Long term term follow-up of tyrosine kinase inhibitors treatments in inoperable or relapsing diffuse type tenosynovial giant cell tumors (dTGCT).

RATIONALE: CSF1R tyrosine kinase inhibitors (TKI) and antibodies yield response rates and tumor control in patients with diffuse type tenosynovial giant cell tumors (dTGCT). The long term management of patients with dTGCT treated with TKI is however not known. PATIENTS AND METHODS: We conducted a retrospective single center study on the 39 patients with advanced and/or inoperable dTGCT referred to the Centre Leon Berard for a medical treatment. The clinical characteristics and treatments of patients who had received at least one line of CSF1R TKI or Ab was collected from the electronic patient records and analyzed, after this study was approved by the Institutional Review Board of the Centre Leon Berard. Statistics were conducted using SPSS 23.0.
RESULTS: Thirty-nine patients received at least one line of TKI among the 101 patients with histologically confirmed dTGCT refered to this center. Imatinib, nilotinib, pexidartinib, emactuzumab were the most frequently used agents. First line treatment was given for a median duration of 7 months. With a median follow-up from the initiation of TKI of 30 months, the progression-free rate at 30 months is 56% for the 39 patients. 15 patients had recurrent disease after first line CSF1R inhibitor: 12 (80%) received a 2nd line treatment for a median duration of 6 months and a median time to progression (TTP) of 12 months. Six patients had afterwards a recurrent disease and 5 (83%) received a 3rd line treatment for a median duration of 5 months and a median TTP of 9 months. Progression-free rate at 30 months was observed in 3 of 12 (25%) after line 2 and 1 of 5 (20%) after line 3. None of the patients refered died with a median follow-up of 67 months.
CONCLUSIONS: CSF1R TKI or Ab provide prolonged tumor control and symptom relief for a majority of patients with inoperable or relapsing dTGCT, in first and subsequent lines. Multiple lines are required for close to 50% of patients with relapsing dTGCT.

Introduction

Diffuse type tenosynovial giant cell tumors (TCGT) is a rare locally aggressive connective tissue tumor of the joints, affecting mostly young adults, with a predominance on the knee and ankle [1-4]. dTGCT frequently present at [1;2] translocation encoding for a fusion gene CSF1/COL6A3 whose protein product plays a key role in tumor growth [5-7]. Surgical resection is the recommended treatment in first line [1-5].

However, local relapses frequently occur resulting in swelling, pain and functional impairement which are the hallmark of the disease [4,5]. Surgery is rarely curative after relapse with a 12% reported LRFS at 5 years in a large study [4]. Amputations may be required only very rarely in very large tumors; dTGCT metastasize very rarely [4].

Before CSF1R antagonists, either tyrosine kinase inhibitors (TKI) or antibodies, the medical treatments for relapsing and inoperable tumors had limited efficacy [1-3]. CSF1R antagonists have been reported to yield volumetric response and symptom relief in patients with inoperable diffuse type tenosynovial giant cell tumors (TCGT) [9-16]. Imatinib exerts CSF1R inhibitory activity, and was first reported as active in TGCT/PVNS in a case report in 2008 [9]. The clinical efficacy of tyrosine kinase inhibitors blocking CSF1R (imatinib, nilotinib, pexidartinib) and antibodies against CSF1R (emactuzumab, cabiralizumab) has been then confirmed in several retrospective clinical studies for imatinib [10,11], as well as prospective clinical trials, with emactuzumab [12], nilotinib [13], pexidatinib [14,15] and cabiralizumab [16].

Recently, Tap et al reported on a pivotal randomized phase III study comparing placebo with pexidartinib showing that tumor response was significantly higher with pexidartinib, and that patient reported outcome and function improved during treatment with pexidartinib as compared to placebo in this randomized double blind study [15]. Pexidartinib was recently approved for the treatment of dTGCT by the FDA. In addition to first demonstrate the clinical value of a TKI in this disease with unmet medical needs, this important study also proves that it is feasible to perform a randomized clinical trial in such a rare disease.

TKIs and Ab are administered during a limited period of time in all these studies, from few weeks to 12 months most often [8-16]. In the nilotinib phase II study, 30% of the patients stable after 12 months relapsed after nilotinib interruption, with 4 year PFS of 54% [13]. The impact of a retreatment with the same TKI or other CSF1R on dTGCT related pain and functional impairement has seldom been reported outside single cases [9,11].

Given the favorable life expectancy of these patients, it would be of importance to define a long term strategy for the medical treatment with CSF1R antagonists of patients with inoperable dTGCT treated with short term duration of TKI.

In the present work, we report a single center retrospective experience of the long term medical treatment of 39 advanced dTGCT, using sequential CSF1R antagonist treatments.

Materials and methods

Patients

Since Jan 2007, 39 patients referred to the Centre Leon Berard for a therapeutic decision for a dTGCT received a systemic treatment. These 39 patients represented 39% of the 101 patients with a central pathology confirmed dTGCT refered to the center during this time period. Central pathology review was obtained for all the patients, within the Reference pathology Centre of the Centre Leon Berard, according to the rules of the French NCI (INCa) with the NETSARC [17,18]. The histological diagnosis of dTGCT was not confirmed in 16 of the 117 patients refered to the center during this time period. Giant cell tumor of the bone was the most frequent histological subtype for those unconfirmed dTGCT (not shown).

Table 1 describes the clinical characteristics of these 39 patients.

Table 1

Characteristics of patients treated with CSF1R inhibitors.

	Mean (Range)	n (%)
Gender
Men		13 (33%)
Women		26 (67%)
Age at diagnosis (years)	34.9 (13.2–59.3)
Age at TKI initiation (years)	40.4 (13.6–65.2)
Disease location
Knee		17 (43.6%)
Ankle		9 (23.1%)
Foot		4 (10.3%)
Elbow		3 (7.7%)
Hip		2 (5.1%)
Wrist		2 (5.1%)
Hand		1(2.6%)
Finger		1 (2.6%)
Previous surgeries for TGCT		29 (74.4%)
Time from diagnosis to CSF1Ri (years)	5 .5 (0.03–37.8)
Time from first surgery to CSF1Ri (years)	6.4 (0.7–37.8)
First line treatment
Imatinib		15 (38.5%)
Nilotinib		4 (10.3%)
Emactuzumab		12 (30.8%)
Pexidartinib		2 (5.1%)
Other		6 (15.4%)

A retrospective collection of clinical history and treatment of these 39 patients was conducted, with the approval of the Institutional Review Board of the Centre Leon Berard (Comité de Revue des Etudes Cliniques, CREC, 28, rue Laennec 69008 Lyon on the date of Jan 19th, 2019, Chair Dr Th. Bachelot), in addition to the data collected within the NETSARC and RREPS programs. Data on initial clinical presentation, past local and systemic treatments, response, outcome after treatment and present status of the patient were collected.

Treatment with TKI were given in 39 patients with tumors deemed inoperable and/or in whom surgery would not bring a clinical benefit. Treatment were given as part of a compassionate off label use, or as part of clinical trials for experimental agents (NCT02371369, NCT01261429) which were previously published in peer reviewed journals [13,15,16]. The diagnosis of operability/non operability was taken by the weekly NETSARC multidisciplinary tumor board (MDT) dedicated to connective tissue tumors in place in the Centre Leon Berard, with a consensus obtained including 2 to 4 surgeons with expertise from connective tissue tumors. Generally, it was considered that surgery was the first treatment of choice if complete macroscopic resection of the tumor was deemed feasible for patients not previously operated. When complete macroscopic resection of the tumor was deemed not achievable at relapse (or would have required an amputation or a mutilating surgery not approved by the patient), patients were considered as “non-operable”. The local extension of the disease, in these patients with mostly with multiple relapses, was often multifocal and involved both joints and tendon sheath.

Statistics

Descriptive analysis of the patient population, and comparison between subgroups were performed using the IBM SPSS 23.0 package (IBM, Paris, France).

Results

Table 1 presents the clinical characteristics of the 39 patients who have received a TKI, as compassionate use (imatinib, nilotinib,…), or within clinical trials for tyrosine kinase inhibitors or CSF1R Ab (Table 1). The median duration of the first line treatment for these 39 patients was 7 months (range 1–30+): 35 of these 39 (89.7%) of patients stopped the treatment for another reason than volumetric progression. With a median follow-up of 30 months since the initiation of first line TKI, 15 (38%) presented a novel volumetric progression and/or worsening symptoms, 11 after treatment discontinuation. Tumor progression was reported in 13 of 15 (87%) and worsening symptoms only in n = 2 (13%). Median time to progression (TTP) is not reached for these 39 patients: progression free rate was 56% at 30 months at the time of the analysis (Table 2 & Fig 1).

Table 2

Description of the lines of treatment.

	N	Duration of Treatment Months1	Volume Response N (%)			Symptom Improvement N (%)	Reason for interruption N(%)			TTP (median)2 (TTP-range5)
			VR	SD	NE		PD	AE 3	Other4
Line 1
All	39	7.0 (1–30)	13 (33)	20 (52)	6 (15)	24 (62)	2 (5)	12 (31)	25 (64)	56%* (3–29)
Imatinib	15	8.5 (1–30)	3 (33)	9(60)	3 (20)	11 (73)	1 (7)	3(21)	11 (72)	12 (3–14)
Nilotinib	4	10.0 (7–12)	0	4 (100)	0	2 (50)	1 (25)	1(25)	2 (50))	17 (9–18)
Emactuzumab	12	3.7 (1–8)	4(33)	6 (50)	2 (17)	7(68)	0	4 (33)	8(66)	70%* (6–15)
Pexidatinib	2	12(12–12)	2(100)	0	0	2 (100)	0	0	2(100)	NA
Others	6	6.7 (2–10)	2(33)	3(50)	1 (17)	3(50)	0	3(50)	3(50)	12 (11–29)
Line 2
All	12	6.1 (2–29)	8 (66)	4(33)	0	10 (84)	2 (17)	3(25)	7(58)	12 (2–37)
Imatinib	7	7.8 (2–29)	6 (86)	1(14)	0	6 (86)	1 (14)	3 (43)	3(43)	11 (6–13)
Nilotinib	1	2	1	0	0	0	1	0	0	2 (n = 1)
Emactuzumab	3	4(2–5)	1(33)	2(66)	0	2 (66)	0	0	3	37 (n = 1)
Others	1	4	0	1(100)	0	1	0	0	1	no PD@ 8 months
Line 3
All	5	5(1–7)	2 (33)	3 (50)	0	3(50)	0	2 (40)	3(60)	9.0 (2–9)
Imatinib	3	5(2–7)	1 (33)	2 (66)	0	2(66)	0	1 (33)	2 (66)	9.0 (6–9)
Pazopanib	1	1	0	1	0	1	0	1	0	2 (n = 1)
Emactuzumab	1	6	1	0	0	0	0	0	1	no PD @ 58 months

1: Median (range)

2: Median (months) or *% progression-free at 30 months if median not reached

3: Adverse event

4: Other: patients in whom the treatment was not interrupted for progression or AE, or patients in whom treatment is still ongoing at the time of the analysis.

5: TTP-range in the subgroup of patients who reprogressed

NA: not applicable

VR: volumetric response.

Fig 1

Time to progression after line 1, 2, and 3.

Twelve of these 15 (80%) patients restarted a TKI in second line, 11/12 (92%) because of volumetric progression with symptoms, 1/12 (8%) because of symptoms without volumetric progression. Median duration of treatment was 6 months (range 2–29). Median TTP was 12 months for a median follow-up of 29 months (Table 2, Fig 2). These 12 patients received the same (n = 2) or another (n = 10) CSF1R antagonist. 6 (50%) patients had progression and worsening symptoms after this second line, including 2 (16%) during second line treatment (Table 2).

Fig 2

Swimmer plot showing the duration of TKI treatment and TTP for the sequential lines in individual patients.

Five of these 6 (83%) patients who received a second line treatment received a 3rd line treatment, for a median duration of 5 months (range 1–7) (Table 2) and with a median time to progression of 9 months (Table 2). 3 patients progressed (60%), 2 (40%) during treatment (imatinib & pazopanib for 1 patient each). Two patients received 4th line (both imatinib) and one received a 5th line treatment (sunitinib).

Fig 2 shows the duration of treatment and TTP for each individual patients and lines. Most patients had a prolonged TTP after treatment interruption. Duration of treatment was not correlated to TTP after interruption (not shown).

The compared duration of treatment, time to progression and time to next treatment according to the different agents used are presented in Table 2. The small number of patients and the retrospective nature of the study precludes the comparison of the outcome according to the different the TKI or Ab used. One patient each received twice imatinib and thrice imatinib, all progressing after the interruption of imatinib. The first one had a shorter duration of efficacy in second line (9 vs 12 months) while the other had a similar duration of treatment efficacy.

Discussion

Tyrosine kinase inhibitors of CSF1R have become the medical treatment of choice for relapsing or inoperable dTGCT, and a growing number of patients are receiving these treatments [9-16]. dTGCT is rarely a life-threatening disease. No deaths were observed in the 101 patients refered to us since 12 years. As a consequence, the majority of patients with inoperable dTGCT will be followed for a long period of time. The long term outcome of patients with dTGCT receiving TKI treatment has rarely been reported, even in prospective studies. The objective of the present study was to provide a description of the long term outcome of patients with dTGCT in the era of tyrosine kinase inhibitors which have been used for advanced dTGCT since 12 years in this center.

The present study shows first that the majority of the 39 patients with inoperable and/or relapsing dTGCT who received first line CSF1R antagonist have not progressed nor required additional treatment after first line treatment interruption during the observation period. While first line median treatment duration was 7 months, the proportion of patients who have not progressed at 30 month is 56%, a proportion consistent with that reported in the previous prospective multicentric nilotinib phase II study [13]. The median follow-up of patients treated with first line TKI is however of 30 months only, and relapses at a longer term are likely to be observed, even though a plateau is observed after this date in this series.

A significant proportion of patients treated with a short term duration of TKI treatment do not progress rapidly after treatment interruption. Actually, four patients of this series are progression-free at 5 years after a duration of treatment inferior to 12 months. It is interesting to note that the majority of these patients still have clinically or radiologically detectable tumor.

Secondary volumetric and/or symptomatic progression occurred however in 15 patients, and 80% of these received a second line of CSF1R TK inhibitors. We used the terminology of line of treatment similar to that used for patients with advanced sarcoma receiving cytotoxics at each progression or symptoms requiring a novel treatment, even if the same treatment (eg imatinib) was reinstated for progression after discontinuation. The treatment was again given for a short period of time, shorter than in first line. However, again most patients benefited from this treatment, with a median time to progression of 12 months. While this is shorter than in first line treatment, 3 (25%) patients again reached a long TTP. These data show that second line CSF1R TKI are active in dTGCT, providing symptom relief and tumor control in a large proportion of patients.

Again, 6 (50%) of patients treated in second line progressed and became more symptomatic. These received a third line TKI, mostly with a different agent, within a clinical trial or as compassionate use. Treatment duration was again shorter in third line, with a median of 7 months, but median TTP was 9 months and 2 patients again benefited from long term tumor control.

The patients of this series received a variety of treatments either in clinical trials or in compassionate use. Similar or different treatment were used in the subsequent lines for the individual patients. A meaningful comparison of the impact of the different treatment is of course not possible in such series, but it will be of importance to report the long term outcome of patients included in clinical trials.

There are several limitations in this study. First it is a single center, retrospective collection of patient observation over a 10 year period. A standardized description of symptoms and/or side effects leading to treatment decisions is lacking because of the retrospective nature of the study. The qualification of inoperable tumor in connective tissue tumors is debated, being related to both local extension, previous treatment in particular. In these patients, and as part of the standard procedure, a tumor is deemed inoperable after multidisciplinary evaluation in the multidisciplinary tumor board with at least 2 specialized surgeons. This is therefore a patient population identified by a multidisciplinary group of investigators specialized in connective tissue tumors. Importantly, only a minority of the patients referred for this team for medical treatment (39/101) were actually considered as inoperable and proposed for a medical treatment. Another limitation is that this retrospective study used an heterogenous set of CSF1R inhibitors with a broad (imatinib nilotinib.) or narrow (Abs, pexidartinib) spectrum of activity on tyrosine kinase; while comparison of agents is not feasible, it is still likely that future agents will be more often TKI or Abs with specific CSF1R inhibitory activities.

In this series, we observed that a short duration of administration of a CSF1R inhibitor can provide long term progression-free survival, after treatment interruption, in over 50% of patients with TGCT. Patients with recurrence of symptoms or progression may receive multiple lines of TKI. These treatments most often provide symptom relief and progression arrest, comparing favorably with those observed with secondary surgery [10]. The mechanisms and biomarkers predicting for long term control of locally TGCT treated with TKI are not known and deserve further investigation, considering in particular the molecular heterogeneity of this disease [19].

The value of secondary surgery has not been assessed in this study. A downstaging previous to surgical removal, instead of prolonged treatment could be a preferred option in relapsing dTGCT. Several considerations precluded the application of surgery in this period of observation: 1) most patients had minor shrinkage, 2) the uncertainty on the benefits of secondary surgical treatment, 3) the reluctance of many patients to undergo surgery in this situation of uncertainty. It is important to note that the benefit of secondary surgery was not obvious in an exploratory substudy of the nilogist trial [13].

In conclusion, relapsing or unresectable dTGCT is a rare neoplasia, for which a large number of active medical treatment providing tumor shrinkage and symptom relief are now described. First line TKI controls tumor progression in over 50% of the 39 patients at 30 months. For the remaining patients with relapsing disease after treatment interruption, the long term therapeutic strategies need to be defined taking into account the very favorable life expectancy of these patient and the functional consequences of tumor progression. Strategies involving short term treatment and drug holiday phases may deserve to be tested prospectively for this chronic disease.

Unidentified data of patients included in this analysis.

(DOCX)

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This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present.

29 Oct 2019

PONE-D-19-26498

Long term term follow-up of tyrosine kinase inhibitors treatments in inoperable or relapsing diffuse-type tenosynovial giant cell tumors (dTGCT).

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Reviewer #1: The authors present a retrospective review of patients treated with multiple tyrosine kinase inhibitors for dTGCT with long term follow up. They present the data and base their conclusion in terms of progression, the line of therapy used, and the medications employed. I am not aware of a similar review at this time and in this regard, feel it offers some valuable information for clinicians and patients.

I have a few questions or concerns.

1. Although the authors state that inclusion criteria included non-operable or relapse disease - they did not describe their rationale for inclusion with any other details. Non-operable disease can be very surgeon-dependent and may cover a broad spectrum. Similarly, recurrence is fairly common and one recurrence following inadequate surgery is very different from 4 recurrences after extensive surgical intervention.

2. Since the most common location is the knee joint and since the ultimate sequel is degenerative joint disease, I would expect that some of these patients would have gone on to joint replacement surgery or at least would be evaluated in terms of joint pain. There is very little information regarding the type of limitations or discomfort and other methods of management.

3. Joint disease is often surgically different from disease arising from the tendon sheath - I am not sure this distinction was made either. It has some implications in terms of surgical approach, ability to access or visualize disease, and ability to debride.

4. While non-specific drugs ie: imantinib initiated the interest in targeted therapy - it is likely more relevant to know the impact of CSF1R specific therapy. I imagine most clinicians would prefer to start with a specific and narrowly targeted agent, rather than a broader or less specific - even if historically these were used. I think the discussion may need to address the fact that this is an evolving landscape and that some of the treatment modalities will be less relevant but still perhaps lend interesting insight.

5. I wonder why there is no mention of using the medication to downstage patients from "in-operable" to "operable"? In other words - were any of the patients more amendable to surgical resection after medical management, were they not, and why? Was this a consideration at the time? I think the relevance is that this is preferably a surgical disease - and most imagine that indefinite medical management will be less preferred.

6. While including many different locations, patients, and medical treatments increases the cohort size - I wonder if it provides instructive information for clinical application. For example - it may be more useful for us to know that in patients with 2 recurrences - following reasonable surgical efforts, use of a CSF1R specific drug resulted in durable PFD for x number of months. This is hard to do with so many different medications, patients, tumors, locations, etc. At a minimum should be discussed.

7. No real limitations to the study are presented or discussed.

8. Some grammatical and stylistic issues need to be addressed. For example - on line 73 it reads "...the treatment of dTGCT by the." The sentence is unfinished.

Reviewer #2: This is a highly relevant topic, with a nice review of a single center's experience with anti-CSF1R treatment for diffuse tenosynovial giant cell tumor. This is an interesting and clinically applicable study population, though the variability of treatments, durations of treatments, and differences in context (compassionate use versus clinical trial) can confuse the interpretation of the findings. Some specific comments are included below:

Abstract -- With a median follow-up of 30 months, the time to progression (TTP) is 56% at 30 months. That is not a time to progression. Please clarify. I think I understand the authors' meaning, but it reads awkwardly.

"Sequential therapeutic strategy should be explored in patients with multiple relapses." I am not sure that the results and findings of this retrospective analysis of only patients on treatment, including only 39 patients, with various therapies, mostly with short followup, is particularly strong in supporting this statement.

The duration of treatment for many of these patients appear to be dictated by clinical trial. Perhaps this is an inaccurate assumption. However, that limits conclusions that can be drawn regarding duration of treatment.

Some spelling errors were identified (line 136, for example). Not sure that “reprogress” is a word in the Oxford English Dictionary (line 209)

In reality, this is a study of 39 patients treated with anti-CSF1R therapy, rather than the 101 suggested, with a median duration of 7 months. There is no clear indication for consideration of the other 62 patients who were not on treatment. There is no comparison of the anti-CSF1R group to those off treatment, so the abstract and manuscript should really more accurately reflect that this is a study of 39 patients.

If 15 patients progressed, but only 4 stopped first line therapy for progression, it begs the question: why didn’t the other patients with progression stop first line treatment for that reason?

Table 2 – combining “Adverse Events” with "patient request" makes conclusions difficult; please also clarify “scheduled treatment discontinuation or ongoing treatment” – as this would seem as though patients with ongoing treatment will be included in the reasons for discontinuation. The numbers don’t seem to reflect that, though. Please clarify.

Line 183 – Please clarify how the two patients who started the same CSF1R inhibitor as second line therapy for either progression with symptoms or symptoms without progression would still count as second line therapy. At first glance, that would seem to be continuation on therapy if the antagonist is the same. Presumably, these are patients who completed treatment, demonstrated progression off treatment, and were re-started on therapy again. To include this scenario (relapse after completion of therapy) together with patients who progressed on therapy really confuses the overall analysis. This is a large limitation of the current study.

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9 Jan 2020

Reviewer #1: The authors present a retrospective review of patients treated with multiple tyrosine kinase inhibitors for dTGCT with long term follow up. They present the data and base their conclusion in terms of progression, the line of therapy used, and the medications employed. I am not aware of a similar review at this time and in this regard, feel it offers some valuable information for clinicians and patients.

I have a few questions or concerns.

1. Although the authors state that inclusion criteria included non-operable or relapse disease - they did not describe their rationale for inclusion with any other details. Non-operable disease can be very surgeon-dependent and may cover a broad spectrum. Similarly, recurrence is fairly common and one recurrence following inadequate surgery is very different from 4 recurrences after extensive surgical intervention.

Answer: We fully agree with this comment. The definition of operability varies considerably according to the surgeon for connective tissue tumors, including across reference centers. In this single-center retrospective study, the diagnosis of operability/non operability was taken by the MDT in place on the site, with a consensus always obtained from 2 to 4 surgeons with expertise from connective tissue tumors. It was considered that surgery was the first treatment of choice in complete macroscopic resection of the tumor was deemed feasible for patients not previously operated. When complete macroscopic resection of the tumor was deemed not achievable at relapse (or would have required an amputation), patients were considered as non-operable. This was added in the material and methods section, chapter description of the patients, in this revised version. Please see page 4.

2. Since the most common location is the knee joint and since the ultimate sequel is degenerative joint disease, I would expect that some of these patients would have gone on to joint replacement surgery or at least would be evaluated in terms of joint pain. There is very little information regarding the type of limitations or discomfort and other methods of management.

Answer: This is an important point indeed. Because of the retrospective nature of the study, it can not be claimed that an exhaustive collection of symptoms was performed: pain, swelling, functional impairment were most often reported. The decision of treatment with TKI was discussed and taken only if clinical symptoms significantly impaired patient life and joint function, and if requested by the patient. Knee replacement was considered for some patients but not performed in any of these patients treated with TKI (yet). This was added in the discussion section. Please see page 7 of this revised version.

3. Joint disease is often surgically different from disease arising from the tendon sheath - I am not sure this distinction was made either. It has some implications in terms of surgical approach, ability to access or visualize disease, and ability to debride.

Answer: We also agree with this comment. The local extension of the disease in these patients who mostly have multiple relapses, was often multifocal and involved both joints and tendon sheath. This was added in the Material and Methods section of the revised version.

4. While non-specific drugs ie: imatinib initiated the interest in targeted therapy - it is likely more relevant to know the impact of CSF1R specific therapy. I imagine most clinicians would prefer to start with a specific and narrowly targeted agent, rather than a broader or less specific - even if historically these were used. I think the discussion may need to address the fact that this is an evolving landscape and that some of the treatment modalities will be less relevant but still perhaps lend interesting insight.

Answer: We agree with this comment. The text was amended accordingly, and now includes a new paragraph in the Discussion section.

5. I wonder why there is no mention of using the medication to downstage patients from "in-operable" to "operable"? In other words - were any of the patients more amendable to surgical resection after medical management, were they not, and why? Was this a consideration at the time? I think the relevance is that this is preferably a surgical disease - and most imagine that indefinite medical management will be less preferred.

Answer: we fully agree with this: a downstaging previous to surgical removal, instead of prolonged treatment should be the preferred option in such a chronic disease/tumor. Several considerations precluded the application of such surgery in this period of observation: 1) most patients had minor shrinkage, 2) the uncertainty of the benefits from secondary surgical treatment, 3) the reluctance of many patients to undergo surgery in this situation of uncertainty. It should be mentioned that the benefit of secondary surgery was not obvious in an exploratory sub-study of the niloGIST trial (Gelderblom et al. Lancet Oncol 2018), as now quoted in the discussion. This topic was expanded in the Discussion section. This important question needs to be addressed in a future study.

6. While including many different locations, patients, and medical treatments increases the cohort size - I wonder if it provides instructive information for clinical application. For example - it may be more useful for us to know that in patients with 2 recurrences - following reasonable surgical efforts, use of a CSF1R specific drug resulted in durable PFD for x number of months. This is hard to do with so many different medications, patients, tumors, locations, etc. At a minimum should be discussed.

Answer: we agreed with this limitation. The rarity and intrinsic heterogenous nature of the clinical presentations of dTGCT makes it difficult to achieve homogenous population. A prospective collection would be required. Considering the rarity of the disease, we nonetheless felt that the real-life setting of this relatively large series, could guide the preparation of future prospective studies. We consequently clarified the limits of the study in a specific chapter of the discussion section in this revised version.

7. No real limitations to the study are presented or discussed.

Answer: This is in the same line of thought as the comment above. We added a specific section on these questions at the end of the revised discussion.

8. Some grammatical and stylistic issues need to be addressed. For example - on line 73 it reads "...the treatment of dTGCT by the." The sentence is unfinished.

Answer: Please accept our apologies for this, we made the appropriate corrections.

Reviewer #2: This is a highly relevant topic, with a nice review of a single center's experience with anti-CSF1R treatment for diffuse tenosynovial giant cell tumor. This is an interesting and clinically applicable study population, though the variability of treatments, durations of treatments, and differences in context (compassionate use versus clinical trial) can confuse the interpretation of the findings. Some specific comments are included below:

Abstract -- With a median follow-up of 30 months, the time to progression (TTP) is 56% at 30 months. That is not a time to progression. Please clarify. I think I understand the authors' meaning, but it reads awkwardly.

Answer: we agree with this comment. We changed the text accordingly in the revised version: «With a median follow-up from the initiation of TKI of 30 months, the progression-free rate at 30 months is 56% for the 39 patients. »

"Sequential therapeutic strategy should be explored in patients with multiple relapses." I am not sure that the results and findings of this retrospective analysis of only patients on treatment, including only 39 patients, with various therapies, mostly with short followup, is particularly strong in supporting this statement.

Answer: We agree with this comment, linked to the limitations of this study, and have downstated this statement in the revised version: « Sequential therapeutic strategy may need to be explored in patients with multiple relapses.»

The duration of treatment for many of these patients appear to be dictated by clinical trial. Perhaps this is an inaccurate assumption. However, that limits conclusions that can be drawn regarding duration of treatment.

Answer: This is indeed the case, the duration of treatment varied according to the context in which the treatment was given, with generally stringent and precise criteria for patients included in clinical trials, and more flexible approaches for off-label use. For this reason, no strong statements can be made on the optimal duration of treatment. This has been added in the discussion section

Some spelling errors were identified (line 136, for example). Not sure that “reprogress” is a word in the Oxford English Dictionary (line 209)

Answer: we made the corrections in the revised manuscript.

In reality, this is a study of 39 patients treated with anti-CSF1R therapy, rather than the 101 suggested, with a median duration of 7 months. There is no clear indication for consideration of the other 62 patients who were not on treatment. There is no comparison of the anti-CSF1R group to those off treatment, so the abstract and manuscript should really more accurately reflect that this is a study of 39 patients.

Answer: We agree that this is a study focusing on the 39 patients. We considered that it was important to mention that only a minority (39/101) of patients referred to us for a dTGCT were finally proposed for a systemic treatment. We detailed this in the abstract and in the text, and also added information on follow-up for the remaining 62 patients in the first chapter of the result section of this revised version.

If 15 patients progressed, but only 4 stopped first line therapy for progression, it begs the question: why didn’t the other patients with progression stop first line treatment for that reason?

Answer: We agree that clarification is needed. These remaining patients actually progressed after TKI discontinuation. This was added in the revised version, Result section page 5.

Table 2 – combining “Adverse Events” with "patient request" makes conclusions difficult; please also clarify “scheduled treatment discontinuation or ongoing treatment” – as this would seem as though patients with ongoing treatment will be included in the reasons for discontinuation. The numbers don’t seem to reflect that, though. Please clarify.

Answer: We agree that these points require further clarification. Combining adverse events and patient request came from the fact that adverse events justifying the request of interruption by patients were qualified by the patients themselves as minimal. For clarification, we keep AE in the table and describe this in the discussion. Table 2 has been modified for clarification.

We also agree that « scheduled treatment discontinuation or ongoing treatment » is unclear. This was replaced by « patients in whom the treatment was not interrupted because of progression or AE, or patients in whom treatment is still ongoing at the time of the analysis » in the revised version in Table 2.

Line 183 – Please clarify how the two patients who started the same CSF1R inhibitor as second line therapy for either progression with symptoms or symptoms without progression would still count as second line therapy. At first glance, that would seem to be continuation on therapy if the antagonist is the same. Presumably, these are patients who completed treatment, demonstrated progression off treatment, and were re-started on therapy again. To include this scenario (relapse after completion of therapy) together with patients who progressed on therapy really confuses the overall analysis. This is a large limitation of the current study.

Answer: The reviewer is right: these are patients who completed treatment, demonstrated progression off treatment, and were re-started on therapy again. We respectfully would like to mention that this is generally reported as second line treatment in patients with advanced sarcoma receiving eg doxorubicin in first line interrupted after 6 courses. We applied the same logic here. Because few patients progressed during the treatment, this is actually the case for the majority of patients. We agree that this was not clear enough in the original version and have therefore amended in the Discussion section in this revised version.

__________________________

End of responses.

5 Mar 2020

PONE-D-19-26498R1

Long term term follow-up of tyrosine kinase inhibitors treatments in inoperable or relapsing diffuse-type tenosynovial giant cell tumors (dTGCT).

PLOS ONE

Dear Dr. Blay,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

In response to the suggestions of the reviewers, please 1) rewrite to make it more obvious that this is a study of 39 patients who received either a TKI or an antibody targeting CSF-1R (this is not a study of all 117 patients referred to your center, nor of the 101 patients who had their diagnosis confirmed), and 2) revise the concluding paragraph to better clarify the "take home message" for clinicians.

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Reviewers' comments:

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Reviewer #1: Yes

Reviewer #2: Partly

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Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: No

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Table 1 presents the clinical characteristics of these patients, at diagnosis. As of Jul 1st 2019, with a median follow-up since diagnosis of 69 months, none of these 101 patients have died and 1 only required an amputation. 62of these 101 patients did not receive TKI or Ab during the observation period. With a median follow-up of 16 months for this cohort, 4 documented progression and/or worsening symptoms were reported between 25 and 38months (not shown)Conversely, 39 (39%) have received so far first line CSF1R TKI as compassionate use (imatinib, nilotinib,...) other tyrosine kinase inhibitors or CSF1R Ab in early clinical trials (Table 1). The median duration of the first line treatment for these 39 patients was 7 months (range 1-30+). 35 of these 39 (89.7%) of patients stopped the treatment for another reason than volumetric progression. With a median follow-up of 30 months since TKI initiation, 15 (38%) presented a novel volumetric progression and/or worsening symptoms, 11 after treatment discontinuation. Tumor progression was reported in 13 of 15 (87%) and worsening symptoms only in n=2 (13%). Median time to progression (TTP) is not reached for these 39 patients: progression free rate was 56% at 30 months at the time of the analysis (Table 2 & Figure 1).

Is the manuscript technically sound, and do the data support the conclusions? (Answer options: Yes, No, Partly) Yes - particularly given that the paper is essentially a retrospective description of the responses to therapy. However, I feel the findings and the results are presented in a somewhat confusing manner. For example, it may be helpful to lay out n broad strokes how many patients ultimately responded to medical treatment overall, how many required 1st line therapy, 2 lines of therapy, etc. This would be a helpful take away message for clinicians and patients - which gets lost in the way the results are presented.

Has the statistical analysis been performed appropriately and rigorously? (Answer options: Yes, No, I don't know, N/A) Well - the statistics are really descriptive - although in methods they allude to comparison between subgroups and use of statistical software. Unless I am missing something, I think this is all descriptive and should be presented as such. There are no formal comparisons that I can see.

Reviewer #2: Some grammatical errors remain, which could be easily edited

Some additional edits may be necessary: "(imatinib, nilotinib,...)"

The manuscript is improved with the changes, though severe limitations remain. In the end, this is still a heterogeneous group of various therapies, in various locations, in a relatively small single center analysis.

The abstract and manuscript should clearly note that this is a study of 39 patients. Since the title suggests that this is an analysis of patients treated with tyrosine kinase inhibition, the abstract results section should lead with the 39 patients eligible, not the 101 screened. The first line of abstract results should read something like:

"Overall, 39 of 101 histologically confirmed dTGCT treated at our institution received at least one TKI." The small number of actually included patients for the primary analysis seems to be buried into the middle of paragraphs, rather than highlighted.

**********

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Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

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26 Mar 2020

Dear Editor,

We would like to thank again the reviewers for their attention to this work and their helpful comments which helped us to improve the quality of our manuscript.

Please find enclosed hereunder a revised version of the manuscript, making it explicit that this is a study on 39 patients with dTGCT. A revised version of the manuscript, tables and figures, with visible modifications and integrated modifications is downloaded on the PLoS One website.

We of course remain at your disposition for any further questions you may have on this work.

With kind regards,

Prof. JY Blay

Submitted filename: Responses.docx

Click here for additional data file.

28 Apr 2020

Long term term follow-up of tyrosine kinase inhibitors treatments in inoperable or relapsing diffuse-type tenosynovial giant cell tumors (dTGCT).

PONE-D-19-26498R2

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6 May 2020

PONE-D-19-26498R2

Long term term follow-up of tyrosine kinase inhibitors treatments in inoperable or relapsing diffuse type tenosynovial giant cell tumors (dTGCT).

Dear Dr. Blay:

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