Bodyweight-adjusted rivaroxaban for children with venous thromboembolism (EINSTEIN-Jr): results from three multicentre, single-arm, phase 2 studies.

BACKGROUND: Rivaroxaban has been shown to be efficacious for treatment of venous thromboembolism in adults, and has a reduced risk of bleeding compared with standard anticoagulants. We aimed to develop paediatric rivaroxaban regimens for the treatment of venous thromboembolism in children and adolescents. METHODS: In this phase 2 programme, we did three studies to evaluate rivaroxaban treatment in children younger than 6 months, aged 6 months to 5 years, and aged 6-17 years. Our studies used a multicentre, single-arm design at 54 sites in Australia, Europe, Israel, Japan, and north America. We included children with objectively confirmed venous thromboembolism previously treated with low-molecular weight heparin, fondaparinux, or a vitamin K antagonist for at least 2 months or, in children who had catheter-related venous thromboembolism for at least 6 weeks. We administered rivaroxaban orally in a bodyweight-adjusted 20 mg-equivalent dose, based on physiologically-based pharmacokinetic modelling predictions and EINSTEIN-Jr phase 1 data in young adults, in either a once-daily (tablets; for those aged 6-17 years), twice-daily (in suspension; for those aged 6 months to 11 years), or three times-daily (in suspension; for those younger than 6 months) dosing regimen for 30 days (or 7 days for those younger than 6 months). The primary aim was to define rivaroxaban treatment regimens that match the target adult exposure range. The principal safety outcome was major bleeding and clinically relevant non-major bleeding. Analyses were per-protocol. The predefined efficacy outcomes were symptomatic recurrent venous thromboembolism, asymptomatic deterioration on repeat imaging at the end of the study treatment period. These trials are registered at ClinicalTrials.gov, numbers NCT02564718, NCT02309411, and NCT02234843. FINDINGS: Between Feb 11, 2013, and Dec 20, 2017, we enrolled 93 children (ten children younger than 6 months; 15 children aged 6 months to 1 year; 25 children aged 2-5 years; 32 children aged 6-11 years; and 11 children aged 12-17 years) into our study. 89 (96%) children completed study treatment (30 days of treatment, or 7 days in those younger than 6 months), and 93 (100%) children received at least one dose of study treatment and were evaluable for the primary endpoints. None of the children had a major bleed, and four (4%, 95% CI 1·2-10·6) of these children had a clinically relevant non-major bleed (three children aged 12-17 years with menorrhagia and one child aged 6-11 years with gingival bleeding). We found no symptomatic recurrent venous thromboembolism in any patients (0%, 0·0-3·9). 24 (32%) of 75 patients with repeat imaging had their thrombotic burden resolved, 43 (57%) patients improved, and eight (11%) patients were unchanged. No patient deteriorated. We confirmed therapeutic rivaroxaban exposures with once-daily dosing in children with bodyweights of at least 30 kg and with twice-daily dosing in children with bodyweights of at least 20 kg and less than 30 kg. Children with low bodyweights (<20 kg, particularly <12 kg) showed low exposures so, for future studies, rivaroxaban dosages were revised for these weight categories, to match the target adult exposure range. 61 (66%) of 93 children had adverse events during the study. Pyrexia was the most common adverse event (ten [11%] events), and anaemia and neutropenia or febrile neutropenia were the most frequent grade 3 or worse events (four [4%] events each). No children died or were discontinued from rivaroxaban because of adverse events. INTERPRETATION: Treatment with bodyweight-adjusted rivaroxaban appears to be safe in children. The treatment regimens that we confirmed in children with bodyweights of at least 20 kg and the revised treatment regimens that we predicted in those with bodyweights less than 20 kg will be evaluated in the EINSTEIN-Jr phase 3 trial in children with acute venous thromboembolism. FUNDING: Bayer AG, Janssen Research and Development.

Severe vitamin C deficiency in a child newly diagnosed with T-cell ALL due to nutrient gap.

A 10-year-old boy developed a perifollicular rash during interim maintenance of T-Cell acute lymphoblastic leukaemia. Differential diagnoses included drug reaction and inflammatory process. Before diagnosis, the patient had a limited diet--low in vegetables and fruits--due to selective eating, with later anorexia and taste aversions due to chemotherapy treatment. Despite nutritional counselling and starting a multivitamin, the patient incurred severe weight loss (18.5% of his usual body weight). Serum levels of ascorbic acid were non-detectable, at <5 µmol/L, indicative of vitamin C deficiency. The patient began vitamin C supplementation containing 125 mg ascorbic acid three times a day for 7 days, then 125 mg once daily for 3 months to normalise serum vitamin C. After ascorbic acid treatment was completed, the patient started a complete multivitamin and made efforts to eat fruits and vegetables rich in vitamin C. His serum ascorbic acid concentrations normalised to 52 µmol/L 3 months after receiving supplementation.

Pseudomonas aeruginosa infection: an uncommon cause of post-renal obstruction following induction therapy for acute lymphoblastic leukemia.

A 14-month-old infant presented with gastroenteritis with febrile pancytopenia and was diagnosed with acute lymphocytic leukemia (ALL). Ten days post induction therapy, the patient developed hypertension that was ascribed to steroid therapy and treated with metoprolol and amlodipine. As leukocyte numbers began to recover the asymptomatic patient became anuric. Ultrasound showed echoic floating structures in the bladder. Following cystoscopy and retrograde pyelography examination, purulent debris was irrigated from the bladder and grew Pseudomonas aeruginosa. Ciprofloxacin therapy was initiated and renal function was restored within 2 days. The case highlights the potential for renal obstruction after neutropenia recovery in children undergoing induction therapy for ALL.