Key questions in the new hemophilia era: update on concomitant use of FVIII and emicizumab in hemophilia A patients with inhibitors

Introduction: Immune tolerance induction (ITI) is the primary therapeutic strategy and only proven method to eradicate inhibitors to coagulation factor VIII (FVIII) in hemophilia A. Emicizumab, a humanized bispecific monoclonal antibody that mimics the function of activated FVIII, has expanded options to treat hemophilia A. The availability of emicizumab necessitates a revisit of recommendations for managing patients with inhibitors. Areas covered: Current evidence is reviewed about the concomitant use of emicizumab and FVIII concentrates during and after ITI. Areas where data are lacking are highlighted and ongoing studies designed to address these issues are described. Expert opinion: Inhibitor eradication remains a desirable goal. All patients with inhibitors should be offered at least one attempt at ITI. Emicizumab monotherapy is an option for inhibitor patients who are not candidates for ITI. Evidence is emerging about the use of emicizumab during ITI to prevent bleeds. Studies are currently addressing the safety, efficacy, and feasibility of concomitant emicizumab and FVIII in ITI. As evidence regarding the risk of inhibitor recurrence and need for continued FVIII to maintain immune tolerance post-ITI is limited, the role of emicizumab alone or in combination with FVIII after ITI is the subject of an upcoming studyThis review is based on presentations from a Grifols-sponsored symposium at the International Society on Thrombosis and Haemostasis 2020 Virtual Congress. The paper is otherwise not funde

Long-Term Safety and Efficacy of Nonacog Beta Pegol (N9-GP) Administered for at Least 5 Years in Previously Treated Children with Hemophilia B.

AbstractLong-term safety and efficacy data of extended half-life factor IX (FIX) prophylaxis in children with hemophilia B (HB) are sparse. paradigm 5 is a multinational, open-label, single-arm, phase III trial assessing once-weekly (40 IU/kg) prophylactic nonacog beta pegol (N9-GP) in previously treated patients (PTPs) aged ≤ 12 years with HB (FIX activity ≤ 2%). Primary endpoint: incidence of anti-FIX inhibitory antibodies (≥ 0.6 Bethesda Units). We present a 5-year analysis (N = 25, including remaining patients with ≥ 5 years' follow-up) and compare with a 1-year analysis (≥ 52 weeks' exposure). The main phase enrolled 25 children; 22 entered the extension phase; 17 remained in trial at data cutoff. Median treatment period: 5.6 years/patient; median total number of N9-GP exposure days: 290.0/patient. No patients developed anti-FIX inhibitory antibodies. No other safety concerns, including thromboembolic events, were reported. Neurological examinations have not revealed any new abnormal findings. Sixteen (64.0%) patients remained free from spontaneous bleeds; all bleeds were mild/moderate in severity; 93.0% were controlled with 1 to 2 N9-GP injections. No intracranial hemorrhages were reported. Annualized bleeding rates (ABRs) were very low at 5 years (median/Poisson-estimated mean overall ABR: 0.66/0.99), having decreased from the 1-year analysis (1.00/1.44). Median/Poisson-estimated mean spontaneous ABRs for the 1- and 5-year analyses: 0.00/0.45 and 0.00/0.33. Mean FIX trough activity at 5 years: 17.9%. Mean polyethylene glycol plasma concentration reached steady state at 6 months, increasing slightly over time, in line with increased FIX trough activity. N9-GP administered for ≥ 5 years shows favorable long-term safety and efficacy in PTPs with HB (FIX activity ≤ 2%)

The use of rapamycin to treat vascular tumours and malformations: A single-centre experience

Objectives: To assess the safety and efficacy of rapamycin in treating children with vascular tumours and malformations. Study design: We performed a retrospective review at a large tertiary care paediatric centre to assess the efficacy and safety of using rapamycin to treat vascular tumours and malformations. Response to therapy was defined by patient-reported symptom improvement, radiological reduction in size of lesions, and/or improvement of laboratory parameters. Results: Forty-two patients (7 with vascular tumours and 35 with vascular malformations) have been treated with rapamycin. Despite 33 of 42 patients being diagnosed in the first year of life, the median age of initiating rapamycin was 11 years. Of the 38 children treated for a minimum of 4 months, 29 (76%) exhibited a clinical response. Twenty-one patients had follow-up imaging studies and of these, 16 (76%) had radiographic decrease in lesion size. Median time to demonstration of response was 49 days. All five children with vascular tumours and all three children with vascular malformations under the age of 4 years showed a clinical response. Response rate was lower for children ≥ 4 years of age (0/2, 0% for vascular tumours; 21/28, 75% for vascular malformations). No patient experienced an infection directly related to rapamycin or discontinued rapamycin due to toxicity. Conclusions: Rapamycin is safe and efficacious in most children with select vascular tumours and malformations. Young children appear to respond better, suggesting that early initiation of rapamycin should be considered

Recombinant FXIII (rFXIII-A(2)) Prophylaxis Prevents Bleeding and Allows for Surgery in Patients with Congenital FXIII A-Subunit Deficiency

Recombinant factor XIII-A(2) (rFXIII-A(2)) was developed for prophylaxis and treatment of bleeds in patients with congenital FXIII A-subunit deficiency.mentor (TM) 2 (NCT00978380), a multinational, open-label, single-arm, multiple-dosing extension to the pivotal mentor (TM) 1 trial, assessed long-term safety and efficacy of rFXIII-A(2) prophylaxis in eligible patients (patients with severe [= 6 years. Patients received 35IU/kgrFXIII-A(2) (exactdosing) every 28 +/- 2 days for >= 52 weeks. Primary endpoint was safety (adverse events including immunogenicity); secondary endpoints were rate of bleeds requiring FXIII treatment, haemostatic response after one 35 IU/kg rFXIII-A(2) dose for breakthrough bleeds and withdrawals due to lack of rFXIII-A(2) efficacy. Steady-state pharmacokinetic variables were also summarized. Elective surgery was permitted during the treatment period. Sixty patients were exposed to rFXIII-A(2); their median age was 26.0 years (range: 7.0-77.0). rFXIII-A(2) was well tolerated without any safety concerns. No non-neutralizing or neutralizing antibodies (inhibitors) against FXIII were detected. Mean annualized bleeding rate (ABR) was 0.043/patient-year. Mean spontaneous ABR was 0.011/patient-year. No patients withdrew due to lack of efficacy. Geometric mean FXIII trough levelwas 0.17 IU/mL. Geometric terminal half-life was 13.7 days. rFXIII-A(2) prophylaxis provided sufficient haemostatic coverage for 12 minor surgeries without the need for additional FXIII therapy; eight procedures were performed within 7 days of the patient's last scheduled rFXIII-A(2) dose, and four were performed 10 to 21 days after the last dose.Peer reviewe

Once-weekly prophylaxis with 40 IU/kg nonacog beta pegol (N9-GP) achieves trough levels of >15% in patients with haemophilia B: Pooled data from the paradigm™ trials.

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Dilemmas on emicizumab in children with haemophilia A: A survey of strategies from PedNet centres.

INTRODUCTION Haemophilia A care has changed with the introduction of emicizumab. Experience on the youngest children is still scarce and clinical practice varies between haemophilia treatment centres. AIM We aimed to assess the current clinical practice on emicizumab prophylaxis within PedNet, a collaborative research platform for paediatricians treating children with haemophilia. METHODS An electronic survey was sent to all PedNet members (n = 32) between October 2022 and February 2023. The survey included questions on the availability of emicizumab, on the practice of initiating prophylaxis in previously untreated or minimally treated patients (PUPs or MTPs) and emicizumab use in patients with or without inhibitors. RESULTS All but four centres (28/32; 88%) responded. Emicizumab was available in clinical practice in 25/28 centres (89%), and in 3/28 for selected patients only (e.g. with inhibitors). Emicizumab was the preferred choice for prophylaxis in PUPs or MTPs in 20/25 centres; most (85%) started emicizumab prophylaxis before 1 year of age (30% before 6 months of age) and without concomitant FVIII (16/20; 80%). After the loading dose, 13/28 centres administered the recommended dosing, while the others adjusted the interval of injections to give whole vials. In inhibitor patients, the use of emicizumab during ITI was common, with low-dose ITI being the preferred protocol. CONCLUSION Most centres choose to initiate prophylaxis with emicizumab before 12 months of age and without concomitant FVIII. In inhibitor patients, ITI is mostly given in addition to emicizumab, but there was no common practice on how to proceed after successful ITI

NBEAL2 mutations and bleeding in patients with gray platelet syndrome

Homozygosity/compound heterozygosity for loss of function mutations in neurobeachin-like 2 (NBEAL2) is causative for Gray platelet syndrome (GPS; MIM #139090), characterized by thrombocytopenia and large platelets lacking α-granules and cargo. Most GPS-associated NBEAL2 mutations generate nonsense codons; frameshifts causing premature translation termination and/or changes in mRNA splicing have also been observed. Data regarding NBEAL2 protein expression in GPS patients is limited. We observed absence of NBEAL2 in platelets from GPS patients with 3 different genotypes, and reduced/truncated platelet NBEAL2 has been reported for others. GPS is commonly associated with mild bleeding, but lifethreatening bleeding has been reported in some cases. A common long-term complication in GPS patients is myelofibrosis; splenomegaly is less common but sometimes of sufficient severity to merit splenectomy. Like GPS patients, mice lacking NBEAL2 expression exhibit macrothrombocytopenia, deficiency of platelet α-granules, splenomegaly, myelofibrosis, impaired platelet function and abnormalities in megakaryocyte development. Animal studies have also reported impaired platelet function in vivo using laser injury and thrombo-inflammation models. NBEAL2 is a large gene with 54 exons, and several putative functional domains have been identified in NBEAL2, including PH (pleckstrin homology) and BEACH (beige and Chediak-Higashi) domains shared with other members of a protein family that includes LYST and LRBA, also expressed by hematopoietic cells. Potential NBEAL2-interacting proteins have recently been identified, and it is expected that current and future efforts will reveal the cellular mechanisms by which NBEAL2 facilitates platelet development and supports hemostatic function

Correlation between phenotype and genotype in a large unselected cohort of children with severe hemophilia A

Phenotypic variability is well recognized in severe hemophilia A. A few studies, mainly in adults treated lifelong on demand, suggest that bleeding phenotype correlates with factor VIII gene (F8) mutation type. Because treatment regimens influence outcomes to a large extent, examining bleeding phenotype during the first years of life may be the most suitable way to define this variability. We set out to analyze the very early phenotypic expression of severe hemophilia A in 621 consecutively enrolled, well-characterized previously untreated patients and to correlate this with patients' F8 mutation. Detailed information was collected on bleeds and treatment of the first 75 exposure days or until inhibitor development. F8 mutation type was known for 531 patients; 402 had null mutations and 129 had non-null mutations. Considering only patients who had not started prophylaxis or developed an inhibitor before select bleeding events, we found that patients with null mutations experienced their first bleed and first joint bleed at younger median ages than patients with non-null mutations (9.7 vs 10.9 months and 13.8 vs 16.1 months, respectively). We conclude that F8 mutation type accounts for only a small component of the significant phenotypic variability found among patients with severe hemophilia A

Practical considerations in choosing a factor VIII prophylaxis regimen : Role of clinical phenotype and trough levels

Current therapy for haemophilia A is guided by severity of the disease, which in turn is best reflected in patients’ endogenous factor VIII activity levels. For patients with severe haemophilia (particularly children), prophylaxis with continuous routine factor replacement has become standard of care in developed countries and is gradually becoming the standard of care in developing countries. The question arises then: what is an appropriate prophylaxis regimen to prevent bleeding events and arthropathy, while also maximizing patient quality of life and taking into consideration the costs of prophylaxis? Should all patients be treated with one standard, fixed prophylaxis regimen, or should prophylaxis be individualised for each patient? If so, what factors need to be considered in choosing the appropriate dose and frequency of factor administration? If prophylaxis is tailored to the individual patient, then patient-related factors (bleeding phenotype, activity profiles, age, joint status) and product-specific factors (half-life of the replacement factor in the individual patient) will determine the choice of regimen, whether it be a fixed-regimen prophylaxis or prophylaxis that is tailored to patient activity and bleeding risk. Regardless of the choice of prophylaxis regimen, for any regimen to be effective, adherence to therapy is key to optimising outcomes