ABSTRACT
BACKGROUND: Congenital thrombotic thrombocytopenic purpura (TTP) results from severe hereditary deficiency of ADAMTS13. The efficacy and safety of recombinant ADAMTS13 and standard therapy (plasma-derived products) administered as routine prophylaxis or on-demand treatment in patients with congenital TTP is not known. METHODS: In this phase 3, open-label, crossover trial, we randomly assigned patients in a 1:1 ratio to two 6-month periods of prophylaxis with recombinant ADAMTS13 (40 IU per kilogram of body weight, administered intravenously) or standard therapy, followed by the alternate treatment; thereafter, all the patients received recombinant ADAMTS13 for an additional 6 months. The trigger for this interim analysis was trial completion by at least 30 patients. The primary outcome was acute TTP events. Manifestations of TTP, safety, and pharmacokinetics were assessed. Patients who had an acute TTP event could receive on-demand treatment. RESULTS: A total of 48 patients underwent randomization; 32 completed the trial. No acute TTP event occurred during prophylaxis with recombinant ADAMTS13, whereas 1 patient had an acute TTP event during prophylaxis with standard therapy (mean annualized event rate, 0.05). Thrombocytopenia was the most frequent TTP manifestation (annualized event rate, 0.74 with recombinant ADAMTS13 and 1.73 with standard therapy). Adverse events occurred in 71% of the patients with recombinant ADAMTS13 and in 84% with standard therapy. Adverse events that were considered by investigators to be related to the trial drug occurred in 9% of the patients with recombinant ADAMTS13 and in 48% with standard therapy. Trial-drug interruption or discontinuation due to adverse events occurred in no patients with recombinant ADAMTS13 and in 8 patients with standard therapy. No neutralizing antibodies developed during recombinant ADAMTS13 treatment. The mean maximum ADAMTS13 activity after recombinant ADAMTS13 treatment was 101%, as compared with 19% after standard therapy. CONCLUSIONS: During prophylaxis with recombinant ADAMTS13 in patients with congenital TTP, ADAMTS13 activity reached approximately 100% of normal levels, adverse events were generally mild or moderate in severity, and TTP events and manifestations were rare. (Funded by Takeda Development Center Americas and Baxalta Innovations; ClinicalTrials.gov number, NCT03393975.).
Subject(s)
ADAMTS13 Protein , Purpura, Thrombotic Thrombocytopenic , Recombinant Proteins , Adolescent , Adult , Child , Female , Humans , Male , Middle Aged , Young Adult , ADAMTS13 Protein/administration & dosage , ADAMTS13 Protein/adverse effects , ADAMTS13 Protein/deficiency , ADAMTS13 Protein/genetics , Cross-Over Studies , Purpura, Thrombotic Thrombocytopenic/congenital , Purpura, Thrombotic Thrombocytopenic/drug therapy , Purpura, Thrombotic Thrombocytopenic/genetics , Recombinant Proteins/administration & dosage , Recombinant Proteins/adverse effects , Child, PreschoolABSTRACT
OBJECTIVES: To compare the diagnostic value of ultrashort echo time (UTE) magnetic resonance imaging (MRI) for the lung versus the gold standard computed tomography (CT) and two T1-weighted MRI sequences in children. METHODS: Twenty-three patients with proven oncologic disease (14 male, 9 female; mean age 9.0 + / - 5.4 years) received 35 low-dose CT and MRI examinations of the lung. The MRI protocol (1.5-T) included the following post-contrast sequences: two-dimensional (2D) incoherent gradient echo (GRE; acquisition with breath-hold), 3D volume interpolated GRE (breath-hold), and 3D high-resolution radial UTE sequences (performed during free-breathing). Images were evaluated by considering image quality as well as distinct diagnosis of pulmonary nodules and parenchymal areal opacities with consideration of sizes and characterisations. RESULTS: The UTE technique showed significantly higher overall image quality, better sharpness, and fewer artefacts than both other sequences. On CT, 110 pulmonary nodules with a mean diameter of 4.9 + / - 2.9 mm were detected. UTE imaging resulted in a significantly higher detection rate compared to both other sequences (p < 0.01): 76.4% (84 of 110 nodules) for UTE versus 60.9% (67 of 110) for incoherent GRE and 62.7% (69 of 110) for volume interpolated GRE sequences. The detection of parenchymal areal opacities by the UTE technique was also significantly higher with a rate of 93.3% (42 of 45 opacities) versus 77.8% (35 of 45) for 2D GRE and 80.0% (36 of 45) for 3D GRE sequences (p < 0.05). CONCLUSION: The UTE technique for lung MRI is favourable in children with generally high diagnostic performance compared to standard T1-weighted sequences as well as CT. Key Points ⢠Due to the possible acquisition during free-breathing of the patients, the UTE MRI sequence for the lung is favourable in children. ⢠The UTE technique reaches higher overall image quality, better sharpness, and lower artefacts, but not higher contrast compared to standard post-contrast T1-weighted sequences. ⢠In comparison to the gold standard chest CT, the detection rate of small pulmonary nodules small nodules ≤ 4 mm and subtle parenchymal areal opacities is higher with the UTE imaging than standard T1-weighted sequences.
Subject(s)
Imaging, Three-Dimensional , Magnetic Resonance Imaging , Adolescent , Breath Holding , Child , Child, Preschool , Female , Humans , Lung/diagnostic imaging , Male , Tomography, X-Ray ComputedABSTRACT
Safety, tolerability, and pharmacokinetics of recombinant ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; BAX 930; SHP655) were investigated in 15 patients diagnosed with severe congenital ADAMTS-13 deficiency (plasma ADAMTS-13 activity <6%) in a prospective phase 1, first-in-human, multicenter dose escalation study. BAX 930 was well tolerated, no serious adverse events occurred, and no anti-ADAMTS-13 antibodies were observed. After single-dose administration of BAX 930 at 5, 20, or 40 U/kg body weight to adolescents and adults, there was approximate dose proportionality with respect to maximum plasma concentration (Cmax [U/mL]) and area under the concentration-time curve (AUC [hâU/mL]). Dose-related increases of individual ADAMTS-13:Ag and activity were observed and reached a maximum within 1 hour. With escalating BAX 930 doses administered, a dose-dependent persistence of ADAMTS-13-mediated von Willebrand factor (VWF) cleavage products and reduced VWF multimeric size were observed. This study demonstrated that pharmacokinetic parameters of BAX 930 were comparable to those estimated in previous plasma infusion studies and provided evidence of pharmacodynamic activity. This study was registered at www.clinicaltrials.gov as #NCT02216084.
Subject(s)
ADAMTS13 Protein/administration & dosage , ADAMTS13 Protein/pharmacokinetics , Purpura, Thrombotic Thrombocytopenic/blood , Purpura, Thrombotic Thrombocytopenic/drug therapy , Adolescent , Adult , Dose-Response Relationship, Drug , Female , Humans , Male , Recombinant Proteins , von Willebrand Factor/metabolismABSTRACT
Multiple blood cell transfusions may cause iron overload or even liver fibrosis, requiring early diagnosis and intervention. SF is the standard for estimating iron levels in the body, but it also increases with inflammation. We hypothesized that T2 * magnetic resonance (MR) relaxometry is a more accurate alternative for follow-up in pediatric patients before and after allogenic SCT. Twenty-three children (mean age 10.2 years, 10 female, 13 male) were evaluated prospectively before SCT as well as at least 1 year after SCT with T2 * relaxometry on a 1.5 T MR-scanner to estimate liver iron concentrations from the T2 * values ("MR-Fe"). The results were compared with SF, while also considering CRP, and correlated with the number of transfusions. Overall, 24.3 transfusions were administered in average, mainly within 100 days of SCT (mean 10.5 units). Both MR-Fe and SF increased after SCT and decreased in the absence of new transfusions 1 year later without chelate therapy. This suggests regeneration of LP and iron loss, although the original states were not reached. Additionally, simultaneous peaks of CRP and SF were observed directly after SCT. MR-Fe did neither reveal these peaks nor was it associated with CRP (P = .39). We postulate that these early CRP and SF peaks after SCT are probably related to inflammatory reactions and not to iron overload. Thus, SF is not reliable for iron overload diagnosis after SCT in every condition. Beside this interaction, SF and MR-Fe revealed similar accuracy. MRI, however, has practical and economical disadvantages in routine estimation of iron.
Subject(s)
Ferritins/blood , Iron Overload/diagnosis , Iron Overload/immunology , Magnetic Resonance Imaging , Postoperative Complications/diagnosis , Postoperative Complications/immunology , Stem Cell Transplantation , Blood Transfusion/statistics & numerical data , Child , Female , Humans , Iron Overload/blood , Male , Postoperative Complications/blood , Prospective Studies , Transfusion Reaction/epidemiologyABSTRACT
BACKGROUND: Children receiving multiple blood cell transfusions are prone to iron overload and successive tissue damage in liver parenchyma, making noninvasive screening options desirable. Ultrasound (US) elastography using acoustic radiation force impulse (ARFI) imaging enables evaluation of liver parenchyma stiffness, and MRI allows for quantification of liver iron concentration. OBJECTIVE: The objective was to correlate US elastography with MRI in children who had undergone bone marrow transplantation and to evaluate the modification of liver tissue with US in combination with clinical parameters at follow-up. MATERIALS AND METHODS: ARFI, T2*-weighted MRI and a clinical score (HepScore, based on parameters of liver function) were performed in 45 patients (24 male; mean age 9.7 years) before and 100 days and 365 days after transplantation. All received multiple blood transfusions (mean number 22.2 up until 1 year after transplantation). We correlated US findings and HepScore with MRI findings. RESULTS: We observed signs of iron accumulation in 29/45 (64.4%) patients on MRI (T2*<10 ms) and 15/45 (33.3%) showed increased tissue stiffness (ARFI>5.5 kPa). Correlation of elastography and MRI was not significant (P=0.57; n=51 matched measurements). Comparing US elastography with HepScore in receiver operating characteristic (ROC) curve analysis indicated a cut-off for affected parenchyma if HepScore was >5 points (sensitivity 67%, specificity 68%). Simultaneous increases of both indicated tissue alteration. CONCLUSION: Combining US and HepScore enabled detection of liver tissue alteration through iron overload, but we found no direct significant effect of estimated iron from MRI on ARFI imaging.
Subject(s)
Blood Component Transfusion/statistics & numerical data , Bone Marrow Transplantation , Elasticity Imaging Techniques/methods , Iron Overload/diagnostic imaging , Liver/diagnostic imaging , Liver/metabolism , Child , Female , Humans , MaleABSTRACT
The terminal complement split product C5a has been described as an important mediator in inflammatory diseases. C5a is generated upon cleavage of C5 and earlier research suggests that, besides the known C5 convertases formed upon activation of the complement pathways, various enzymes could activate C5 directly. We demonstrate that eculizumab effectively blocks C5 activation when mediated by C5-convertase formation, but fails to block C5a generation resulting from direct enzymatic cleavage by trypsin and thrombin. C5a generated by these enzymes is shown to be fully biologically functional and can be blocked by IFX-1, a specific monoclonal anti-human C5a antibody. We further report clinical cases of atypical hemolytic uremic syndrome (aHUS) and C3 Glomerulonephritis (C3GN) patients under treatment with eculizumab presenting substantially elevated C5a levels. Thus, blocking the C5 convertase mediated activation of C5 may not be efficient to control C5a-mediated effects in human disease and that a targeted approach is warranted.
Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Atypical Hemolytic Uremic Syndrome/immunology , Complement C5a/immunology , Glomerulonephritis/immunology , Antibodies, Monoclonal, Humanized/therapeutic use , Atypical Hemolytic Uremic Syndrome/drug therapy , Complement C3-C5 Convertases/immunology , Glomerulonephritis/drug therapy , Humans , Thrombin/immunology , Trypsin/immunology , Zymosan/pharmacologySubject(s)
BNT162 Vaccine/adverse effects , COVID-19/prevention & control , Purpura, Thrombotic Thrombocytopenic/diagnosis , Purpura, Thrombotic Thrombocytopenic/etiology , SARS-CoV-2 , Aged, 80 and over , BNT162 Vaccine/administration & dosage , BNT162 Vaccine/immunology , Biomarkers , Female , Humans , Platelet Count , SARS-CoV-2/immunology , Symptom Assessment , Vaccination/adverse effectsABSTRACT
BACKGROUND: Antithrombin [AT]-, protein C [PC]- or protein S [PS]-deficiency [D] constitutes a major risk factor for venous thromboembolism [VTE]. Primary study objective was to evaluate if the clinical presentation at first VTE onset differs between children and adults and to compare the individual recurrence risk among patients with respect to age at onset and their thrombophilia status ATD, PCD or PSD. METHODS/PATIENTS/RESULTS: In 137 of 688 consecutively enrolled pediatric and adult VTE patients we calculated the absolute risk of VTE recurrence and event-free-survival adjusted for thrombophilia and positive family VTE history. At first VTE children manifested i) with a lower rate of pulmonary embolism, ii) a higher rate of cerebral vascular events or multiple VTEs, and iii) showed a higher proportion of unprovoked VTE compared to adolescents and adults. Adult patients reported more often a positive VTE history compared to younger study participants. The adjusted odds of recurrence in adults was 2.05 compared to children. CONCLUSION: At disease manifestation children and adults differ with respect to i) thrombotic locations, ii) percentage of unprovoked versus provoked VTE, and iii) different rates of positive VTE family histories. Furthermore, adults showed a two-fold increase risk of VTE recurrence compared to children.
Subject(s)
Thrombophilia/complications , Venous Thromboembolism/pathology , Adolescent , Adult , Age Factors , Child , Child, Preschool , Cohort Studies , Humans , Medical History Taking , Middle Aged , Protein C Deficiency , Protein S Deficiency , Recurrence , Risk Factors , Venous Thromboembolism/etiology , Young AdultABSTRACT
Acquired thrombotic thrombocytopenic purpura (TTP) is the consequence of a severe ADAMTS13 deficiency resulting from autoantibodies inhibiting ADAMTS13 or accelerating its clearance. Despite the success of plasma exchange the risk of relapse is high. From 2 patients (A and B), splenectomized for recurrent episodes of acquired TTP, the splenic B-cell response against ADAMTS13 was characterized through generation of human monoclonal anti-ADAMTS13 autoantibodies (mAbs) by cloning an immunoglobulin G (IgG)4κ- and IgG4λ-Fab library using phage display technology and by Epstein-Barr virus transformation of switched memory B cells (CD19+/CD27+/IgG+). Sequence analysis of the anti-ADAMTS13 IgGs of both patients revealed that the VH gene use was limited in our patients to VH1-3 (55%), VH1-69 (17%), VH3-30 (7%), and VH4-28 (21%) and contained 8 unique and thus far not reported heavy-chain complementarity determining region 3 motifs, of which 4 were shared by the 2 patients. The discovery of several highly similar anti-ADAMTS13 autoantibodies in 2 unrelated TTP patients suggests that the autoimmune response is antigen driven, because the probability that such similar immunoglobulin rearrangements happen by chance is very low (< 10(-9)).
Subject(s)
ADAM Proteins/immunology , Autoantibodies/chemistry , Autoantibodies/metabolism , Protein Interaction Domains and Motifs , Purpura, Thrombotic Thrombocytopenic/immunology , Spleen/immunology , ADAMTS13 Protein , Adult , Antigen-Antibody Complex/chemistry , Autoimmunity/immunology , Child , Female , Humans , Protein Binding , Purpura, Thrombotic Thrombocytopenic/metabolism , Purpura, Thrombotic Thrombocytopenic/surgery , Remission Induction , Spleen/metabolism , SplenectomyABSTRACT
Accumulation of CD3(+) T-cell receptor (TCR)αß(+)CD4(-)CD8(-) double-negative T cells (DNT) is a hallmark of autoimmune lymphoproliferative syndrome (ALPS). DNT origin and differentiation pathways remain controversial. Here we show that human ALPS DNT have features of terminally differentiated effector memory T cells reexpressing CD45RA(+) (TEMRA), but are CD27(+)CD28(+)KLRG1(-) and do not express the transcription factor T-bet. This unique phenotype was also detected among CD4(+) or CD8(+) ALPS TEMRA cells. T-cell receptor ß deep sequencing revealed a significant fraction of shared CDR3 sequences between ALPS DNT and both CD4(+) and CD8(+)TEMRA cells. Moreover, in ALPS patients with a germ line FAS mutation and somatic loss of heterozygosity, in whom biallelic mutant cells can be tracked by absent Fas expression, Fas-negative T cells accumulated not only among DNT, but also among CD4(+) and CD8(+)TEMRA cells. These data indicate that in human Fas deficiency DNT cannot only derive from CD8(+), but also from CD4(+) T cells. Furthermore, defective Fas signaling leads to aberrant transcriptional programs and differentiation of subsets of CD4(+) and CD8(+) T cells. Accumulation of these cells before their double-negative state appears to be an important early event in the pathogenesis of lymphoproliferation in ALPS patients.
Subject(s)
Autoimmune Lymphoproliferative Syndrome/immunology , Autoimmune Lymphoproliferative Syndrome/pathology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/pathology , fas Receptor/deficiency , fas Receptor/genetics , Adolescent , Adult , Autoimmune Lymphoproliferative Syndrome/genetics , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , Cell Differentiation/genetics , Cell Differentiation/immunology , Child , Child, Preschool , Genetic Association Studies , Germ-Line Mutation , Humans , Immunologic Memory , Leukocyte Common Antigens/metabolism , Loss of Heterozygosity , Receptors, Antigen, T-Cell, alpha-beta/metabolism , T-Box Domain Proteins/metabolism , T-Lymphocyte Subsets/metabolism , Young AdultABSTRACT
Haemophagocytic lymphohistiocytosis (HLH) in the context of malignancy is mainly considered a challenge of adult haematology. While this association is also observed in children, little is known regarding inciting factors, appropriate treatment and prognosis. We retrospectively analysed 29 paediatric and adolescent patients for presenting features, type of neoplasm or preceding chemotherapy, treatment and outcome. Haemophagocytic lymphohistiocytosis was considered triggered by the malignancy (M-HLH) in 21 patients, most of whom had T- (n = 12) or B-cell neoplasms (n = 7), with Epstein-Barr virus as a co-trigger in five patients. In eight patients, HLH occurred during chemotherapy (Ch-HLH) for malignancy, mainly acute leukaemias (n = 7); an infectious trigger was found in seven. In M- and Ch-HLH, median overall survival was 1·2 and 0·9 years, and the 6 month survival rates were 67% and 63%, respectively. Seven of 11 deceased M-HLH patients exhibited active malignancy and HLH at the time of death, while only two out of five deceased Ch-HLH patients had evidence of active HLH. To overcome HLH, malignancy- and HLH-directed treatments were administered in the M-HLH cohort; however, it was not possible to determine superiority of one approach over the other. For Ch-HLH, treatment ranged from postponement of chemotherapy to the use of etoposide-containing regimens.
Subject(s)
Epstein-Barr Virus Infections , Leukemia , Lymphohistiocytosis, Hemophagocytic , Acute Disease , Adolescent , Adult , Child , Child, Preschool , Disease-Free Survival , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/drug therapy , Epstein-Barr Virus Infections/mortality , Female , Humans , Infant , Infant, Newborn , Leukemia/drug therapy , Leukemia/mortality , Lymphohistiocytosis, Hemophagocytic/etiology , Lymphohistiocytosis, Hemophagocytic/mortality , Lymphohistiocytosis, Hemophagocytic/therapy , Male , Retrospective Studies , Survival RateABSTRACT
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/Lâ×âh). 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.
Subject(s)
Granulomatous Disease, Chronic/therapy , Hematopoietic Stem Cell Transplantation/methods , Transplantation Conditioning/methods , Adolescent , Adult , Alemtuzumab , Antibodies, Monoclonal, Humanized/administration & dosage , Antilymphocyte Serum/administration & dosage , Busulfan/administration & dosage , Child , Child, Preschool , Drug Therapy, Combination , Graft Survival/drug effects , Graft vs Host Disease/prevention & control , HLA Antigens , Humans , Immunosuppressive Agents/administration & dosage , Infant , Prospective Studies , Transplantation Chimera/physiology , Treatment Outcome , Vidarabine/administration & dosage , Vidarabine/analogs & derivatives , Young AdultABSTRACT
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.
Subject(s)
Antibodies, Monoclonal, Murine-Derived/therapeutic use , Antineoplastic Agents/therapeutic use , Purpura, Thrombotic Thrombocytopenic/drug therapy , Adolescent , Adult , B-Lymphocytes/drug effects , B-Lymphocytes/pathology , Child , Female , Follow-Up Studies , Humans , Male , Neoplasm Staging , Prognosis , Purpura, Thrombotic Thrombocytopenic/pathology , Recurrence , Remission Induction , Rituximab , Time Factors , Young AdultABSTRACT
Introduction: Purified factor IX (FIX) concentrate (IMMUNINE®, Takeda Manufacturing Austria AG, Vienna, Austria) is indicated for the treatment and prophylaxis of bleeding episodes in patients with congenital hemophilia B. Data on the use of purified FIX concentrate in patients ≤6 years old with congenital hemophilia B are limited. Aim: Document real-world clinical experience with purified FIX concentrate in routine practice for pediatric patients with hemophilia B. Methods: This prospective post-authorization safety surveillance study enrolled patients ≤6 years old with moderate or severe hemophilia B (baseline FIX ≤5%) who were prescribed purified FIX concentrate, as determined by the treating physician. The planned observation period for each patient was either 12 months or ≥50 exposure days, whichever occurred first. The primary endpoints were the occurrence of treatment-related adverse events (AEs) and serious AEs (SAEs), and inhibitor development. Results: Thirteen male patients (mean ± standard deviation age, 3.80 ± 1.76 years) enrolled and received ≥1 treatment with purified FIX concentrate. Thirty-two AEs were reported in 6 patients; 4 were SAEs. No AEs were considered related to purified FIX concentrate. No patients developed inhibitory antibodies. Inhibitor testing was not conducted in 2 patients. Eighteen bleeding episodes were treated with purified FIX concentrate in 6 patients. Hemostatic efficacy was rated as either "excellent" or "good" in all patients with an available rating. Conclusion: No treatment-related AEs were reported, and purified FIX concentrate was shown to be effective in treating and preventing bleeding episodes in pediatric patients ≤6 years old with hemophilia B.
ABSTRACT
Clinical and genetic heterogeneity renders confirmation or exclusion of autoimmune lymphoproliferative syndrome difficult. To re-evaluate and improve the currently suggested diagnostic approach to patients with suspected FAS mutation, the most frequent cause of autoimmune lymphoproliferative syndrome, we prospectively determined 11 biomarkers in 163 patients with splenomegaly or lymphadenopathy and presumed or proven autoimmune cytopenia(s). Among 98 patients sequenced for FAS mutations in CD3(+)TCRα/ß(+)CD4(-)CD8(-) "double negative" T cells, 32 had germline and six had somatic FAS mutations. The best a priori predictor of FAS mutations was the combination of vitamin B12 and soluble FAS ligand (cut-offs 1255 pg/mL and 559 pg/mL, respectively), which had a positive predictive value of 92% and a negative predictive value of 97%. We used these data to develop a web-based probability calculator for FAS mutations using the three most discriminatory biomarkers (vitamin B12, soluble FAS ligand, interleukin-10) of the 11 tested. Since more than 60% of patients with lymphoproliferation and autoimmune cytopenia(s) in our cohort did not harbor FAS mutations, 15% had somatic FAS mutations, and the predictive value of double-negative T-cell values was rather low (positive and negative predictive values of 61% and 77%, respectively), we argue that the previously suggested diagnostic algorithm based on determination of double-negative T cells and germline FAS sequencing, followed by biomarker analysis, is not efficient. We propose vitamin B12 and soluble FAS ligand assessment as the initial diagnostic step with subsequent decision on FAS sequencing supported by a probability-calculating tool.
Subject(s)
Fas Ligand Protein/blood , Fas Ligand Protein/genetics , Lymphoproliferative Disorders/blood , Lymphoproliferative Disorders/genetics , Vitamin B 12/blood , Adolescent , Autoimmune Diseases/blood , Autoimmune Diseases/diagnosis , Autoimmune Diseases/genetics , Biomarkers/blood , Cohort Studies , Female , Humans , Lymphoproliferative Disorders/diagnosis , MaleSubject(s)
CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , Immunologic Deficiency Syndromes/diagnosis , STAT1 Transcription Factor/metabolism , STAT3 Transcription Factor/metabolism , Adult , Female , Flow Cytometry , Humans , Immunologic Deficiency Syndromes/metabolism , Male , PhosphorylationABSTRACT
The histomorphology of liboblastoma is highly variable and comprises different patterns that are found admixed or in pure form within a tumor. The most important features - mature lipomatous, fibrotic, lipofibrous, and myxoid - overlap with the histomorphology of several other pediatric tumor entities. Regarding the morphologic overlaps, molecular diagnostics with identification of fusion transcripts involving PLAG1 or HMGA2 is essential to identify lipoblastomas. This paper describes the diagnostic procedure in general and two new fusion transcripts of lipoblastoma, MEG3-PLAG1 and COL1A1-PLAG1. In conclusion, the algorithm to diagnose lipoblastomas among this group of pediatric fibrotic, lipofibrous and mature lipomatous tumors essentially includes histomorphology, immunohistochemistry, and molecular diagnostics.
Subject(s)
5-Aminolevulinate Synthetase/genetics , Iron/administration & dosage , Protoporphyria, Erythropoietic/diagnosis , Anemia/drug therapy , Anemia/prevention & control , Child , Humans , Iron/therapeutic use , Liver/injuries , Liver Diseases/drug therapy , Liver Diseases/prevention & control , Male , Protoporphyria, Erythropoietic/classification , Protoporphyria, Erythropoietic/therapy , Protoporphyrins/bloodABSTRACT
Thrombotic microangiopathies (TMA) represent a spectrum of related disorders associated with newly formed thrombi that block perfusion and thus affect the function of either renal or neurological organs and tissue. Recent years have seen a dramatic development in the field of TMA and for the two major forms hemolytic uremic syndrome (HUS) and thrombocytopenic purpura (TTP), new genetic causes and also autoimmune forms have been identified. This development indicates a similar pathophysiology and suggests that the two acute disorders are based on common principles. HUS is primarily a kidney disease and TTP also develops in the kidney and at neurological sites. In HUS thrombi formation is likely due to a deregulated complement activation and inappropriate platelet activity. In TTP thrombi formation occurs because of inappropriate processing of released multimers of von Willebrand Factor (vWF). Defining both the similarities and the unique features of each disorder will open up new ways and concepts that are relevant for diagnosis, for therapy, and for the prognostic outcome of kidney transplantations. Here we summarize the most relevant topics and timely issues that were presented and discussed at the 4th International Workshop on Thrombotic Microangiopathies held in Weimar in October 2009 (www.hus-ttp.de).
Subject(s)
Hemolytic-Uremic Syndrome , Purpura, Thrombotic Thrombocytopenic , HumansABSTRACT
BACKGROUND: Routine assessment of body iron load in patients with acute leukemia is usually done by serum ferritin (SF) assay; however, its sensitivity is impaired by different conditions including inflammation and malignancy. OBJECTIVE: To estimate, using MRI, the extent of liver iron overload in children with acute leukemia and receiving blood transfusions, and to examine the association between the degree of hepatic iron overload and clinical parameters including SF and the transfusion iron load (TIL). MATERIAL AND METHODS: A total of 25 MRI measurements of the liver were performed in 15 children with acute leukemia (mean age 9.75 years) using gradient-echo sequences. Signal intensity ratios between the liver and the vertebral muscle (L/M ratio) were calculated and compared with SF-levels. TIL was estimated from the cumulative blood volume received, assuming an amount of 200 mg iron per transfused red blood cell unit. RESULTS: Statistical analysis revealed good correlation between the L/M SI ratio and TIL (r = -0.67, P = 0.002, 95% confidence interval CI = -0.83 to -0.34) in patients with acute leukemia as well as between L/M SI ratio and SF (r = -0.76, P = 0.0003, 95% CI = -0.89 to -0.52). CONCLUSION: SF may reliably reflect liver iron stores as a routine marker in patients suffering from acute leukemia.