At the ASH 2014 Special Program, Frits van Rhee presented “Updates on Castleman Disease Treatment.” The frequently accepted 5-year overall survival rate in patients with MCD is 65% (Dispenzieri A, et al. Am J Hematol. 2012;87:997-1002), but newer targeted treatments are changing that value, van Rhee suggested. Three treatment strategies have been used based on our understanding of iMCD, including anti-inflammatory and immunosuppressive therapies, cytotoxic elimination of cells responsible for hypercytokinemia, and the blockade of IL-6 signaling with monoclonal antibodies.
Corticosteroids can improve symptoms during acute exacerbations of iMCD, but most patients relapse during steroid tapering. Immunosuppressive therapies, particularly cyclosporine A, are being used more frequently, because some physicians are treating iMCD more as a systemic inflammatory disease. Rituximab, which is a frequent first- or second-line therapy in iMCD, is only partially effective and typically does not provide long-term disease control. Cytotoxic lymphoma-based chemotherapies (eg, cyclophosphamide, doxorubicin, vincristine, and prednisone) induce responses in a large portion of the most severely ill patients with iMCD by eliminating a large portion of hypercytokine secreting cells, but relapses are common and side effects are significant.
Over the past decade, treatments directly targeting IL-6 have been used. Tocilizumab, an anti–IL-6 receptor monoclonal antibody, has demonstrated effectiveness at inducing and maintaining remission. Siltuximab, an anti–IL-6 monoclonal antibody, has demonstrated durable tumor and symptomatic response at a significantly higher rate compared with placebo in the first randomized phase 2 study in MCD (34% vs 0%, respectively; Wong RS, et al. Blood. 2013;122. Abstract 505). Both agents have shown clinical activity in iMCD and are potential candidates for frontline therapy; however, they require lifelong administration and are not effective in all patients. Anti–IL-6 and anti–CD-20 therapies may not be effective in all cases of iMCD, because hypercytokinemia and B-cell proliferation are 2 common results seen in iMCD but not necessarily the drivers of the underlying pathogenesis. Additional variability may be a result of disease heterogeneity, misclassification or misdiagnosis, and timing of therapy.
Recently, therapeutic approaches targeting pathways upstream of IL-6 have been reported in iMCD, and these deserve further exploration, particularly for patients with refractory anti–IL-6. Bortezomib, a selective proteasome inhibitor that preferentially targets plasma cells, has lowered IL-6 levels and has induced remission in 4 cases of iMCD. Bortezomib may work in iMCD via direct inhibition of nuclear factor-?B by degrading the I?B kinase. Thalidomide, an immunomodulator that inhibits tumor necrosis factor-alpha, IL-1, IL-6, IL-12, and VEGF, and stimulates T-cells potentially via cereblon inhibition, has demonstrated effectiveness at inducing remission, decreasing IL-6 levels, and lowering C-reactive protein in patients with iMCD. Anakinra, an IL-1 receptor antagonist, has also been reported to induce remission in a pediatric case of iMCD and in a patient who did not respond to anti–IL-6 therapy.
Further elucidation of iMCD pathogenesis is urgently needed to provide additional candidate-targeted therapies.
van Rhee then proposed an algorithm for treating IL-6–driven iMCD that he uses in treating patients:
