Treatment of refractory/relapsed Diamond-Blackfan anaemia with eltrombopag

Abstract

Diamond-Blackfan anaemia (DBA) is a rare, inherited bone marrow failure syndrome with a ribosomal defect causing slowed globin chain production with normal haem synthesis, causing an overabundance of reactive iron/haem and erythroid-specific cellular toxicity. Eltrombopag, a non-peptide thrombopoietin receptor agonist, is a potent intracellular iron chelator and induced a robust durable response in an RPS19-mutated DBA patient on another trial. We hypothesized eltrombopag would improve RBC production in DBA patients. We conducted a single-centre, single-arm pilot study (NCT04269889) assessing safety and erythroid response of 6 months of daily, fixed-dose eltrombopag for DBA patients. Fifteen transfusion-dependent (every 3-5 weeks) patients (median age 18 [range 2-56]) were treated. One responder had sustained haemoglobin improvement and >50% reduction in RBC transfusion frequency. Of note, 7/15 (41%) patients required dose reductions or sustained discontinuation of eltrombopag due to asymptomatic thrombocytosis. Despite the low response rate, eltrombopag has now improved erythropoiesis in several patients with DBA with a favourable safety profile. Dosing restrictions due to thrombocytosis may cause insufficient iron chelation to decrease haem production and improve anaemia in most patients. Future work will focus on erythropoiesis dynamics in patients and use of haem synthesis inhibitors without an impact on other haematopoietic lineages.

Keywords: Diamond–Blackfan anaemia; chelation; eltrombopag.

Figure 1.

Transfusion Rates Pre- and Post-Eltrombopag Figure 1. Number of transfusions per 8-week period for each patient at baseline and at the 6-month primary endpoint after eltrombopag treatment. Each line represents one patient. Red line is the responder.

Figure 2.

Eltrombopag Increases the Platelet Count of DBA Patients Figure 2. Box-and-whisker plots show the distribution of the maximum platelet count observed across the subjects at each dose level with median, 25th and 75th quartiles, and outliers indicated. Color shading indicates the dose intervention required: green (<400,000/μL) continue dose, orange (≥400,000/μL) reduce dose, red (≥600,000/μL) hold for at least one week and until under 400,000/μL and then reduce dose.

Figure 3.

Eltrombopag Exposure Figure 3. Percent of goal eltrombopag exposure (100%) for individual patients. Each dot represents one patient. Red dot is the responder.