Review Question - QID 220561

The patient has diffuse, recurrent tenosynovial giant cell tumor, or pigmented villonodular synovitis (PVNS), of the knee. Pexidartinib is a colony-stimulating factor 1 (CSF-1) receptor inhibitor that can be used for recalcitrant or unresectable disease, and is known to cause hair color depigmentation and transient elevation in liver enzymes as side effects (Answer 4).

Pigmented villonodular synovitis (PVNS) is a locally aggressive neoplastic synovial disease characterized by joint effusions, expansion of the synovium, and bony erosions. It usually presents in patients between 30 and 40 years old with recurrent atraumatic knee hemarthroses, with MRI studies showing synovial expansion, arthrocentesis revealing a brown murky fluid, and biopsy revealing hemosiderin-stained multinucleated giant cells. Treatment generally consists of partial or total surgical synovectomy, depending on the presence of localized or diffuse PVNS, with recalcitrant cases often using the immunomodulating agent Pexidartinib as an adjunct.

Lewis et al. described the long-term hepatic safety profile of Pexidartinib in the treatment of patients with Tenosynovial Giant Cell Tumors. The authors note that of 140 patients treated with the drug, 95% experienced a hepatic adverse reaction (AR); however, 91% had reversible, low-grade dose-dependent isolated AST/ALT elevations without significant ALP elevations. They concluded that long-term treatment with pexidartinib has a predictable effect on hepatic aminotransferases and an unpredictable risk of serious cholestatic or mixed liver injury.

Tap et al. published a randomized Phase 3 trial looking at Pexidartinib versus placebo for advanced tenosynovial giant cell tumor. The authors included 120 patients and found serious adverse events occurred in eight (13%) of 61 patients in the pexidartinib group and one (2%) of 59 patients in the placebo group, with hair color changes (67%), fatigue (54%), aspartate aminotransferase increase (39%), nausea (38%), alanine aminotransferase increase (28%), and dysgeusia (25%) being the most frequent pexidartinib-associated adverse events. They concluded that Pexidartinib is the first systemic therapy to show a robust tumor response in TGCT with improved patient symptoms and functional outcomes, with mixed or cholestatic hepatotoxicity being an identified risk of the treatment.

Figure A is a T1-weighted coronal MRI sequence of a knee showing extensive bony erosions of the femur with dark, diffuse, multifocal, and irregular synovial thickening. Figure B is a fluid-sensitive sagittal MRI sequence of the knee again showing irregular, synovial thickening and proliferation giving rise to a villonodular appearance involving the anterior and posterior joint recesses, and supra and infrapatellar pouches, including the popliteal bursae.

Incorrect Answers:
Answer 1: Pexadartinib is a CSF-1 receptor inhibitor, not an activator, and causes hair color depigmentation, not hair loss.
Answer 2: This is the mechanism of action of Doxorubicin, an anthracycline chemotherapeutic agent used in the treatment of osseous malignancies.
Answer 3: This is the mechanism of action of Imatinib, or "Gleevec," used in the treatment of leukemia.
Answer 5: This is the mechanism of action of Anakinra, an agent used in the management of rheumatoid arthritis, not PVNS.