The Immunomodulatory Effect and Clinical Efficacy of Daratumumab in a Patient With Cold Agglutinin Disease

Anna Zaninoni,Bruno Fattizzo,Wilma Barcellini,Juri A Giannotta,Anna Gallì,Paola Bianchi,Rosangela Artuso,Luca Malcovati

doi:10.3389/fimmu.2021.649441

Abstract

Daratumumab is a monoclonal antibody directed against the transmembrane glycoprotein CD38 expressed on plasma cells and lymphoplasmocytes, with a proven efficacy in multiple myeloma. Here we show its clinical efficacy in a patient with cold agglutinin disease (CAD) relapsed after multiple lines of therapy. CAD is caused by cold reactive autoantibodies that induce complement mediated hemolysis and peripheral circulatory symptoms. The disease is also characterized by the presence of monoclonal IgM gammopathy and of a lymphoid bone marrow infiltration that benefits from B-cell targeting therapies (i.e., rituximab) but also from plasma cell directed therapies, such as proteasome inhibitors. In the patient described, we also show that daratumumab therapy influenced the dynamics of several immunoregulatory cytokine levels (IL-6, IL-10, IL-17, IFN-γ, TNF-α, TGF-β) indicating an immunomodulatory effect of the drug beyond plasma cell depletion. In addition, we provide a literature review on the use of daratumumab in autoimmune conditions, including multi-treated and refractory patients with autoimmune hemolytic anemia (both CAD and warm forms), Evans syndrome (association of autoimmune hemolytic anemia and immune thrombocytopenia) and non-hematologic autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis.

Highlights

Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia (AIHA) [1, 2] generally caused by an IgM autoantibody
To have a deep insight into mutational landscape of the CAD patient, we performed generation sequencing at high depth of coverage and did not identify any pathogenic variant in the 54 tested genes
We report the efficacy of daratumumab therapy in a patient with CAD and show for the first time its immunomodulatory effect on several cytokines

Summary

INTRODUCTION

Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia (AIHA) [1, 2] generally caused by an IgM autoantibody The latter has an optimum temperature of reaction at 3–4◦C and is able to fix complement with positivity of the direct antiglobulin test (DAT) for the C3d fraction. Plasma cells directed therapies like bortezomib, a proteasome inhibitor used in multiple myeloma (MM), represent a novel approach in CAD patients with 30% response rate in a phase 2 clinical trial [5] Another interesting anti-MM treatment is daratumumab a human IgG1κ MoAb directed against the transmembrane glycoprotein CD38 [6, 7]. Patient’s cytokine levels have been compared with median values of 40 healthy controls

RESULTS

Review of the Literature

DISCUSSION

ETHICS STATEMENT