Siltuximab Reverses Muscle Wasting In Patients With Multicentric Castleman’s Disease

Multicentric Castleman’s disease (MCD) is a rare lymphoproliferative disease characterized by fevers, night sweats, fatigue, anorexia, and wasting. Interleukin-6 (IL-6) plays a pivotal role in MCD and is involved in muscle wasting. Siltuximab (CNTO328) is a chimeric IgG1κ mab that binds IL-6 and prevents its interaction with IL-6 receptors. We analyzed prospectively collected computed tomography (CT) scans to determine siltuximab’s effects on muscle mass.

CT scans of MCD patients (pts) from a phase 1 siltuximab study were studied for changes in body composition from siltuximab treatment. Pts (n=37) were treated with CNTO328 q weekly, 2 wks or 3 wks at doses ranging from 2.8 to 11 mg/kg, and 34/37 pts had CT scans that were suitable for evaluating body composition. The median age was 49 (range 18-76) with 18 M/16 F. Median body weight was 78 kg (mean 87 kg, range 40 to 170 kg). Eleven pts had not received prior treatment; the other 23 pts had a median of 2 prior therapies, range 1 to 5. Pts’ histology was hyaline vascularity (n=17), plasmacytic (n=15), and mixed cellularity (n=2). CT scans for each pt at each time point in their treatment were landmarked at the axial 3rd lumbar vertebra (L3). L3 images were then tissue cross sectional area analyzed using Slice-O-Matic® (Tomovision, Montreal, Canada) with Hounsfield units (HU) set at different levels for each tissue: skeletal muscle within the range of -29 HU to 150 HU, visceral adipose tissue within -150 HU to -50 HU, intramuscular adipose tissue within -190 HU to -30 HU, and subcutaneous adipose tissue within -190 HU to -30 HU. Tissue areas were used to estimate tissue mass Shen et al. 2004 J Appl Physiol 97:2333-2338).

The median duration of treatment in this phase I study was 703 days (range 21 to 1843 days). During siltuximab treatment 38% of pts gained > 1 kg of muscle, mean 2.3 kg ± 1.1 kg (all mean values reported as mean±SD), 47% of pts had a stable muscle mass, muscle gain or loss less than 1 kg, mean 0.2 kg ± 0.5 kg and 15% of pts lost more than 1 kg, mean loss 3.1 ± 1.7 kg. Over the entire patient population (n=34) the mean gain in muscle was 0.5 kg (median 0.6 kg, range -5.5 to 4.4 kg); and the mean gain in adipose tissue was 3.1 kg (median 3.05, range -13.8 to 35.8 kg). By MCD histology the gain in muscle was 0.25 kg for hyaline vascular, 0.33 kg for mixed cellularity, and 0.85 kg for plasmacytic. Changes in fat mass by MCD histology was 5.1 kg for hyaline vascular, 5.8 for mixed cellularity, and 3.8 kg for plasmacytic. By Cheson radiologic disease response criteria the change in muscle mass was 0.9 kg for pts with partial response (PR, n=11), 0.5 kg for patients with stable disease (SD, n=22), and -3.7 kg for the one patient with progressive disease (PD). The change in fat mass was 8.5 kg for patients with PR (n=11), 2.85 kg for patients with SD (n=22) and -0.6 kg for the one patient with PD. At the recommended phase II dose of 11mg/kg q 3 wks (n=17), the mean gain in muscle mass was 0.6 kg (median 0.9 kg, range -5.5 kg to 4.4 kg). The pattern of muscle and fat mass gain was interesting in that the fat mass increased first followed by a delay and then muscle gains occurred. Pts who continued to respond to siltuximab continued to gain muscle mass up to the time that they were censored.

In addition to objective responses that were durable in MCD (median duration of response was not reached at follow-up of 29.4 months), siltuximab caused reversal of muscle wasting in 38% of patients, stabilization of muscle wasting in another 47% and in only 15% of patients did muscle wasting worsen. This stabilization and improvement in muscle wasting could lead to functional status improvements in MCD patients.

Kurzrock:Janssen Research & Development: Research Funding. van Rhee:Janssen Research & Development: Research Funding. Ming:Janssen Research & Development: Employment. Vermeulen:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership.