Biomarkers of erythropoiesis response to intravenous iron in a crossover pilot study in unexplained anemia of the elderly.

Anemia is common in older adults, but often unexplained. Previously, we conducted a randomized, controlled trial of intravenous (IV) iron sucrose to study its impact on the 6-minute walk test and hemoglobin in older adults with unexplained anemia and ferritin levels of 20-200 ng/mL. In this report, we present for the first time the response of hemoglobin, as well as the dynamic response of biomarkers of erythropoiesis and iron indices, in a pooled analysis of the initially IV iron-treated group of 9 subjects and the subsequently IV iron treated 10 subjects from the delayed treatment group. We hypothesized that there would be a reproducible hemoglobin response from IV iron, and that iron indices and erythropoietic markers would reflect appropriate iron loading and reduced erythropoietic stress. To investigate the biochemical response of anemia to IV iron, we studied the dynamics of soluble transferrin receptor (STfR), hepcidin, erythropoietin (EPO), and iron indices over 12 weeks after treatment. In total, all 19 treated subjects were evaluable: 9 from initial treatment and 10 after cross-over. Hemoglobin rose from 11.0 to 11.7 g/dL, 12 weeks after initiating IV iron treatment of 1000 mg divided weekly over 5 weeks. We found early changes of iron loading after 1-2 IV iron dose: serum iron increased by 184 mcg/dL from a baseline of 66 mcg/dL, ferritin by 184 ng/mL from 68 ng/mL, and hepcidin by 7.49 ng/mL from 19.2 ng/mL, while STfR and serum EPO declined by 0.55 mg/L and 3.5 mU/mL from 19.2 ng/mL and 14 mU/mL, respectively. The erythroid response and evidence of enhanced iron trafficking are consistent with the hypothesis that IV iron overcomes iron deficient or iron-restricted erythropoiesis. These data provide new insight that iron-restricted erythropoiesis is a potential and targetable mechanism for patients diagnosed with unexplained anemia of the elderly and offers support for larger prospective trials of IV iron among anemic older adults of low to normal ferritin.

Evaluating ravulizumab for the treatment of children and adolescents with paroxysmal nocturnal hemoglobinuria.

INTRODUCTION: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal stem cell disease harvesting a somatic mutation in the phosphatidylinositol glycan class A (PIG-A) gene. This mutation results in a deficiency in cell membrane complement regulators leading to activation of the terminal complement pathway, clinically presenting as hemolytic anemia and thrombosis, and frequently associated with bone marrow failure. This condition was historically managed with supportive care and bone marrow transplant. AREAS COVERED: This paper will review primary data on the pharmacology, efficacy, and safety of ravulizumab in the pediatric/adolescent population gathered from literature search from PubMed, abstracts from annual meetings, and medication package inserts. Eligible clinical trials identified on the clinicaltrials.gov website are also briefly discussed. EXPERT OPINION: The discovery of eculizumab, a monoclonal antibody against complement protein 5, has revolutionized the PNH landscape, with decreased hemolysis and risk of thrombosis, improved quality-of-life, and has become the standard of care. Ravulizumab, a longer-acting C5-inhibitor with 4 times the half-life of eculizumab, was recently approved for pediatric patients with PNH. Ravulizumab is effective, safe, and has the potential to improve quality of life further. In addition, ongoing clinical trials using second-generation complement inhibitors may provide promising new interventions in PNH.