Mina, Syeda

ABSTRACT Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by antibody‐mediated platelet destruction, often driven by long‐lived plasma cells (LLPCs) resistant to conventional therapies. While most patients respond to corticosteroids and intravenous immunoglobulin (IVIG), a subset develops life‐threatening refractory disease. In this case series, we describe three patients aged 39, 85, and 58 with life‐threatening, multi‐agent refractory ITP and platelet nadirs < 2 × 10 9 /L who failed corticosteroids, IVIG, and thrombopoietin receptor agonists (TPO‐RAs). Following salvage therapy with daratumumab, a monoclonal antibody targeting CD38, all three patients achieved rapid hematologic recovery, with platelet count normalization within 1 week. This accelerated response allowed for urgent clinical stabilization, including safe anticoagulation and surgical intervention. The efficacy of daratumumab likely stems from a dual mechanism: the depletion of CD38+ LLPCs and the immediate modulation of Fc‐receptor‐mediated platelet clearance. These observations suggest that CD38‐targeted therapy can bypass traditional treatment resistance to achieve near‐immediate remission in high‐complexity, high‐risk clinical settings. While these results are compelling, prospective clinical trials are warranted to define the long‐term safety, durability, and optimal dosing of anti‐CD38 therapies in refractory ITP populations.