Multicentric Castleman’s disease (MCD) is a rare lymphoproliferative disease driven by interleukin (IL)-6 overproduction. There is no established standard of care for MCD, and patients are usually managed by a variety of strategies with only modest success. Treatment with siltuximab, an anti-IL-6 mAb, demonstrated clinical and radiologic responses in MCD patients in a phase 1 study (Kurzrock et al. Clin Cancer Res 2013;19:3659-70). A phase 2 extension study to assess the safety of long-term treatment with siltuximab in MCD patients is currently ongoing.

We report the interim analysis results based on 19 patients who had sustained disease control on siltuximab in the phase 1 study and continued to receive siltuximab 11 mg/kg q3w IV in the phase 2 extension study. Safety monitoring focused on infections, hyperlipidemia, neutropenia, thrombocytopenia, GI perforations, and liver function based on the potential risks from the mechanism of action of IL-6 blockade. Investigator assessed disease control and survival status were also collected.

When these 19 patients started the phase 1 study, median age was 44 (range 18, 76) yrs, 63% were male, median disease duration was 4.8 mos (37% newly diagnosed), 53% had hyaline vascular and 47% had plasmacytic histological type, all were HIV- and HHV-8-negative, 32% were therapy-naïve, and 68% had prior therapy (including 21% with prior cancer-related surgery and 63% with prior systemic therapy for MCD). At the data cutoff for this interim analysis of the extension study (January 2013), patients had received in total a median of 81 doses (maximum 129) of siltuximab during a median treatment duration of 5.1 (range 3.4, 7.2) yrs, with 74% of patients treated >4 yrs. All 19 patients are alive and continuing siltuximab treatment.

Over the entire treatment duration (ie, both studies), upper respiratory tract infection (89%); nausea (63%); vomiting (58%); diarrhea (53%); hypercholesterolemia (47%); hypertriglyceridemia, pain in extremities, headache, rash, and hepatic function abnormal (each 42%) were most commonly reported. The incidence of AEs reported in the different system-organ classes was similar or lower in the treatment periods of 2 to 4 yrs and more than 4 yrs compared with the treatment period of 0 to 2 yrs. 63% of patients reported at least one grade ≥3 AE (mostly grade 3, none grade 5) during the entire treatment period, most commonly in the following system-organ classes: gastrointestinal (32%); infections (26%); and blood/lymphatic system disorders or general disorders/administration-site conditions (each 21%). Grade ≥3 hypertension was reported in 3 patients; grade ≥3 nausea, cellulitis, and fatigue in 2 patients each; other grade ≥3 AEs were reported in single patients.

Two patients had at least one serious infection during phase 1, and none were reported during phase 2 extension study (overall incidence 0.0226 per pt-yr). Eight patients had low-grade hypertriglyceridemia in phase 1, with no additional cases reported during extension study (overall incidence 0.1250 per pt-yr). No patient had grade ≥3 thrombocytopenia, and only 1 patient had grade ≥3 neutropenia during the entire treatment period (overall incidence 0.0103 per pt-yr). Only 1 case of grade ≥3 abnormal hepatic function was reported (in phase 1). No GI perforations occurred. No patient developed infusion-related reactions during the extension study. Only 3 patients had SAEs during the extension study, including unrelated syncope and dyspnea. One patient developed grade 3 polycythemia (Hb 18.8 g/dL), which was controlled without complications.

Based on independent radiologic review of images from the phase 1 study, 1 patient had CR, 11 had PR, and 7 had SD at initiation of extension study. All 19 patients have sustained disease control (SD or better) by investigator assessment, including 8 patients who had their dosing interval increased to q6w after established prolonged PR/CR (median q6w treatment duration 11 mos). After a median follow-up of 5.1 yrs, the OS rate in these 19 patients is 100%.

In conclusion, the 19 patients with MCD in this extension study have received siltuximab for a prolonged period of time (median 5.1 yrs, up to 7.2 yrs). All patients are alive and maintain disease control. Prolonged siltuximab treatment is well tolerated, with no evidence of new or cumulative toxicity or treatment discontinuations and with a low rate of serious adverse events including serious infections.


Van Rhee:Janssen Research & Development: Research Funding. Casper:Janssen Research & Development: Research Funding. Voorhees:Janssen Research & Development: Research Funding; Abbott: Consultancy; GlaxoSmithKline: Consultancy; Celgene: Membership on an entity’s Board of Directors or advisory committees; MedImmune: Membership on an entity’s Board of Directors or advisory committees. van de Velde:Johnson & Johnson: Equity Ownership; Janssen Research & Development: Employment. Vermeulen:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Qin:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Qi:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Tromp:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Kurzrock:Janssen Research & Development: Research Funding.

Author notes


Asterisk with author names denotes non-ASH members.

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