NEW ORLEANS — A novel monoclonal antibody could become the first treatment for multicentric Castleman's disease (MCD), according to data presented here at the American Society of Hematology 55th Annual Meeting.
One quarter of patients treated with the investigational agent siltuximab (Janssen) achieved a durable complete response, whereas none treated with placebo did (P = .0037). The same pattern was seen for durable tumor and symptomatic response (34% vs 0%; P = .0012).
"About 1 in 3 patients actually achieved a durable tumor response for at least 18 weeks," said lead author Raymond S. Wong, MBChB, MD, from the Prince of Wales Hospital and the Chinese University of Hong Kong, during a press briefing. He added that "1 in 4 achieved a complete symptom response for at least 18 weeks in the siltuximab arm."
"This is very exciting, because none of the patients in the placebo arm had a response," he noted. In addition, "the time to treatment failure for those who received placebo was 134 days, while the time to treatment failure has not yet been reached in the siltuximab arm."
These results "highlight the potential for siltuximab to be a new and valuable treatment option for MCD patients who, unfortunately, had no previously available treatment options," he noted.
No Standard Options
MCD disease is a rare lymphoproliferative disorder with high morbidity, and symptoms can have a significant impact on quality of life, explained Dr. Wong. Its signs and symptoms are driven by dysregulated interleukin (IL)-6 production. Although not a malignancy, the multicentric form of this disease has similarities to lymphoma, and patients can progress to non-Hodgkin's lymphoma.
Infection with HIV is a risk factor, and Castleman's disease is much more common in people who are HIV positive. There is currently no standard therapy for MCD, which can be fatal.
Siltuximab is a chimeric IgG1κ monoclonal antibody that binds to human IL-6 with high affinity, preventing IL-6 from interacting with the IL-6 receptor.
First Randomized Trial
The researchers enrolled 79 patients with MCD in a phase 2 randomized double-blind controlled multicenter study. This is the only such study of its kind conducted in this disease, Dr. Wong noted. The MCD patients were symptomatic, with measurable disease, and were negative for HIV and human herpesvirus-8.
Patients newly diagnosed or pretreated were randomized in a 2:1 ratio to siltuximab 11 mg/kg or placebo administered by intravenous infusion every 3 weeks. All patients also received best supportive care to manage their MCD symptoms.
The treatment groups were well balanced, and median age was 48 years of age. About half (48%) were Asian, 39% were white, 66% were male, 30% were using corticosteroids, and 58% had received previous systemic therapy.
The most common baseline symptoms reported were fatigue (86%), malaise (61%), night sweats (52%), peripheral sensory neuropathy (38%), anorexia (37%), and pruritus (37%).
Siltuximab was given until protocol-defined treatment failure. After that, patients assigned to placebo could cross over to unblinded siltuximab. The primary analysis was performed after the last treated patient completed assessments at 48 weeks.
The median duration of treatment was longer with siltuximab than with placebo (375 vs 152 days), and more patients in the siltuximab group completed the full 48 weeks of treatment (64% vs 27%).
Responses Seen With Siltuximab
In the siltuximab group, there was 1 complete response and 17 partial responses; in the placebo group, there were no responses. There was a higher percentage of durable tumor and symptomatic response with siltuximab than with placebo (34% vs 0%; P = .0012), and the median duration of tumor and symptomatic response of 340 days with siltuximab indicates prolonged disease control, Dr. Wong reported.
He noted that patients who received siltuximab had a rapid and significant reduction of the inflammatory parameters, such as C-reactive protein and fibrinogen. This was not observed in the placebo group.
"Patients who received siltuximab also had a significant improvement in anemia and hemoglobin level," he said. More patients in the siltuximab group than in the placebo group experienced improvement in hemoglobin of at least 15 g/L at week 13 (61% vs 0%; P = .0002).
Table. Outcomes in the Siltuximab and Placebo Groups
| Outcome | Siltuximab Group | Placebo Group | P Value |
| Tumor response rate on central radiology review | 38% | 38% | .0022 |
| Median time to treatment failure | Not reached | 134 days | .0084 |
| Median time to next treatment | Not reached | 280 days | .0013 |
| Durable symptomatic response rate | 57% | 19% | .0018 |
| Complete symptom resolution | 25% | 0% | .0037 |
Siltuximab was well tolerated, Dr. Wong noted. The frequency of adverse events were similar in the 2 groups, despite the longer duration of treatment with siltuximab. The most frequently occurring grade 3 events were fatigue (9%) and night sweats (8%) in the siltuximab group, and anemia (12%) in the placebo group.
Other adverse effects (>30%) include pruritus, rash, fatigue, and peripheral edema in the siltuximab group, and fatigue and dyspnea in the placebo group.
Thirteen of the 26 patients originally in the placebo group crossed over to siltuximab.
"Clinical benefit was confirmed by marked improvement of time to treatment failure, MCD-related symptoms, hemoglobin levels, and sustained reduction in inflammatory markers," Dr. Wong concluded.
American Society of Hematology (ASH) 55th Annual Meeting: Abstract 505. Presented December 9, 2013.
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