Siltuximab, a Novel Anti-Interleukin-6 Monoclonal Antibody, for Castleman's Disease

Fox Chase Cancer Center, Filadelfia, Pennsylvania, United States
Journal of Clinical Oncology (Impact Factor: 18.43). 08/2010; 28(23):3701-8. DOI: 10.1200/JCO.2009.27.2377
Source: PubMed


Interleukin-6 (IL-6) has emerged as a key factor in the pathogenesis of the atypical lymphoproliferative disorder Castleman's disease (CD). Siltuximab is a new anti-IL-6, chimeric monoclonal antibody with potential therapeutic benefit in patients with CD.
We report interim results from an open-label, dose-finding, seven-cohort, phase I study in which patients with symptomatic, multicentric or unresectable, unicentric CD received siltuximab at 1-, 2-, or 3-week intervals. The main efficacy end point of clinical benefit response (CBR) was defined as a composite of clinical and laboratory measures relevant to the management of CD. In addition, radiologic response was independently assessed by using modified Cheson criteria.
Eighteen (78%) of 23 patients (95% CI, 56% to 93%) achieved CBR, and 12 patients (52%) demonstrated objective tumor response. All 11 patients (95% CI, 72% to 100%) treated with the highest dose of 12 mg/kg achieved CBR, and eight patients (73%) achieved objective tumor response. Overall objective-response duration ranged from 44 to > or = 889 days, and one patient had complete response for > or = 318 days. Hemoglobin increased markedly in 19 patients (median increase, 2.1 g/dL; range, 0.2 to 4.7 g/dL) in the absence of transfusion or erythropoiesis-stimulating agents. No dose-limiting toxicity was reported, and only three patients had grade 3 or higher adverse events after a median exposure of 331 days (range, 1 to 1,148 days).
These interim results strongly suggest that siltuximab is an effective treatment with favorable safety for the management of CD. An additional study is planned to fully evaluate safety and efficacy at the recommended dose of 12 mg/kg every 3 weeks.

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    • "Another anti-IL-6-based therapy that has been attempted is siltuximab, a chimeric murine monoclonal antibody neutralizing IL-6. Interim results from a phase1 trial with siltuximab in patients with HIV-negative HHV-8-negative CD are available from 23 patients, all but one of whom had MCD [102]. None of those patients had drug-limiting toxicity and the treatment was well tolerated at a dose of up to 12 mg/kg weekly. "
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    ABSTRACT: Castleman and Towne described a disease presenting as a mediastinal mass resembling thymoma. It is also known as "giant lymph node hyperplasia", "lymph node hamartoma", "angiofollicular mediastinal lymph node hyperplasia", and "angiomatous lymphoid hyperplasia". The pathogenesis is unknown, but the bulk of evidence points toward faulty immune regulation, resulting in excessive B-lymphocyte and plasma-cell proliferation in lymphatic tissue. In addition to the mediastinal presentation, extrathoracic involvement in the neck, axilla, mesentery, pelvis, pancreas, adrenal gland, and retroperitoneum also have been described. There are 2 major pathologic variations of Castleman disease: (1) hyaline-vascular variant, the most frequent, characterized by small hyaline-vascular follicles and capillary proliferation; and (2) the plasma-cell variant, in which large lymphoid follicles are separated by sheets of plasma cells. The hyaline-vascular cases usually are largely asymptomatic, whereas the less common plasma-cell variant may present with fever, anemia, weight loss, and night sweats, along with polyclonal hypergamma-globulinemia. Castleman disease is a rare lymphoproliferative disorders. Few cases have been described world widely. In this article we reviewed the classification, pathogenesis, pathology, radiological features and up to date treatment with special emphasis on the role of viral stimulation, recent therapeutic modalities and the HIV-associated disease.
    Full-text · Article · Sep 2012 · The Korean journal of hematology
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    • "However, using a monoclonal antibody that specifically blocks IL-6 signaling, siltuximab, Guo et al. demonstrated that although the combination of siltuximab with paclitaxel increased the sensitivity of ovarian tumor cells to paclitaxel in vitro, the combination was ineffective in vivo in xenogrft mouse model [36]. Although clinical trials of monoclonal antibodies to IL-6 for the treatment of other types of cancer have shown encouraging results [37,38], a clear benefit for patients with ovarian cancer remains to be demonstrated. Finally, the high levels of IL-6 could enhance the immune suppressive status of the tumor microenvironment by inducing B7-H4 expression on tumor associated macrophages and promote apoptosis in these cells [39]. "
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    ABSTRACT: The acellular fraction of epithelial ovarian cancer (EOC) ascites promotes de novo resistance of tumor cells and thus supports the idea that tumor cells may survive in the surrounding protective microenvironment contributing to disease recurrence. Levels of the pro-inflammatory cytokines IL-6 and IL-8 are elevated in EOC ascites suggesting that they could play a role in tumor progression. We measured IL-6 and IL-8 levels in the ascites of 39 patients with newly diagnosed EOC. Commercially available enzyme-linked immunosorbent assay (ELISA) was used to determine IL-6 and IL-8 ascites levels. Ascites cytokine levels were correlated with clinicopathological parameters and progression-free survival. Mean ascites levels for IL-6 and IL-8 were 6419 pg/ml (SEM: 1409 pg/ml) and 1408 pg/ml (SEM: 437 pg/ml) respectively. The levels of IL-6 and IL-8 in ascites were significantly lower in patients that have received prior chemotherapy before the surgery (Mann-Whitney U test, P = 0.037 for IL-6 and P = 0.008 for IL-8). Univariate analysis revealed that high IL-6 ascites levels (P = 0.021), serum CA125 levels (P = 0.04) and stage IV (P = 0.009) were significantly correlated with shorter progression-free survival. Including these variables in a multivariate analysis revealed that elevated IL-6 levels (P = 0.033) was an independent predictor of shorter progression-free survival. Elevated IL-6, but not IL-8, ascites level is an independent predictor of shorter progression-free survival.
    Full-text · Article · May 2011 · BMC Cancer
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    ABSTRACT: ObjectiveTo describe the clinical characteristics and diagnostic features of giant lymph node hyperplasia or Castleman’s disease found in rare locations. MethodsTwo cases of Castleman’s disease (1 abdominal and 1 retroperitoneal) were confirmed histopathologically. The clinical and medical imaging features were described and relative literatures were reviewed. ResultsOne patient had no clinical symptoms and the other had epigastric discomfort. The location of the benign tumor was retroperitoneal and left adrenal gland, respectively. Both cases were of solitary tumor, 1 was a hyaline-vascular type and the other was a mixed type with plasma cell and hyaline-vascular type. Both were successfully treated by surgical excision. Patients were followed up for 3 and 4 years respectively with no signs of recurrence on CT imaging. ConclusionsAbdominal Castleman’s disease lacks specific clinical manifestations. Definitive diagnosis requires histologic examination and excisional surgery is the method of choice for treatment. KeywordsGiant lymph node hyperplasia–Castleman’s disease–Diagnosis–CT imaging–Surgery
    Full-text · Article · Oct 2011 · Central European Journal of Medicine
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