Idiopathic Multicentric Castleman Disease Unresponsive to One IL-6 Inhibitor May Respond to Another IL-6 Inhibitor

Idiopathic multicentric Castleman disease (iMCD) is a rare hematologic disorder defined by lymphadenopathy with distinctive histopathology and systemic inflammation that can progress to multiorgan failure. Siltuximab, a monoclonal antibody targeting the interleukin-6 (IL-6) cytokine, is the only FDA-approved treatment for iMCD and is considered first-line therapy. Tocilizumab, an IL-6 receptor antagonist, approved for iMCD in Japan and used off-label is often viewed as clinically interchangeable with siltuximab due to shared pathway inhibition. Limited treatment alternatives exist for patients whose disease is refractory to IL-6 inhibition. Using two independent iMCD patient registries, we identified patients who received siltuximab and tocilizumab at different periods and had an assessable response to each inhibitor. Eight out of 14 patients who received both therapies were refractory to the first and then responsive to the second IL-6 inhibitor; six patients were refractory to both IL-6 inhibitors. Responses were durable over available follow-up and were accompanied by significant improvements in inflammatory markers and disease severity scores. While a subset of patients may have had improved response to the second IL-6 inhibitor due to shorter treatment durations or the use of other medications, all were refractory after receiving at least three doses of the first IL-6 inhibitor. These findings suggest that there may be different IL-6-related mechanisms across patients and that selected patients who do not respond to an initial IL-6 inhibitor should be considered for a second IL-6 inhibitor.