Castleman's Disease and Interleukin-6
By William B. Ershler, MD
Castleman's disease (CD), angiofollicular lymph- node hyperplasia, was initially described a half century ago in asymptomatic patients with a mediastinal mass.1 Since then, a number of variants have been described, including hyaline-vascular, plasmacytic, mixed-cellularity, and plasmablastic.2 CD is further defined as localized (unicentric) or systemic (multicentric). Unicentric CD is commonly cured by surgical excision, although, if this is not possible, radiation and/or chemotherapy have been used successfully.3 Multicentric CD (MCD) is a systemic disorder more commonly observed with advancing age, characterized by both nodal disease and hepatosplenomegaly and the appearance of constitutional symptoms, including fever, night sweats, and weight loss.4-6 The disorder is known to occur in patients with HIV infection and, in that case, is most often associated with HHV-8 co-infection. In patients who are HIV negative, evidence for HHV-8 infection is present in approximately 40% of cases in some series.6,7 MCD also has been associated with Epstein-Barr virus, although this is not commonly observed.
Most, but not all, cases of MCD are polyclonal. It has long been recognized that interleukin-6 (IL-6) is of pathogenetic importance, and vascular endothelial growth factor may be as well.8,9 In fact, the bulk of constitutional symptoms associated with CD have been attributed to IL-6.2,3
There is no standard approach to the treatment of MCD, and numerous modalities, including steroids, radiation therapy, and chemotherapeutic agents,10,11 have been used with success. Antiviral therapy with ganciclovir has resulted in regression of disease for some, but not all HHV-8/HIV MCD patients.12 Rituximab® also has been variably successful, but has resulted in exacerbation in Kaposi's sarcoma and is, therefore, not generally advised for HIV-positive patients.13
Inasmuch as dysregulated IL-6 is considered central to the pathogenesis of CD, it has long been considered a target for novel therapies. Treatment with murine anti-IL-6 monoclonal antibody resulted in clinical improvement in patients with CD, although efficacy was transient because of development of neutralizing anti-murine antibody.14 Subsequently, the use of a humanized anti-IL6-receptor antibody was found to result in symptomatic relief and partial or complete regression of the adenopathy in patients with MCD.15 Most recently, CNTO 328 (Siltuximab®), a chimeric, human-murine monoclonal antibody that binds and neutralizes IL-6, was reported to be effective in patients with CD.16 Of 23 patients, 18 obtained clinical benefit and 12 had objective tumor regression. This was a dose-escalation study, and all 11 patients treated with the highest dose (12 mg/kg at variable ([1, 2, or 3] weekly intervals) achieved benefit, with 8 patients demonstrating clinical regression of tumor. Of note, there were no patients enrolled on this study with HIV- or HHV-8-associated disease. This was an interim report, and 15 of the enrolled 23 patients remained on study at the time of publication. That stated, there was no dose-limiting toxicity observed, and the majority (87%) experienced no toxicity greater than grade 2, and no significant adverse events were attributable to the antibody treatment.
CD is a heterogeneous diagnosis ranging from localized benign tumor masses to extremely aggressive disseminated proliferations. Although histologic variants have some features in common, the subtypes are substantially distinct, such that a common therapeutic approach is unlikely to be successful. For multicentric CD, including the recently described plasmablastic variant, dysregulated IL-6 appears to be a common feature in pathogenesis, and targeting this cytokine is of demonstrable clinical benefit. Notably, HIV and HHV-8 are associated with multicentric CD, and appropriate anti-viral therapies should be highly considered in this subset.
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