Response to imatinib in villonodular pigmented synovitis (PVNS) resistant to nilotinib

Abstract

BackgroundPigmented villonodular synovitis (PVNS) is a rare locally aggressive tumor. PVNS is characterized in most cases by a specific t(1;2) translocation, which fuses the colony stimulating factor-1 (CSF1) gene to the collagen type VIa3 (COL6A3) promoter thus leading through a paracrine effect to the attraction of non-neoplastic inflammatory cells expressing CSF1-receptor. Imatinib is a tirosin-kinase inhibitors (TKI) active against CSF1-receptor whose activity in naïve PVNS was already described. We report on two PVNS patients who responded to imatinib after failure to nilotinib, another CSF1-receptor inhibitor.MethodsSince August 2012, 2 patients with progressive, locally advanced PVNS resistant to nilotinib (Patient 1: man, 34 years; Patient 2: woman, 24 years) have been treated with second-line imatinib 400 mg/day. Both patients are evaluable for response.ResultsBoth patients are still on treatment (7 and 4 months). Patient 1 had a dimensional response by MRI after 2 months from starting imatinib, together with symptomatic improvement. In Patient 2 a metabolic response was detected by [18F]fluorodeoxyglucose–positron emission tomography (PET) at 6 weeks coupled with tumor shrinkage by MRI, and symptomatic improvement.ConclusionsImatinib showed antitumor activity in 2 patients with nilotinib-resistant PVNS. This observation strengthen the idea that targeted agent with similar profile can give a different clinical result, as already described for gastrointestinal stromal tumor (GIST) patients treated with the same agents. Molecular studies are needed to clarify the biologic mechanism(s) underlying the response.

Colony-Stimulating Factor-1 Antibody Lacnotuzumab in a Phase 1 Healthy Volunteer Study and Mechanistic Investigation of Safety Outcomes

“…Likewise, a phase 1b study of PD-0360324 (a human IgG2 monoclonal antibody that inhibits CSF-1 binding to CSF-1R) in patients with cutaneous lupus erythematosus (N = 28) demonstrated target engagement, but no therapeutic effects were observed (Masek-Hammerman et al, 2016). The most promising effects of CSF-1/CSF-1R inhibition have been reported in patients with PVNS, with several studies demonstrating clear therapeutic benefits (i.e., tumor volume regression, objective response, complete response, and symptomatic improvement) (Cassier et al, 2012;Stacchiotti et al, 2013;Cassier et al, 2015;Tap et al, 2015).…”

Imatinib mesylate induces mitochondria-dependent apoptosis and inhibits invasion of human pigmented villonodular synovitis fibroblast-like synovial cells

“…Imatinib mesylate (IM), a tyrosine kinase inhibitor, is the first-line drug of choice for chronic myeloid leukemia (18) and a gastrointestinal stromal cell tumor. A number of recent studies have reported a significant clinical effect of IM on PVNS (1,(19)(20)(21). The effect of IM on PVNS was initially documented by Blay et al (1).…”

The Role of Radiotherapy in the Treatment of Pigmented Villonodular Synovitis

“…55 Infliximab, an inhibitor of tumour necrosis factor alpha (TNF-alpha), is thought to be effective due to the inflammatory state of synovial tissue in PVNS and the high levels of TNF-alpha. 56 There is evidence that imatinib, a tyrosine kinase inhibitor, may be effective for PVNS by inhibiting the CSF1 receptor, improving symptoms and reducing tumour size [57][58][59] ; toxicity is associated with its chronic use. 58 One of our patients with right-knee PVNS had stable disease after RT and imatinib.…”