Nilotinib in locally advanced pigmented villonodular synovitis: a multicentre, open-label, single-arm, phase 2 trial.

BACKGROUND: Pigmented villonodular synovitis (alternatively known as diffuse-type giant cell tumour) is a rare, locally aggressive tumour driven by a specific translocation resulting in the overexpression of colony-stimulating factor 1 (CSF1). CSF1 receptor (CSF1R) inhibitors (ie, tyrosine kinase inhibitors and antibodies) induce a response in patients with pigmented villonodular synovitis. We investigated the safety and efficacy of a CSF1R tyrosine kinase inhibitor, nilotinib, in patients with locally advanced non-resectable pigmented villonodular synovitis. METHODS: In this phase 2, open-label, single-arm study, we enrolled patients from 11 cancer centres of hospitals in four countries (France, Netherlands, Italy, and Australia). Eligible patients were aged at least 18 years with a WHO performance status of 2 or less, and histologically confirmed progressive or relapsing pigmented villonodular synovitis that was inoperable, or resectable only with mutilating surgery. Patients received oral nilotinib (400 mg twice per day) until disease progression, unacceptable toxicity, or completion of 1 year of treatment. The primary endpoint was the proportion of patients who were progression free at 12 weeks, which was centrally assessed according to Response Evaluation Criteria in Solid Tumors version 1.1. Analyses were by modified intention to treat (ie, all patients with no major protocol violations who were treated with nilotinib for at least 3 weeks were included). All participants who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT01261429, and the results presented here are the final analysis of the trial. FINDINGS: Between Dec 15, 2010, and Sept 28, 2012, we enrolled 56 patients with pigmented villonodular synovitis and treated them with nilotinib. Five (9%) patients discontinued study treatment before week 12; therefore, 51 patients were evaluable for the primary endpoint at 12 weeks. The estimated proportion of patients who were progression free at 12 weeks was 92·6% (95% credible interval 84·3-97·9). 54 (96%) of 56 patients had a treatment-related adverse event. Six (11%) of 56 patients had at least one grade 3 treatment-related adverse event (headache, dizziness, and hepatic disorders [n=1], pruritus and toxidermia [n=1], diarrhoea [n=1], increased γ-glutamyl transferase concentration [n=1], anorexia [n=1], and increased headache [n=1]). No grade 4 or 5 adverse events were reported. One patient had a treatment-related serious adverse event (toxidermia) and two patients had serious adverse events not considered to be related to the study drug (borderline ovarian tumour [n=1] and pilonidal cyst excision [n=1]). INTERPRETATION: More than 90% of patients with locally advanced unresectable progressive pigmented villonodular synovitis achieved disease control with 12 weeks of nilotinib treatment. These results indicate that CSF1R tyrosine kinase inhibitors have anti-tumour activity with manageable toxicity in patients with inoperable progressive pigmented villonodular synovitis. Randomised trials investigating the efficacy of nilotinib for patients with unresectable pigmented villonodular synovitis are warranted. FUNDING: Novartis, Institut National du Cancer, EuroSARC, French National Cancer Institute, General Directorate of Care Supply, Lyon Research Innovation for Cancer, L'Agence nationale de la recherche, Laboratory of Excellence, Fondation ARC pour la recherche sur le cancer, Ligue contre le Cancer (comité de l'Ain), Info Sarcomes, and Association DAM'S.

Expression of metalloproteinases in pigmented villonodular synovitis.

Pigmented villonodular synovitis (PVNS) is an idiopathic proliferative synovial process composed of two predominant cell types: mononuclear histiocytic cells and giant cells. This lesion can be locally invasive and can result in bone cyst formation and late cartilage and bone loss. Because metalloproteinases have been implicated in the joint destruction occurring in inflammatory arthritis and in the ability of certain tumors to invade adjacent tissues, their presence in PVNS was determined. Synovial tissue samples were collected at surgical synovectomy from the knees of 10 patients with a prior histological diagnosis of PVNS. Pigmented villonodular synovitis synovium was examined for the presence of the metalloproteinases collagenase and stromelysin. Messenger RNA (mRNA) for collagenase and stromelysin was present in all patient samples, although in varying amounts. In situ hybridization studies on synovial tissue sections identified synovial lining cells as the predominant cells expressing these metalloproteinases. Occasional infiltrating mononuclear histiocytic cells also were producing metalloproteinase mRNA. Giant cells did not express mRNA for the metalloproteinases collagenase and stromelysin. These results suggest that collagenase and stromelysin may be among the mediators of cartilage and bone loss that can occur in PVNS.

Strong expression of Bcl-2 in pigmented villonodular synovitis of the knee with aggressive clinical behaviour.

OBJECTIVE: To determine the expression of bcl-2, p53, and caspase 3, and measure the Ki-67 proliferation index as well as DNA content and DNA fragmentation in a case of diffuse pigmented villonodular synovitis (PVNS) of the knee with aggressive clinical behaviour. METHODS: Expression of p53, Bcl-2 and Ki-67 was investigated using immunohistochemistry. In addition, multiparametric flow cytometry was performed for expression of p53, bcl-2, and caspase 3, as well as analysis of DNA content and distribution of cell cycle phases. DNA fragmentation was detected by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL). RESULTS: A strong cytoplasmic positivity for Bcl-2 protein, a key factor in regulation of apoptosis, was found in the majority of proliferating synovial cells. No apoptotic cell fraction was found by analysis of DNA content. DNA fragmentation was observed in 6.8% of cells. No elevated expression of p53 and caspase 3 was detected. CONCLUSION: Our results indicate a possible role of dysregulation of apoptosis in this case of PVNS. This aspect in the pathogenesis of PVNS should be clarified in further studies.

Pigmented villonodular synovitis. A clinicopathologic study of 52 cases.

Clinicopathologic, enzyme histochemical and electron microscopic findings in 52 patients with pigmented villonodular synovitis (PVS) are reported. The lesion was by far the most common in the knee joint (48%), followed by the ankle joint (25%). As to sex incidence, there seemed to be no predilection (46% in men, 54% in women). Microscopically, the PVS showed thin or thick villous projections of the involved synovial membrane, associated with or without nodular formation. The nodule of PVS consisted essentially of a proliferation of histiocyte-like cells with phagocytic activities. Another characteristic feature was large clefts and pseudoglandular or alveolar spaces lined by synovial cells. Enzyme histochemical studies revealed that the lesional cells had functional properties of macrophages. Electron microscopically, the lesion consisted essentially of histiocyte-like and fibroblast-like cells, together with intermediate cells and myofibroblasts.