Summary
Inhibitor development is a major complication of treatment with factor VIII concentrates in nonsevere haemophilia A. It has been suggested that plasma‐derived factor VIII (FVIII) concentrates ...elicit fewer inhibitors than recombinant FVIII concentrates, but studies in severe haemophilia A patients have shown conflicting results. We designed a case‒control study to investigate the clinical and genetic risk factors for inhibitor development in nonsevere haemophilia A patients. We investigated whether the type of FVIII concentrate was associated with inhibitor development in nonsevere haemophilia A patients. This nested case‒control study includes 75 inhibitor patients and 223 controls, from a source population of the INSIGHT study, including all nonsevere haemophilia A patients (FVIII:C 2–40%) that were treated with FVIII concentrates in 33 European and one Australian centre. Cases and controls were matched for date of birth and cumulative number of exposure days (CED) to FVIII concentrate. A conditional logistic regression model was used to calculate unadjusted and adjusted odds ratios. No increased risk for inhibitor development was found for any type of FVIII concentrate; either when comparing recombinant FVIII concentrates to plasma‐derived FVIII concentrates (adjusted odds ratio 0·96, 95% confidence interval (CI) 0·36–2·52) or for specific types of FVIII concentrates.
Introduction
Emicizumab, a bispecific humanized monoclonal antibody administered subcutaneously, bridges FIXa and FX to restore the function of missing FVIIIa, and is being developed to prevent ...bleeds in patients with hemophilia A (PwHA) with and without inhibitors. An interim analysis of the HAVEN 2 study (n=20) in patients aged 2-12 years (data cutoff 28 Oct, 2016) showed that subcutaneous, once-weekly emicizumab prophylaxis successfully prevented or reduced bleeds, provided clinically meaningful reductions in annualized bleed rate (ABR) versus prior bypassing agent (BPA) treatment, and was well tolerated (Young et al. RPTH 2017;1 (S2):Abstract OC 24.1). Here we present an updated, much larger (40 additional patients, 60 total) analysis of efficacy, safety and pharmacokinetics (PK) of once-weekly subcutaneous (SC) emicizumab prophylaxis in pediatric PwHA with inhibitors.
Methods
The study (NCT02795767) enrolled PwHA with inhibitors aged 2-12 years (or 12-17 years if <40 kg), and currently enrolling those <2 years of age, previously treated with BPAs to receive emicizumab prophylaxis for ≥52 weeks. Efficacy analyses included ABR and bleed reduction vs ABR on prior BPA treatment from prospective non-interventional study (NIS; NCT02476942). Health-related quality of life (HRQoL), aspects of caregiver burden and safety parameters were also assessed.
Results
The updated analysis (8 May, 2017 cutoff) included approximately 6 additional months of data vs the first interim analysis; 60 PwHA with inhibitors aged 1-15 (median 7) years; 57 aged <12 years including 2 aged <2 years were included in the efficacy analyses. Three patients aged ≥12 years and <40kg were enrolled. The median observation time was 9 (range 1.6-41.6) weeks; 20 patients had been observed ≥24 weeks, and 2 patients aged <2 years for approximately 5 and 2 weeks. Efficacy data for patients aged <12 years are shown in the Table. Overall, 54/57 (94.7%) patients had zero treated bleeds. Only 3 treated bleeds were reported, with 1 occurring in a joint, 1 occurring in a muscle, and 1 hip bleed that was classified as “other”; all were safely treated with rFVIIa. Only 1 of these 3 treated bleeds was a spontaneous bleed. In total, 37/57 patients (64.9%) reported no bleeds. A total of 65 bleeds were reported in 20 patients, with 8 occurring in a joint, 2 occurring in a muscle, and 55 being classified as “other”; of the 55 “other” bleeds, 26 (40.0%) were spontaneous, 36 (55.4%) traumatic and 3 (4.6%) due to procedure/surgery.
Twenty-three patients <12 years of age were followed for ≥12 weeks and therefore included in the ABR population calculation. The ABR was 0.2 (95% CI 0.06; 0.62) for treated bleeds (Table). Eighteen patients <12 years old had previously participated in the NIS. Of these, 13 patients had been on HAVEN 2 for ≥12 weeks and were therefore included in the intra-individual comparison; a substantial reduction in ABR of 99% with emicizumab prophylaxis vs prior BPA treatment was observed in these patients. Individual patient data are shown in Fig 1.
Considerable improvements in HRQoL, and aspects of caregiver burden were observed.
Emicizumab was well tolerated; the most common AEs were viral upper respiratory tract infection and injection site reactions (16.7% of patients each). Six patients experienced 7 serious AEs (2 muscle hemorrhage, 1 eye pain, 1 catheter site infection, 1 device-related infection, 1 mouth hemorrhage, 1 appendicitis), with none deemed related to emicizumab; no thromboembolic or thrombotic microangiopathy events were reported. No patients tested positive for anti-drug antibodies. Mean steady state trough emicizumab concentrations of approximately 50 µg/mL were maintained with longer follow-up (Fig 2). PK profiles were consistent across age groups and body weight.
Conclusion
HAVEN 2 is the largest study in pediatric PwHA with inhibitors to date, and demonstrates that emicizumab prophylaxis prevented or substantially reduced bleeds and was well tolerated in this patient population. PK remained consistent with that seen in adolescent/adult PwHA. Weekly subcutaneous emicizumab has the potential to reduce overall treatment and disease burden and may provide a new standard of care for hemophilia management by providing an effective, safe and convenient option for pediatric PwHA with inhibitors.
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Young:CSL Behring: Honoraria; Novo Nordisk: Consultancy. Sidonio:Bioverativ: Research Funding; Novo Nordisk: Consultancy; Shire: Consultancy, Research Funding; Grifols: Research Funding; CSL Behring: Consultancy; Bioverativ: Consultancy; Bayer: Consultancy. Liesner:NovoNordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxalta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; SOBI: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bio Products Laboratory: Consultancy, Membership on an entity's Board of Directors or advisory committees; SOBI/Bioverativ: Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Oldenburg:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Honoraria, Investigator Clinical Studies and Research Funding, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Investigator Clinical Studies and Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Chang:Genentech: Employment, Equity Ownership. Uguen:F. Hoffmann-La Roche Ltd: Employment. Dhalluin:F. Hoffmann-La Roche Ltd: Employment. Schmitt:F. Hoffmann-La Roche Ltd: Employment. Levy:Genentech, Inc.: Employment. Shima:Pfizer: Honoraria, Research Funding; Baxalta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Honoraria, Research Funding; Biogen: Consultancy, Honoraria; Kaketsuken: Honoraria; Novo: Honoraria, Research Funding; Bayer: Honoraria, Research Funding. Mahlangu:Catalyst Biosciences: Consultancy, Research Funding; Baxalta: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biogen: Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biotest: Speakers Bureau; Bayer: Research Funding, Speakers Bureau; Alnylam: Consultancy, Research Funding, Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alnylam: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Research Funding, Speakers Bureau; NovoNordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biotest: Speakers Bureau; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biogen: Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau; Catalyst Biosciences: Consultancy, Research Funding; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; NovoNordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau.
Heritable bleeding and platelet disorders (BPD) are heterogeneous and frequently have an unknown genetic basis. The BRIDGE-BPD study aims to discover new causal genes for BPD by high throughput ...sequencing using cluster analyses based on improved and standardised deep, multi-system phenotyping of cases.
We report a new approach in which the clinical and laboratory characteristics of BPD cases are annotated with adapted Human Phenotype Ontology (HPO) terms. Cluster analyses are then used to characterise groups of cases with similar HPO terms and variants in the same genes.
We show that 60% of index cases with heritable BPD enrolled at 10 European or US centres were annotated with HPO terms indicating abnormalities in organ systems other than blood or blood-forming tissues, particularly the nervous system. Cases within pedigrees clustered closely together on the bases of their HPO-coded phenotypes, as did cases sharing several clinically suspected syndromic disorders. Cases subsequently found to harbour variants in ACTN1 also clustered closely, even though diagnosis of this recently described disorder was not possible using only the clinical and laboratory data available to the enrolling clinician.
These findings validate our novel HPO-based phenotype clustering methodology for known BPD, thus providing a new discovery tool for BPD of unknown genetic basis. This approach will also be relevant for other rare diseases with significant genetic heterogeneity.
Historically, haematology analyser flags for abnormal white blood cells (WBCs) show good sensitivity but lower specificity, causing unnecessary blood film reviews. While the WBC differential channel ...on Sysmex XE and XN instruments reports a combined flag for blasts/abnormal lymphocytes, the new white precursor cell channel (WPC) on the XN series has been introduced to separate this into a specific flag for either cell type or, if no abnormality, remove the flag entirely.
To compare the efficiency of abnormal WBC flags from the XN WPC to our existing analyser and determine whether WPC can reduce false positive flags and blood films required.
Abnormal WBC flags from the Sysmex XE-5000 and XN-1000 were compared to manual differential and blood film morphology on 300 K2EDTA samples from infants and children.
The XN WPC flag for blasts was more sensitive and specific than flags indicating blasts on the XE-5000, with a reduction in false positives from 64% (XE) to 36% (XN). Overall efficiency of the WPC flag for abnormal lymphocytes was 94% vs 79% on the XE. WPC reduced false positive flags for blasts and abnormal lymphocytes on neonatal samples by 50%. Automatic reflex analysis by WPC correctly removed a false positive flag from the white cell differential channel on 46% of samples. Total abnormal WBC flags from XN WPC were less (73) than the XE-5000 (92).
XN WPC demonstrated superior efficiency of abnormal WBC flags on paediatric samples, compared to the XE-5000, with greater sensitivity and specificity of flagging, reducing blood films for review.
ObjectiveThe extent that inherited bleeding disorders affect; number, size and location of bruises in young children <6 years.DesignProspective, longitudinal, observational ...study.SettingCommunity.Patients105 children with bleeding disorders, were compared with 328 without a bleeding disorder and classified by mobility: premobile (non-rolling/rolling over/sitting), early mobile (crawling/cruising) and walking and by disease severity: severe bleeding disorder factor VIII/IX/XI <1 IU/dL or type 3 von Willebrand disease.InterventionsNumber, size and location of bruises recorded in each child weekly for up to 12 weeks.OutcomesThe interventions were compared between children with severe and mild/moderate bleeding disorders and those without bleeding disorders. Multiple collections for individual children were analysed by multilevel modelling.ResultsChildren with bleeding disorders had more and larger bruises, especially when premobile. Compared with premobile children without a bleeding disorder; the modelled ratio of means (95% CI) for number of bruises/collection was 31.82 (8.39 to 65.42) for severe bleeding disorders and 5.15 (1.23 to 11.17) for mild/moderate, and was 1.81 (1.13 to 2.23) for size of bruises. Children with bleeding disorders rarely had bruises on the ears, neck, cheeks, eyes or genitalia.ConclusionsChildren with bleeding disorder have more and larger bruises at all developmental stages. The differences were greatest in premobile children. In this age group for children with unexplained bruising, it is essential that coagulation studies are done early to avoid the erroneous diagnosis of physical abuse when the child actually has a serious bleeding disorder, however a blood test compatible with a mild/moderate bleeding disorder cannot be assumed to be the cause of bruising.
Aims
Population pharmacokinetic (PK) models are increasingly applied to perform individualized dosing of factor VIII (FVIII) concentrates in haemophilia A patients. To guarantee accurate performance ...of a population PK model in dose individualization, validation studies are of importance. However, external validation of population PK models requires independent data sets and is, therefore, seldomly performed. Therefore, this study aimed to validate a previously published population PK model for FVIII concentrates administrated perioperatively.
Methods
A previously published population PK model for FVIII concentrate during surgery was validated using independent data from 87 children with severe haemophilia A with a median (range) age of 2.6 years (0.03–15.2) and body weight of 14 kg (4–57). First, the predictive performance of the previous model was evaluated with MAP Bayesian analysis using NONMEM v7.4. Subsequently, the model parameters were (re)estimated using a combined dataset consisting of the previous modelling data and the data available for the external validation.
Results
The previous model underpredicted the measured FVIII levels with a median of 0.17 IU mL−1. Combining the new, independent and original data, a dataset comprising 206 patients with a mean age of 7.8 years (0.03–77.6) and body weight of 30 kg (4–111) was obtained. Population PK modelling provided estimates for CL, V1, V2, and Q: 171 mL h−1 68 kg−1, 2930 mL 68 kg−1, 1810 mL 68 kg−1, and 172 mL h−1 68 kg−1, respectively. This model adequately described all collected FVIII levels, with a slight median overprediction of 0.02 IU mL−1.
Conclusions
This study emphasizes the importance of external validation of population PK models using real‐life data.
Hermansky-Pudlak syndrome (HPS) may present to the ophthalmologist with signs suggestive of oculocutaneous albinism. Consideration of HPS as a differential diagnosis is important due to its potential ...systemic complications. HPS6 is a rarely reported subtype.
Three patients from two families underwent clinical examination, imaging and targeted systemic investigations. Electrophysiology with visual-evoked potentials (VEPs) was performed in both children of family 1. Whole exome sequencing (WES) was performed on the proband of family 1. Bidirectional Sanger sequencing of the single exon and intron-exon boundaries of
was performed on all affected patients and segregation confirmed in available relatives.
Two siblings presented in infancy with nystagmus and reduced vision. They were initially diagnosed with isolated foveal hypoplasia with no aberrant chiasmal misrouting on VEPs. WES performed in the proband when 10 years of age identified a novel homozygous missense variant in
and further questioning elicited a history of nose bleeds and mild bruising
Segregation supported causality of this variant in the affected younger sibling. In the third unrelated patient, an initial diagnosis of ocular albinism was made at 3 months with HPS only diagnosed at 26 years. Biallelic, truncating mutations in
were identified by candidate Sanger sequencing and included a novel variant. Abnormal platelet function consistent with HPS was confirmed in all patients.
The diagnosis of HPS in all patients was delayed due to a mild systemic phenotype. Next-generation sequencing can aid diagnosis of syndromic conditions with important consequences for preventing morbidity.
Introduction: Long-term, real-world data on natural history of hemophilia A patients, safety and treatment outcome are still insufficient, particularly as far as the impact of bleeding on patient ...lives is concerned, as most of clinical trials and PASS studies are limited in study population size and length of follow-up, often no longer than 12 months.
Methods: The AHEAD study is a non-interventional, prospective long-term cohort study including severe and moderate hemophilia A patients treated with ADVATE. Study endpoints include long-term joint health outcomes, annualized (joint) bleeding rates (ABR/AJBR), factor consumption, quality of life and safety data. Globally, AHEAD aims to evaluate data on approximately 1,000 patients, with a maximum follow-up period of up to 8 years. This interim data report includes 3 years of follow-up after study start.
Results: The interim data report includes 522 patients from 21 countries (German study arm is not included in this analysis), for overall 1160 patient years. Of these, 334 completed year 1, 238 year 2 and 136 year 3 study visits. Median age at screening was 17 years (min-max: 0 - 78) and 57% of patients had severe HA (FVIII<1%); 78% were on prophylaxis, 21% were on demand (OD) and 1% on ITI treatment.
The median ABRs in year 1, 2 and 3 were 1.2/1.2/1.9 respectively in patients on prophylaxis and 8.4/10.0/7.2, respectively in patients on OD. Median AJBRs were 0.9/0.9/1.0 in the prophylaxis group and 6.4/5.5/5.9 for patients on OD in the first three years of observation. Very similar data were reported taking only severe hemophilia A patients on prophylaxis into account (ABR: 1.9/1.7/2.5 and AJBR: 1.0/1.0/1.1)
Overall, 56% of patients on prophylaxis and 32% of patients OD had an AJBR <1 in the first year, 54% and 33% in the second year and 52% and 22% in the third year. In the OD group about half of the patients had an AJBR ≥ 6, in the 3 years of follow up, while only 10% of patients in the prophylaxis group.
Median annualized total dose in the prophylaxis group was consistently approximately 245,000IU while the FVIII consumption in the OD group was ranging from 26,000 to 47,000. Effectiveness of prophylaxis assessed by investigators was excellent/good in 93-96% of cases in the three years of observation.
Functionality assessment using the hemophilia activity level (HAL) questionnaire showed a median summary score of 77.3-86.7 for patients on prophylaxis and 67.9-71.3 in patients OD over the 3 year follow up period. Differences of health related quality of life (HRQoL) as assessed by the SF-12 were found in the domain physical functioning (median score of 75-100 vs. 50-75 in patients on prophylaxis and OD, respectively) and role physical (median scores of 75 vs. 62.5-75 in patients on prophylaxis and OD, respectively).
There were 7 treatment-related adverse events (AEs): 6 serious AEs (5 transient low titer inhibitors and 1 transient high titer inhibitor). The remaining non serious treatment-related adverse event was a mild allergic cutaneous reaction with rhinitis. All patients continued to receive ADVATE.
Conclusion: Interim read-out of 3 year follow-up of patients enrolled in the AHEAD study show a clinically meaningful difference in ABR/AJBR, HAL, HRQoL of patients on prophylaxis or OD treatment. This study represents the largest cohort of hemophilia patients with the longest follow-up period.
Tsakiris:Baxalta, now part of Shire: Consultancy, Honoraria, Research Funding; Bayer Switzerland GmbH: Consultancy, Honoraria, Research Funding. Hermans:Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Investigator Clinical Studies. Liesner:Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Octapharma: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sobi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; BPL: Research Funding; Cangene: Research Funding; CSL Behring: Membership on an entity’s Board of Directors or advisory committees. Khair:Pfizer: Research Funding; NovoNordisk: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Study Investigator, Research Funding; Octapharma: Consultancy, Equity Ownership, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Study Investigator, Patents & Royalties, Research Funding, Speakers Bureau; Sobi/Biogen: Research Funding. Mazzucconi:Baxalta, now part of Shire: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Bayer: Speakers Bureau; NovoNordisk: Speakers Bureau; Pfizer: Speakers Bureau; Roche: Membership on an entity’s Board of Directors or advisory committees; Amgen: Speakers Bureau; Novartis: Speakers Bureau; Shire: Speakers Bureau. Steinitz-Trost:Baxalta, now part of Shire: Employment. Spotts:Shire: Employment. Reininger:Baxalta, now part of Shire: Employment, Equity Ownership. Gringeri:Shire: Employment, Equity Ownership.
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