The early and rapid response to daratumumab in children with chronic refractory immune thrombocytopenia from a referral single centre of China.

Chronic refractory primary immune thrombocytopenia (CRITP) is currently defined as refractory to multiple therapeutic of second-line agents with or without splenectomy, faced with the threat of severe bleeding and challenging to obtain effective treatment. Although stable and effective drug therapy is needed, it is tough to find one. Daratumumab (Dara), an anti-CD38 monoclonal antibody presented the target cloned plasma cells in multiple myeloma, has also been reported to be effective in refractory autoimmune cytopenia in some case or series reports and ongoing clinical trials for adult patients with CRITP. Here, we report the early and durable response of Dara combination with avatrombopag in three CRITP patients (2 male and 1 female aged 12, 5 and 7 years, respectively) in our centre, with a follow-up period of more than 25 weeks. Before Dara, the duration of immune thrombocytopenia was 9, 1.4 and 4 years, respectively, a baseline platelet count of 4, 6, 9 × 109/L, the bleeding score was all above level 2 and the number of previous drugs was >3. The time to response (R: Plt ≥30 × 109/L with at least a twofold increase in the baseline count) of Dara was on Day 45, 6 and 4 and achieved complete response (CR: Plt ≥100 × 109/L) on Day 51, 6 and 8, the sustained response (SR: Plt >30 × 109/L following Dara at ≥75% of the platelet count assessment at follow-up end-point since the patient achieved response) was 48, 175 and 204 days with the follow-up time of 39.1, 25.9 and 29.7 weeks. The bleeding score decreased from grade 3 to grade 0 during follow-up. No significant treatment-related adverse events were found during follow-up. Dara combination with avatrombopag may be a safe and efficacious therapy for children with CRITP, but it needs to be further explored.

Outcomes of switching to avatrombopag following treatment failure with eltrombopag in paediatric immune thrombocytopenia: A real-world study in China.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by isolated thrombocytopenia and a haemorrhagic risk. Thrombopoietin receptor agonists (TPO-RAs) are highly effective for ITP and are widely used to treat patients with steroid treatment failure or dependency. However, although treatment response to TPO-RAs may differ according to the type, the potential impact of switching from eltrombopag (ELT) to avatrombopag (AVA) with respect to efficacy or tolerance in children remains unknown. This study aimed to evaluate the outcomes of switching from ELT to AVA in paediatric patients with ITP. We retrospectively evaluated children with chronic immune thrombocytopenia (cITP) switched from ELT to AVA owing to treatment failure at the Hematology-Oncology Center of Beijing Children's Hospital between July 2021 and May 2022. Overall, 11 children (seven and four boys and girls respectively) with a median age of 8.3 (range: 3.8-15.3) years were included. The overall response and complete response (platelet [PLT] count ≥100 × 109 /L) rates during AVA treatment were 81.8% (9/11) and 54.6% (6/11) respectively. The median PLT count was significantly increased from ELT to AVA (7 [range: 2-33] × 109 /L vs. 74 [15-387] × 109 /L; p = 0.007). The median time to PLT count ≥30 × 109 /L was 18 (range: 3-120) days. Overall, 7/11 patients (63.6%) used concomitant medications, and concomitant medication use was gradually discontinued within 3-6 months after AVA initiation. In conclusion, AVA after ELT is effective in the heavily pretreated paediatric cITP population, with high response rates even in those with an inadequate response to a prior TPO-RA.

Anti-glycoprotein autoantibodies are related to bleeding severity in children with newly diagnosed ITP and very low platelet counts.

BACKGROUND AND OBJECTIVE: Immune thrombocytopenia (ITP) is an autoimmune-mediated hemorrhagic disease. Anti-glycoprotein autoantibodies play a key role in the pathophysiology of ITP, but the relationship between platelet-specific antibodies and bleeding severity is unclear. This study aimed to analyze the relationship between anti-glycoprotein autoantibodies and bleeding severity in children with newly diagnosed ITP and platelet count less than 10 × 109 /L. METHOD: This was a single-center prospective observational study that analyzed children with newly diagnosed ITP and platelet count less than 10 × 109 /L between June 2018 and September 2021 at our hospital. The children were classified into the mild and severe groups based on the bleeding scores. The type and titer of anti-glycoprotein autoantibodies were detected using an enzyme-linked immunosorbent assay (ELISA) kit (PAKAUTO). We analyzed the relationship between bleeding severity and anti-glycoprotein autoantibodies. RESULTS: A total of 86 cases were enrolled, including 42 in the mild group and 44 in the severe group. Patients with anti-GPIIb/IIIa or anti-GPIb/IX antibodies suffered more severe bleeding than patients without them (χ2 = 7.303, p = .007; χ2 = 3.875, p = .049), but there was no significant difference between patients with or without anti-GPIa/IIa antibodies (χ2 = 0.745, p = .388). When antibodies were analyzed together, patients with three antibodies suffered more severe bleeding than those without three antibodies (χ2 = 5.053, p = .025). Patients with higher antibody titer in the eluent, but not in the plasma, suffered more severe bleeding in all three antibodies (Z = -2.389, p = .017; Z = -2.108, p = .035; Z = -2.557, p = .011). CONCLUSION: Anti-glycoprotein autoantibodies led to more severe bleeding in children under 18 years of age without drug treatment with newly diagnosed ITP and platelet count less than 10 × 109 /L.

In vitro and in silico perspectives on estrogenicity of tanshinones from Salvia miltiorrhiza.

This work aims to investigate the structure-activity relationship for binding and activation of human estrogen receptor α ligand binding domain (hERα-LBD) with tanshinones by a combination of in vitro and in silico approaches. The recombinant hERα-LBD was expressed in E. coli strain. The direct binding interactions of tanshinones with hERα-LBD and their ERα agonistic potency were investigated by fluorescence polarization (FP) and reporter gene assays, respectively. FP assay suggested that the tested tanshinones can bind to hERα-LBD as affinity ligands. Tanshinones acted as agonists of hERα as demonstrated by transactivation of estrogen response element (ERE) in transiently transfected MCF-7 cells and by molecular docking of these compounds into the hydrophobic binding pocket of hERα-LBD. Interestingly, comparison of the calculated binding energies versus Connolly solvent-excluded volume and experimental binding affinities showed a good correlation. This work may provide insight into chemical and pharmacological characterization of novel bioactive compounds from Salvia miltiorrhiza.