Long-term tolerability, immunogenicity and efficacy of Nuwiq® (human-cl rhFVIII) in children with severe haemophilia A.

INTRODUCTION: Nuwiq® (human-cl rhFVIII, simoctocog alfa) is a 4th generation recombinant human FVIII, without chemical modification or fusion with any other protein, produced in a human cell line. AIM/METHODS: This study (GENA-13) was an extension of the GENA-03 study in which previously treated children aged 2-12 years with severe haemophilia A received Nuwiq® prophylaxis for ≥6 months. GENA-13 examined long-term tolerability, immunogenicity and efficacy of Nuwiq® prophylaxis in children. RESULTS: Of 59 patients enrolled in GENA-03, 49 continued Nuwiq® prophylaxis in GENA-13 for a median (range) of 30.0 (9.5-52.0) months. No patient withdrew due to drug-related adverse events or developed inhibitors. Only 2 of 20 518 infusions were associated with possibly related adverse events (dyspnoea, fever). The estimated annualized bleeding rate (ABR) was 0.67 (95% CI: 0.44, 1.02) for spontaneous and 2.88 (95% CI: 1.86, 4.46) for all bleeds. Younger children (2-5 years) had lower ABRs than children aged 6-12 years. Annualized bleeding rates were reduced in GENA-13 vs GENA-03, especially for spontaneous bleeds in younger children (71% reduction; ABR ratio 0.29 [95% CI: 0.11, 0.74]). Nuwiq® efficacy was rated as excellent/good in the treatment of 83.0% of 305 evaluated breakthrough bleeds. Surgical prophylaxis with Nuwiq® was rated as excellent for all 17 assessed procedures. CONCLUSION: Long-term treatment with Nuwiq® for the prevention of bleeds in children with severe haemophilia A was well tolerated, effective and reduced spontaneous bleeding by up to 70% compared with GENA-03.

Immunogenicity, efficacy and safety of Nuwiq® (human-cl rhFVIII) in previously untreated patients with severe haemophilia A-Interim results from the NuProtect Study.

INTRODUCTION: Nuwiq® (Human-cl rhFVIII) is a fourth generation recombinant FVIII, produced in a human cell line, without chemical modification or protein fusion. No inhibitors developed in studies with Nuwiq® in 201 previously treated patients with haemophilia A (HA). The immunogenicity, efficacy and safety of Nuwiq® in previously untreated patients (PUPs) with severe HA are being assessed in the ongoing NuProtect study. METHODS: The study, conducted across 38 centres worldwide, is evaluating 110 true PUPs of all ages and ethnicities enrolled for study up to 100 exposure days (EDs) or 5 years maximum. The primary objective is to assess the immunogenicity of Nuwiq® (inhibitor activity ≥0.6 BU) using the Nijmegen-modified Bethesda assay at a central laboratory. RESULTS: Data for 66 PUPs with ≥20 EDs from a preplanned interim analysis were analysed. High-titre (HT) inhibitors developed in 8 of 66 patients after a median of 11.5 EDs (range 6-24). Five patients developed low-titre inhibitors (4 transient). The cumulative incidence (95% confidence interval) was 12.8% (4.5%, 21.2%) for HT inhibitors and 20.8% (10.7%, 31.0%) for all inhibitors. During inhibitor-free periods, median annualized bleeding rates during prophylaxis were 0 for spontaneous bleeds and 2.40 for all bleeds. Efficacy was rated as "excellent" or "good" in treating 91.8% of bleeds. Efficacy of surgical prophylaxis was "excellent" or "good" for 8 (89%) procedures and "moderate" for 1 (11%). No tolerability concerns were evident. CONCLUSION: These interim data show a cumulative incidence of 12.8% for HT inhibitors and convincing efficacy and tolerability in PUPs treated with Nuwiq® .

Late effects of intensive treatment for acute myeloid leukemia and myelodysplasia in childhood.

PURPOSE: To perform a comprehensive assessment of the late effects of short-term intensive chemotherapy for childhood acute myeloid leukemia (AML) and myelodysplasia, and compare the sequelae of intensive chemotherapy alone with those of total-body irradiation (TBI). PATIENTS AND METHODS: Of 33 survivors studied, 26 (group A) received intensive chemotherapy including anthracyclines, one also received busulfan, cyclophosphamide (Bu/Cy), and bone marrow transplantation (BMT). Seven patients (group B) received chemotherapy, TBI, and BMT. Hearing, sight, growth, and endocrine, renal, and cardiac function were assessed. RESULTS: The mean height standard deviation score of 25 nontransplanted group A patients was +0.67 at diagnosis, -0.11 following treatment (P = .016), and +0.34 7 years later (P > .05), indicating no long-term growth impairment. The patients had normal gonadal function and the girls had normal uterine size and ovarian volume. The Bu/Cy patient had primary ovarian failure. Four group B children required growth hormone and four sex steroids for growth or gonadal failure. The girls had reduced uterine size and ovarian volume. Three had thyroid dysfunction and six had cataracts. Abnormalities of renal function were found in both groups and hearing loss in group A only. The mean cardiac shortening fraction was significantly reduced at 29.2% in group A and 28.6% in group B compared with 36% in normal subjects. Two group A patients have developed cardiac failure. CONCLUSION: Chemotherapy and TBI before BMT for AML has resulted in growth failure, gonadal and thyroid damage, and cataracts in most children, whereas chemotherapy alone caused cardiac, renal, and hearing abnormalities only.

Prophylaxis in haemophilic children.

Prophylaxis with recombinant factor concentrates is the standard for children with severe haemophilia at the end of the 1990s but there are still many who are not given this optimal therapy for a variety of reasons; the dominant one globally is almost certainly financial, and efforts over the next decade must concentrate on ways of reducing costs and reducing factor concentrate requirements. Dosing according to kinetic principles can give a more cost-effective use of concentrate and a computerized pharmacokinetic model can be used. Another possibility is the introduction of an implantable sustained-release pump delivery system connected to a central venous access system, which can deliver factor concentrate to maintain a constant level of around 5% and thus reduce the overall amount of factor used. The dose of factor required with this system has been estimated as 700-875 IU/kg per year to keep the plasma level at 2% and 1700-2200 IU/kg per year to maintain it at 5%.

Plasma and albumin-free recombinant factor VIII: pharmacokinetics, efficacy and safety in previously treated pediatric patients.

BACKGROUND: The pharmacokinetics of factor VIII replacement therapy in preschool previously treated patients (PTPs) with hemophilia A have not been well characterized. OBJECTIVES: To assess the pharmacokinetics, efficacy and safety of a plasma-free recombinant FVIII concentrate, ADVATE [Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method, rAHF-PFM], in children < 6 years of age with severe hemophilia. PATIENTS/METHODS: Fifty-two boys, one girl, mean (+/- SD) age 3.1 +/- 1.5 years and >or= 50 days of prior FVIII exposure, were enrolled in a prospective study of ADVATE rAHF-PFM at 23 centers. RESULTS: The mean terminal phase half-life (t(1/2)) was 9.88 +/- 1.89 h, and the mean adjusted in vivo recovery (IVR) was 1.90 +/- 0.43 IU dL(-1) (IU kg(-1))(-1). Over the 1-6-year age range, t(1/2) of rAHF-PFM increased by 0.40 h year(-1). IVR increased by 0.095IU dL(-1)(IU kg(-1))(-1) (kg m(-2))(-1) in relation to body mass index (BMI). Patients primarily received prophylaxis. Median (range) annual joint bleeds were 0.0 (0.0-5.8), 0.0 (0.0-6.1) and 14.2 (0.0-34.5) for standard prophylaxis, modified prophylaxis and on-demand treatment, respectively. Bleeds were managed in 90% (319/354) of episodes with one or two rAHF-PFM infusions; response was rated excellent/good in 93.8% of episodes. Over a median 156 exposure days, no FVIII inhibitors were detected and no related severe adverse events or unusual non-serious adverse events were seen. CONCLUSIONS: Children < 6 years of age appear to have shorter FVIII t(1/2) and lower IVR values than older subjects. However, these parameters increased with age (t(1/2)) and BMI (adjusted IVR), respectively. rAHF-PFM was clinically effective and well tolerated, with no signs of increased immunogenicity in previously treated young children with hemophilia A.

The impact of prophyactic treatment on children with severe haemophilia.

Twenty-seven children with severe haemophilia receiving regular prophylactic factor concentrate were evaluated to examine the overall effectiveness of prophylaxis in modern haemophilia care. The median age at the start of prophylaxis was 6.2 years (range 1.3-15.9 years) and the cumulative length of follow-up was 808 months (mean 30, rang 7-76 months). Nine patients required a central venous catheter for venous access (age range 1.3-5.2 years), eight boys could cannulate themselves and in 10 the parents performed regular venepuncture. The mean dose of concentrate given at the time of study was 31.8 U/kg three times weekly (range 12.5.6 U/kg) or 4900 U/kg/year (range 1900-8200). None developed an inhibitor on prophylaxis, though four had previously had an antibody. The median average annual number of bleeds in the 27 patients prior to prophylaxis was 14.7 (range 3.7-35.4). On prophylaxis this fell to 1.5 (range 0-12.5) (P<0.001) and in the group as a whole the frequency of bleeds diminished in successive years on prophylaxis. All 20 children with evidence of arthropathy improved on prophylaxis and eight had reversal of chronic damage such that their joints appeared normal at the time of study. There were reductions in the need for walking aids, in hospital admissions, and in numbers of school days lost for bleeding episodes. All families feel that prophylaxis has brought about an improvement in quality of life.

Use of central venous catheters in children with severe congenital coagulopathy.

From two U.K. centres 23 children with severe congenital coagulopathy had a total of 27 port-a-cath devices inserted to facilitate factor VIII or IX prophylaxis (eight patients), domiciliary therapy (seven patients), immunotolerance (four patients), or a combination thereof (four patients). Six children had a factor VIII inhibitor at the time of insertion. The mean age at operation was 30 months, with a range of 9-76 months. The cumulative length of follow-up is 639 months with a mean of 27.8 months and a range of 5-79 months. Haemostasis was achieved peri- and post-operatively with high-purity concentrate in the majority of patients without an inhibitor. All those with an inhibitor had porcine factor VIII, except one who had recombinant factor VIIa. The post-operative complication rate was 27% (6/23): three had a port-site haematoma (one required removal and replacement), two had post-operative infection, and one had swelling caused by extravasation. To date there have been 13 documented infections in 10/23 patients (five with inhibitor): a rate of 0.24 per follow-up year or 0.67 per 1000 patient-days. Six were caused by Gram-positive and seven by Gram-negative organisms. Six infections could not be eradicated by antibiotics and the port-a-cath system had to be removed; in three it was replaced by a second port-a-cath. Although there are risks involved in the use of port-a-caths in this population, both clinicians and parents involved in the care of these children believe that the benefits are considerable and the potential hazards are acceptable.

Malignant mesenchymoma associated with a congenital lung cyst in a child: case report and review of the literature.

Primary lung tumors are uncommon in children, and malignant mesenchymal tumors form only a small proportion of these. Leiomyosarcomas occur more commonly than rhabdomyosarcomas, whereas malignant mesenchymomas are exceedingly rare. Of the total number of primary pulmonary rhabdomyosarcomas and malignant mesenchymomas of lung reported in children, 50% have occurred in association with congenital lung cysts. The relationship between abnormal morphogenesis and neoplasia is well documented in the kidney. A similar relationship may exist in the lung between cystic parenchymal maldevelopment and embryonal mesenchymal tumors. We report a 4-year-old boy with a malignant mesenchymoma of lung arising within a congenital lung cyst; one similar case has previously been reported to our knowledge.