ALBERT

Description: Following allogeneic hematopoietic stem cell transplantation (alloHSCT), children are at risk of life-threatening pneumococcal infections. Whereas vaccination with polysaccharide vaccines fails to elicit protective immunity in most alloHSC transplant recipients, pneumococcal conjugate vaccines may effectively prevent invasive disease by eliciting T-cell–dependent antibody responses. Here, we report safety and immunogenicity in 53 children immunized with a regimen of 3 consecutive doses of a heptavalent pneumococcal conjugate vaccine (7vPCV) in monthly intervals starting 6 to 9 months after alloHSCT. Immunization was well tolerated with no vaccine-related serious adverse events. Serologic response rates evaluable in 43 patients ranged from 41.9% to 86.0% and 58.1% to 93.0% after 2 and 3 vaccinations, respectively, with 55.8% and 74.4% of patients achieving protective antibody levels to all 7 vaccine serotypes. Our study provides the first evidence that vaccination with 7vPCV is safe and elicits protective antipneumococcal antibody responses in pediatric recipients of related or unrelated donor alloHSC transplants within the first year following transplantation. This trial was registered at www.clinicaltrials.gov as NCT00169728.

Description: A large proportion of patients with mutations in the Wiskott Aldrich syndrome (WAS) protein gene exhibit the milder phenotype termed X-linked thrombocytopenia (XLT). Intravenous immunoglobulin and antibiotic prophylaxis until stem cell transplantation (SCT) at an early age is the treatment of choice for classical WAS patients. For patients with XLT the optimal treatment is much less clear. Most of them reach adulthood without significant problems. However, severe complications such as infections, bleeding, autoimmune disorders and malignancies have been observed in these patients, albeit at a lower rate than in classical WAS patients. In order to provide a basis for treatment decisons in XLT patients we intended to define the natural course of disease in XLT patients and assess the probability of severe disease related complications. A retrospective survey at centers treating primary immunodeficiency patients was carried out and data were collected for patients with a documented WASP gene mutation and a WAS disease severity score of 2 or less, implicating thrombocytopenia and mild eczema and minor infections only. Data from a total of 182 patients from 12 countries could be analyzed. Median age at last follow-up was 11.2 years (range 0.4–74.6). Overall probability of survival censored for SCT was favorable in this cohort with 95%, 86% and 78% at 20, 40 and 60 years of age respectively. We did however observe a high rate of severe disease related events such as potentially life threatening infection or bleeding, autoimmune disease or malignancy. Therefore the probability to be alive without a serious event was only 66%, 45% and 29% at 20, 40 and 60 years respectively. Out of all 182 patients 13 (7%) developed severe infectious events, 3 of which were fatal. Severe bleeding episodes occurred in 23/182 (13%), 4 of which were fatal. Autoimmune disease developed in 22/182 (12%) and 9/182 (5%) were diagnosed with malignancy, 6 of whom have died. Overall and event free survival probabilities were not significantly influenced by the type of mutation or the presence of WASProtein. Patients receiving any antibiotic prophylaxis or IVIG had no survival benefit compared to others. Splenectomy, which was performed in 39/182 patients (21%), posed a significant risk to experience a severe infectious event (p

Description: 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

Description: Children undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are at significant risk for life-threatening infections with Streptococcus pneumoniae especially in the first two years after transplantation. Due to immaturity of the immune system, immunization with conventional pneumococcal polysaccharide vaccine fails to elicit protective immunity in the majority of pediatric HSCT recipients. The heptavalent pneumococcal conjugate vaccine Prevenar™ (PCV7; Wyeth Pharma) provides effective protection from invasive disease in infants, who like aHSCT recipients are unable to respond to polysaccharide vaccines due to immunologic immaturity. Currently there is a dearth of data on the safety and efficacy of PCV7 vaccination in pediatric transplant recipients. Here we report tolerability and profound immunogenicity of PCV7 in children after HSCT and show for the first time that PCV7 provides early protective anti-pneumococcal antibody responses in a homogeneously treated cohort of pediatric HSCT recipients recruited into a prospective, multicenter vaccination trial. 53 children (median age 8,3 (1,416,9) years), who underwent HSCT from related (n=24) or unrelated (n=29) donors were immunized with three doses of PCV7 in monthly intervals starting at 6–9 months after HSCT. PCV7 was administered in combination with a hexavalent vaccine against Tetanus, Diphtheria, Pertussis, Poliovirus, Haemophilus influenzae type B and Hepatitis B (Infanrix hexa™; GlaxoSmithKline Pharma). Serum was obtained at baseline and 4–6 weeks after the 2nd and 3rd vaccine and local and systemic adverse events were recorded for 28 days after each vaccination. Responses, defined as seroconversion to protective serotype-specific antibody concentrations (Ab conc.) of 0,5 mg/ml or 〉2-fold increase were detected in 41.9% – 86.0% of patients (pts) after the 2nd vaccine and in 58.1% – 90.7% of pts after the 3rd vaccine (n=43). As a result of a highly significant increase in mean geometric Ab conc. (GMCs) (p

Description: Complex immune dysregulation is a hallmark of sepsis. The occurring phases of immunosuppression and hyperinflammation require rapid detection and close monitoring. Reliable tools to monitor patient’s immune status are yet missing. Currently, microRNAs are being discussed as promising new biomarkers in sepsis. However, no suitable internal control for normalization of miRNA expression by qPCR has been validated so far, thus hampering their potential benefit. We here present the first evaluation of endogenous controls for miRNA analysis in human sepsis. Novel candidate reference miRNAs were identified via miRNA microArray. TaqMan qPCR assays were performed to evaluate these microRNAs in T-cells and whole blood cells of sepsis patients and healthy controls in two independent cohorts. In T-cells, U48 and miR-320 proved suitable as endogenous controls, while in whole blood cells, U44 and miR-942 provided best stability values for normalization of miRNA quantification. Commonly used snRNA U6 exhibited worst stability in all sample groups. The identified internal controls have been prospectively validated in independent cohorts. The critical importance of housekeeping gene selection is emphasized by exemplary quantification of imuno-miR-150 in sepsis patients. Use of appropriate internal controls could facilitate research on miRNA-based biomarker-use and might even improve treatment strategies in the future.

Description: Purpose Results of the prospective trial "CML-PAED-II" assessing treatment efficacy and side effects in children and adolescents with newly diagnosed chronic myeloid leukemia (CML) are reported. Patients and Methods 156 patients (age range 1.3-18.0 years, 91 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 upfront (300 mg/m², 400 mg/m², 500 mg/m², respectively). Therapy response, progression-free survival, causes of treatment failure and proportion of patients undergoing stem cell transplantation were analyzed in 148 patients with complete data. Results Event-free survival rate at 18 months for pediatric patients diagnosed in CML-CP (median follow-up time 25 months, range: 0.1-120) was 97% (95% CI, 94.2%-99.9%). According to the 2006 ELN-criteria complete hematologic response at month 3, complete cytogenetic response (CCyR) at month 12, and molecular response (MR3.0) at month 18 were achieved in 98%, in 63%, and 59% of the patients, respectively. At month 36 on continuous first line imatinib or 2nd generation tyrosine kinase inhibitor treatment, 86% of the patients achieved CCyR and 74% achieved MR3.0. 66% of the patients experienced at least one side effect. Imatinib-related anemia was the most frequent toxicity observed if all grades were considered (N=98; 66%) while neutropenia was the most frequently reported grade 3/4 hematologic adverse effect (N=22; 15%). Among non-hematologic toxicities, all grades of gastrointestinal toxicity were observed most frequently (N=57, 38%), however, it occurred at lower grades 1/2 in all but one patient. Higher grade 3/4 musculoskeletal pain was also frequent (N=53, 36%). Twenty-seven patients (18%) had to discontinue treatment temporarily while nine patients permanently terminated imatinib due to non-tolerable side effects (neutropenia N= 4, muscle cramps N= 3, skin N= 1, liver N= 1). Thirty-eight patients (27%) experienced imatinib failure because of unsatisfactory response (N= 27) or intolerance (N= 9). 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). Conclusion This large pediatric trial provides evidence confirming that first line imatinib in children is highly effective. Observed adverse effects are acceptable and mainly comprise hematological side effects. Long term outcome and effects of a potentially life-long TKI treatment have to be registered in cooperation with adult hematologists in extended surveillance follow-up studies. Disclosures Suttorp: Novartis: Research Funding. Schrappe: JAZZ Pharma: Consultancy, Research Funding; Baxalta: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; SigmaTau: Consultancy, Research Funding; Medac: Consultancy, Research Funding. Thiede: Novartis: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Roche: Consultancy; Agendix: Employment.