Treatment of Refractory Diamond-Blackfan Anemia with Eltrombopag

Diamond-Blackfan Anemia (DBA) is a congenital macrocytic anemia characterized by red cell aplasia with reticulocytopenia that is commonly treated with steroids and red blood cell transfusions. The majority of patients with DBA have heterozygous mutations in genes encoding ribosomal proteins. The erythroid defect in DBA has been hypothesized to result from slowed globin chain production in the setting of normal heme synthesis, leading to an overabundance of reactive iron/heme and erythroid-specific cellular toxicity (Yang et al., Sci Trans Med, 2016). Eltrombopag has potent intracellular iron chelation activity (Vlachodimitropoulou et al., Blood, 2017; Young et al., AJH, 2022) and demonstrated robust efficacy in a single RPS19-mutated DBA patient enrolled on a clinical trial using eltrombopag for moderate aplastic anemia and hypoproliferative unlineage cytopenias, with a durable response maintained over 3 years (Fan et al., Blood, 2020; Doty et al., Blood, 2022). These data led to the hypothesis that eltrombopag may improve red blood cell production in patients with DBA via slowing heme synthesis and rebalancing globin/heme production.

We conducted a single-center, single-arm pilot study (ClinicalTrials.gov: NCT04269889) to assess the safety and efficacy of daily, fixed-dose eltrombopag starting at 150 mg daily or pediatric weight-based equivalent for 6 months in patients with DBA. Primary outcomes studied were toxicity and erythroid response within 6 months. Secondary outcomes include duration of response, rates of clonal evolution as measured by karyotypic changes, platelet count at 3 and 6 months, long-term drug safety and tolerability, impact on iron parameters, and health-related quality of life measurements. Eligible patients were over 2 years of age with weight of 12kg or greater who were diagnosed with relapsed and/or steroid-refractory or intolerant DBA and had clinically significant anemia (hemoglobin <9.0 g/dL or RBC transfusion in 8 weeks prior to enrollment). Exclusion criteria included platelets >400,000/uL, creatinine > 2.5 mg/ dL or GFR < 30 mL/min/1.73 m², direct bilirubin >2.0mg/dL, SGOT or SGPT >5 times upper limit of normal, and androgen or corticosteroid treatment within 4 weeks of initiating eltrombopag. Response was defined as a pretreatment hemoglobin <9g/dL that demonstrated a rise in hemoglobin of >1.5g/dL and/or had a reduction in PRBC transfusions by at least 50% during 8 consecutive weeks prior to response assessment compared to transfusions in the 8 weeks preceding drug initiation.

A total of 17 patients were screened, and 15 were enrolled and begun on eltrombopag. The median age was 18 years (2-56 years). All patients were analyzed for DBA gene mutations via a targeted clinical exome sequencing panel. Six (40%) had mutations in RPS19, 3 (20%) in RPL11, 5 (33%) in other ribosomal protein genes, and 3 (20%) had no identifiable mutations in known DBA genes, similar to previously reported mutation frequencies. All patients enrolled were transfusion-dependent, requiring transfusions every 3-5 weeks.

One of 15 patients met response criteria of sustained improvement in hemoglobin and >50% reduction in RBC transfusion frequency. This young adult patient (18-years-old at start of eltrombopag) had an RPL11 mutation. Of note, 7/15 (41%) patients required dose reductions or sustained discontinuation of eltrombopag due to thrombocytosis, based on protocol requirements for discontinuation of drug for platelets ≥600,00/ul or dose reduction for platelets ≥400,000/ul.

Despite the low response rate, eltrombopag has improved erythropoiesis in several patients with DBA. Dosing restrictions due to thrombocytosis may not allow attainment of sufficient iron chelation to slow heme synthesis in most patients. Future work will focus on analysis of erythropoiesis dynamics in these patients and use of heme synthesis inhibitors that do not impact on other hematopoietic lineages.

No relevant conflicts of interest to declare.

Eltrombopag is a thrombopoietin receptor agonist developed to increase platelet production in patients with various forms of thrombocytopenia. It also has intracellular iron chelation activity for which it was used in this trial. Eltrombopag was supplied by Novartis through a CRADA with Dr. Dunbar.