TURALIO® Risk Evaluation and Mitigation Strategy Program (tREMS): 3-year retrospective hepatic safety assessment.

Aim: Hepatic safety data assessment from the TURALIO® (pexidartinib) Risk Evaluation and Mitigation Strategy (tREMS) Program. Methods: Retrospective 3-year assessment (August 2019 to June 2022) of hepatic events from the TURALIO® (pexidartinib) Risk Evaluation and Mitigation Strategy Program. Results: A total of 451 patients, 369 prescribers, 2 wholesalers/distributors and 2 pharmacies were enrolled and certified. Twenty-one (4.7%) patients met the criteria for a hepatic adverse event or laboratory abnormality suggestive of serious and potentially fatal liver injury, all with onset within 2 months of therapy. No new hepatic safety signals were identified. Conclusion: Results are consistent with the phase 3 ENLIVEN trial data. Liver enzyme monitoring, combined with early intervention, including dose modification and discontinuation, conducted in patients treated with pexidartinib mitigate the risk of potential hepatotoxicity.

Safety findings from the 3-year data collected in the TURALIO^® Risk Evaluation and Mitigation Strategy ProgramPexidartinib (TURALIO^®) is an oral drug that is used to treat adults with tenosynovial giant cell tumor (TGCT) that cannot be fixed with surgery. TGCTs are rare, noncancerous tumors that cause pain, stiffness and difficulty moving. Pexidartinib works by blocking a protein that helps these tumors grow. Before pexidartinib, there were no good treatments for TGCT and surgery often could not remove all the tumors, so they would frequently grow back.Pexidartinib was approved in 2019 after a clinical trial showed it worked well in adults with TGCT. However, pexidartinib can sometimes cause serious liver harm for some patients. To handle this risk, a program called the tREMS (TURALIO^® Risk Evaluation and Mitigation Strategy) was established to ensure that pexidartinib is used safely.The tREMS Program teaches doctors, pharmacists and patients about the safe use of pexidartinib and potential liver risks and enrolls patients in a registry to watch their health. Doctors and pharmacies must be certified, and patients need regular liver tests. In the first 3 years, 451 patients and 369 doctors joined the program. Unintended liver issues were found in around 5% of patients, a rate that is about the same as that seen in pexidartinib clinical trials, and no new safety concerns were found. About half of patients with liver issues could reverse them by stopping pexidartinib. No patient had permanent liver damage, needed a transplant or died from liver problems. These results show that the tREMS Program is working well to keep patients with TGCT safe while taking pexidartinib.

Long-term outcomes of pexidartinib in tenosynovial giant cell tumors.

BACKGROUND: The objective of this study was to report on the long-term effects of pexidartinib on tenosynovial giant cell tumor (TGCT). METHODS: This was a pooled analysis encompassing 3 pexidartinib-treated TGCT cohorts: 1) a phase 1 extension study (NCT01004861; 1000 mg/d; n = 39), 2) ENLIVEN patients randomized to pexidartinib (1000 mg/d for 2 weeks and then 800 mg/d; n = 61), and 3) ENLIVEN crossover patients (NCT02371369; 800 mg/d; n = 30). Eligible patients were 18 years old or older and had a histologically confirmed TGCT that was unresectable and symptomatic. Efficacy endpoints included the best overall response (complete or partial response) and the duration of response (DOR) by the Response Evaluation Criteria in Solid Tumors (RECIST) and the tumor volume score (TVS). The safety assessment included the frequency of treatment-emergent adverse events (TEAEs) and hepatic laboratory abnormalities (aminotransferase elevations and mixed/cholestatic hepatotoxicity). The data cutoff was May 31, 2019. RESULTS: One hundred thirty patients with TGCT received pexidartinib (median treatment duration, 19 months; range, 1 to 76+ months); 54 (42%) remained on treatment at the end of the analysis (26 months after initial data cut of March 2017). The RECIST overall response rate (ORR) was 60%; the TVS ORR was 65%. The median times to response were 3.4 (RECIST) and 2.8 months (TVS), with 48 of the responding patients (62%) achieving a RECIST partial response by 6 months and with 72 (92%) doing so by 18 months. The median DOR was reached for TVS (46.8 months). Reported TEAEs were mostly low-grade, with hair color changes being most frequent (75%). Most liver abnormalities (92%) were aminotransferase elevations; 4 patients (3%) experienced mixed/cholestatic hepatotoxicity (all within the first 2 months of treatment), which was reversible in all cases (recovery spanned 1-7 months). CONCLUSIONS: This study demonstrates the prolonged efficacy and tolerability of long-term pexidartinib treatment for TGCT.

Management of Pigmented Villonodular Synovitis (PVNS): an Orthopedic Surgeon's Perspective.

PURPOSE OF REVIEW: Pigmented villonodular synovitis (PVNS) or tenosynovial giant cell tumor (TGCT) encompasses a wide spectrum of disease and is divided into localized and diffuse variants. Surgical resection remains the principal treatment for nearly all localized type disease and most diffuse type. Recent mechanistic understanding of the disease led to drug discovery that has opened new avenues for patients with recalcitrant disease. In this manuscript, we review the current treatment options for TGCT, presenting outcomes from traditional surgical approaches as well as those from nonsurgical approaches. RECENT FINDINGS: Arthroscopic and/or open surgery remains the mainstay of treatment for TGCT for the vast majority of patients. While radiosynoviorthesis and external beam radiation have been used for recalcitrant disease, recent understanding of the colony stimulating factor 1 receptor (CSF1R) pathway and its paracrine and autocrine role in TGCT has led to the development of targeted inhibitors. Their optimal role and efficacy are unclear due to limited number of high-quality studies and contradictory results; however, recent and ongoing studies suggest there may be a role for their use, especially in diffuse and/or refractory disease. Surgery remains the most common treatment for TGCT, however, there may be an increasing role for adjuvant therapies, including the new targeted agents. Weighing the side effects of these treatments against the symptomatic benefit on a patient-by-patient basis in this benign disease remains critical.

A rare case of long-term joint swelling caused by pigmented villonodular synovitis in a 3-year-old girl: a case report.

The clinical symptoms of pigmented villonodular synovitis (PVNS) are usually insidious and non-specific; therefore, delays in diagnosis and treatment are common. Here, we describe a case of a 3-year-old patient presenting with long-term joint swelling to highlight the significance of considering PVNS as a differential diagnosis in children to prevent misdiagnosis and ensure early treatment. After arthroscopic debridement, our patient had a favorable clinical outcome and was free of recurrence.

Diffuse-Type Tenosynovial Giant Cell Tumor Arising in the Temporomandibular Joint Extending to the External Auditory Canal: A Case Report and Literature Review.

A 74-year-old Japanese woman with a 1-year history of right preauricular pain and a 2-month history of bleeding from the right ear was admitted to our department. Tumor was observed in the anterior wall in the right external auditory canal. Bony swelling of the right preauricular area was palpated. Computed tomography revealed an ill-defined, osteogenic tumor around the mandibular condyle with a destructive bony lesion involving the temporal bone. Magnetic resonance imaging revealed a 2.0 × 1.5 × 1.3-cm solid tumor around the mandibular condyle, exhibiting a low-intensity signal on T1-weighted imaging and an isointense central area surrounded by low-signal intensity on T2-weighted imaging. Histological examination of biopsy specimens revealed diffuse-type tenosynovial giant cell tumor (D-TGCT). After the feeding arteries for the tumor were embolized, the patient underwent surgery with combined temporal craniotomy and mandibular condylectomy. The soft and cystic tumor with calcification located in the extradural space was totally resected along with the mandibular condyle. No facial paralysis or recurrence was evident as of 6 months postoperatively. To date, only 23 cases of D-TGCT arising in the temporomandibular joint (TMJ) with ear involvement have been reported since 2011. We report successful resection of a rare case of D-TGCT arising in the TMJ.

Surgical treatment of spinal tenosynovial giant cell tumor: Experience from a single center and literature review.

Introduction: Spinal tenosynovial giant cell tumor (TGCT) is a rare benign primary spinal tumor with aggressive behavior. The treatment strategy and prognosis of spinal TGCT remain unclear. This retrospective study aimed to evaluate the effectiveness of surgical treatment of spinal TGCT. Methods: We enrolled 18 patients with spinal TGCT who underwent surgical treatment in our hospital between January 2002 and January 2021. Additionally, we reviewed 72 cases of spinal TGCT with surgical treatment reported in the previous literature. Therefore, a total of 90 cases of spinal TGCT were evaluated for their clinical characteristics, surgical details, radiotherapy, and prognosis. Results: In terms of the extent of resection, 73 cases (81.1%) underwent gross total resection (GTR), and 17 cases (18.9%) underwent subtotal resection (STR). Regarding the technique of GTR, 12 cases (16.7%) underwent en bloc resection, while 60 cases (83.3%) underwent piecemeal resection. During a median follow-up duration of 36 months (range: 3-528 months), 17.8% (16/90) cases experienced local recurrence/progression. The local recurrence/progression rate in cases that underwent GTR was 8.2% (6/73), which was significantly lower than that in cases with STR (58.8%, 10/17) (p<0.001). The local recurrence/progression rate of en bloc resection was 8.3% (1/12), and that of piecemeal resection was 8.3% (5/60). Twelve cases underwent perioperative adjuvant radiotherapy, and one (8.3%, 1/12) of them showed disease progression during follow-up. Six recurrent/progressive lesions were given radiotherapy and all of them remained stable in the subsequent follow-up. Eight recurrent/progressive lesions were only treated with re-operation without radiotherapy, and half of them (50.0%, 4/8) demonstrated repeated recurrence/progression in the subsequent follow-up. Conclusion: Surgical treatment could be effective for spinal TGCT cases, and GTR is the preferred surgical strategy. Piecemeal resection may be appropriate for spinal TGCT cases with an acceptable local recurrence/progression rate. Perioperative adjuvant radiotherapy may reduce the risk of postoperative local recurrence/progression, and radiotherapy plays an important role in the treatment of recurrent/unresectable spinal TGCT lesions.

Randomized placebo-controlled double-blind phase II study of zaltoprofen for patients with diffuse-type and unresectable localized tenosynovial giant cell tumors: The REALIZE study.

Background: A tenosynovial giant cell tumor (TGCT) is a locally aggressive benign neoplasm arising from intra- or extra-articular tissue, categorized as localized (L-TGCT, solitary lesion) and diffuse (D-TGCT, multiple lesions) TGCT. Surgical excision is the mainstay of the treatment, and a high local recurrence rate of approximately 50% has been reported. We focused on zaltoprofen, a nonsteroidal anti-inflammatory drug that can activate peroxisome proliferator-activated receptor gamma (PPARγ) and inhibit the proliferation of TGCT stromal cells. Therefore, we conducted a randomized trial to evaluate the safety and effectiveness of zaltoprofen in patients with D-TGCTs or unresectable L-TGCTs. Methods: This randomized, placebo-controlled, double-blind, multicenter trial evaluated the safety and efficacy of zaltoprofen. In the treatment group, zaltoprofen (480 mg/day) was administered for 48 weeks; the placebo group received similar dosages without zaltoprofen. The primary outcome was progression-free rate (PFR) 48 weeks after treatment administration. Disease progression was defined as the following conditions requiring surgical intervention: 1) repetitive joint swelling due to hemorrhage, 2) joint range of motion limitation, 3) invasion of the adjacent cartilage or bone, 4) severe joint space narrowing, and 5) increased tumor size (target lesion). Results: Forty-one patients were allocated to the zaltoprofen (n=21) or placebo (n=20) groups. The PFR was not significant between the zaltoprofen group and the placebo group at 48 weeks (84.0% and 90.0%, respectively; p=0.619). The mean Japanese Orthopedic Association knee score significantly improved from baseline to week 48 in the zaltoprofen group (85.38 versus 93.75, p=0.027). There was a significant difference between the values at 48 weeks of placebo and zaltoprofen group (p=0.014). One severe adverse event (grade 3 hypertension) was observed in the zaltoprofen group. Discussion: This is the first study to evaluate the efficacy and safety of zaltoprofen in patients with TGCT. No significant differences in PFR were observed between the groups at 48 weeks. Physical function significantly improved after zaltoprofen treatment. The safety profile of zaltoprofen was acceptable. This less invasive and safer treatment with zaltoprofen, compared to surgical removal, could be justified as a novel approach to treating TGCT. Further analysis of long-term administration of zaltoprofen should be considered in future studies. Clinical Trial Registration: University Hospital Medical Information Network Clinical Trials Registry, identifier (UMIN000025901).

Effect of Mild and Moderate Hepatic Impairment (Defined by Child-Pugh Classification and National Cancer Institute Organ Dysfunction Working Group Criteria) on Pexidartinib Pharmacokinetics.

Pexidartinib is a novel oral small-molecule tyrosine kinase inhibitor targeting the colony-stimulating factor 1 receptor. Pexidartinib undergoes extensive hepatic metabolism via multiple cytochrome P450 and uridine 5'-diphospho-glucuronosyl transferase enzymes, with ZAAD-1006a as the only major metabolite in human plasma. As pexidartinib is extensively metabolized, hepatic impairment (HI) could lead to increased exposure to pexidartinib. The objective of the two phase 1, open-label studies was to determine the pharmacokinetics of pexidartinib after a single 200-mg dose in subjects with mild and moderate HI, based on Child-Pugh classification (PL3397-A-U123: 8 mild HI and 8 moderate HI vs 16 matched healthy controls) and National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria (PL3397-A-U129: 8 moderate HI versus 8 matched healthy controls [NCT04223635]). Based on Child-Pugh classification, exposure to pexidartinib (maximum observed concentration [Cmax ], area under the plasma concentration-time curve up to the last measurable concentration [AUClast ], and extrapolated to infinity [AUCinf ]) was similar in subjects with mild and moderate HI and in respective matched healthy controls, whereas ZAAD-1006a exposure (AUC) was approximately 27% to 28% and 41% to 48% higher in mild and moderate HI, respectively. According to NCI-ODWG criteria, total pexidartinib exposure was 42% to 46% higher in subjects with moderate HI, compared with healthy controls, and total ZAAD-1006a exposure was 70% to 79% higher for subjects with moderate HI, compared with matched healthy controls with normal hepatic function. These findings were used to develop appropriate dose recommendations in patients with hepatic impairment.

Expanding the molecular spectrum of tenosynovial giant cell tumors.

Background: While great advances in clinical and pathological description of tenosynovial giant cell tumors (TGCT) have been made, TGCT molecular heterogeneity represents an ongoing challenge. The canonical oncogenic fusion CSF1::COL6A3 is not systematically observed, suggesting that other oncogenic mechanisms are involved in tumorigenesis. This study aims to explore by RNA sequencing a retrospective series of tumors diagnosed as TGCT, in order to provide a better description of their molecular landscape and to correlate molecular features with clinical data. Methods: We analyzed clinicopathological data and performed whole-exome RNA sequencing on 41 TGCT samples. Results: RNAseq analysis showed significant higher CSF1 and CSF1-R expression than a control panel of 2642 solid tumors. RNA sequencing revealed fusion transcripts in 14 patients including 6 not involving CSF1 and some previously unreported fusions. Unsupervised clustering on the expression profiles issued from this series suggested two distinct subgroups: one composed of various molecular subtypes including CSF1 and FN1 rearranged samples and one composed of four tumors harboring an HMGA2::NCOR2 fusion, suggesting distinct tumor entities. Overall, 15 patients received at least one systemic anti-CSF1R treatment and clinical improvement was observed in 11 patients, including patients from both clusters. Discussion: This study reported molecular heterogeneity in TGCT, contrasting with the clinical and pathological homogeneity and the ubiquitous high CSF1 and CSF1R expression levels. Whether molecular diversity may impact the efficacy of systemic treatments needs to be further investigated.

Patient-reported Symptoms of Tenosynovial Giant Cell Tumors.

PURPOSE: Tenosynovial giant cell tumor (TGCT), a rare locally aggressive neoplasm of the synovium of joints and tendon sheaths, is associated with joint destruction, inflammation, pain, and swelling, in part due to colony-stimulating factor 1 receptor-bearing macrophages recruited to the tumor by genetic elevation of colony-stimulating factor 1 activity. The most common treatment is surgery, although promising pharmacologic treatments are in development. Patient-reported outcome (PRO) instruments are critical end points in demonstrating the clinical relevance of standard oncologic outcome measures and the overall impact of novel pharmacologic therapies in nonmalignant neoplastic conditions such as TGCT. The content validity of PROs relevant to patients with TGCT has not been formally investigated, and instruments to evaluate such outcomes do not exist for this condition. METHODS: PRO instruments of potential relevance were evaluated by using a literature review and by clinical and PRO experts. Patients with TGCT were recruited through clinical sites and the Internet for participation in qualitative research interviews to identify predominant symptoms and to test the relevance and content validity of several PRO measures. Select PRO measures were included in a Phase I clinical trial, and preliminary results of the PRO end points are reported descriptively. FINDINGS: Of the 22 subjects who participated in qualitative interviews, 73% were female, and their mean age was 42.5 years (range, 27-56 years). The TGCTs (19 diffuse and 3 localized) were located in the knee (n = 15), hip (n = 3), ankle (n = 2), elbow (n = 1), and forearm (n = 1). The most common symptoms cited were pain (82%), swelling (86%), stiffness (73%), reduced range of motion (64%), and joint instability (64%), which were consistent with clinical expert input and with the content of instruments chosen by PRO experts. The worst pain numeric rating scale, Patient Reported Outcomes Measurement Information System physical functioning items, and the Western Ontario and McMaster Universities Osteoarthritis Index, as well as a worst stiffness numeric rating scale developed for TGCT, were confirmed as meaningful measures of TGCT patient symptoms and were well understood in qualitative interviews. Results from the Phase I trial showed trends of improvement in both pain and stiffness over time. IMPLICATIONS: This study is the first to gather information directly from patients with TGCT regarding their symptom experiences. Pain, stiffness, and physical functioning are important treatment outcomes in patients with TGCT. We have identified content-valid PRO measures of these concepts, which are included in an ongoing Phase III TGCT clinical trial with pexidartinib (PLX3397) (NCT02371369).