A case for CD38 targeted therapy in multi-refractory immune thrombocytopenia Free

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by autoantibody-mediated platelet destruction and bleeding complications. While up to two thirds of patients respond to initial therapy with steroids and/or intravenous immunoglobulin, the remainder of adults develop refractory disease—defined by persistent thrombocytopenia and bleeding. Subsequent lines of therapy include rituximab, thrombopoietin receptor agonists (TPO-RAs), immunosuppressants, and splenectomy. Often these patients face persistent, life-threatening bleeding and more effective therapies are needed.

These autoantibodies that are inappropriately produced in B lymphocytes. Many therapies, such as steroids and rituximab, directly target these B cells to mediate their therapeutic effect. About 60% of rituximab treated patients will experience a platelet count response after therapy. Rituximab is an anti-CD20 monoclonal antibody; CD20 is expressed during most stages of B-cell differentiation, from pre-B cells to early plasmablasts. Interestingly, mature plasma cells lose CD20 and secrete large quantities of antibodies. Given this, we hypothesize that patients who do not respond to rituximab may have a more mature plasma cell population secreting antibodies and do not express CD20. These plasma cells highly express CD38, which, fortunately, can be targeted therapeutically.

Based on this rationale, we present a case of a critically ill patient with multi-refractory ITP that achieved a durable platelet response and clinical recovery after treatment with a daratumumab—a monoclonal antibody targeting CD38. This 62-year-old man with a remote history of Hodgkin and diffuse large B-cell lymphoma presented with new-onset thrombocytopenia (platelet nadir 1,000/μL) and severe mucocutaneous bleeding. Evaluation of nutritional, infectious, hepatic, malignant and primary bone marrow causes was unrevealing—establishing the diagnosis of primary ITP. Initial treatment with high-dose dexamethasone and IVIG was ineffective. He subsequently received rituximab, eltrombopag and avatrombopag. After seven weeks of persistent, severe thrombocytopenia, he underwent splenectomy, which resulted in a brief, short-lived platelet recovery (peak 29,000/uL). During weeks 8–14, he was treated with romiplostim, a second steroid pulse, mycophenolate, cyclophosphamide, and cyclosporine without response. During this time he was repeatedly hospitalized with severe bleeding managed with platelet transfusions. At week 17, we initiated off-label treatment with daratumumab (anti-CD38 monoclonal antibody) combined with fostamatinib and danazol. Within five days his platelet count returned to normal. Danazol and fostamatinib were discontinued. He completed 12 weekly doses of daratumumab and has remained in stable remission with platelet counts >300,000/μL, now 14 months post-diagnosis.

This case highlights both the challenges of managing multi-refractory ITP and the potential of plasma cell directed therapy for this disease. The standard therapies for ITP largely target B cells but fail to eliminate long-lived plasma cells—likely underappreciated producers of pathogenic autoantibodies. In this case, CD38, expressed on plasma cells, was targeted using daratumumab, which induces cell death via multiple mechanisms including complement activation and phagocytosis. Already there is a growing body of literature suggesting that plasma cell directed therapy may have efficacy in other autoimmune hematologic disorders including autoimmune hemolytic anemia, post-transplant cytopenias and refractory ITP. This was the motivation for the Scandinavian DART study. While this study is ongoing, we present this case to highlight that daratumumab can be associated with a rapid platelet recovery in multi-refractory ITP, was safe and well tolerated with fostamatinib and danazol, and produced a durable response after a finite treatment course (12 weekly doses). In conclusion, for patients with prolonged, severe ITP unresponsive to conventional treatments, daratumumab offers a rational, mechanism-based intervention. Our case contributes to growing evidence supporting anti-CD38 immunotherapy in ITP and underscores the need for clinical trials to more broadly evaluate other plasma cell directed therapies for the treatment of ITP.