Plasma Cell Directed Therapy for Immune Thrombotic Thrombocytopenic Purpura (iTTP)

Immune thrombotic thrombocytopenic purpura (iTTP) is a microangiopathic hemolytic anemia (MAHA) underpinned by autoreactivity against the von Willebrand factor (vWF) cleaving protease, ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). Autoantibody mediated ADAMTS13 inhibition leads to the accumulation of ultra-large vWF multimers which activate platelets and endothelium to initiate microvascular thrombosis. In the absence of urgent therapeutic intervention, iTTP is rapidly fatal due to cumulative organ dysfunction including catastrophic neurological and cardiac sequalae. Therapeutic plasma exchange (TPE) is the mainstay of initial therapy and aims to remove pathological autoantibodies and ultra-large vWF multimers while replenishing ADAMTS13. Immunosuppression is an important treatment adjunct, as attainment of remission and successful TPE cessation is strongly associated with suppression of anti-ADAMTS13 antibody production. More recently, caplacizumab, an antibody fragment blocking the interaction between vWF multimers and platelets, has been incorporated into acute TTP management to mitigate end-organ damage while awaiting suppression of anti-ADAMTS13 activity. In most cases, remission is achieved using corticosteroids alone or in combination with the B-cell depleting antibody, rituximab. However, some patients are refractory to front-line immunosuppression in the context of ‘inhibitor boosting’ whereby the exposure to homologous plasma exacerbates the underlying autoimmune flare. As such cases have been observed in the context of likely effective B-cell depletion, it has been hypothesized that plasma cells (ie, terminally differentiated B-cells) may provide a therapy-resistant nidus of anti-ADAMTS13 production as has been demonstrated in other autoimmune disease settings. Autoreactive plasma cells can be targeted by conventional and novel therapeutics, including those developed for malignant plasma cells in the context of multiple myeloma. Here we review the rationale and evidence for plasma cell directed therapy in refractory iTTP, with a focus on the proteasome inhibitor, bortezomib, and the CD38 monoclonal antibody, daratumumab.