Volume 128, Issue 3 pp. 478-488

REVIEW ARTICLE

Open Access

Multimodal management of tenosynovial giant cell tumors (TGCT) in the landscape of new druggable targets

Lizz van der Heijden MD, PhD,

Corresponding Author

Lizz van der Heijden MD, PhD

[email protected]

orcid.org/0000-0003-4440-793X

Department of Orthopedic Surgery, Leiden University Medical Center, Leiden, The Netherlands

Department of Pediatric Orthopedic Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands

Correspondence Lizz Heijden, MD PhD, and Michiel A. J. Sande, MD, PhD, Leiden University Medical Center, Postzone J11-R70, PO Box 9600, 2300 RC Leiden, The Netherlands.

Email: [email protected] and [email protected]

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Geert Spierenburg,

Geert Spierenburg

orcid.org/0000-0002-0236-7338

Department of Orthopedic Surgery, Leiden University Medical Center, Leiden, The Netherlands

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Joseph K. Kendal MD, MSc,

Joseph K. Kendal MD, MSc

Department of Orthopedic Surgery, University of California-Los Angeles, Los Angeles, California, USA

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Nicholas M. Bernthal MD,

Nicholas M. Bernthal MD

orcid.org/0000-0003-3338-5878

Department of Orthopedic Surgery, University of California-Los Angeles, Los Angeles, California, USA

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Michiel A. J. van de Sande MD, PhD,

Corresponding Author

Michiel A. J. van de Sande MD, PhD

[email protected]

orcid.org/0000-0002-9156-7656

Department of Orthopedic Surgery, Leiden University Medical Center, Leiden, The Netherlands

Department of Pediatric Orthopedic Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands

Correspondence Lizz Heijden, MD PhD, and Michiel A. J. Sande, MD, PhD, Leiden University Medical Center, Postzone J11-R70, PO Box 9600, 2300 RC Leiden, The Netherlands.

Email: [email protected] and [email protected]

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Lizz van der Heijden MD, PhD,

Corresponding Author

Lizz van der Heijden MD, PhD

[email protected]

orcid.org/0000-0003-4440-793X

Department of Orthopedic Surgery, Leiden University Medical Center, Leiden, The Netherlands

Department of Pediatric Orthopedic Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands

Correspondence Lizz Heijden, MD PhD, and Michiel A. J. Sande, MD, PhD, Leiden University Medical Center, Postzone J11-R70, PO Box 9600, 2300 RC Leiden, The Netherlands.

Email: [email protected] and [email protected]

Search for more papers by this author

Geert Spierenburg,

Geert Spierenburg

orcid.org/0000-0002-0236-7338

Department of Orthopedic Surgery, Leiden University Medical Center, Leiden, The Netherlands

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Joseph K. Kendal MD, MSc,

Joseph K. Kendal MD, MSc

Department of Orthopedic Surgery, University of California-Los Angeles, Los Angeles, California, USA

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Nicholas M. Bernthal MD,

Nicholas M. Bernthal MD

orcid.org/0000-0003-3338-5878

Department of Orthopedic Surgery, University of California-Los Angeles, Los Angeles, California, USA

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Michiel A. J. van de Sande MD, PhD,

Corresponding Author

Michiel A. J. van de Sande MD, PhD

[email protected]

orcid.org/0000-0002-9156-7656

Department of Orthopedic Surgery, Leiden University Medical Center, Leiden, The Netherlands

Department of Pediatric Orthopedic Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands

Correspondence Lizz Heijden, MD PhD, and Michiel A. J. Sande, MD, PhD, Leiden University Medical Center, Postzone J11-R70, PO Box 9600, 2300 RC Leiden, The Netherlands.

Email: [email protected] and [email protected]

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First published: 04 August 2023

https://doi.org/10.1002/jso.27410

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Abstract

Tenosynovial giant cell tumor (TGCT) is a rare, benign, locally aggressive synovial based neoplastic process that can result in functional debilitation and end-stage arthrtitis. Although surgical resection is the primary treatment modality, novel systemic therapies are emerging as part of the multimodal armamentarium for patients with unresectable or complex disease burden. This review discusses the pathogenesis of TGCT, potential druggable targets and therapeutic approaches. It also evaluates the safety and efficacy of different systemic therapies.

KEYPOINTS

TGCT is a monoarticular neoplasm driven by an overexpression of CSF1, leading to an increase in neoplastic TGCT cells and an accumulation of CSF1R presenting cells
TGCT is mainly treated by surgery, but achieving cure can be challenging, requiring additional therapies for relapsing or inoperable tumors
Several molecular pathways have been suggested as drug targets, but the CSF1-CSF1R axis is most targeted to date
CSF1R inhibitors can have antitumor activity, but adverse events often occur.
The only CSF1R inhibitor that is FDA approved and thus available in the US for TGCT treatment to date is pexidartinib, but new therapies are being investigated
Future drug development should focus on targeting the neoplastic TGCT cell.

1 INTRODUCTION

Tenosynovial giant cell tumor (TGCT) is a typically mono-articular synovial based tumor that occurs in intra- and juxta-articular locations.^{1, 2} There are two main subtypes of TGCT: Localized-type TGCT (L-TGCT) and Diffuse-type TGCT (D-TGCT), which were previously referred to as Giant Cell Tumor of Tendon Sheath and Pigmented Villonodular Synovitis, respectively.³ Although different names have been used in the past to refer to these subtypes, they are now unified as TGCT due to common pathogenesis and morphology.^{4, 5}

TGCT is a rare disease, classified as an orphan disease. The reported incidence for L-TGCT and D-TGCT are 30–39 and 5–8 per million person-years, respectively.^{6, 7} Females are more affected than males, with a ratio of 1:1.5. Both subtypes primarily affect a relatively young population (most commonly in those aged 30–50), although they can occur at any age, even in children.⁸ L-TGCT is commonly located in the digits of the hand and feet, while D-TGCT tends to affect larger joints, particularly the knee.⁹ L-TGCT and D-TGCT are separate clinical entities that behave differently. Common symptoms include pain, swelling, stiffness, limited range of motion and instability.¹⁰ These symptoms are notably nonspecific and can lead to delayed diagnosis.¹¹ Patients may experience a decrease in quality of life (QoL) including interference with daily activities, need for domestic help, and decreased work productivity.^12-14 The potential for TGCT to have a profound impact on patient QoL emphasizes the need for optimized treatment strategies.

Magnetic resonance imaging (MRI) is the most reliable imaging technique utilized for TGCT, providing a comprehensive evaluation of the disease extent, presence of joint effusion, and secondary degenerative changes. MRI sequences should include gradient-echo sequences for detecting hemosiderin typically related to tumor bleeding in TGCT. Intravenous gadolinium contrast should be administered to facilitate tumor detection on the images and for follow-up after surgery.¹⁵ L-TGCT is typically characterized by a distinct, focal lesion, while D-TGCT is defined by multilobulated lesions with synovial thickening, villous projections and hemosiderin deposits, often extending into the extra-articular tissues.¹⁶ D-TGCT is frequently associated with bone erosions, cartilage loss, and osteophyte formation, leading to end stage arthritis in more advanced stages.¹⁷ Histological confirmation of the diagnosis is mainly obtained through excisional biopsy, arthroscopic biopsy, or core needle biopsy.¹¹

2 ETIOLOGY AND PATHOPHYSIOLOGY

The etiology of TGCT has been a historic topic of controversy. In 1941, Jaffe et al.¹⁸ suggested that TGCT had an inflammatory or reactive origin. Subsequent cytogenetic studies revealed numerical and structural chromosomal alterations, suggesting a neoplastic process.^{19, 20} In 2006, the discovery of recurrent translocations in several TGCT patients by West et al.²¹ led to a paradigm shift in the understanding of its pathogenesis. These translocations affect the region 1p11-13, where the colony-stimulator factor 1 (CSF1) gene is located. CSF1, also known as macrophage CSF, regulates macrophage survival, proliferation, differentiation, and function by binding to its receptor (CSF1R).^{22, 23} In TGCT, most cells express CSF1R, while CSF1 (the ligand of CSF1R) is only present in a small percentage of cells. Due to the translocation, neoplastic TGCT cells produce high levels of CSF1, resulting in an autocrine loop that leads to an increase in more neoplastic cells and a paracrine loop that causes an accumulation of non-neoplastic CSF1R-expressing cells of the macrophage lineage. This results in what is known as the landscape effect.²¹

The most frequent translocation partner of CSF1 is collagen type VI alpha-3 (COL6A3), located on chromosome 2p37, resulting in t(1;2)(p13;p37).^{24, 25} However, recent studies have shown that this fusion is only present in a subset of patients. Other fusion partners have been identified which lead to additional mechanisms underlying CSF1 upregulation.^25-28 For example, the deletion of CSF1 exon 9, a negative regulator of CSF1 expression, and truncation of the 3′-untranslated region, may account for CSF1 overexpression in more cases instead of overexpression of full-length CSF1 via promoter swapping.^{29, 30} Moreover, CBL (Cas-Br-Murine ecotropic retroviral transforming sequence) mutations are present in more than a third of TGCT cases, although they are not mutually exclusive to CSF1 fusions.^{29, 30} CBL associates with receptor tyrosine kinases and could be the driver event in some cases where CSF1 rearrangements are not present.³⁰ However, there is no consensus regarding the effect of different fusions or truncations, levels of CSF1 overexpression, and the role of CBL mutations on clinical behavior.^31-33 The gene expression profile of TGCT is consistent with apoptosis resistance, inflammation, and matrix degradation, contributing to ongoing proliferation and joint destruction. Highly expressed genes include CD53, ALOX5AP, SPP1, MMPs 1 and 9, whereas tumor suppressor genes such as TP53 are downregulated.³⁴

TGCTs are fibrohistiocytic tumors, and the tumor microenvironment is composed of a heterogeneous cell population.² The tumors consist of varying proportions of mononuclear cells, multinucleated (osteoclast-like) giant cells, foamy macrophages (xanthoma cells), inflammatory cells, siderophages (hemosiderin-laden macrophages), and stromal hyalinization.^35-37 Within the mononuclear cell compartment, two principal cell types are described in varying proportions: small histiocyte-like cells with round to oval nuclei, and larger epithelioid cells with abundant cytoplasm and larger nuclei.² The origin of these cells is still unknown. Although osteoclast-like giant cells are the most distinctive histological feature of TGCT, they may be sparse or absent.^38-40 Within the joint fluid of affected joints, various inflammatory factors are present, such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), indicating a highly inflammatory microenvironment.⁴¹ In addition to conventional subtypes, malignant TGCT is reported incidentally, which has a high potential for metastasis, mainly in pulmonary and regional lymph nodes.⁴² Malignant TGCT cells are suggested to be derived from clusterin-positive large mononuclear cells, but the etiology is not well understood.⁴³

3 GENERAL APPROACH

Complete excision of TGCT remains a standard treatment, when feasible. L-TGCT can usually be easily removed through arthroscopy or open surgery, with a recurrence rate of approximately 10%. However, excision of D-TGCT can be challenging due to its location and irregular, poorly demarcated boundaries. D-TGCT, therefore, has a high recurrence rate and often requires re-excision, with a relapse-free survival rate of approximately 40% at 10 years.^{6, 44} The optimal surgical approach for D-TGCT is still unclear, with some specialists preferring open surgery for better access for extensive synovectomy, while others advocate for arthroscopic resection due to decreased surigical morbidity. This is discussed further below.

Radiotherapy (RT), including radiosynoviorthesis (RSO) and external beam RT, has been used but with low-level evidence and mixed results. RSO (application of intra-articular radioisotopes) has been associated with serious complications such as skin necrosis. A meta-analysis suggested that surgery combined with RT may reduce recurrence rates, but more long-term studies are needed since RT can cause serious adverse effects such as radiation-induced malignancies, which is not acceptable in a benign or intermediate disease.⁴⁵ In 2008, Blay et al.⁴⁶ reported the successful use of imatinib in a patient with TGCT, leading to complete remission. This discovery paved the way for targeted therapies in TGCT, particularly for patients who are not suitable for surgery. The interest in systemic therapies has grown rapidly, resulting in the development and clinical testing of new and available drugs, which may enhance the current therapeutic options for TGCT patients.⁴³

4 ACTIVE AND POTENTIAL THERAPEUTIC TARGETS

Several molecular pathways have been explored as potential therapeutic strategies, and are summarized here and in Table 1.

Table 1. Potential TGCT drug targets.

Molecular target	Biological target	Related drugs applied in TGCT
B-Arrestin2	Cell survival, apoptosis, migration, and proliferation of Fibroblast-like synoviocytes	None
Cadherin-11	Cytokine and metalloproteinase production and migration and invasion of Fibroblast-like synoviocytes	None
cIAP2	Cell apoptosis	None
CSF1-CSF1R axis	Tumor cell proliferation and monocyte/macrophage survival, proliferation and differentiation	Imatinib, nilotinib, pexidartinib, vimseltinib, lacnotuzumab, emactuzumab, cabiralizumab
JAK2	Cytokine activity	None
PD-L1	Regulation of immune response on tumor cells	None
PPARγ	Tumor cell proliferation, invasion, differentiation and apoptosis	Zaltoprofen
RANKL	Differentiation and activation of osteoclasts	None
TNF-α	Inflammatory conditions and monocyte, macrophage, osteoclast proliferation and differentiation	Infliximab, etanercept
VEGF	Angiogenesis	Bevacizumab

Abbreviations: PD-L1, programmed cell death ligand 1; PPARγ, proliferator-activated receptor gamma; TGCT, tenosynovial giant cell tumor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.

One of the most studied therapeutic targets in TGCT is the CSF1 and its receptor (CSF1R) axis, as it is often overexpressed in neoplastic cells of TGCT patients.^{20, 26, 28, 47} The antitumor effects of targeting this pathway have been suggested by blocking CSF1R using different approaches, including CSF1R antibodies and tyrosine kinase inhibitors (TKIs).²⁷

Janus-kinase-2 (JAK2) is another therapeutic target, as CBL mutations in TGCT have been found to prolong the phosphorylation of JAK2, resulting in enhanced cell proliferation, increased JAK2 expression, and worse disease outcomes.²⁸ Inhibiting JAK2 has been suggested as a possible new therapeutic strategy, although as noted above, the CBL mutation is not mutually exclusive to CSF1 fusions.^{28, 29}

The antiapoptotic protein, cellular inhibitor of apoptosis 2 (cIAP2), is another target, as its deregulation is associated with TGCT development and progression.⁴⁸ High levels of cIAP2 in TGCT patients have been linked with poor prognosis, suggesting that the cIAP2 gene may have a promising role in prognostication and targeted therapy in DTGCT.⁴⁹

Beta-arrestin2 (ARRB2) is highly expressed in TGCT and is associated with cell survival, apoptosis, migration, and proliferation in several tumor types.⁵⁰ Knockdown of ARRB2 has been shown to inhibit cell proliferation and increase apoptosis of fibroblast-like synovitis (FLS), suggesting that ARRB2 could be a potential molecular target in TGCT treatment.⁵⁰

Proliferator-activated receptor gamma (PPARγ), a member of the nuclear receptor superfamily of transcription factors, is expressed at high levels in adipose tissue and monocyte-derived macrophages and stimulates adipocyte and macrophage differentiation.⁵¹ Ligand activation of PPARγ in monocytes/macrophages inhibits inflammatory mediator and cytokine production. It is also expressed in a variety of cancer cells, and specific ligands can induce growth inhibition and apoptosis.⁵²

Elevated levels of macrophages and proinflammatory cytokines, such as TNF-α, have been observed in the gene expression pattern of TGCT.³³ TNF-α blockade predominantly antagonizes the inflammatory cascade, and the synergistic paracrine loop between TNF-α and CSF1.⁵³

Vascular endothelial growth factor (VEGF) promotes endothelial cell proliferation and new blood vessel formation, which is crucial for tumor development. CSF1 can activate multiple cell signaling pathways leading to VEGF production, and VEGF inhibition is associated with reducing tumor growth by blocking angiogenesis.⁵⁴

Receptor-activator of nuclear factor kappa-B ligand (RANKL) is a cytokine involved in differentiation and activation of osteoclasts.⁵⁵ The monoclonal antibody denosumab has shown successful inhibition of RANKL expression in various tumors including giant cell tumor of bone (GCTB). RANKL expression has been observed in soft tissue tumors, including TGCTs, and can be induced by proinflammatory cytokines like TNF-α and ILs. Although RANKL levels in TGCT were lower compared to GCTB, RANKL antibody treatment could still inhibit giant cells.⁵⁵ However, the efficacy of RANKL blockage may differ for multinucleated cells derived from synovial tumors and bone tumors. Moreover, targeting giant cells alone may not address underlying pathogenesis mechanisms, such as the CSF1-CSF1R axis.

Programmed cell death ligand 1 (PD-L1) plays a role in central and peripheral immune tolerance, and in tumor immune evasion. PD-L1 expression was highly positive in 53% of CSF1-activated TGCT cases, expressed on mononuclear cells, multinucleated giant cells, and foam cells. Larger tumor sizes were also positively correlated with PD-L1 expression. Combining anti-PD-L1 immunotherapy with other molecular targeted therapy may improve outcomes of antitumor therapy in patients with CSF1/CSF1R signaling. However, the variable expression of PD-L1 limits its value as a prognostic marker. PD-L1 is expressed on monocytic myeloid derived suppressor cells (M-MDSCs). Perhaps it is M-MDSCs that are recuited. Notably these cells can also be targeted with CSF-1R inhibition, same with M2 macrophages.^56-58

Last, cadherin-11 is involved in synovium lining layer formation and FLS adhesion, as well as stimulating FLS to produce inflammatory cytokines and MMP. IL-1β and TNF-α in the joint fluid can increase cadherin-11 expression through the PI3K-Akt pathway, promoting proliferation, migration, and invasion of FLS through a positive feedback loop. This molecular mechanism can cause joint destruction, relapses, or even metastasis and may serve as a prognostic marker for D-TGCT. Cadherin-11 inhibition could be a potential treatment strategy to weaken FLS migration and invasion.

5 SYSTEMIC THERAPIES

Muyltiple systemic therapies have been evaluated (Table 2) including repurposed established TKIs, specific CSF1R inhibitors including Pexidartinib, monoclonal antibodies against CSF1 Lacnotuzumab and Cabiralizumab, and a potently selective oral CSF1R inhibitor called Vimseltinib. Other therapeutic strategies discussed include TNF-α blockade and VEGF blockade (bevacizumab).

Table 2. Systemic treatment studies.

Authors	Year	Drug	Class	Therapeutic target	Administration	Type of study	Patients
Blay et al.⁴⁶	2008	Imatinib	TKI	CSF1R	Oral	Case-report	1
Cassier et al.⁵⁹	2012	Imatinib	TKI	CSF1R	Oral	Retrospective cohort	29a
Stacchiotti et al.⁶⁰	2013	Imatinib	TKI	CSF1R	Oral	Case-report	2
Verspoor et al.¹³	2019	Imatinib	TKI	CSF1R	Oral	Retrospective cohort	62a
Mastboom et al.⁶¹	2020	Imatinib	TKI	CSF1R	Oral	Retrospective cohort	25
Cassier et al.⁶²	2015	Emactuzumab	CSF1R AB	CSF1R	Intravenous	Phase I	29
Cassier et al.⁶³	2020	Emactuzumab	CSF1R AB	CSF1R	Intravenous	Phase I	63a
Gelderblom et al.⁶⁴	2018	Nilotinib	TKI	CSF1R	Oral	Phase II	56
Tap et al.⁶⁵	2015	Pexidartinib	TKI	CSF1R	Oral	Phase I/II	41 + 23
Tap et al.⁶⁶	2019	Pexidartinib	TKI	CSF1R	Oral	Phase III	120 (59 placebo)
Gelderblom et al.⁶⁷	2020	Pexidartinib	TKI	CSF1R	Oral	Retrospective cohort	130a
Cheng et al.⁶⁸^,b	2015	Lacnotuzumab	CSF1 AB	CSF1	Intravenous	Phase II, abstract	5
Sankhala et al.⁶⁹^,b	2017	Cabiralizumab	CSF1R AB	CSF1R	Intravenous	Phase I/II, abstract	22
Smith et al.⁷⁰^,b	2021	Vimseltinib	TKI	CSF1R	Oral	Phase I/II, abstract	3
Gelderblom et al.⁷¹^,b	2021	Vimseltinib	TKI	CSF1R	Oral	Phase I/II, abstract	68a
Kroot et al.⁷²	2005	Infliximab	Anti-TNF-α	TNF-α	Intra-articular	Case-report	1
Fiocco et al.⁷³	2006	Etanercept	Anti-TNF-α	TNF-α	Intra-articular	Case-report	2
Fiocco et al.⁵³	2010	Etanercept	Anti-TNF-α	TNF-α	Intra-articular	Case-series	4
Nissen et al.⁷⁴	2014	Bevacizumab	VEGF AB	VEGF	Intra-articular	Case-report	1
Takeuchi et al.⁷⁵^,b	2019	Zaltoprofen	NSAID	PPARγ	Oral	Phase II, abstract	10

Abbreviations: AB, antibody; CSF1, colony-stimulating factor 1; CSF1R, colony-stimulating factor 1 receptor; NSAID, nonsteroidal anti-inflammatory drug; PPARγ, proliferator-activated receptor gamma; TKI, tyrosine kinase inhibitor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.
a Included patients that were involved in a prior study.
^b Studies representing preliminary results.

5.1 Imatinib

Imatinib inhibits multiple tyrosine kinases, including CSF1R. Before being applied in TGCT, imatinib was already indicated for chronic myeloid leukemia and gastrointestinal stromal tumors. In a retrospective study of 29 patients with advanced or metastatic D-TGCT, imatinib led to an objective response rate of 20% and symptomatic/functional improvement in 74% of patients.⁴⁶ However, toxicity forced six patients to discontinue treatment, and four patients discontinued without any apparent medical reason. The same study group reported that, in a cohort of 62 patients, 31% had a radiological response and 78% had clinical improvement, but a drop-off rate of 59% within a year suggested an unfavorable efficacy/toxicity balance, with grade 3–4 toxicities occurring in 11%.⁵⁹ All four patients with metastatic TGCT progressed rapidly on imatinib. Another study reported a partial response in 32% of patients after imatinib use, consistent with previous reports, and a significant decrease in the maximum standardized uptake value on PET-CT after imatinib.⁶¹ However, 80% of patients discontinued treatment due to poor response or intended surgery. Finally, Stachiotti et al reported antitumor activity following imatinib in two patients resistant to nilotinib and suggested that targeting agents with similar profiles could induce different clinical results, but further research is needed.^{46, 47, 59-61}

5.2 Emactuzumab

Emactuzumab is a recombinant, humanized monoclonal immunoglobulin 1 antibody directed against CSF1R.⁷⁶ In a phase I trial, Cassier et al determined the safety, tolerability, and clinical activity of emactuzumab in 28 patients.⁶² After a median follow-up of 12 months, 86% of the patients showed an objective response, of which 2 achieved complete response; one patient had a relapse. The most frequent adverse events (AEs) were facial edema, asthenia, pruritus, and rash. Five serious AEs were reported, of which three were grade 3, including two cases of lupus erythematosus. Overall, emactuzumab was well tolerated, but 20% of patients dropped out due to AEs. Interestingly, eight patients who were resistant to either imatinib or nilotinib or both achieved objective tumor response. The authors hypothesized that the difference in activity between imatinib, nilotinib and emactuzumab could be attributed to the fact that imatinib and nilotinib are weaker inhibitors of CSF1R. The same research group evaluated the long-term clinical benefit and safety in 63 patients.⁶³ The best overall response rate (ORR) of 71% was observed, and responses were durable at 1 and 2 years at 70% and 64%, respectively. Stable disease was achieved in 98%, which changed to 93% at 1- and 2-year follow-up. In addition, a significant improvement in the EQ-5D-3L QoL and WOMAC was observed. Reported AEs were comparable with the previous study. Nine patients (14%) withdrew from the study due to AEs. Finally, a reduction in tumor-associated CD68/CD163-positive and CSF1R-positive cells was shown. Durable responses were seen despite a relatively short treatment duration, which can be interpreted as an advantage. A third study estimated the optimal biological dose (OBD) based on the previous phase I study. They recommended an OBD of 1000 mg intravenously every 2 weeks. Dosing flexibility is possible by dosing emactuzumab once every 3 weeks.⁷⁷

5.3 Nilotinib

Nilotinib, an oral TKI that targets Abl, KIT, PDGFR, and CSF1R, was investigated in a phase II trial for nonresectable D-TGCT.⁶⁴ Of 51 evaluable patients, 96% were progression-free at 12 weeks, and 90% were progression-free at 24 weeks. After 1 year of treatment, three patients achieved a partial response, and 90% had stable disease. Common AEs included headache, nausea, increased alanine aminotransferase (ALT) concentrations, fatigue, and asthenia. Ten patients had disease progression during the study period, and six discontinued nilotinib due to progression or toxicity. A post hoc analysis showed a progression-free survival rate of 57% at 48 months, but the authors noted that selection biases may have influenced the results.

5.4 Pexidartinib

The drug pexidartinib is a novel treatment targeting TGCT.⁷⁸ Pexidartinib selectively inhibits CSF1R dependent cells and has limited cross-reactivity with other kinases. In addition, it also inhibits KIT and fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD).⁶⁵ A phase I study by Tap et al.⁶⁶ enrolled 41 patients in various dose-escalation cohorts. The maximum tolerated dose was set at 1000 mg per day taken orally. In the phase II extension study, 23 patients with diffuse TGCT were enrolled, and 19 (83%) had disease control, of which 12 had a partial response. The same study group performed a phase III, randomized, double-blind, open-label trial with Pexidartinib (ENLIVEN).⁶⁶ One hundred twenty patients were randomly assigned to pexidartinib or placebo treatment. At 25 weeks, the ORR in the pexidartinib group was 39% according to Response Evaluation Criteria in Solid Tumors (RECIST) and 56% by tumor volume score (TVS) compared to 0% in the placebo group for both measurements. Secondary endpoints including patient-reported outcomes were also improved at week 25, including improvements in relative range of motion, stiffness, and in reported physical function (assessed by PROMIS). However, 98% of the patients in the pexidartinib group experienced AEs, and grade 3–4 AEs occurred in 44%, mainly consisting of increased levels of liver enzymes and hypertension. Subsequently, 30 patients from the placebo group were assigned to a crossover group with 800 mg pexidartinib daily.

Finally, the same study group described the long-term outcomes of pexidartinib by pooling analysis encompassing the three pexidartinib-treated TGCT cohorts. One hundred thirty patients received pexidartinib for a median duration of 19 months at data cut-off. The RECIST ORR was 60%, the TVS ORR was 65%.⁶⁷ Because of the risk of hepatotoxicity, frequent monitoring of liver function is needed to help balance the benefit-to-risk. Monitoring is especially required in the first 2 months. In the EU, the European Medicines Agency (EMA) refused market authorization due to uncertainties on the risk-benefit ratio. In the United States, pexidartinib was Food and Drug Administration (FDA) approved and available through the risk evaluation management system (REMS) program.^78-80

5.5 Lacnotuzumab

Lacnotuzumab (MCS110) is a monoclonal antibody against CSF1. Preliminary results of lacnotuzumab in TGCT patients in a phase Ib/II study have been presented.⁶⁸ Five patients were treated with a single dose of 10 mg/kg intravenously. Lacnotuzumab was well tolerated with no drug-related AEs. Four weeks after dose administration, the tumor volume by MRI was reduced by 40%. Improvement in clinical symptoms and pharmacodynamics effects were also observed. Results of study extension, with multiple-dose administration and a goal of tumor ablation, are awaited.

5.6 Cabiralizumab

In 2017, preliminary results of a phase I/II study of cabiralizumab were presented.⁶⁹ Cabiralizumab is a monoclonal antibody that inhibits the interaction of CSF1 and IL-34 ligands with their shared receptor CSF1R. Cabiralizumab was intravenously administered in 22 patients with inoperable D-TGCT every 2 weeks for 6 months in different dosages. Functional status improvements by Ogilvie-Harris scores (pain, synovitis, range of motion and functional capacity on a scale of 0–12) were noted in objective responders (from 2 to 7). Most reported AEs were creatine kinase elevations, rash and other skin disorders, fatigue and edema; 10 grade 3 AEs were reported. Updated results are anticipated.

5.7 Vimseltinib

Vimseltinib is a selective, orally administered inhibitor of CSF1R. In contrast to small-molecule inhibitors of CSF1R, this drug is designed to have potent CSF-1R selectivity and not affect closely related kinases.⁷⁰ This selectivity potentially leads to a more optimal CSF1R suppression. It is currently being evaluated in a phase I/II clinical study for the treatment of TGCT. The first three TGCT patients, included in the phase I trial, showed rapid, preliminary antitumor activity by three cycles with deepening response over time. Vimseltinib was generally well tolerated in these patients, although the authors concluded it was too premature to draw safety conclusions on this limited data set.⁷⁰ Results of the first 68 patients included in this phase I/II clinical study were recently presented at the European Society for Medical Oncology congress 2021.⁷¹ The majority of common treatment-emergent AEs were grade 2 or lower; most common grade 3 or 4 AEs were increased serum levels of creatine phosphokinase. Two serious AEs were reported, consisting of metabolic encephalopathy and vaginal hemorrhage and three (4%) patients discontinued treatment due to treatment-emergent AEs. The median duration of treatment in the phase 1 cohort was 10.1 months and a high ORR of 50% according to RECIST was observed. In the phase II cohort, an ORR of 42% was seen in evaluable patients. The study is still ongoing with continuing follow-up evaluation and a randomized, placebo-controlled, phase III trial evaluating the effect vimseltinib is ongoing (MOTION study, NCT05059262).

5.8 TNF-α blockade

Three studies have reported the effect of TNF-α blockade treatment, with only seven patients in total receiving this treatment.^{53, 72, 73} Off-label intra-articular infliximab injection was administered in one patient and etanercept in six. Improvement in knee function, regression in synovial stromal fibrosis and vasculogenesis, reduction of cellularity and synovial fluid and decreased thickness were observed. No decrease in CSF1 protein of messenger RNA expression nor synovial tumor shrinkage was seen after infliximab administration. TNF-α blockade treatment affects the reactive component of TGCT but less likely the neoplastic cells. Although Fiocco et al considered anti-TNF-α antibody injections as a possible neoadjuvant treatment before synovectomy, they concluded that TNF-α blockade alone does not seem to lead to stable remission of D-TGCT and is ineffective in blocking CSF1 secretion.⁵³

5.9 Bevacizumab

Among other activators such as hypoxic stress, CSF1 is also reported to induce angiogenesis via VEGF expression in monocytes, essential for tumorigenesis.^{54, 81} Bevacizumab is a humanized monoclonal VEGF antibody and thus inhibits angiogenesis. Nissen et al investigated the effect of intra-articular injections with bevacizumab as adjuvant therapy after arthroscopic synovectomy in one patient with relapsing D-TGCT located in the knee.⁷⁴ During follow-up, complete response was observed, and the patient reported no symptoms nor AEs. Dosage, number of injections and total follow-up duration were not described. Additionally, the effect of synovectomy before bevacizumab is unknown.

5.10 Zaltoprofen

Based on the approaches with zaltoprofen in rheumatoid arthritis and targeted therapy activating PPARγ in other types of cancer, the antitumor effect of zaltoprofen was investigated on primary cultured TGCT cells.⁷⁵ Zaltoprofen, a nonsteroidal anti-inflammatory drug (NSAID), was found to inhibit cell proliferation via activation of PPARγ. A pilot study of zaltoprofen in D-TGCT affecting the knee and ankle joints was conducted, including ten patients. Oral zaltoprofen was given daily for 48 weeks or until disease progression. At 48 weeks, eight patients had stable disease, and one patient showed progressive disease at 72 weeks. Zaltoprofen was well-tolerated. With the results of this pilot study, a study protocol of a double-blind phase II study of zaltoprofen for D-TGCT and unresectable L-TGCT was published. Results are awaited.

6 SURGICAL TREATMENT

Before the advent of systemic targeted therapies, complete surgical resection of TGCT was the mainstay and goal of treatment. Surgical resection still plays a vital role in TGCT treatment, albeit not without recurrence risk and morbidity. Patient cohorts undergoing various surgical treatment regimens remain subject of many multinational research projects.

In a retrospective single institution cohort study, outcomes after surgical management of 144 diffuse-type TGCT related to large joints were evaluated.⁸² The effect of incomplete resections and presence of postoperative tumor on MRI was evaluated in relation to radiological and clinical outcomes. A total of 144 patients underwent open surgery for D-TGCT, out of which 58 individuals (40%) had received prior treatment. The median follow-up period was 65 months. Among the patients, 125 underwent open surgeries, and in 25 cases (20%), incomplete removal of D-TGCT was intentionally performed. The presence of postoperative tumor was observed in 64% of cases on the initial postoperative MRI. Both incomplete resections and the presence of postoperative tumor were associated with higher rates of radiological progression (73% vs. 44%; p = 0.021) and clinical deterioration (59% vs. 7%; p < 0.001), respectively. Additionally, patients with postoperative tumor presence experienced more frequent clinical worsening compared to those without (49% vs. 24%; p = 0.003). As a result, it is advisable for surgeons to strive for complete removal of D-TGCT when feasible, and explore additional multimodal therapeutic approaches to improve patient outcomes.

The knee is the most frequently affected large joint by TGCT. When dealing with the intra- and extra-articular expansion of diffuse-type TGCT around the knee, it is often necessary to perform both anterior and posterior surgical approaches to facilitate a comprehensive synovectomy. The staging of anterior and posterior synovectomies (single vs. two stage) has been a topic of investigation. A multicenter retrospective study was conducted involving 191 D-TGCT patients from nine sarcoma centers worldwide.⁸³ The authors aimed at comparing short-term outcomes and secondary factors such as rates of radiological progression and subsequent treatments between the two treatment approaches. Between 2000 and 2020, 117 patients underwent one-stage synovectomies, while 74 patients underwent two-stage synovectomies. The study found that both groups achieved similar maximum range of motion within 1 year after the surgery (flexion: 123–120°, p = 0.109; extension: 0°, p = 0.093). However, patients who underwent two-stage synovectomies had a longer hospital stay compared to those who had one-stage synovectomies (6 vs. 4 days, p < 0.0001). Although complications occurred more frequently in the two-stage synovectomy group, the difference was not statistically significant (36% vs. 24%, p = 0.095). It was observed that patients treated with two-stage synovectomies experienced more radiological progression and required subsequent treatments more often than those treated with one-stage synovectomies (52% vs. 37%, p = 0.036; 54% vs. 34%, p = 0.007). Based on these findings, the authors concluded that if feasible, D-TGCT of the knee requiring two-sided synovectomies should be treated in one-stage. This approach allows patients to achieve a similar range of motion, experience comparable complication rates, and have a shorter hospital stay.

Another topic of investigation has been that of open versus arthroscopic synovectomy versus a hybrid approach for D-TGCT. In a 2017 study assessing 114 cases of D-TGCT treated at a tertiary referral center, there was a significantly higher risk of recurrence with arthroscopic treatment versus open synovectomy (83.3% vs. 44.8%), however only 12 patients were treated with arthroscopy alone.⁴⁴ Colman et al.⁸⁴ assessed recurrence rates in 48 patients managed with either hybrid arthroscopy/open, all arthroscopy and all open, and reported lowest recurrence rates in those managed with a hybrid approach (9% vs. 64% vs. 62%; p = 0.008). This hybrid approach of a single stage arthroscopic anterior synovectomy (with a skilled arthroscopist) with open posterior synovectomy with an orthopaedic oncology surgeon has been adopted by several centers.^{11, 85, 86}

In general, the role of the orthopaedic oncologist in the surgical management of TGCT (particularly D-TGCT) is evolving. Orthopaedic surgeons treating TGCT must have a thorough knowledge of the current disease landscape, systemic therapies and indications for use. Given the multimodal therapeutic approach, clinicains must work in conjunction with a knowledgable multi-disciplinary team to facilitate optimal patient management.

7 DISCUSSION

7.1 Summary

TGCT is a rare, benign, locally aggressive synovial based neoplastic process that can result in functional debilitation and end-stage arthrtitis. Surgical excision remains a standard care treatment modality for TGCT, but there is a need for alternative therapies for patients with unresectable and complex disease patterns. Recently, novel systemic therapies emerged as part of the multimodal armamentarium for these patients. The use of neoadjuvant RT is controversial due to its potential serious long-term side effects. Advances in understanding the pathogenesis of TGCT have led to the development of new systemic approaches. This review discusses the pathogenesis of TGCT, potential druggable targets and therapeutic approaches. It also evaluates the safety and efficacy of different systemic therapies.

7.2 CSF1R inhibitors

The discovery of CSF1 translocations in TGCT made the CSF1-CSF1R axis the primary pathway to target. Imatinib was one of the first TKIs used off-label for TGCT. Nilotinib was assumed to have a favorable tolerability profile, but its radiological response was inferior to imatinib, and a significant number of patients discontinued treatment.^{46, 64} Pexidartinib, another TKI, was designed to have higher selectivity against CSF1R, leading to a better response and improvements in patient reported outcomes; however, rare but serious liver injuries occurred, resulting in marketing authorization refusal by the EMA, although Pexidartinib is FDA approved and available for use in the United States.⁸⁰ Most CSF1R inhibitors also target closely related tyrosine kinases, leading to off-target activity which contributes a potentially unfavorable risk-benefit ratio for a subset of patients. The long-term efficacy of most of the CSF1R inhibitors is also still unknown. Accordingly, new drugs such as vimseltinib are being investigated, aiming to have less off target effects with other tyrosine kinases than CSF1R, resulting in a more favorable safety profile.^{70, 71} In addition, the effect of intra-articular injections with CSF1R inhibitors is being studied, hoping to cause fewer systemic AEs but having at least comparable local efficacy (AMB-05X, NCT04731675). Finally, modulation of other targets than CSF1 or overlapping pathways may provide new solutions in the future.^{29, 41, 49, 50, 75}

7.3 Patient-tailored TGCT treatment

Until now, only patients with inoperable D-TGCT or patients with expected morbidity of operative treatment qualified for TKI therapy, yet inoperable TGCT is not clearly defined. The expertise of a multidisciplinary tumor boards are ideally used to determine which patients should receive systemic treatment. To advance tailored treatment of TGCT, identifying predictive and/or prognostic markers to select patients who would benefit from specific drug agents would be a massive step forward. However, questions remain about treatment nuances, such as the optimal treatment duration or length of response. In pexidartinib, tumor response often occurred within 6 months after the first treatment, but even more tumor responses occurred after long-term treatment.⁶⁷ However, chronic treatment in a relatively young population is undesirable. Emactuzumab showed durable responses despite a relatively short treatment duration, which could also be an advantage for intermittent treatment. A study to evaluate discontinuation and re-treatment with systemic therapy in patients with TGCT is now open for inclusion (ClinicalTrials.gov NCT04526704).

Although systemic therapies are primarily used as a stand-alone treatment in patients with advanced TGCT, their role as neoadjuvant therapy and in an earlier stage of the disease is yet to be explored. Starting earlier with such treatment could prevent disease progression. In addition, these therapies may be leveraged to permit surgical downstaging in inoperable cases to decrease expected morbidity. However, post hoc analysis showed no additional effect of surgery performed directly after nilotinib treatment.⁶⁴ Second, the effect of CSF1R inhibition on angiogenesis and the role of macrophages, which are essential in the postoperative course, needs to be further elucidated.⁸⁷ Besides the role as neoadjuvant therapy, the efficacy of CSF1R inhibitors combined with other therapies, such as anti-VEGF therapy, requires further investigation.

7.4 Future perspectives

In light of the low incidence of complete response, future studies should focus on achieving a stable state of disease or improving QoL, rather than complete response. Current systemic therapies mainly target the CSF1/CSF1R axis, but they may not eliminate neoplastic cells, making it impossible to achieve a true complete response. Therefore, future studies should focus on targeting the neoplastic cell components. Additionally, the role of systemic therapies as neoadjuvant therapy and in earlier stages of the disease needs to be further explored to prevent disease worsening and secondary joint deterioration. Finally, there is an unmet medical need for broader availability of TGCT-related drugs, but drug approval can be challenging in rare diseases.⁸⁸

Open Research

DATA AVAILABILITY STATEMENT

Not available.

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SYNOPSIS

TGCT is a monoarticular neoplasm driven by an overexpression of CSF1, leading to an increase in neoplastic TGCT cells and an accumulation of CSF1R presenting cells and mainly treated by surgery, but achieving cure can be challenging, requiring additional therapies for relapsing or inoperable tumors.

Volume128, Issue3

Special Issue:Emerging Innovations and Advancements in the Field of Musculoskeletal Oncology

September 2023

Pages 478-488

Multimodal management of tenosynovial giant cell tumors (TGCT) in the landscape of new druggable targets

Abstract

KEYPOINTS

1 INTRODUCTION

2 ETIOLOGY AND PATHOPHYSIOLOGY

3 GENERAL APPROACH

4 ACTIVE AND POTENTIAL THERAPEUTIC TARGETS

5 SYSTEMIC THERAPIES

5.1 Imatinib

5.2 Emactuzumab

5.3 Nilotinib

5.4 Pexidartinib

5.5 Lacnotuzumab

5.6 Cabiralizumab

5.7 Vimseltinib

5.8 TNF-α blockade

5.9 Bevacizumab

5.10 Zaltoprofen

6 SURGICAL TREATMENT

7 DISCUSSION

7.1 Summary

7.2 CSF1R inhibitors

7.3 Patient-tailored TGCT treatment

7.4 Future perspectives

Open Research

DATA AVAILABILITY STATEMENT

REFERENCES

SYNOPSIS

References

Information

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Multimodal management of tenosynovial giant cell tumors (TGCT) in the landscape of new druggable targets

Abstract

KEYPOINTS

1 INTRODUCTION

2 ETIOLOGY AND PATHOPHYSIOLOGY

3 GENERAL APPROACH

4 ACTIVE AND POTENTIAL THERAPEUTIC TARGETS

5 SYSTEMIC THERAPIES

5.1 Imatinib

5.2 Emactuzumab

5.3 Nilotinib

5.4 Pexidartinib

5.5 Lacnotuzumab

5.6 Cabiralizumab

5.7 Vimseltinib

5.8 TNF-α blockade

5.9 Bevacizumab

5.10 Zaltoprofen

6 SURGICAL TREATMENT

7 DISCUSSION

7.1 Summary

7.2 CSF1R inhibitors

7.3 Patient-tailored TGCT treatment

7.4 Future perspectives

Open Research

DATA AVAILABILITY STATEMENT

REFERENCES

SYNOPSIS

References

Related

Information