ALBERT

Description: This open-label, single-arm, prospective cohort trial is the first phase 3 safety study to describe outcomes in children treated with dabigatran etexilate for secondary venous thromboembolism (VTE) prevention. Eligible children aged 12 to

Description: The age-adjusted incidence of new factor VIII inhibitors was analyzed in all United Kingdom patients with severe hemophilia A between 1990 and 2009. Three hundred fifteen new inhibitors were reported to the National Hemophilia Database in 2528 patients with severe hemophilia who were followed up for a median (interquartile range) of 12 (4-19) years. One hundred sixty (51%) of these arose in patients ≥ 5 years of age after a median (interquartile range) of 6 (4-11) years' follow-up. The incidence of new inhibitors was 64.29 per 1000 treatment-years in patients 〈 5 years of age and 5.31 per 1000 treatment-years at age 10-49 years, rising significantly (P = .01) to 10.49 per 1000 treatment-years in patients more than 60 years of age. Factor VIII inhibitors arise in patients with hemophilia A throughout life with a bimodal risk, being greatest in early childhood and in old age. HIV was associated with significantly fewer new inhibitors. The inhibitor incidence rate ratio in HIV-seropositive patients was 0.32 times that observed in HIV-seronegative patients (P 〈 .001). Further study is required to explore the natural history of later-onset factor VIII inhibitors and to investigate other potential risk factors for inhibitor development in previously treated patients.

Description: Although genetic and environmental factors explain approximately half of the interindividual variability in warfarin dose requirement in adults, there is limited information available in children. In a cross-sectional study of anticoagulated children from 5 tertiary care centers, 120 children with a stable warfarin dose were genotyped for VKORC1 (−1639G 〉 A; rs9923231), CYP2C9 (*2 and *3 alleles; rs1799853 and rs1057910), and CYP4F2 (V433M; rs2108622) polymorphisms. Clinical and demographic features were recorded. Multiple regression analysis of the data showed that, although CYP4F2 made no contribution to the dose model, 72.4% of the variability in warfarin dose requirement is attributed to by patient height, genetic polymorphisms in VKORC1 and CYP2C9, and indication for warfarin. The recently published International Warfarin Pharmacogenetics Consortium pharmacogenetic-based warfarin dosing algorithm (based on data derived from anticoagulated adults) consistently overestimated warfarin dose for our cohort of children. A similar proportion of the interindividual variability in warfarin dose is explained by genetic factors in children compared with adult patients, although height is a greater predictor in children. A pharmacogenomic approach to warfarin dosing has the potential to improve the efficacy and safety of warfarin therapy in children. However, algorithms should be derived from data in children if their potential benefit is to be realized.

Description: Gray platelet syndrome (GPS) is a rare recessive disorder caused by biallelic variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet α-granules, splenomegaly, and bone marrow (BM) fibrosis. Due to the rarity of GPS, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathologic features, we performed a detailed clinical genotypic and phenotypic study of 47 patients with GPS and identified 32 new etiologic variants in NBEAL2. The GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. Novel clinical phenotypes were also observed, including reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4 lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One-quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data show that, in addition to the well-described platelet defects in GPS, there are immune defects. The abnormal immune cells may be the drivers of systemic abnormalities such as autoimmune disease.

Description: Key Points Kogenate Bayer/Helixate NexGen was associated with a higher inhibitor incidence than Advate in 407 consecutive UK severe hemophilia A previously untreated patients. Other risk factors for inhibitor development were factor VIII genotype, ethnicity, and intensive treatment episodes.

Description: Cerebral venous thrombosis (CVT) is a significant complication of therapy in children and young adults with acute lymphoblastic leukaemia (ALL). Previous reports indicate a considerable risk of mortality and morbidity in relation to CVT. In addition, there is potential for suboptimal treatment of ALL due to avoidance of Asparaginase and the need for reversal of anticoagulant therapy for invasive procedures such as intrathecal chemotherapy. Anticoagulation may be complicated by haemorrhage. This retrospective study aimed to identify the clinical features, therapy and outcome of CVT occurring during treatment of ALL in individuals, aged 1 to 24 years, who participated in the Medical Research Council UK ALL 2003 (MRC UKALL 2003) randomised controlled trial. Cases of CVT were identified from adverse event reporting. All reports were screened for central nervous system thrombosis and grade 4 serious adverse events in the category of coagulation/thrombosis. Reporting centres were asked for additional clinical information. 3126 children and young adults were enrolled in the study between 2003 and 2011, with median age 5 years, including 1776 males (56.8%). The 3 initial treatment regimens: A, B and C: corresponded to standard-risk, intermediate-risk and high-risk, respectively. 55% were treated with regimen A, 32% regimen B and 13% regimen C. 48 individuals (1.5%) developed CVT and data were returned for 42. Median age was 10 (range: 1 to 18) years and 25 cases were male (59.5%). 71.4% of cases (30/42) occurred during induction therapy. 18 cases were in individuals treated with regimen A, 22 regimen B and 2 regimen C. Median time between the most recent Asparaginase dose and CVT was 12.5 days (range: 1-111 days). 29 cases (68.4%) had received 2 doses of Asparaginase prior to thrombosis, 5 cases 〉2 doses and 8 cases 1 dose. Presenting symptoms were: seizures, 22 cases (52.3%); neurological impairment, 20 (47.6%); headache, 19 (45.2%); reduced conscious level, 8 (19.0%); nausea/vomiting, 8 (19.0%). Identified thrombotic risk factors included: hospitalisation, 22 (52.3%); active infection, 5; recent immobility, 5; dehydration, 6; combined oral contraceptive pill, 2. None were obese, had a high white cell count at time of CVT diagnosis or a history of recent major surgery. 13 (31.0%) had 〉1 thrombotic risk factor and 16 (38.1%) had no additional clinical risk factor identified. 10 had a thrombophilia screen performed, one with a repeatedly low protein S level (male, 1 year of age). 7 cases (16.7%) had cerebral infarction on imaging and 11 (26.2%) were complicated by intracranial haemorrhage (ICH). 38 cases (90.5%) received anticoagulant therapy, 37 of which received low molecular weight heparin (LMWH) and one unfractionated heparin. One case had catheter-directed thrombolysis. 4 were not anticoagulated, 3 due to ICH. 2 received Antithrombin replacement therapy. Anticoagulation therapy was continued for a median of 3 months. 65.0% of cases due more Asparaginase were re-exposed (26/40), 19 of which received thromboprophylaxis during re-exposure. 2 remain on long-term therapeutic anticoagulation. In 23 cases (54.8%) CVT resulted in a delay or change to planned treatment. Neurological morbidity was reported in 4 cases (9.5%): seizure disorder, 2; hemiplegia, 1; residual hemiplegia and hemianopia with severe developmental delay, 1. 36 cases (85.7%) remain in first remission. Survival in those with CVT was 90.1%, comparable to actuarial 5-year survival of the entire cohort (91.5%). There were 4 deaths, three due to leukaemia (two in first relapse) and one due to pneumonia as a complication of stem cell transplant. There were no deaths due to CVT or bleeding on anticoagulant therapy. This study highlights the clinical features of CVT in children and young adults treated for ALL in the MRC UKALL 2003 trial, in particular the timing in relation to Asparaginase treatment, presenting features and neurological outcome. These data support LMWH as safe treatment for CVT in this clinical setting. We have demonstrated the tendency of clinicians to adjust treatment regimen and/or avoid further Asparaginase exposure in response to CVT. However, overall survival at 5 years did not differ for the cohort with CVT. Future studies should aim to further evaluate clinical predictors, alongside potential coagulation and genetic markers, in order to identify a high-risk group that may benefit from measures to reduce CVT during ALL therapy. Disclosures No relevant conflicts of interest to declare.

Description: Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by a lack of the terminal complement inhibitor CD59 on erythrocytes that renders these cells susceptible to chronic hemolysis resulting in anemia, fatigue, abdominal pain, kidney dysfunction, pulmonary hypertension, and life-threatening thromboembolism (TE). During pregnancy, hemolysis frequently worsens and the incidence of TE increases, posing a high risk of both fetal and maternal mortality. Eculizumab is a terminal complement inhibitor that reduces hemolysis, transfusion requirements, and TE while improving fatigue and quality of life in patients with PNH. Eculizumab contains a hybrid constant region with components of both IgG2 and IgG4. Whether eculizumab crosses the placenta is not known. The eculizumab clinical trial protocols specified withdrawal of patients who became pregnant during the study. There were 5 reported pregnancies during the PNH clinical trials (n=195) prior to withdrawal from the study. To evaluate the safety and efficacy of eculizumab in the management of PNH during pregnancy, we reviewed the physician-reported adverse events (AEs), PK/PD, and distribution of eculizumab, duration of drug exposure during gestation, complications during and after pregnancy, and general health of the newborn in patients with PNH who became pregnant during the eculizumab clinical trials. Of the 5 reported pregnancies, one patient elected termination and 3 patients withdrew from eculizumab therapy between 4 to 16 weeks of gestation and continued pregnancy through term. There were no apparent complications or AEs related to drug and all 3 patients delivered healthy newborns. One patient was treated with low molecular weight heparin (LMWH) from the time she discontinued eculizumab to three months after delivery. She developed hyperpyrexia and was diagnosed with fever of unknown origin shortly after delivery. She was treated and then discharged. There have been no reported postpartum complications in any of these deliveries to date. The fifth patient withdrew from the study but continued on eculizumab treatment throughout the whole pregnancy and post-partum. She initiated eculizumab treatment in 2002 reducing her LDH from 10,300U/L to 490 U/L (normal range 150 to 480 U/L). Her transfusion requirement reduced from 4 units every 6 weeks to 2 units per year in order to maintain her hemoglobin above 8 g/dl. She was commenced on LMWH at week 8 of gestation and she remained on it for the duration of her pregnancy and postpartum. During pregnancy, she was transfused more frequently to maintain her hemoglobin above 9 g/dl. At week 28 of gestation, she experienced an episode of hemoglobinuria and abdominal pain for 3–4 days prior to her next dose of eculizumab and therefore the dosing interval was adjusted from 14 to 12 days (11 days to avoid weekends) as per the approved 900mg dose. She had no further episodes of breakthrough and her LDH levels were maintained below 450 U/L. The patient was induced at term and delivered a healthy newborn. On the day of delivery, there was no detectable eculizumab in the cord blood (see table). At day 1 and 9 postpartum, there was no detectable eculizumab in breast milk samples. To date, the patient shows no clinical signs of thrombosis or other morbidities typically associated with PNH. The first evaluation of eculizumab treatment from conception to delivery in a patient with PNH treated with eculizumab demonstrated that the drug was tolerated and the pregnancy was successful. There was no evidence of thromboses or other morbidities during the postpartum period. There have been no reported events of congenital anomaly/birth defects in the offspring of any patient with PNH who became pregnant during participation in our clinical studies. Further, there are currently two patients being followed who received eculizumab treatment either during the last trimester (started eculizumab at week 26) or throughout gestation to term. Pregnancy in PNH is associated with an extremely high maternal risk. A review of the 5 clinical trial cases demonstrated that patients receiving eculizumab during pregnancy had no obvious complications through the post-partum period and that a slightly higher dose of eculizumab may be required during pregnancy than in non-pregnant patients with PNH. In addition, eculizumab does not appear to cross the placenta or to be secreted into breast milk. Eculizumab therapy may play a significant role in the management of pregnancy in patients with PNH. Table. Eculizumab levels at delivery Eculizumab Levels (μg/ml)* Post Partum Day 0 Day1 Day 9** NM. Not Measured *, a level of 35 μg/ml or more has been shown to completely block terminal complement activation **An additional dose was given between Day 1 and Day 9 Eculizumab serum levels in mother 116.1 81.3 146 Eculizumab serum levels in cord blood 0 NM NM Eculizumab in breast milk 0 0 0

Description: Patients with severe haemophilia A (SHA, FVIII 4000 2 4 None No NA NA NA NA 156 6 Cauc Frame shift C1876 780 1 4 200/kg/d Steroid NA NA NA NA 156 2 African Inv 22 6300 1 4 200/kg/d No NA NA NA NA 56 37 Cauc No data 780 1 4 None No NA NA NA NA 104 A negative Bethesda titre was achieved in 5 patients (33%) and was sustained in 2 (13%). Of the 3 who relapsed, 2 achieved a second negative Bethesda after further treatment (one with FVIII and one with FVIII + rituximab). The other did not respond to further rituximab without FVIII. Of the 5 patients with a PR one relapsed but 4 continue to be managed on FVIII with prolonged follow up and without significant bleeding. They appear to have been converted from high to low responders. Therefore, 8 of 15 (53%) of patients have had a prolonged benefit from rituximab treatment. There were 5 non responders, including all 3 who did not receive concomitant FVIII. Therefore, 8 of 12 (67%) patients who received FVIII had a clinical benefit. These data are a consecutive national cohort with prolonged follow up and are therefore less likely to be affected by reporting bias. The results are inferior to the published literature but demonstrate that, in patients with SHA and inhibitors resistant to standard ITI, rituximab in association with FVIII leads to sustained clinical improvement in a significant proportion of patients, although complete eradication of the inhibitor is uncommon.

Description: The development of anti-FVIII antibodies (i.e., inhibitors) is the major side effect of severe hemophilia A treatment. Inhibitors mainly develop in children during the first 50 exposure days and are classified in low-and high-titer (i.e., peak titer 〈 or 〉 5 UB/ml). High-titer inhibitors have the major clinical impact. At diagnosis however, the real nature of the antibody is not clear in all patients, since some low-titer inhibitors may progress to high-titer. The determinants of the evolution from low- to high-titer inhibitors are still unclear and the aim of the present study was to investigate potential risk factors associated with the progression from low- to high-titer inhibitors. This study is a follow-up study of the PedNet Registry and includes 260 children with severe hemophilia A and clinically relevant inhibitors, born between 1990 and 2009 and consecutively recruited from 31 hemophilia centers in 16 countries. Clinical and laboratory data were collected from the date of first positive inhibitor test and covered a minimum of 3-years follow-up. Factors potentially associated with progression from low- to high-titer inhibitor development were analyzed using univariate and multivariate logistic regression. F8 mutation type was known in 247 patients (95%), including 202 (82%) null mutations (i.e., large deletions, nonsense mutations and inversions). Positive family history of inhibitors was present in 37 of 99 (37%) with positive family history of hemophilia. At diagnosis 49% (n=127) had low-titer inhibitors, however, upon FVIII re-exposure, 50% of low-titer inhibitors progressed to high-titer and only 25% of patients (n=69) had persistent low-titer inhibitors. Within the first 3 years of follow-up, immune tolerance induction (ITI) was equally implemented in around 80% of low-and high-titer patients but it was started later in children with high-titers (median time to ITI start 4.5 vs 0.3 months; p

Description: Patients with transfusion-dependent β-thalassaemia (TDT) require regular red blood cell (RBC) transfusions to treat anaemia, with regular monitoring and obligatory iron chelation therapy to address inevitable iron overload. We conducted a retrospective chart review with cross-sectional patient and caregiver surveys in 9 National Health Service (NHS) centres across the United Kingdom (UK) to evaluate routine management of TDT, and patient and caregiver health-related quality of life (HRQoL). Eligible patients had a documented diagnosis of TDT (index event) ≥2 years prior to data collection. The observation period was the 2-5 year period prior to data collection or death. Patient-reported outcomes (PRO) were completed at enrolment, including EuroQoL EQ-5D, Work Productivity and Activity Impairment (WPAI), and disease-specific TranQoL. The primary endpoint was the number of blood transfusion episodes per patient per year. A total of 165 patients were included (median age at data collection 24.1 [interquartile range (IQR) 11.8-37.2] years; 50% (n=82) male; one patient was deceased); 135 patients completed ≥1 PRO questionnaire; 37 caregivers completed caregiver questionnaires. Median age at index event was 1.0 (IQR 0.5-8.0) years and median disease duration was 11.6 (IQR 6.4-21.7) years. The most commonly recorded comorbidities (n=156 patients, at start of observation period) included hypogonadotrophic hypogonadism (20% [n=31]), vitamin D deficiency (16% [n=25]) and osteoporosis (14% [n=22]). Twenty percent (n=31) were splenectomised. During a mean observation period of 4.7 (standard deviation [SD] 0.7) years, patients had a mean of 13.5 (SD 3.6) transfusion episodes per year (79% had ≥12 per year) and a median of 32.4 (IQR 25.3-37.7) units transfused per year. Mean pre-transfusion haemoglobin (Hb, from 8041 tests) was 99.1 (SD 10.0) g/L; patients had a mean of 10.3 (SD 5.0) Hb tests per year. Median age at initiation of chelation therapy (n=91) was 2.9 (IQR 1.8-12.1) years. All patients received ≥1 iron chelator during the observation period, including deferasirox (80% [n=132]), desferrioxamine (52% [n=85]), deferiprone (35% [n=57]) or combination therapies (20% [n=33]). At data collection 161 patients were receiving chelators. Patients had a mean of 10.7 (SD 4.3) serum ferritin (SF) measurements/year; median SF closest to data collection was 1792.0 (IQR 997.0-2883.0) ng/ml (≤1000 ng/ml [25%, n=42]; 〉1000≤2500 ng/ml [39%, n=64]; 〉2500 ng/ml [36%, n=59]). Median interval between liver iron concentration (LIC) tests was 1.9 (IQR 1.3-2.5) years; median R2 LIC closest to data collection (n=120) was 5.4 (IQR 2.9-11.5) mg/g (