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® .

Auxological changes in UK survivors of childhood acute lymphoblastic leukaemia treated without cranial irradiation.

BACKGROUND: As most children with acute lymphoblastic leukaemia (ALL) achieve long-term survival, minimising late effects of treatment is a priority. Acute lymphoblastic leukaemia survivors treated historically with protocols including cranial irradiation demonstrate increased weight gain. METHODS: We retrospectively studied all 134 patients treated on the MRC/UKALL97 protocol (without cranial irradiation as standard therapy) at a single centre, with 77 inclusions. Height-, weight- and body mass index (BMI) standard-deviation scores (SDS) were recorded at diagnosis and annually until 3 years out (YO) from end of treatment (EoT); changes across time were explored using a univariate model (significance P ≤ 0.001 to account for multiple comparisons). RESULTS: Whole-group height SDS was lower from 1 year into treatment until 2 YO, whereas weight- and BMI-SDS remained higher until 3 YO. In females, height-SDS was lower until EoT, but higher weight- and BMI-SDS persisted until 3 YO. In males, height-SDS was lower at EoT and at 2 YO; differences in BMI-SDS had resolved by 2 YO. By WHO criteria, more patients were overweight or obese at 3 YO than at diagnosis (P=0.01). CONCLUSION: Survivors of childhood ALL, particularly females, exhibit adverse changes in height-, weight- and BMI-SDS, which arise during treatment and persist into follow-up. Patients should be supported with appropriate dietary and lifestyle advice during ALL treatment and follow-up, which may minimise these changes and reduce associated long-term morbidity.

Severe factor X deficiency due to a homozygous mutation (Cys364Arg) that disrupts a disulphide bond in the catalytic domain.

Severe factor X deficiency (<0.01 IU mL(-1)) is a rare disorder producing a major bleeding tendency including umbilical cord, joint and intracranial haemorrhage. We present the first case of a child homozygous for a g.1177T > C missense alteration, predicted to disrupt the catalytic domain, and resulting in severe FX deficiency. The child suffered intracranial haemorrhage and now receives regular prophylaxis with a prothrombin complex concentrate. Our experience and a review of the literature suggest that optimal frequency of dosing is likely to be two or three times weekly and that the risk of thrombosis is very small.

An unusual cause of bruising in an 80-year-old woman.

PRESENTATION: a previously fit 80-year-old woman presented with a 2-week history of spontaneous and extensive bruising affecting all four limbs. The severity was such that she required a transfusion of 8 units of blood. RESULTS OF INVESTIGATIONS: a markedly prolonged activated partial thromboplastin time which was only partially corrected with normal plasma; tests for lupus anticoagulant were negative. Factor VIII levels were reduced and the Bethesda assay indicated an acquired inhibitor to factor VIII. She was treated with a combination of intravenous immunoglobulin and immunosuppression. OUTCOME: the response to treatment was excellent, with a marked reduction in anti-factor VIII antibody levels and resolution of the bruising over the next few weeks.