A new population pharmacokinetic model for recombinant factor IX-Fc fusion concentrate including young children with haemophilia B.

AIMS: Recombinant factor IX Fc fusion protein (rFIX-Fc) is an extended half-life factor concentrate administered to haemophilia B patients. So far, a population pharmacokinetic (PK) model has only been published for patients aged ≥12 years. The aim was to externally evaluate the predictive performance of the published rFIX-Fc population PK model for patients of all ages and develop a model that describes rFIX-Fc PK using real-world data. METHODS: We collected prospective and retrospective data from patients with haemophilia B treated with rFIX-Fc and included in the OPTI-CLOT TARGET study (NTR7523) or United Kindom (UK)-EHL Outcomes Registry (NCT02938156). Predictive performance was assessed by comparing predicted with observed FIX activity levels. A new population PK model was constructed using nonlinear mixed-effects modelling. RESULTS: Real-world data were obtained from 37 patients (median age: 16 years, range 2-71) of whom 14 were aged <12 years. Observed FIX activity levels were significantly higher than levels predicted using the published model, with a median prediction error of -48.8%. The new model showed a lower median prediction error (3.4%) and better described rFIX-Fc PK, especially for children aged <12 years. In the new model, an increase in age was correlated with a decrease in clearance (P < .01). CONCLUSIONS: The published population PK model significantly underpredicted FIX activity levels. The new model better describes rFIX-Fc PK, especially for children aged <12 years. This study underlines the necessity to strive for representative population PK models, thereby avoiding extrapolation outside the studied population.

A review of the pharmacokinetics, efficacy and safety of high-purity factor X for the prophylactic treatment of hereditary factor X deficiency.

INTRODUCTION: Hereditary factor X (FX) deficiency (FXD) is a rare autosomal recessive bleeding disorder. Plasma-derived FX (pdFX) is a high-purity FX concentrate approved in the United States and Europe for the treatment and prophylaxis of bleeding episodes and for peri-operative management in patients with hereditary FXD (HFXD). AIM: To review pharmacokinetic dosing, efficacy, and safety data for pdFX as routine prophylaxis for HFXD. METHODS: Summary of the published pharmacokinetic and safety data from TEN01, TEN02, TEN05, and real-world publications of pdFX for prophylaxis. RESULTS: Pharmacokinetic modelling data from the phase 3 TEN01 study supported administration of pdFX 25 IU/kg twice weekly for routine prophylaxis in adolescents/adults (aged ≥12 years). Results from nine paediatric patients in the phase 3 TEN02 study and eight adolescents/adults (aged ≥12 years) in the retrospective data-collection TEN05 study, along with real-world evidence, showed that routine prophylaxis with pdFX ≈40 IU/kg twice weekly in patients aged <12 years and pdFX ≈25 IU/kg twice weekly in patients aged ≥12 years was effective in bleeding prevention. CONCLUSIONS: pdFX was well tolerated in clinical studies, with no new safety signals identified during routine prophylactic use. Based on current evidence, it is recommended that routine prophylaxis with pdFX be initiated at 25 IU/kg twice weekly in adults/adolescents ≥12 years of age, and at a dosage of 40 IU/kg twice weekly in children <12 years of age. Thereafter, FX levels should be closely monitored, and dosages should be adjusted according to clinical response and to maintain trough levels ≥5 IU/dl.

Immune tolerance induction in severe haemophilia A: A UKHCDO inhibitor and paediatric working party consensus update.

INTRODUCTION: In good risk patients (historic inhibitor peak < 200BU), the International Immune Tolerance Study demonstrated equal efficacy to induce tolerance between high (200iu/kg/day) and low dose (50iu/kg ×3 times/week) immune tolerance induction (ITI) regimens. However, the trial stopped early on account of the excessive bleed rate in the low dose ITI arm. METHODS: United Kingdom Haemophilia Centre Doctors' Organization (UKHCDO) Paediatric and Inhibitor working parties considered available ITI data alongside the bi-phenotypic antibody emicizumab (Hemlibra®) efficacy and safety data to develop a consensus guideline for the future UK ITI guideline. RESULTS: This revision of UKHCDO ITI guidance incorporates the recommendation to use emicizumab as a prophylaxis haemostatic agent to reduce bleeding rates and to facilitate low dose and reduced frequency of FVIII CFC for ITI in the majority of children. CONCLUSION: This consensus protocol will facilitate future evaluation of ITI outcomes in the evolving landscape of haemophilia therapeutics and ITI strategies.

Safety and efficacy of rivaroxaban in pediatric cerebral venous thrombosis (EINSTEIN-Jr CVT).

Anticoagulant treatment of pediatric cerebral venous thrombosis has not been evaluated in randomized trials. We evaluated the safety and efficacy of rivaroxaban and standard anticoagulants in the predefined subgroup of children with cerebral venous thrombosis (CVT) who participated in the EINSTEIN-Jr trial. Children with CVT were randomized (2:1), after initial heparinization, to treatment with rivaroxaban or standard anticoagulants (continued on heparin or switched to vitamin K antagonist). The main treatment period was 3 months. The primary efficacy outcome, symptomatic recurrent venous thromboembolism (VTE), and principal safety outcome, major or clinically relevant nonmajor bleeding,were centrally evaluated by blinded investigators. Sinus recanalization on repeat brain imaging was a secondary outcome. Statistical analyses were exploratory. In total, 114 children with confirmed CVT were randomized. All children completed the follow-up. None of the 73 rivaroxaban recipients and 1 (2.4%; CVT) of the 41 standard anticoagulant recipients had symptomatic, recurrent VTE after 3 months (absolute difference, 2.4%; 95% confidence interval [CI], -2.6% to 13.5%). Clinically relevant bleeding occurred in 5 (6.8%; all nonmajor and noncerebral) rivaroxaban recipients and in 1 (2.5%; major [subdural] bleeding) standard anticoagulant recipient (absolute difference, 4.4%; 95% CI, -6.7% to 13.4%). Complete or partial sinus recanalization occurred in 18 (25%) and 39 (53%) rivaroxaban recipients and in 6 (15%) and 24 (59%) standard anticoagulant recipients, respectively. In summary, in this substudy of a randomized trial with a limited sample size, children with CVT treated with rivaroxaban or standard anticoagulation had a low risk of recurrent VTE and clinically relevant bleeding. This trial was registered at clinicaltrials.gov as #NCT02234843.

A Novel, Enriched Population Pharmacokinetic Model for Recombinant Factor VIII-Fc Fusion Protein Concentrate in Hemophilia A Patients.

BACKGROUND: The currently published population pharmacokinetic (PK) models used for PK-guided dosing in hemophilia patients are based on clinical trial data and usually not externally validated in clinical practice. The aim of this study was to validate a published model for recombinant factor VIII-Fc fusion protein (rFVIII-Fc) concentrate and to develop an enriched model using independently collected clinical data if required. METHODS: Clinical data from hemophilia A patients treated with rFVIII-Fc concentrate (Elocta) participating in the United Kingdom Extended Half-Life Outcomes Registry were collected. The predictive performance of the published model was assessed using mean percentage error (bias) and mean absolute percentage error (inaccuracy). An extended population PK model was developed using nonlinear mixed-effects modeling (NONMEM). RESULTS: A total of 43 hemophilia A patients (FVIII ≤ 2 IU/dL), aged 5 to 70 years, were included. The prior model was able to predict the collected 244 rFVIII-Fc levels without significant bias (-1.0%, 95% CI: -9.4 to 7.3%) and with acceptable accuracy (12.9%). However, clearance and central distribution volume were under predicted in patients <12 years, which was expected as this age group was not represented in the previous model population. An enriched population PK model was constructed, which was able to successfully characterize PK profiles of younger children. CONCLUSION: We concluded that the existing rFVIII-Fc population PK model is valid for patients ≥ 12 years. However, it is not reliable in younger patients. Our alternative model, constructed from real world patient data including children, allows for better description of patients ≥5 years.

Genotype analysis and identification of novel mutations in a multicentre cohort of patients with hereditary factor X deficiency.

: The objective was to examine the genotypic and phenotypic characteristics of individuals with hereditary factor X deficiency (FXD), a rare autosomal recessive bleeding disorder caused by mutations in the F10 gene located on chromosome 13q34-ter. To date, 149 F10 mutations have been identified as contributory to FXD. Three open-label phase 3 trials enrolled individuals with mild, moderate, or severe FXD. Individuals received plasma-derived factor X concentrate as routine prophylaxis, to treat bleeds, and/or during or after surgery. F10 genotyping was performed (studies 1 and 2) or genotype data was collected at screening (study 3), and identified F10 mutations were compared against the Human Gene Mutation Database to assess novelty. Genotype data were combined to evaluate the number, type, and novelty of the F10 mutations identified. Genotype data were available for 24 of 27 individuals with mild (n = 2), moderate (n = 2), or severe (n = 20) FXD. Analyses identified 22 separate mutations, including 15 missense mutations, 2 deletions, 4 splice site mutations, and 1 nonsense mutation. Sixteen individuals had homozygous mutations; 8 had compound heterozygous mutations. Eleven unique novel mutations (all compound heterozygous) were identified in seven individuals: six missense mutations, three splice site mutations, one exon deletion, and one nonsense mutation. In silico analyses strongly supported the pathogenicity of all novel mutations. The identification of 11 novel F10 mutations provides a substantial contribution to the mutations known to cause FXD.

Strategies to Prevent and Manage Thrombotic Complications of Acute Lymphoblastic Leukemia in Children and Young People Vary Between Centers in the United Kingdom.

There is a lack of evidence-based guidance for the prevention and management of thrombosis in children and young people treated for acute lymphoblastic leukemia. To determine current UK practice, a survey was sent to 28 centers participating in the Medical Research Council UKALL 2011 trial. Marked variation in practice was noted. In total, 43% of centers defer central venous access device insertion until end of induction for treatment of low-risk disease. Central venous access devices are removed at the end of intensive blocks in 38% and end of treatment in 42%. Duration of anticoagulation for line-associated thrombosis is 6 weeks in 43% and 3 months in 33% and for cerebral sinovenous thrombosis is 3 months in 71% and 6 months in 24%. Platelet transfusion to maintain platelet count >50×10/L, in preference to interrupting therapeutic anticoagulation, is used by 50% for line-associated thrombosis and 73% for cerebral sinovenous thrombosis. Conformity of practice was seen in some areas. In total, 70% treat thrombosis with twice-daily low-molecular weight heparin and 86% monitor antifactor Xa activity levels. In total, 91% reexpose individuals to asparaginase following a thrombotic event. Given this variation in practice, in the absence of high-quality evidence, consensus guidelines may be helpful.

Venous thromboembolism occurring during adolescence.

OBJECTIVE: Risk assessment for venous thromboembolism (VTE) and thromboprophylaxis in those with risk factors is established in adult practice. Evidence to support efficacy and safety of this approach in adolescents is lacking. We aimed to describe thrombotic risk factors and to determine the proportion of potentially preventable events in a retrospective cohort study of adolescents with VTE. DESIGN, SETTING AND PATIENTS: Data were collected between 2008 and 2014 from eight tertiary UK centres. Qualifying events were radiologically confirmed VTE in subjects aged 12-17 years. Central venous line-related upper venous system events were excluded. RESULTS: 76 cases were identified, 41 males, median age 15 years. Frequent risk factors were: reduced mobility, 45%; thrombophilia, 24%; malignancy, 20%; surgery, 18%; combined oral contraceptive pill, 12%; congenital venous anomaly, 5%. 28 (37%) had no significant underlying diagnosis and no provoking event/hospitalisation, presenting as outpatients with VTE which was considered 'unpreventable'. Of 48 where there had been opportunity for risk assessment, chemical thromboprophylaxis was not indicated in 26 and was contraindicated in 8. 14/76 (18%) had an indication to consider thromboprophylaxis and no contraindication. Of these, four had cerebral palsy, five malignancy and two inflammatory bowel disease. All had reduced mobility with recent surgery in eight. Four received chemical thromboprophylaxis prior to presentation. CONCLUSIONS: Among a cohort of adolescents with VTE, a small proportion (13%) had an indication to consider chemical thromboprophylaxis but did not receive it. VTE risk assessment and prevention should focus on adolescents with immobility or surgery, particularly in those with malignancy.

Comparison of primary human cytotoxic T-cell and natural killer cell responses reveal similar molecular requirements for lytic granule exocytosis but differences in cytokine production.

Cytotoxic lymphocytes, encompassing cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, kill pathogen-infected, neoplastic, or certain hematopoietic cells through the release of perforin-containing lytic granules. In the present study, we first performed probability-state modeling of differentiation and lytic granule markers on CD8(+) T cells to enable the comparison of bona fide CTLs with NK cells. Analysis identified CD57(bright) expression as a reliable phenotype of granule marker-containing CTLs. We then compared CD3(+)CD8(+)CD57(bright) CTLs with NK cells. Healthy adult peripheral blood CD3(+)CD8(+)CD57(bright) CTLs expressed more granzyme B but less perforin than CD3(-)CD56(dim) NK cells. On stimulation, such CTLs degranulated more readily than other T-cell subsets, but had a propensity to degranulate that was similar to NK cells. Remarkably, the CTLs produced cytokines more rapidly and with greater frequency than NK cells. In patients with biallelic mutations in UNC13D, STX11, or STXBP2 associated with familial hemophagocytic lymphohistiocytosis, CTL and NK cell degranulation were similarly impaired. Therefore, cytotoxic lymphocyte subsets have similar requirements for Munc13-4, syntaxin-11, and Munc18-2 in lytic granule exocytosis. The present results provide a detailed comparison of human CD3(+)CD8(+)CD57(bright) CTLs and NK cells and suggest that analysis of CD57(bright) CTL function may prove useful in the diagnosis of primary immunodeficiencies including familial hemophagocytic lymphohistiocytosis.

Aspects of anticoagulation in children.

The number of children receiving anticoagulation is increasing. Thromboembolic events are associated with significant risk of morbidity and mortality although the optimal management of asymptomatic events remains unclear. Specific challenges in paediatrics include the diagnosis of thrombosis, delivery and monitoring of anticoagulation in a wide range of ages from neonates through to adolescents. The development of the haemostatic system as children age results in changing pathophysiology of thrombosis and response to anticoagulation agents. Although registry and observational studies have provided vital information, specific paediatric, prospective anticoagulation studies have been few and limited in design. The result is that much of current practice is extrapolated from adult studies. Traditional anticoagulants have significant limitations. Both heparin and warfarin are in widespread use but many fundamental questions regarding dose, therapeutic range, efficacy and optimum duration have not been fully answered. Alternative agents, such as direct thrombin inhibitors and the selective anti-factor Xa inhibitor fondaparinux, may have advantages for children. Clinical trials in adults and preliminary data in children are promising but caution should be applied until specific paediatric studies have demonstrated safety and efficacy.

The impact of risk stratification by early bone-marrow response in childhood lymphoblastic leukaemia: results from the United Kingdom Medical Research Council trial ALL97 and ALL97/99.

The 1997 acute lymphoblastic leukaemia (ALL) trial (ALL97) was a randomised comparison of prednisolone versus dexamethasone and of 6-mercaptopurine versus 6-thioguanine. During the first 2 years of the trial, review of survival data showed the preceding trial, UKALL XI, was no better than its predecessor and that survival for childhood ALL in the UK had not improved in the fashion witnessed by other cooperative treatment groups. The therapy template was therefore altered to an American Children's Cancer Group (CCG) style regimen, including stratification by age, white cell count and early response to therapy by assessment of the bone marrow. This phase of the trial was designated ALL97/99. Comparison of the two phases showed that the event-free survival (EFS) for both ALL97 and ALL97/99 was better than previous UKALL trials, as was overall survival (OS) for ALL97/99. Both EFS and OS were significantly better in ALL97/99 than in ALL97 (at five years, 80.0% vs. 74.0%, P = 0.002; and 88.0% vs. 83.5%, P = 0.005, respectively). Isolated central nervous system (CNS) relapse for patients in ALL97/99 was half that in ALL97 (3.0% vs. 4.9%), P = 0.03) and the overall CNS relapse rate was halved in ALL97/99 (4.4% vs. 9.6%, P < 0.00005). There were no significant differences for non-CNS relapse, induction deaths or deaths in remission between the two phases of the trial.

Thrombosis and acute lymphoblastic leukaemia.

Venous thrombosis is more frequent in patients treated for acute lymphoblastic leukaemia (ALL) than other malignancies and has distinctive causes, clinical features and remedies. The reported incidence varies from 1% to 36%, depending on the chemotherapy protocol and whether the reported cases are symptomatic or detected on screening radiography. The risk is thought to arise from increased thrombin generation at diagnosis combined with reduced thrombin inhibitory capacity due to depletion of circulating anti-thrombin (AT) by asparaginase. A number of patient and treatment variables have been reported to influence the risk of thrombosis including hereditary thrombophilia, early insertion of central venous catheters and exposure to a combination of steroids and asparaginase during induction. Erwinia asparaginase is associated with a lower risk of thrombosis compared with Escherichia coli asparaginase. The majority of symptomatic thromboses are related to central venous catheters and involve the upper venous system. Central nervous system thrombosis involving the cerebral venous sinuses is a unique feature of asparaginase-related thrombosis and is reported to occur in 1-3% of patients. Conclusive evidence to support the use of anti-coagulant treatment or AT concentrates for primary prevention is lacking, as is evidence for the efficacy of AT concentrates in the management of established thrombosis. Preventative strategies are hampered by conflicting data on factors that would enable identification of those at highest risk of thrombosis.

Fatal pulmonary hemorrhage associated with micrococcal infection in two children with acute lymphoblastic leukemia.

Pulmonary hemorrhage is a rare cause of death in patients with acute leukemia. Within a 2-month period the authors observed two fatal pediatric cases, which were associated with opportunistic organisms of the genus Micrococcus. Both patients were receiving consolidation treatment for acute lymphoblastic leukemia. The authors discuss the causes of pulmonary hemorrhage in patients with leukemia and review the relevant literature. Micrococci have previously been considered as non-pathogenic, but there is considerable evidence for morbidity and mortality occurring, particularly in immunocompromised patients. The authors propose that micrococcal infection may have been a major predisposing factor for pulmonary hemorrhage in these thrombocytopenic patients.