHD receiving MSC products. We developed a novel MSC manufacturing protocol characterized by high in vitro potency and near-identity of individual doses, referred to as "MSC-Frankfurt am Main (MSC-FFM)". Herein, we report outcomes of the 69 patients who have received MSC-FFM. These were 51 children and 18 adults with refractory aGvHD grade II (4%), III (36%) or IV (59%). Patients were refractory either to frontline therapy (steroids) (29%) or to steroids and 1-5 additional lines of immunosuppressants (71%) were given infusions in four weekly intervals. The day 28 overall response rate was 83%; at the last follow-up, 61% and 25% of patients were in complete or partial remission. The median follow-up was 8.1 months. Six-month estimate for cumulative incidence of non-relapse mortality was 27% (range, 16-38); leukemia relapse mortality was 2% (range, 0-5). This was associated with a superior six-month overall survival (OS) probability rate of 71% (range, 61-83), compared to the outcome of patients not treated with MSC-FFM. This novel product was effective in children and adults, suggesting that MSC-FFM represents a promising therapy for steroid refractory aGvHD.

Background Standard myeloablative conditioning regimens for children with hematological malignancies undergoing allogeneic HSCT are based mainly on total body irradiation or busulfan. Their serious short- and long-term side effects warranted the exploration of less toxic alternatives. Treosulfan is increasingly used for adults and children before HSCT due to its potent immunosuppressive and cytotoxic effects combined with low organ toxicity. Procedure To further investigate the role of treosulfan conditioning in children, the EBMT Pediatric diseases working party performed a retrospective analysis of 193 children with hematological malignancies (ALL n = 71, AML n = 47, MDS/MPS n = 40, other leukemia/lymphoma n = 25) undergoing allogeneic HSCT following treosulfan between January 2005 and July 2010. Results Early regimen-related toxicity was low and mainly gastrointestinal. Veno-occlusive disease and neurological toxicity were rare. There was no association of toxicity with type of disease or treosulfan dose. High-grade early toxicity was not higher in infants or patients undergoing second or later transplantation. Treatment related mortality was low at 14%. Three-year event-free survival was 45 ± 4% and not significantly influenced by number of transplants, however it appeared to be significantly better for infants (P = 0.022). When compared to treosulfan plus fludarabine, the combination of treosulfan, fludarabine and an alkylator (either thiotepa or melphalan) resulted in significantly better overall survival (OS, P = 0.048) and a trend toward better EFS. Conclusions Treosulfan based conditioning is a safe and effective approach for children with hematological malignancies, including and importantly for infants and those patients undergoing second or later transplantation. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.

Introduction Acquired thrombotic-thrombocytopenic purpura (TTP) is an autoimmune disorder characterized by autoantibodies directed against the von Willebrand metalloprotease. Depletion of B-cells can prevent synthesis of this antibody and presumably induce remission of the disease. In adults, Rituximab (RTX) was effective in relapsed or refractory acute idiopathic TTP. Procedure We report the long-term follow-up of five children and two adolescents (age at diagnosis 6–19 years, median 15 years) who were treated with RTX for recurrent or refractory TTP. Some of the patients suffered from recurrent refractory TTP with long histories of previous unsuccessful treatments. One had TTP associated with pancreatitis. Results Three patients have been in complete remission after one treatment course with RTX. Four relapsed after 1 to 5 years, respectively, and responded to additional courses of RTX. One of them is in long-term remission after a third course of RTX and splenectomy. Compared to literature reports with a median follow up of 1.4 years (3–46 month), follow-up of our patients after treatment with RTX was very long (2–12.7 years, median 7.7 years). RTX therapy could induce long-term remissions in children with refractory recurrent TTP. Median duration of remission was longer and relapses per patient-years less frequent in patients receiving RTX compared to patients not receiving it. Remissions were achieved in children within one week, much faster than in adults. Conclusion Because of the rapid induction of remissions, RTX may be suitable for first-line therapy in pediatric acquired antibody-mediated TTP. Pediatr Blood Cancer 2015;62:823–829. © 2015 Wiley Periodicals, Inc.

WOS: 000352238600022, PubMed ID: 25595268, Background: Common variable immunodeficiency (CVID) is usually well controlled with immunoglobulin substitution and immunomodulatory drugs. A subgroup of patients has a complicated disease course with high mortality. For these patients, investigation of more invasive, potentially curative treatments, such as allogeneic hematopoietic stem cell transplantation (HSCT), is warranted. Objective: We sought to define the outcomes of HSCT for patients with CVID. Methods: Retrospective data were collected from 14 centers worldwide on patients with CVID receiving HSCT between 1993 and 2012. Results: Twenty-five patients with CVID, which was defined according to international criteria, aged 8 to 50 years at the time of transplantation were included in the study. The indication for HSCT was immunologic dysregulation in the majority of patients. The overall survival rate was 48%, and the survival rate for patients undergoing transplantation for lymphoma was 83%. The major causes of death were treatment-refractory graft-versus-host disease accompanied by poor immune reconstitution and infectious complications. Immunoglobulin substitution was stopped in 50% of surviving patients. In 92% of surviving patients, the condition constituting the indication for HSCT resolved. Conclusion: This multicenter study demonstrated that HSCT in patients with CVID was beneficial in most surviving patients; however, there was a high mortality associated with the procedure. Therefore this therapeutic approach should only be considered in carefully selected patients in whom there has been extensive characterization of the immunologic and/or genetic defect underlying the CVID diagnosis. Criteria for patient selection, refinement of the transplantation protocol, and timing are needed for an improved outcome., German Federal Ministry of Education and Research (BMBF)Federal Ministry of Education & Research (BMBF) [01 EO 0803]; Dutch Cancer SocietyKWF Kankerbestrijding [2013-5883]; Medical Research CouncilMedical Research Council UK (MRC) [G0501468], Supported by the German Federal Ministry of Education and Research (BMBF 01 EO 0803). C.L. is supported by a clinical fellowship from the Dutch Cancer Society (2013-5883).

Advances in allogeneic hematopoietic stem cell transplantation (HSCT) in malignant and non-malignant diseases result in more long-term survivors, in whom cardiovascular (CV) disease is one leading non-cancer cause of death. This study aimed to evaluate risk factors and subclinical CV organ damage in survivors after HSCT in pediatric age. We enrolled 64 children in a cross-sectional approach 3.3 ± 3.1 years after HSCT. Anthropometric data, laboratory values, office and 24-h ambulatory blood pressure monitoring (ABPM) were evaluated, showing a high prevalence of obesity, hypertension and dyslipidemia. CV organ damage was determined by non-invasive measurements of aortic pulse wave velocity (PWV), left ventricular mass index (LVMI), and carotid intima media thickness (IMT). Increased IMT and elevated PWV reflecting subclinical vascular damage were detected in 48% (IMT) and 6% (PWV) of our population. For IMT, physical activity had a positive impact and was worsened by time after HSCT. Our results show a surprisingly high rate of subclinical CV organ damage and classical risk factors. Therefore, diagnosis and management of well-known CV risk factors belong to clinical care after HSCT.

Human adenovirus (HAdV) infection after hematopoietic stem cell transplantation (HSCT) is associated with significant morbidity and mortality in children. The optimal surveillance and treatment strategies are under discussion. Here, we present data from 238 consecutive pediatric allogeneic HSCT recipients who underwent transplantation in a single center who were included in a prospective, weekly HAdV DNAemia monitoring program by quantitative PCR. HAdV loads >1000 copies/mL were detected in 15.5% of all patients. Despite a low mortality directly attributed to HAdV infection (2 patients, 0.84%), blood HAdV loads >10,000 copies/mL (6.7% of all patients) were significant and independent risk factors for poor survival. We searched for patient, virus, and treatment-related risk factors of HAdV DNAemia and disease. Detection of HAdV in blood before day 50 post transplantation was a major independent risk factor for the development of blood HAdV loads >10,000 copies/mL. HAdV typing revealed A31, C1, and C2 as the predominant pathogens among several other HAdV strains with type C species detected in most patients with severe HAdV disease. Stool HAdV loads were prospectively monitored in 111 patients and correlated with but did not significantly precede detection in blood. Treatment with cidofovir led to stable or reduced viral load in 70% of patients with blood HAdV loads >1000 copies/mL. Thus, early occurrence of HAdV-DNA in blood of pediatric HSCT recipients predisposes for development of high viral loads. Control of HAdV infections was attempted by preemptive cidofovir treatment of patients with high blood HAdV loads or with symptomatic organ infections and correlated with low HAdV-attributed mortality.

ZusammenfassungAngeborene Thrombozytopathien sind komplexe Erkrankungen. Zur optimalen Blutungsprophylaxe und -behandlung empfehlen wir eine Abklärung und Diagnose der zugrunde liegenden Funktionsstörung. Dazu steht eine interdisziplinäre Leitlinie zur Verfügung (AWMF # 86–003 S2K; Hämostaseologie 2014; 34: 201–212).Die Behandlung ist auf den Defekt, die Thrombozytenzahl, das Lebensalter und die klinischen Umstände abzustimmen. Die Transfusion von Thrombozyten allein kann wegen der damit verbundenen Risiken unangemessen sein. Empfohlen wird ein stufenweiser und individualisierter Behandlungsplan. Antifibrinolytika sind generell anwendbar, besonders bei der Quebec-Erkrankung. Desmopressin ist älteren Kindern vor behalten und vor allem zur Behandlung der Storage- Pool-Erkrankungen und nicht klassifizierter Defekte geeignet. Rekombinanter FVIIa ist zwar nur für die Behandlung der Thrombasthenie Glanzmann mit Alloantikörpern zugelassen, wird jedoch in der klinischen Praxis auch bei Thrombozytendefekten mit schwerer Blutungsneigung eingesetzt. Das Ziel dieser Leitlinie ist die Behandlung von Patienten mit angeborenen Thrombozytenfunktionsstörungen bestmöglich zu unterstützen.

Abnormal transcranial Doppler velocities (TCD) indicate an increased risk of stroke in patients with sickle cell anemia (SCA) and require regular blood transfusions. Hematopoietic stem cell transplantation (HSCT) is under discussion as an alternative to chronic transfusion in these patients. This retrospective analysis includes 9 patients with SCA undergoing HSCT at a single center in Germany. Special focus was given to the neurologic follow-up and to the results of TCD studies. High risk of stroke or previous stroke was an HSCT-indication in 8 of 9 patients, although most patients had more than one indication for HSCT. TCD was normalized in all 5 patients after HSCT in whom this test was available. None of the patients developed a stroke after HSCT. No further strokes occurred even in patients that experienced recurrent strokes during chronic transfusion before HSCT. 2 of the 9 patients received a 10/10 HLA-matched unrelated donor graft, the others matched related grafts. All patients were alive, free of SCA symptoms and transfusion-independent with stable chimerism 3–11 years after HSCT. Pulmonary function tests normalized in 1 patient with severe sickle cell lung disease. HSCT is able to prevent stroke in patients with SCA. Its perspectives and limitations should be discussed early during the treatment of a patient with complicated SCA.

Allogeneic hematopoietic stem cell transplantation is required as rescue therapy in about 20% of pediatric patients with acute lymphoblastic leukemia. However, the relapse rates are considerable, and relapse confers a poor outcome. Early assessment of the risk of relapse is therefore of paramount importance for the development of appropriate measures. We used the EuroChimerism approach to investigate the potential impact of lineage-specific chimerism testing for relapse-risk analysis in 162 pediatric patients with acute lymphoblastic leukemia after allogeneic stem cell transplantation in a multicenter study based on standardized transplantation protocols. Within a median observation time of 4.5 years, relapses have occurred in 41/162 patients at a median of 0.6 years after transplantation (range, 0.13-5.7 years). Prospective screening at defined consecutive time points revealed that reappearance of recipient-derived cells within the CD34(+) and CD8(+) cell subsets display the most significant association with the occurrence of relapses with hazard ratios of 5.2 (P=0.003) and 2.8 (P=0.008), respectively. The appearance of recipient cells after a period of pure donor chimerism in the CD34(+) and CD8(+) leukocyte subsets revealed dynamics indicative of a significantly elevated risk of relapse or imminent disease recurrence. Assessment of chimerism within these lineages can therefore provide complementary information for further diagnostic and, potentially, therapeutic purposes aiming at the prevention of overt relapse. This study was registered at clinical.gov with the number NC01423747.

To circumvent donor-to-donor heterogeneity which may lead to inconsistent results after treatment of acute graft-versus-host disease with mesenchymal stromal cells generated from single donors we developed a novel approach by generating these cells from pooled bone marrow mononuclear cells of 8 healthy "3(rd)-party" donors. Generated cells were frozen in 209 vials and designated as mesenchymal stromal cell bank. These vials served as a source for generation of clinical grade mesenchymal stromal cell end-products, which exhibited typical mesenchymal stromal cell phenotype, trilineage differentiation potential and at later passages expressed replicative senescence-related markers (p21 and p16). Genetic analysis demonstrated their genomic stability (normal karyotype and a diploid pattern). Importantly, clinical end-products exerted a significantly higher allosuppressive potential than the mean allosuppressive potential of mesenchymal stromal cells generated from the same donors individually. Administration of 81 mesenchymal stromal cell end-products to 26 patients with severe steroid-resistant acute graft-versus-host disease in 7 stem cell transplant centers who were refractory to many lines of treatment, induced a 77% overall response at the primary end point (day 28). Remarkably, although the cohort of patients was highly challenging (96% grade III/IV and only 4% grade II graft-versus-host disease), after treatment with mesenchymal stromal cell end-products the overall survival rate at two years follow up was 71±11% for the entire patient cohort, compared to 51.4±9.0% in graft-versus-host disease clinical studies, in which mesenchymal stromal cells were derived from single donors. Mesenchymal stromal cell end-products may, therefore, provide a novel therapeutic tool for the effective treatment of severe acute graft-versus-host disease.

Chronic granulomatous disease (CGD) can be cured by allogeneic hemopoietic stem cell transplantation (HSCT). Complications include graft failure, graft-versus-host disease (GVHD), infection, and transplant-related mortality; therefore, reduced-intensity conditioning regimens are being used to improve outcomes. In this retrospective study, the aim was to determine the outcome of treosulfan-based conditioning in HSCT for pediatric patients with CGD. The following data were collected: risk features pre-HSCT, additional conditioning agents, donor type and stem cell source, toxicity, engraftment, GVHD, chimerism, viral reactivation, post-HSCT complications, length of follow-up, and outcome. Seventy patients (median age, 107 months; interquartile range [IQR], 46-232 months) from 16 centers worldwide were transplanted between 2006 and 2015. Ninety-one percent had high-risk features. Fifty-seven HLA-matched donors, 12 HLA-mismatched donors, and 1 CD3(+)TCR ??/CD19 depleted parental haploidentical transplants were performed. No major toxicity was reported. Median times to neutrophil and platelet engraftment were 17 (IQR, 15-35) and 16 (IQR, 13-50) days. At a median follow-up of 34 months (IQR, 13-102 months), the overall survival was 91.4%, and event-free survival was 81.4%. The cumulative incidence of acute grade III-IV GVHD was 12%. Nine patients developed chronic GVHD. When split cell chimerism was available, 95% or more myeloid donor chimerism was documented in 80% of surviving patients. Secondary graft failure occurred in 12% of patients. Treosulfan-containing conditioning regimens can be used safely in HSCT for children with CGD and high-risk clinical features, achieving excellent survival with high myeloid chimerism. Further studies are needed to compare with other regimens and evaluate the long-term outcome, particularly on fertility.

Germline GATA2 mutations cause cellular deficiencies with high propensity for myeloid disease. We investigated 426 children and adolescents with primary myelodysplastic syndrome (MDS) and 82 cases with secondary MDS enrolled in two consecutive prospective studies of the European Working Group of MDS in Childhood (EWOG-MDS) conducted in Germany over a period of 15 years. Germline GATA2 mutations accounted for 15% of advanced and 7% of all primary MDS cases, but were absent in children with MDS secondary to therapy or acquired aplastic anemia. Mutation carriers were older at diagnosis and more likely to present with monosomy 7 and advanced disease as compared to wildtype cases. For stratified analysis according to karyotype 108 additional primary MDS patients registered with EWOG-MDS were studied. Overall, we identified 57 MDS patients with germline GATA2 mutations. GATA2 mutations were highly prevalent among patients with monosomy 7 (37%, all ages) reaching its peak in adolescence (72% of adolescents with monosomy 7). Unexpectedly, monocytosis was more frequent in GATA2-mutated patients. However, when adjusted for the selection bias from monosomy 7, mutational status had no effect on the hematological phenotype. Finally, overall survival and outcome of hematopoietic stem cell transplantation (HSCT) were not influenced by mutational status. This study identifies GATA2 mutations as the most common germline defect predisposing to pediatric MDS with a very high prevalence in adolescents with monosomy 7. GATA2 mutations do not confer poor prognosis in childhood MDS. However, the high risk for progression to advanced disease must guide decision-making towards timely HSCT.

Risk stratification criteria for patients with Ewing's sarcoma family of tumors (ESFT) are still limited. We hypothesized divergent human leukocyte antigen (HLA) patterns in ESFT patients and compared HLA-A, -B and -DR phenotype frequencies of patients with advanced ESFT with those of healthy controls.HLA types of all German Caucasian patients with advanced ESFT and available HLA-A, -B and -DR data registered in the European Group for Blood and Marrow Transplantation, Paediatric Registry for Stem Cell Transplantation and the MetaEICESS data bases (study group, n=30) were retrospectively compared with HLA types of healthy German stem cell donors (control group, n=8 862 for single HLA frequencies and n=8 839 for allele combinations). Study group patients had been immuno-typed due to eligibility for allogeneic stem cell transplantation for high risk of treatment failure, and thus constituted a selected subgroup of ESFT patients.After Bonferroni correction for multiple testing (PC), phenotype frequencies of HLA-A24 remained significantly higher in the study group compared to controls (PC

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.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.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.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.Gentium SpA, European Group for Blood and Marrow Transplantation.

SummaryHere, we report about a boy (age: 18 years) who developed an acquired factor VIII inhibitor at the age of 9 years. He presented with bleeding in his right ankle, multiple haematomas and a high-titer factor VIII type II inhibitor (400 BU). Therapy: He received treatment with MMF (CellCept→), dexamethasoneimmunoglobulin pulses, and rituximab together with high dose FVIII (Hannover protocol). His inhibitor titer decreased rapidly, and half-life and recovery normalized. Inhibitor titres increased after reduction of the factor VIII dose, and increased further after MMF was stopped. A second treatment course with MMF again resulted in reduction of the titre, improvement in half life and recovery, and no more bleedings. Inhibitor reappeared with MMF dose reduction, again accompanied by severe bleeding. Additional rituximab stopped the bleedings, and treatment with MMF has been continued since. Conclusion: Although the laboratory parameters showed no complete remission, severe bleedings and expensive factor replacement could be avoided by long-term treatment with MMF.

Grigull L, Sykora K-W, Tenger A, Bertram H, Meyer-Marcotty M, Hartmann H, Bultmann E, Beilken A, Zivicnjak M, Mynarek M, Osthaus AW, Schilke R, Kollewe K, Lucke T. Variable disease progression after successful stem cell transplantation: Prospective follow-up investigations in eight patients with Hurler syndrome. Pediatr Transplantation 2011: 15: 861–869. © 2011 John Wiley & Sons A/S. Abstract: We report the results of a prospective, standardized follow-up programme of eight children (median age at SCT 1.2 yr) with mucopolysaccharidosis (MPS1H, M. Hurler) transplanted using a fludarabine-based SCT. SCT resulted in stable engraftment without transplant-related mortality. All patients are alive, engrafted and in ambulatory care. During follow-up (median five yr, 1.9–8 yr), six of eight showed developmental delay (two severe, two mild/no), all eight had spinal deformities and one received hip surgery for acetabular dysplasia. Hand surgery for carpal tunnel release and trigger digits was required in five of the patients. The cranio-cervical junction was narrowed in four patients, one child having already received surgery. CC was present in all patients prior to SCT. It remained unchanged in seven and regressed in one child. Severe cardiac dysfunction was present in two of the eight children before SCT. Cardiac pump function was normal in six patients and ameliorated in two, while valve abnormalities could be detected in six patients. Currently, transplantation seems no longer the major obstacle for MPS1H patients, but the variable musculoskeletal disease progression after successful SCT remains a challenge. Patients with Hurler syndrome need specialized follow-up care because of their manifold health problems. The standardized follow-up presented here is a step to optimize care for MPS children and their families after SCT.

Alpha-mannosidosis is a rare lysosomal storage disease. Hematopoietic SCT (HSCT) is usually recommended as a therapeutic option though reports are anecdotal to date. This retrospective multi institutional analysis describes 17 patients that were diagnosed at a median of 2.5 (1.1–23) years and underwent HSCT at a median of 3.6 (1.3–23.1) years. In all, 15 patients are alive (88%) after a median follow-up of 5.5 (2.1–12.6) years. Two patients died within the first 5 months after HSCT. Of the survivors, two developed severe acute GvHD (>=grade II) and six developed chronic GvHD. Three patients required re-transplantation because of graft failure. All 15 showed stable engraftment. The extent of the patients’ developmental delay before HSCT varied over a wide range. After HSCT, patients made developmental progress, although normal development was not achieved. Hearing ability improved in some, but not in all patients. We conclude that HSCT is a feasible therapeutic option that may promote mental development in alpha-mannosidosis.

PV and AL contributed equally Multiple studies from the EBMT registry and others have shown excellent survival rates after allogeneic haematopoietic stem cell transplantation (HSCT)for Wiskott-Aldrich syndrome (WAS) patients (Ozsahin et al, Blood 2008). The importance of myeloid engraftment for full disease correction has also been demonstrated (Moratto et al, Blood 2011). However, the vast majority of HSCTs in these studies were performed with (oral) busulfan/cyclophosphamide-based conditioning and in the early 2000 years or before. In 2005, the inborn errors working party (IEWP) of EBMT and ESID first recommended busulfan/fludarabine (BuFlu) or treosulfan/fludarabine (TreoFlu) based conditioning for primary immunodeficiencies such as WAS, with some centers deciding to add thiotepa (TT) to the conditioning. We performed a retrospective analysis via the EBMT and SCETIDE registries of WAS patients transplanted between 01/01/20006 and 12/31/2016 with these two regimens. The primary objective was to compare the overall (OS) and event-free survival (EFS) after HSCT with either BuFlu±TT or TreoFlu±TT conditioning. Secondary objectives included the influence of either conditioning regimen on acute and chronic GVHD, the degree of donor chimerism, incidence of secondary procedures after HSCT (2nd HSCT, stem cell boost, DLI, gene therapy or splenectomy) and rates of disease-specific complications after HSCT. At the time of this interim analysis, 174 patients were included, 92 (53%) with BuFlu±TT and 82 (47%) with TreoFlu±TT conditioning with a median age of 1.57 years (range 0.21-29.96) at HSCT and a median follow-up of 32.9 months (range 1.5-128.9). The donor was an HLA-matched sibling (MSD) in 30, a matched related donor (MRD) in 5, a matched unrelated donor (MUD, 9/10 or 10/10) in 105, a mismatched unrelated donor (MMUD, 5 years had a worse OS as compared to those 5 years or younger at HSCT (74.9% vs. 90.8%; log-rank test p=0.005). The type of donor had no influence on OS: 96.4% for MSD/MFD, 86.8% for MUD/MMUD and 87.7% for MMFD (log-rank test p=0.4). Whole blood chimerism was complete (>90% donor) in 60/75 evaluable patients (80%) at last follow-up or before secondary procedure (if a patient had one), 39/40 (98%) in the BuFlu±TT group and 21/35 (60%) in the TreoFlu±TT group. Twenty-six patients required a secondary procedure: stem cell boost in 4 patients, donor lymphocyte infusion in 9, 2nd HSCT in 15 and splenectomy in 1. Twenty-two of these 26 (84.6%) are alive and 14 of 16 with available chimerism data have a complete donor chimerism (>90%donor) at last follow-up. The 2-year cumulative incidence (CI) of secondary procedures was higher at 33.9% in the TreoFlu±TT versus 12.8% in the BuFlu±TT group (Gray's test p=0.017), and 2-year EFS (secondary procedure or death as event) was 61.4% in the TreoFlu±TT and 75.0% in the BuFlu±TT group (log-rank test p=0.2). Grade II-IV acute GVHD had the same incidence in both groups (100 day CI 24.4% vs. 26.3%; Gray's test p=0.849) and chronic GVHD of any grade was borderline more frequent in the TreoFlu±TT group (2 year CI 17.2% vs 6.7%; Gray's test p=0.054). The cumulative incidence of disease-specific complications occurring more than 6 months post HSCT (severe infections, bleeding, autoimmunity) was not different between the two groups (6.5% vs. 6.4%; Gray's test p=0.92). There was no malignancy reported after HSCT except for one EBV-post-transplant lymphoproliferative disorder (PTLD) 2.7 months after HSCT. In summary, HSCT with either BuFlu±TT or TreoFlu±TT conditioning reliably cures almost 90% of patients with WAS regardless of donor type. WAS-related complications are very rare events more than 6 months post HSCT. More patients required secondary procedures after treosulfan-based than busulfan-based conditioning. These data confirm the feasibility and efficacy of the regimens currently recommended by the IEWP. Disclosures Slatter: Medac: Other: Travel assistance. Chiesa:Gilead: Consultancy; Bluebird Bio: Consultancy. Kalwak:Sanofi: Other: travel grants; medac: Other: travel grants. Locatelli:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria. Sykora:Aventis-Behring: Research Funding; medac: Research Funding. Zecca:Chimerix: Honoraria. Veys:Pfizer: Honoraria; Servier: Research Funding; Novartis: Honoraria.

Biallelic mutations of mismatch repair genes cause constitutional mismatch repair deficiency associated with an increased risk for childhood leukemia/lymphoma. We report on a case with constitutional mismatch repair deficiency caused by a novel MSH6 mutation leading to a T-cell lymphoma and colonic adenocarcinoma at six and 13 years of age, respectively. A review of the literature on hematologic malignancies in constitutional mismatch repair deficiency showed that in almost half of the 47 known constitutional mismatch repair deficiency families, at least one individual is affected by a hematologic malignancy, predominantly T-cell lymphomas. However, diagnosing constitutional mismatch repair deficiency may be difficult when the first child is affected by leukemia/lymphoma, but identification of the causative germline mutation is of vital importance: (i) to identify relatives at risk and exclude an increased risk in non-mutation carriers; (ii) to prevent hematopoietic stem cell transplantation from sibling donors also carrying a biallelic germline mutation; and (iii) to implement effective surveillance programs for mutation carriers, that may reduce constitutional mismatch repair deficiency-associated mortality.

BACKGROUND: Delayed donor red blood cell chimerism (DRCC), pure red blood cell aplasia (PRCA), and autoimmune hemolytic anemia (AIHA) are poorly documented complications after hematopoietic cell transplantation (HCT). The clinical variable “prolonged isolated red blood cell transfusion requirement” (PRTR) was evaluated as a trigger for an extended diagnostic workup. STUDY DESIGN AND METHODS: PRTR was defined as the need for red blood cell (RBC) transfusions beyond Day 60 after HCT. We analyzed 487 patients transplanted between 2000 and 2006. Median age was 37 years (range, 0-70 years). Peripheral blood stem cells (n = 344), marrow (n = 138), and cord blood (n = 5) from 278 unrelated and 209 family donors were used. RESULTS: Univariate analysis identified age (incidence of 18.3% among elderly patients, 10.5% in adults, and 2.0% among children [p = 0.002]), ABO incompatibility (16.4% after major incompatible, 2.9% after minor incompatible, and 9.4% after ABO-compatible transplantations [p = 0.003]), conditioning (15.2% after reduced-intensity regimens vs. 7.3% after myeloablative conditioning; p = 0.006), donor type (13.2% after HLA-matched unrelated, 13.6% after mismatched unrelated, 5.7% after matched related, and 0.0% after mismatched related grafts; p = 0.026), and acute graft-versus-host disease (aGVHD; 7.1% with aGVHD vs. 12.5% without aGVHD; p = 0.046) as predisposing factors. In multivariate analysis minor ABO incompatibility (odds ratio [OR] = 0.2, p = 0.01), younger age (OR = 0.1, p = 0.02), and matched related HCT (OR = 0.4, p = 0.02) remained independent protective factors. CONCLUSIONS: PRTR could serve as a trigger for a standardized screening for DRCC, PRCA, and AIHA after HCT.