High-dose chemotherapy with autologous haematopoietic stem cell transplantation in patients with isolated vitreoretinal lymphoma: A LOC network study

High-dose chemotherapy with autologous haematopoietic stem cell transplantation in patients with isolated vitreoretinal lymphoma: A LOC network study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article High-dose chemotherapy with autologous haematopoietic stem cell transplantation in patients with isolated vitreoretinal lymphoma: A LOC network study Adam Mainguy, Carole Soussain, Valérie Touitou, Amin Bennedjai, and 21 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4730575/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Nov, 2024 Read the published version in Bone Marrow Transplantation → Version 1 posted 6 You are reading this latest preprint version Abstract Despite its indolent evolution, vitreoretinal lymphoma (VRL) has a poor prognosis due to a major risk of relapse in the central nervous system (CNS) and may necessitate aggressive therapy. However, the use of high-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) is poorly documented. We retrospectively analysed from the French LOC network database the adult immunocompetent patients treated with HCT-ASCT for isolated VRL. Thirty-eight patients underwent consolidation with HCT-ASCT for isolated VRL between 2008 and 2019 after induction chemotherapy. Twenty patients had primary VRL, and 18 had an isolated VRL relapse of a primary CNS lymphoma. Three patients underwent HCT-ASCT in first-line treatment, 24 in second-line treatment, and 11 in subsequent lines. At HCT-ASCT, the median age was 61 years, and the median KPSwas 90. Thirty-two patients (84%) received high-dose thiotepa-based HCT. One patient (3%) died from HCT-ASCT toxicity. Nineteen (50%) patients relapsed after HCT-ASCT, including 17 cases occurring in the brain. The median progression-free survival, brain-free survival and overall survival from HCT-ASCT were 96, 113 and 92 months, respectively. HCT-ASCT represents an effective therapeutic strategy for select VRL patients, with a tolerable safety profile. However, the risk of subsequent brain relapse remains significant. Health sciences/Health care/Therapeutics/Stem-cell therapies Health sciences/Health care/Prognosis/Disease-free survival Vitreoretinal Lymphoma Autologous Haematopoietic Stem Cell Transplantation High-dose Chemotherapy CNS Lymphoma Figures Figure 1 Figure 2 Introduction Vitreoretinal lymphoma (VRL) is a rare type of lymphoma, most often of the diffuse large B-cell type ( 1 ). Patients have a median age of 70 years at the time of diagnosis ( 2 ). VRL can be either isolated (primary VRL [PVRL]), isolated intraocular relapse of primary central nervous system lymphoma (PCNSL) or exceptionally isolated intraocular relapse of systemic lymphoma) or associated with PCNSL, the latter in 10–20% of cases ( 3 – 6 ). Isolated VRL is an indolent disease that often causes few or no symptoms, and it typically progresses slowly without treatment, in contrast to the highly symptomatic and rapidly progressing nature of PCNSL. This indolent progression contrasts with a poor long-term prognosis due to the significant risk of developing central nervous system lymphoma (CNSL), which has a worse prognosis. Forty to 90% of patients with PVRL develop central nervous system (CNS) disease after 30 months of follow-up ( 1 , 7 – 9 ). Patients with VRL associated with CNS involvement have a poor prognosis, with a median overall survival (OS) of 18 to 34 months ( 8 , 10 , 11 ), compared to 37 to 75 months for patients with isolated VRL ( 2 , 7 , 12 ). Like the brain, the eye is considered an immune-privileged site isolated from the remaining blood system ( 13 ), which represents a therapeutic challenge. The treatment of VRL remains controversial and poorly standardized due to its rarity and the absence of prospective studies ( 1 , 14 , 15 ). Consequently, a multidisciplinary approach involving ophthalmologists, haematologists, and neurologists is needed. The optimal treatment for relapsing VRL, in the absence of cerebral involvement, is even more controversial. Therapeutic strategies range from local intraocular treatments to more aggressive treatments with several systemic chemotherapies ( 1 , 10 , 12 , 14 ). The choice of systemic treatment is based on an analogy with what is done in PCNSL, with the frequent use of high-dose methotrexate ( 1 , 2 ). Despite the rather grim disease prognosis, there are limited data available in the literature regarding HCT-ASCT in the context of VRL ( 16 – 19 ), and to our knowledge, there is no dedicated study on HCT-ASCT in the context of isolated VRL. In France, HCT-ASCT appears to be a justified treatment for VRL, given the unfavourable prognosis of the disease, and it has been included in the treatment recommendations for PVRL since the end of the 2000s. Therefore, the aim of this study was to retrospectively review a national case series of VRL patients treated with consolidative HCT-ASCT to assess the efficacy and safety of this therapeutic strategy. Patients and methods This work is based on the analysis of the French LOC (“Lymphomes Oculo-Cérébraux”) network database, a nationwide database centralizing information from 28 different centres in France, representing the main centres involved in PCNSL management. The database was approved by the institutional ethical committee of the coordinating centre and by the French data protection agency (CNIL: Commission Nationale de l’Informatique et des Libertés). All patients provided informed consent to participate in the database and for the use of their data. The study was carried out following the tenets of the Declaration of Helsinki. Patients were retrospectively selected from the LOC database according to the following criteria: 1) isolated vitreoretinal lymphoma at the beginning of the line of treatment when HCT-ASCT was performed: either primary VRL or isolated intraocular relapse of either primary VRL or PCNSL. Cerebral and cerebrospinal fluid (CSF) involvement had to be excluded by cerebral MRI and lumbar puncture. Patients with isolated vitreoretinal relapses of systemic lymphomas were excluded from the present work; 2) HCT-ASCT applied as a consolidation treatment after induction therapy at any line of treatment; 3) aged > 18 years; 4) immunocompetent status; 5) pathological diagnosis or cytological diagnosis in the vitreous at initial diagnosis. Patients were selected in January 2020, and data were analysed in October 2023. The main outcome endpoints were response after HCT-ASCT, OS, progression-free survival (PFS), brain-free survival (BFS) and toxicity of HCT-ASCT. The response to HCT-ASCT was assessed according to the IPCG criteria with the following criteria: complete response (CR): no evidence of residual disease in the anterior chamber, vitreous or retina; partial response (PR): >50% reduction in ophthalmological findings; progressive disease (PD): worsening of ocular findings or new ocular lesions; and stable disease (SD): none of the previous items ( 20 ). Clinical evaluation was completed by measuring interleukin 6 (IL-6) and 10 (IL-10) levels in the aqueous humour when available. The IL-10 concentration in the aqueous humour was considered elevated, with a cut-off of 30 pg/ml ( 21 ). Depending on the analysis, the endpoints were calculated either from the day of infusion of the stem cells or from the initial diagnosis. PFS was defined as the time without relapse (whatever its location) or without death (whatever its cause). BFS was defined as the time without brain relapse. Survival rates were calculated using the Kaplan‒Meier method. Toxicity was assessed according to the Common Terminology Criteria for Adverse Events version 4. The log-rank test was used to test for the equality of the survival distributions. Two-sided p values < 0.05 were considered significant. The statistical analyses were carried out with R software (R Core Team (2022). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/ .)). Results Patient characteristics Thirty-eight patients (22 females and 16 males) from 15 centres who were diagnosed with CNS DLBCL between 1995 and 2018 and treated with HCT-ASCT between 2008 and 2019 were included in the study. The main characteristics of the patients before HCT-ASCT are indicated in Tables 1 and 2 . Table 1 Patient characteristics before HCT-ASCT Patient’s characteristics before the line of treatment of HCT-ASCT N 38 Age at initial diagnosis, median [Min, Max] 59.5 [40–71] Female gender (N, %) 22 (58%) Localization of initial lymphomatous involvement (N, %) CNS CNS + VR VR CNS involvement at any time before HCT-ASCT 11 (29%) 7 (18%) 20 (53%) 18 (47%) Previous treatments (N, %) HD-MTX Rituximab HD-AraC WBRT 37 (97%) 21 (55%) 31 (82%) 8 (21%) Refractory after the 1st line of treatment (N, %) 11 (29%) Patient’s characteristics at the beginning of the line of treatment of HCT-ASCT Treatment line of HCT-ASCT (N, %) 1st 2nd > 2nd 3 (8%) 24 (63%) 11 (29%) Characteristics of ophthalmologic involvement (%) at the beginning of the induction treatment before HCT-ASCT Unilateralinvolvement Visual acuity decrease Floaters 16/29 (55%) 20/27 (74%) 6/27 (22%) IL-10 dosage in the anterior chamber at the beginning of the induction treatment before HCT-ASCT Number of IL-10 dosages available IL-10 level (pg/ml): median (Min-Max) Elevated IL-10 (> 30 pg/ml) % with a positive ISOLD score (Costopoulos et al.( 21 )) IL-10/IL-6 ratio (> 1) 22 (58%) 360 (2-5000) 17/22 (77%) 16/22 (73%) 18/22 (82%) Induction chemotherapy used before HCT-ASCT (N, %) Systemic chemotherapy (R)-ICE HD-MTX-based CT HD-AraC-based CT Temozolomide Local treatment (intravitreal MTX) Alone Combined with systemic chemotherapy 35 (92%) 19/35 (54%) 8/35 (23%) 6/35 (17%) 2/35 (6%) 6 (16%) 3/6 (50%) 3/6 (50%) N: number of patients; %: proportion of patients; CNS: central nervous system; VR: vitreoretinal; HCT-ASCT: high-dose chemotherapy with autologous haematopoietic stem cell transplantation; HD-MTX: high-dose methotrexate; HD-AraC: high-dose cytarabine; WBRT: whole-brain radiotherapy; IL-10: interleukin 10; IL-6: interleukin 6; (R)-ICE: (rituximab)-ifosfamide, carboplatin, etoposide; CT: chemotherapy. Table 2 Patient characteristics at the time of HCT-ASCT N 38 Delay between initial diagnosis and HCT-ASCT: median (range), months 21.6 (4.9-116.3) Delay between isolated ophthalmological relapse (or diagnosis for HCT-ASCT in the 1st line) and HCT-ASCT: median (range), months 4.9 (2.6–7.2) Age at HCT-ASCT, median [Min-Max] 61 [42–73] KPS, median [Min, Max] at HCT-ASCT 90 [60,100] Mean best corrected visual acuity at HCT-ASCT (decimal scale) 6.33 ± 2.26 Tumoral status at HCT-ASCT (N, %) Complete response Partial response Stable disease Progressive disease 29 (76%) 7 (18%) 1 (3%) 1 (3%) IL-10 dosage in the anterior chamber just before HCT-ASCT Number of dosages available IL-10 level (pg/ml): median (Min-Max) Elevated IL-10 (> 30 pg/ml) IL-10/IL-6 ratio > 1 13 (34%) 10 (0-265) 5/13 (38%) 6/13 (46%) N: number of patients; %: proportion of patients; HCT-ASCT: high-dose chemotherapy with autologous haematopoietic stem cell transplantation; KPS: Karnofsky Performance Status; IL-10: interleukin 10; IL-6: interleukin 6. At initial diagnosis, 20/38 (53%) patients had PVRL, and 18/38 (47%) had PCNSL (including 7/38 (18%) who also had ocular involvement). None of the PVRL patients had previous CNS involvement at any time before HCT-ASCT. The median age at the time of HCT-ASCT was 61 years (range 42–73 years), with 7/38 (18%) patients older than 65 years. The median KPS before HCT-ASCT was 90 (range 60–100). The median interval between initial diagnosis and HCT-ASCT was 21.6 months (range: 4.9-116.3). Three of the 38 (8%) patients received HCT-ASCT in the first-line of treatment; 24/38 (63%), in the second line of treatment; and 11/38 (29%), in subsequent lines of treatment. The induction treatments used before HCT-ASCT consolidation are listed in Table 1 . At the time of HCT-ASCT, 29/38 patients (76%) had a complete response (CR), 7/38 (18%) had a partial response (PR), 1/38 (3%) had stable disease (SD) and 1/38 (3%) had progressive disease (PD); additionally, 5/13 patients still had elevated IL-10 levels in the aqueous humour (including 3 patients in CR, 1 in PR and 1 in SD). HCT-ASCT and follow-up after HCT-ASCT (Table 3 ) Table 3 HCT-ASCT and follow-up after HCT-ASCT N 38 HCT regimens (N, %) TBC TTP-BCNU TTP-Bu BEAM 23 (61%) 7 (18%) 2 (5%) 6 (16%) Tumour response after HCT-ASCT (N, %) Complete response Partial response Stable disease Progressive disease Not assessable (toxic death) 33 (87%) 2 (5%) 0 (0%) 2 (5%) 1 (3%) Mean best corrected visual acuity after HCT-ASCT (decimal scale) 8.20 ± 1.72 p* = 0.001 Location of the first relapse (N, %) CNS CNS and ocular Ocular Systemic 6/19 (32%) 4/19 (21%) 8/19 (42%) 1/19 (5%) Location of relapses throughout the disease after HCT-ASCT (N, %) Only ocular relapse(s) At least one brain relapse Systemic, ocular and meningeal relapse 1/19 (5%) 17/19 (90%) 1/19 (5%) Relapse rate after HCT-ASCT according to the HCT-ASCT treatment line (N, %) 1st line 2nd line > 2nd line 1/3 (33%) 12/24 (50%) 6/11 (55%) Relapse rate after HCT-ASCT according to the type of HCT (N, %) TBC or TTP-Bu TTP-BCNU BEAM 11/25 (44%) 4/7 (57%) 4/6 (67%) Brain relapse rate after HCT-ASCT according to the initial localization of the disease (N, %) PVRL PCNSL 9/20 (45%) 8/18 (44%) N: number of patients, %: proportion of patients. TBC: Thiotepa-busulfan-cyclophosphamide; TTP-BCNU: Thiotepa-carmustine; BEAM: Carmustine, etoposide, cytarabine, melphalan; TTP-Bu: Thiotepa, busulfan. HCT-ASCT: high-dose chemotherapy with autologous haematopoietic stem cell transplantation; PVRL: primary vitreoretinal lymphoma; PCNSL: primary central nervous system lymphoma *Paired Student’s t test comparing the mean best corrected visual acuity before and after HCT-ASCT Thirty-two of 38 patients (84%) received thiotepa-based HCT, 23/32 patients (72%) received thiotepa-busulfan-cyclophosphamide (TBC), 7/32 patients (22%) received thiotepa-carmustine (TTP-BCNU), and 2/32 patients (6%) received thiotepa-busulfan (TTP-Bu). Six of 38 patients (16%) received carmustine-etoposide-cytarabine-melphalan (BEAM)-based HCT. Thirty-three of 38 patients (87%) achieved CR after HCT-ASCT. Among the 33 patients who achieved CR, 10 patients (30%) had aqueous-humour IL-10 levels available after HCT-ASCT, with a median IL-10 level of 2.5 pg/ml (range: 0–7). Two patients (5%) experienced progressive disease with active vitritis after HCT-ASCT (one who was in CR with a normal IL-10 level in the aqueous humour before HCT-ASCT and one with SD and increased IL-10 levels before HCT-ASCT). The median follow-up from HCT-ASCT was 79 months (95% CI: 64–111). Nineteen of the 38 patients (50%) experienced relapse during the follow-up after HCT-ASCT. There was brain involvement in 10/19 (53%) patients at the 1st relapse following HCT-ASCT. A total of 17/38 (45%) patients (including 9/20 patients (45%) with initial PVRL and 8/18 patients (44%) with initial PCNSL) experienced brain relapse during follow-up, while one patient experienced only one isolated vitreoretinal relapse, and one patient experienced lumboaortic relapse followed by ocular and meningeal relapse. Of the 3 patients who received HCT-ASCT in first-line treatment, one experienced relapse (ocular relapse 56.8 months after HCT-ASCT with BEAM, followed by cerebral relapse 72 months after HCT-ASCT and death at 83 months), while the other 2 patients who received TBC were still disease free at 60 and 109 months. Among the five patients with persistent increased IL-10 levels in the aqueous humour at the time of HCT-ASCT, three relapsed, one died from HCT-ASCT toxicity, and only one did not relapse. The median PFS was 96 months (95% CI: 34-NA). The 2-year and 5-year PFS rates were 68% (95% CI: 59–88) and 50.2% (95% CI: 36–74), respectively (Fig. 1 A). In the 35 patients who underwent HCT-ASCT in the setting of relapse, the PFS from HCT-ASCT (2-year PFS: 66% (95% CI: 52–83%)) was significantly longer than the PFS between initial diagnosis and first relapse (2-year PFS: 29% (17–48%)) (p < 0.001). The median BFS was 113 months (95% CI: 45-NA). The 2-year and 5-year BFS rates were 75% (95% CI: 59–88) and 57% (95% CI: 36–74), respectively (Fig. 1 B). Fifteen patients (40%) died during follow-up. One patient (3%) died from HCT-ASCT toxicity, and the other 14 (37%) died from cerebral progression of lymphoma. The median OS from HCT-ASCT was 92 months (95% CI: 77-NA). The 2-year and 5-year OS rates were 87% (95% CI: 72–96) and 71% (95% CI: 46–82), respectively (Fig. 1 C). The median OS from initial diagnosis was 185 months (95% CI: 83-NA), with a 5-year OS rate of 79% (95% CI: 67–94). Toxicity The grade 3–4 adverse events related to HCT-ASCT are represented in Fig. 2 . One hundred percent and 88% of patients experienced grade 4 neutropenia and thrombocytopenia, respectively. The median duration of grade 4 neutropenia was 9 days (range: 3–18). The median duration of grade 4 thrombocytopenia was 4 days (range: 0–83). The median hospitalization duration for patients who underwent HCT-ASCT was 21 days (range: 13–129). One patient died from HCT-ASCT toxicity following acute respiratory distress syndrome after pneumonitis in the context of grade 4 neutropenia. He was a 62-year-old patient with a KPS of 80 who received HCT-ASCT (TBC) as a consolidation of 2nd -line treatment for ocular relapse of a PCNSL. Prognostic factors No factors, most notably age, KPS, initial diagnosis (PVRL vs. PCSNL) (Supplemental Fig. 1) and line of treatment with HCT-ASCT (Supplementary Fig. 2), were significantly associated with OS according to univariate analysis (Table 4 ). Table 4 Prognostic factors for overall survival (univariate analysis) Univariate analysis N Median OS (months) Hazard Ratio 95% CI p value Age at HCT-ASCT ≤ 60 years Age at HCT-ASCT > 60 years 18 20 92.2 158 1.15 (0.39–3.34) 0.79 Female sex Male sex 22 16 76.8 158 0.37 (0.12–1.10) 0.06 KPS at HCT-ASCT ≤ 80 KPS at HCT-ASCT > 80 12 26 92.2 158 0.62 (0.21–1.81) 0.38 No initial cerebral involvement Initial cerebral involvement 20 18 92.2 NA 1.29 (0.45–3.70) 0.63 HCT-ASCT in the first line HCT-ASCT in the 2nd line HCT-ASCT in the > 2nd line 3 24 11 83.1 92.2 158 2.10 1 .12 (0.26–16.6) (0.12–10.8) 0.48 0.92 Unilateral ocular involvement before HCT-ASCT Bilateral ocular involvement before HCT-ASCT 16 13 158 92.2 3.26 (0.62–17.1) 0.16 TBC or TTP-BU conditioning TTP-BCNU conditioning BEAM conditioning 25 7 6 158 53.6 61.6 2.87 2.09 (0.82-10.0) (0.53–8.15) 0.10 0.29 In CR after salvage chemotherapy Not in CR after salvage chemotherapy 29 9 92.2 NA 0.96 (0.26–3.48) 0.96 Elevated IL-10 level before HCT-ASCT Normal IL-10 level before HCT-ASCT 5 8 53.6 NA 4.45 (0.46–42.8) 0.19 N: number of patients. KPS: Karnofsky Performance Status. TBC: Thiotepa-busulfan-cyclophosphamide; TTP-BCNU: Thiotepa-carmustine; BEAM: Carmustine, etoposide, cytarabine, melphalan; TTP-Bu: Thiotepa, busulfan. HCT-ASCT: high-dose chemotherapy with autologous haematopoietic stem cell transplantation. CR: complete remission. There was no significant difference in terms of BFS between patients with PVRL (median: 113 months) and patients with PCNSL at initial diagnosis (median: not reached) (p = 0.3). Discussion To our knowledge, this work represents the first large study with a long follow-up dedicated to HCT-ASCT in patients with isolated VRL. Autologous stem cell transplantation with a thiotepa-based conditioning regimen has been the standard first-line consolidation treatment for PCNSL, according to two major randomized phase II studies ( 22 – 24 ). However, this treatment is still underutilized in PVRL, with limited data available in the literature. However, several studies from our team since the 2000s have shown the feasibility and effectiveness of HCT-ASCT for the treatment of VRL. Soussain et al. conducted a pilot study in 1996 involving five patients with refractory PVRL who underwent HCT, demonstrating its feasibility and showing encouraging results, with no cerebral relapse observed during the follow-up period (between 16 and 26 months) ( 25 ). Soussain et al. conducted another study in 2001, which further demonstrated the feasibility of this treatment and revealed promising outcomes (3-year overall survival of 63.7% in 22 patients, including 3 with relapsed VRL and 6 with isolated vitreoretinal relapse of PCNSL) ( 16 ). Subsequently, two additional studies were conducted: there was a 2-year OS rate of 69% after HCT-ASCT in a study of 43 relapsed patients including 5 with VRL ( 17 ), and a median OS of 86 months after HCT-ASCT in 19 patients with relapsed VRL ( 26 ). More recently, Lee et al. described two patients with VRL treated with first-line HCT-ASCT who achieved long-term survival with follow-up durations of 7 and 8 years, respectively( 27 ). The results observed in our study were generally favourable (median OS, BFS, and PFS from HCT-ASCT of 92, 113 and 96 months, respectively). The PFS from HCT-ASCT was much longer than the PFS from initial diagnosis. These results represent a better prognosis than that usually described in the literature for PVRL (median overall survival from initial diagnosis ranging from 37 to 75 months in the main studies, with heterogeneous treatments ranging from local treatments to systemic treatment mainly based on high-dose methotrexate or to combined systemic and local treatments) ( 2 , 10 , 12 ) as well as for isolated ocular relapses of PCNSL (median overall survival from the date of isolated ocular relapse: 57.1 months) ( 19 ). We can reasonably imagine that most of the patients who were still disease-free 5 years after HCT-ASCT were definitely cured with this strategy. However, these results must be interpreted cautiously, especially given the retrospective nature of this study, with a high proportion of young patients having a good KPS, which is a factor well known to be associated with a better prognosis in PCNSL ( 5 , 28 , 29 ). Most of the patients in our study received a thiotepa-based HCT. Due to the limited number of patients, it was difficult to compare the effectiveness of the various regimens or of thiotepa-based HCT versus BEAM. However, with 4 of 6 patients who relapsed following BEAM and given the poor results of this regimen in PCNSL cases ( 18 , 30 ), our recommendation would be to prefer thiotepa-based regimens. Despite the favourable survival outcomes, the post-HCT-ASCT relapse rate, particularly the cerebral relapse rate, remains high, both in patients with PVRL and in patients with PCNSL at initial diagnosis (45% at 5 years, 45% in patients with initial PVRL, 44% in patients with initial PCNSL). An important issue that could partly explain this high rate of relapse is the difficulty in adequately evaluating the quality of response in VRL patients. Currently, according to the IPCG criteria ( 20 ), the response to treatment is assessed by a rather subjective clinical ophthalmological evaluation. There is no measurable mass in VRL, and many patients maintain residual abnormalities that may be either only a scar or the persistence of an active disease ( 31 ). We could therefore hypothesize that some patients from our cohort did not exhibit a good response at the time of HCT-ASCT, which is a well-known adverse prognostic factor regarding the efficacy of HCT-ASCT in PCNSL ( 32 ). The systematic assessment of IL-10 in the aqueous humour might be an interesting tool ( 1 ). This marker may have a greater sensitivity than clinical examination in detecting relapses early, although further research is needed to confirm this issue. In our cohort, we had limited data, with only 13 patients whose IL-10 levels were measured prior to HCT-ACST. However, three of five patients with elevated IL-10 levels at the time of HCT-ASCT subsequently relapsed. The majority of the patients in our series received HCT-ASCT in second line or subsequent lines of treatment. In PCNSL patients, the relapse rate is low following HCT-ASCT performed as a 1st-line treatment (5-year PFS of approximately 75%) ( 18 ) but is significantly higher in the setting of relapse, with rates close to those observed in our series (2nd -line treatment: 5-year PFS of 48% in PCNSL patients ( 18 ) vs. 44% in VRL patients in our series). In our cohort, only three patients received first-line HCT-ASCT, two of whom never relapsed after 5 and 9 years of follow-up. However, this represents a cohort that was too small to draw any adequate conclusions. Considering the similarity of the results observed in PCNSL and in PVRL, we could hypothesize that the results of HCT-ASCT in the 1st-line treatment of PVRL would be better than those in the setting of relapse. In light of the poor long-term prognosis of this disease, the use of HCT-ASCT as a 1st-line treatment for VRL should be discussed, especially considering the fact that most PVRL patients experience relapse after "conventional" first-line treatments (with a 5-year PFS of approximately 25% ( 2 , 12 )). Given the good KPS of most PVRL patients, this strategy could be used in many of these individuals up to a fairly advanced age, as is done in select elderly patients with PCNSL ( 22 , 33 , 34 ). The toxicity profile observed was close to what is usually observed in other studies involving HCT-ASCT ( 18 ). There was a 3% rate of toxicity-related mortality, which is slightly lower than the 5 to 10% range reported for PCNSL ( 17 , 23 , 26 , 35 ). Even if this toxic mortality rate appears to be acceptable, HCT-ASCT remains a toxic treatment that is difficult for many patients to tolerate, and patients should be aware of the limited but real risk of toxic death. Optimizing induction treatments for PVRL, potentially through the incorporation of novel drugs (imids, iBTK, etc.) ( 36 – 38 ), could limit the need for HCT-ASCT by increasing the rate of complete response. We also currently lack molecular prognostic factors that could indicate whether patients belong to a group with a higher or a lower risk of relapse. Several recent studies have revealed promising prognostic molecular factors in PCNSL cases ( 39 , 40 ), but reliable tools for identifying these factors in patients with VRLs are lacking. There might also be a role for the use of CAR T-cells, which has yet to be determined. Indeed, in systemic lymphomas, therapeutic strategies using CAR T-cells compare favourably to standard strategies, including HCT-ASCT ( 41 , 42 ). Promising preliminary data on CNS lymphoma treated with CAR T-cells have been published in recent years, but there are limited data regarding ophthalmological involvement ( 43 , 44 ). Conclusion Intensive chemotherapy followed by autologous stem cell transplantation is an aggressive therapeutic approach for VRL but appears to provide interesting efficacy results for select patients, with a tolerable safety profile. However, the relapse rate, notably in the brain, following such a strategy remained high in a cohort of patients who mainly received 2nd or subsequent lines of treatment with HCT-ASCT. Several options might improve the prognosis: using HCT-ASCT in 1st -line treatment, as in PCNSL, improving the quality of the response prior to HCT-ASCT by incorporating new drugs into the induction chemotherapy regimen or using new strategies such as treatment with CART-cells. Declarations Financial support : None Conflict of interest statement: The authors have no proprietary interest in the materials used in this study and declare no conflicts of interest. Acknowledgments: The French National Institute of Cancer (INCa : Institut National du Cancer). Philippe Agapé 1 , Jérôme Paillassa 2 , Eve Rousseau 3 Ibrahim Jdid 4 and all the members of the LOC network. 1 Department of Medical Oncology, Institut de Cancérologie de l’Ouest, Saint Herblain, France 2 Department of Hematology, Angers University Hospital, Angers University, Angers, France 3 Department of Ophthalmology, Clermont Ferrand University Hospital, France 4 Department of Hematology, Orleans Hospital, France Authorship statement: Caroline Houillier, Carole Soussain and Valérie Touitou designed the research study; Adam Mainguy and Caroline Houillier wrote the paper, acquired, analysed and interprated data ; Carole Soussain, Sylvain Choquet,Sara Touhami, Amin Bennedjai, Jean-Baptiste Ducloyer, Denis Malaise, Valérie Touitou, Laurent Kodjikian, Hervé Ghesquières, Gandhi Damaj, Rémy Gressin, Olivier Chinot, Anaïs Vautier, Cécile Moluçon-Chabrot, Guido Ahle, Luc Taillandier, Jean Pierre Marolleau, Adrien Chauchet, Fabrice Jardin, Nathalie Cassoux, Adélaïde Toutée, Magali Le Garff-Tavernier and Khê Hoang-Xuan provided data, assisted in the preparation of the paper, and made significant contributions to the critical revision of the manuscript. 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Long-lasting CRs after ibrutinib monotherapy for relapse or refractory primary CNS lymphoma (PCNSL) and primary vitreoretinal lymphoma (PVRL): Long-term results of the iLOC study by the Lymphoma Study Association (LYSA) and the French Oculo-Cerebral Lymphoma (LOC) Network (clinical trial number: NCT02542514). Eur J Cancer Oxf Engl 1990. août 2023;189:112909. Mutter JA, Alig SK, Esfahani MS, Lauer EM, Mitschke J, Kurtz DM, et al. Circulating Tumor DNA Profiling for Detection, Risk Stratification, and Classification of Brain Lymphomas. J Clin Oncol Off J Am Soc Clin Oncol. 20 mars 2023;41(9):1684–94. Hernández-Verdin I, Kirasic E, Wienand K, Mokhtari K, Eimer S, Loiseau H, et al. Molecular and clinical diversity in primary central nervous system lymphoma. Ann Oncol Off J Eur Soc Med Oncol. févr 2023;34(2):186–99. Locke FL, Miklos DB, Jacobson CA, Perales MA, Kersten MJ, Oluwole OO, et al. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. 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Am J Hematol. 8 avr 2024; Supplementary Figures Supplementary Figures are not available with this version Additional Declarations The authors have declared there is NO conflict of interest to disclose. Cite Share Download PDF Status: Published Journal Publication published 19 Nov, 2024 Read the published version in Bone Marrow Transplantation → Version 1 posted Review # 1 received at journal 06 Aug, 2024 Reviewer # 1 agreed at journal 04 Aug, 2024 Reviewers invited by journal 15 Jul, 2024 Submission checks completed at journal 15 Jul, 2024 Editor assigned by journal 12 Jul, 2024 First submitted to journal 12 Jul, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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13:20:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4730575/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4730575/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41409-024-02477-y","type":"published","date":"2024-11-19T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":62055923,"identity":"565c37cc-3d07-46ba-8b2e-de5307aa2edf","added_by":"auto","created_at":"2024-08-08 19:41:56","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":125769,"visible":true,"origin":"","legend":"\u003cp\u003eOutcome of patients with VRL treated with HCT-ASCT (A: progression-free survival, B: brain-free survival, C: overall survival). N = Number at risk for each timepoint.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4730575/v1/52c0383a285a42471b601c7b.png"},{"id":62055922,"identity":"9c5425c6-8803-4208-82b1-ab7b27a8ced1","added_by":"auto","created_at":"2024-08-08 19:41:56","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":63143,"visible":true,"origin":"","legend":"\u003cp\u003eGrade 3-4 adverse events related to HCT-ASCT\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4730575/v1/eb8dd4481a768ddca8471f1d.png"},{"id":69422619,"identity":"db563eef-8959-4851-a008-2413a92a274d","added_by":"auto","created_at":"2024-11-20 08:07:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":856179,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4730575/v1/b98e5a56-7b72-4d7c-9a53-9a2ddf4cea5d.pdf"}],"financialInterests":"The authors have declared there is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"High-dose chemotherapy with autologous haematopoietic stem cell transplantation in patients with isolated vitreoretinal lymphoma: A LOC network study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eVitreoretinal lymphoma (VRL) is a rare type of lymphoma, most often of the diffuse large B-cell type (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Patients have a median age of 70 years at the time of diagnosis (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). VRL can be either isolated (primary VRL [PVRL]), isolated intraocular relapse of primary central nervous system lymphoma (PCNSL) or exceptionally isolated intraocular relapse of systemic lymphoma) or associated with PCNSL, the latter in 10\u0026ndash;20% of cases (\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIsolated VRL is an indolent disease that often causes few or no symptoms, and it typically progresses slowly without treatment, in contrast to the highly symptomatic and rapidly progressing nature of PCNSL. This indolent progression contrasts with a poor long-term prognosis due to the significant risk of developing central nervous system lymphoma (CNSL), which has a worse prognosis. Forty to 90% of patients with PVRL develop central nervous system (CNS) disease after 30 months of follow-up (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Patients with VRL associated with CNS involvement have a poor prognosis, with a median overall survival (OS) of 18 to 34 months (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e), compared to 37 to 75 months for patients with isolated VRL (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eLike the brain, the eye is considered an immune-privileged site isolated from the remaining blood system (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), which represents a therapeutic challenge. The treatment of VRL remains controversial and poorly standardized due to its rarity and the absence of prospective studies (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Consequently, a multidisciplinary approach involving ophthalmologists, haematologists, and neurologists is needed. The optimal treatment for relapsing VRL, in the absence of cerebral involvement, is even more controversial. Therapeutic strategies range from local intraocular treatments to more aggressive treatments with several systemic chemotherapies (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). The choice of systemic treatment is based on an analogy with what is done in PCNSL, with the frequent use of high-dose methotrexate (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDespite the rather grim disease prognosis, there are limited data available in the literature regarding HCT-ASCT in the context of VRL (\u003cspan additionalcitationids=\"CR17 CR18\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e), and to our knowledge, there is no dedicated study on HCT-ASCT in the context of isolated VRL. In France, HCT-ASCT appears to be a justified treatment for VRL, given the unfavourable prognosis of the disease, and it has been included in the treatment recommendations for PVRL since the end of the 2000s. Therefore, the aim of this study was to retrospectively review a national case series of VRL patients treated with consolidative HCT-ASCT to assess the efficacy and safety of this therapeutic strategy.\u003c/p\u003e"},{"header":"Patients and methods","content":"\u003cp\u003eThis work is based on the analysis of the French LOC (\u0026ldquo;Lymphomes Oculo-C\u0026eacute;r\u0026eacute;braux\u0026rdquo;) network database, a nationwide database centralizing information from 28 different centres in France, representing the main centres involved in PCNSL management. The database was approved by the institutional ethical committee of the coordinating centre and by the French data protection agency (CNIL: Commission Nationale de l\u0026rsquo;Informatique et des Libert\u0026eacute;s). All patients provided informed consent to participate in the database and for the use of their data. The study was carried out following the tenets of the Declaration of Helsinki.\u003c/p\u003e \u003cp\u003ePatients were retrospectively selected from the LOC database according to the following criteria: 1) isolated vitreoretinal lymphoma at the beginning of the line of treatment when HCT-ASCT was performed: either primary VRL or isolated intraocular relapse of either primary VRL or PCNSL. Cerebral and cerebrospinal fluid (CSF) involvement had to be excluded by cerebral MRI and lumbar puncture. Patients with isolated vitreoretinal relapses of systemic lymphomas were excluded from the present work; 2) HCT-ASCT applied as a consolidation treatment after induction therapy at any line of treatment; 3) aged\u0026thinsp;\u0026gt;\u0026thinsp;18 years; 4) immunocompetent status; 5) pathological diagnosis or cytological diagnosis in the vitreous at initial diagnosis. Patients were selected in January 2020, and data were analysed in October 2023.\u003c/p\u003e \u003cp\u003eThe main outcome endpoints were response after HCT-ASCT, OS, progression-free survival (PFS), brain-free survival (BFS) and toxicity of HCT-ASCT. The response to HCT-ASCT was assessed according to the IPCG criteria with the following criteria: complete response (CR): no evidence of residual disease in the anterior chamber, vitreous or retina; partial response (PR): \u0026gt;50% reduction in ophthalmological findings; progressive disease (PD): worsening of ocular findings or new ocular lesions; and stable disease (SD): none of the previous items (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Clinical evaluation was completed by measuring interleukin 6 (IL-6) and 10 (IL-10) levels in the aqueous humour when available. The IL-10 concentration in the aqueous humour was considered elevated, with a cut-off of 30 pg/ml (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Depending on the analysis, the endpoints were calculated either from the day of infusion of the stem cells or from the initial diagnosis. PFS was defined as the time without relapse (whatever its location) or without death (whatever its cause). BFS was defined as the time without brain relapse. Survival rates were calculated using the Kaplan‒Meier method. Toxicity was assessed according to the Common Terminology Criteria for Adverse Events version 4. The log-rank test was used to test for the equality of the survival distributions. Two-sided p values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered significant. The statistical analyses were carried out with R software (R Core Team (2022). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.R-project.org/\u003c/span\u003e\u003cspan address=\"https://www.R-project.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.)).\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eThirty-eight patients (22 females and 16 males) from 15 centres who were diagnosed with CNS DLBCL between 1995 and 2018 and treated with HCT-ASCT between 2008 and 2019 were included in the study. The main characteristics of the patients before HCT-ASCT are indicated in Tables\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics before HCT-ASCT\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePatient\u0026rsquo;s characteristics before the line of treatment of HCT-ASCT\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at initial diagnosis, median [Min, Max]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e59.5 [40\u0026ndash;71]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale gender (N, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (58%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocalization of initial lymphomatous involvement (N, %)\u003c/p\u003e \u003cp\u003eCNS\u003c/p\u003e \u003cp\u003eCNS\u0026thinsp;+\u0026thinsp;VR\u003c/p\u003e \u003cp\u003eVR\u003c/p\u003e \u003cp\u003eCNS involvement at any time before HCT-ASCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (29%)\u003c/p\u003e \u003cp\u003e7 (18%)\u003c/p\u003e \u003cp\u003e20 (53%)\u003c/p\u003e \u003cp\u003e18 (47%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious treatments (N, %)\u003c/p\u003e \u003cp\u003eHD-MTX\u003c/p\u003e \u003cp\u003eRituximab\u003c/p\u003e \u003cp\u003eHD-AraC\u003c/p\u003e \u003cp\u003eWBRT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (97%)\u003c/p\u003e \u003cp\u003e21 (55%)\u003c/p\u003e \u003cp\u003e31 (82%)\u003c/p\u003e \u003cp\u003e8 (21%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRefractory after the 1st line of treatment (N, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (29%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePatient\u0026rsquo;s characteristics at the beginning of the line of treatment of HCT-ASCT\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment line of HCT-ASCT (N, %)\u003c/p\u003e \u003cp\u003e1st\u003c/p\u003e \u003cp\u003e2nd\u003c/p\u003e \u003cp\u003e\u0026gt; 2nd\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (8%)\u003c/p\u003e \u003cp\u003e24 (63%)\u003c/p\u003e \u003cp\u003e11 (29%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics of ophthalmologic involvement (%) at the beginning of the induction treatment before HCT-ASCT\u003c/p\u003e \u003cp\u003eUnilateralinvolvement\u003c/p\u003e \u003cp\u003eVisual acuity decrease\u003c/p\u003e \u003cp\u003eFloaters\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16/29 (55%)\u003c/p\u003e \u003cp\u003e20/27 (74%)\u003c/p\u003e \u003cp\u003e6/27 (22%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIL-10 dosage in the anterior chamber at the beginning of the induction treatment before HCT-ASCT\u003c/p\u003e \u003cp\u003eNumber of IL-10 dosages available\u003c/p\u003e \u003cp\u003eIL-10 level (pg/ml): median (Min-Max)\u003c/p\u003e \u003cp\u003eElevated IL-10 (\u0026gt;\u0026thinsp;30 pg/ml)\u003c/p\u003e \u003cp\u003e% with a positive ISOLD score (Costopoulos et al.(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e))\u003c/p\u003e \u003cp\u003eIL-10/IL-6 ratio (\u0026gt;\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (58%)\u003c/p\u003e \u003cp\u003e360 (2-5000)\u003c/p\u003e \u003cp\u003e17/22 (77%)\u003c/p\u003e \u003cp\u003e16/22 (73%)\u003c/p\u003e \u003cp\u003e18/22 (82%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInduction chemotherapy used before HCT-ASCT (N, %)\u003c/p\u003e \u003cp\u003eSystemic chemotherapy\u003c/p\u003e \u003cp\u003e(R)-ICE\u003c/p\u003e \u003cp\u003eHD-MTX-based CT\u003c/p\u003e \u003cp\u003eHD-AraC-based CT\u003c/p\u003e \u003cp\u003eTemozolomide\u003c/p\u003e \u003cp\u003eLocal treatment (intravitreal MTX)\u003c/p\u003e \u003cp\u003eAlone\u003c/p\u003e \u003cp\u003eCombined with systemic chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (92%)\u003c/p\u003e \u003cp\u003e19/35 (54%)\u003c/p\u003e \u003cp\u003e8/35 (23%)\u003c/p\u003e \u003cp\u003e6/35 (17%)\u003c/p\u003e \u003cp\u003e2/35 (6%)\u003c/p\u003e \u003cp\u003e6 (16%)\u003c/p\u003e \u003cp\u003e3/6 (50%)\u003c/p\u003e \u003cp\u003e3/6 (50%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eN: number of patients; %: proportion of patients; CNS: central nervous system; VR: vitreoretinal; HCT-ASCT: high-dose chemotherapy with autologous haematopoietic stem cell transplantation; HD-MTX: high-dose methotrexate; HD-AraC: high-dose cytarabine; WBRT: whole-brain radiotherapy; IL-10: interleukin 10; IL-6: interleukin 6; (R)-ICE: (rituximab)-ifosfamide, carboplatin, etoposide; CT: chemotherapy.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics at the time of HCT-ASCT\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelay between initial diagnosis and HCT-ASCT: median (range), months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21.6 (4.9-116.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelay between isolated ophthalmological relapse (or diagnosis for HCT-ASCT in the 1st line) and HCT-ASCT: median (range), months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.9 (2.6\u0026ndash;7.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at HCT-ASCT, median [Min-Max]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61 [42\u0026ndash;73]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKPS, median [Min, Max] at HCT-ASCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e90 [60,100]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean best corrected visual acuity at HCT-ASCT (decimal scale)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.33\u0026thinsp;\u0026plusmn;\u0026thinsp;2.26\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumoral status at HCT-ASCT (N, %)\u003c/p\u003e \u003cp\u003eComplete response\u003c/p\u003e \u003cp\u003ePartial response\u003c/p\u003e \u003cp\u003eStable disease\u003c/p\u003e \u003cp\u003eProgressive disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (76%)\u003c/p\u003e \u003cp\u003e7 (18%)\u003c/p\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIL-10 dosage in the anterior chamber just before HCT-ASCT\u003c/p\u003e \u003cp\u003eNumber of dosages available\u003c/p\u003e \u003cp\u003eIL-10 level (pg/ml): median (Min-Max)\u003c/p\u003e \u003cp\u003eElevated IL-10 (\u0026gt;\u0026thinsp;30 pg/ml)\u003c/p\u003e \u003cp\u003eIL-10/IL-6 ratio\u0026thinsp;\u0026gt;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (34%)\u003c/p\u003e \u003cp\u003e10 (0-265)\u003c/p\u003e \u003cp\u003e5/13 (38%)\u003c/p\u003e \u003cp\u003e6/13 (46%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eN: number of patients; %: proportion of patients; HCT-ASCT: high-dose chemotherapy with autologous haematopoietic stem cell transplantation; KPS: Karnofsky Performance Status; IL-10: interleukin 10; IL-6: interleukin 6.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAt initial diagnosis, 20/38 (53%) patients had PVRL, and 18/38 (47%) had PCNSL (including 7/38 (18%) who also had ocular involvement). None of the PVRL patients had previous CNS involvement at any time before HCT-ASCT. The median age at the time of HCT-ASCT was 61 years (range 42\u0026ndash;73 years), with 7/38 (18%) patients older than 65 years. The median KPS before HCT-ASCT was 90 (range 60\u0026ndash;100). The median interval between initial diagnosis and HCT-ASCT was 21.6 months (range: 4.9-116.3). Three of the 38 (8%) patients received HCT-ASCT in the first-line of treatment; 24/38 (63%), in the second line of treatment; and 11/38 (29%), in subsequent lines of treatment. The induction treatments used before HCT-ASCT consolidation are listed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. At the time of HCT-ASCT, 29/38 patients (76%) had a complete response (CR), 7/38 (18%) had a partial response (PR), 1/38 (3%) had stable disease (SD) and 1/38 (3%) had progressive disease (PD); additionally, 5/13 patients still had elevated IL-10 levels in the aqueous humour (including 3 patients in CR, 1 in PR and 1 in SD).\u003c/p\u003e \u003cp\u003e \u003cb\u003eHCT-ASCT and follow-up after HCT-ASCT\u003c/b\u003e (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eHCT-ASCT and follow-up after HCT-ASCT\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHCT regimens (N, %)\u003c/p\u003e \u003cp\u003eTBC\u003c/p\u003e \u003cp\u003eTTP-BCNU\u003c/p\u003e \u003cp\u003eTTP-Bu\u003c/p\u003e \u003cp\u003eBEAM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (61%)\u003c/p\u003e \u003cp\u003e7 (18%)\u003c/p\u003e \u003cp\u003e2 (5%)\u003c/p\u003e \u003cp\u003e6 (16%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumour response after HCT-ASCT (N, %)\u003c/p\u003e \u003cp\u003eComplete response\u003c/p\u003e \u003cp\u003ePartial response\u003c/p\u003e \u003cp\u003eStable disease\u003c/p\u003e \u003cp\u003eProgressive disease\u003c/p\u003e \u003cp\u003eNot assessable (toxic death)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (87%)\u003c/p\u003e \u003cp\u003e2 (5%)\u003c/p\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003cp\u003e2 (5%)\u003c/p\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean best corrected visual acuity after HCT-ASCT (decimal scale)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.20\u0026thinsp;\u0026plusmn;\u0026thinsp;1.72\u003c/p\u003e \u003cp\u003ep* = 0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocation of the first relapse (N, %)\u003c/p\u003e \u003cp\u003eCNS\u003c/p\u003e \u003cp\u003eCNS and ocular\u003c/p\u003e \u003cp\u003eOcular\u003c/p\u003e \u003cp\u003eSystemic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6/19 (32%)\u003c/p\u003e \u003cp\u003e4/19 (21%)\u003c/p\u003e \u003cp\u003e8/19 (42%)\u003c/p\u003e \u003cp\u003e1/19 (5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocation of relapses throughout the disease after HCT-ASCT (N, %)\u003c/p\u003e \u003cp\u003eOnly ocular relapse(s)\u003c/p\u003e \u003cp\u003eAt least one brain relapse\u003c/p\u003e \u003cp\u003eSystemic, ocular and meningeal relapse\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1/19 (5%)\u003c/p\u003e \u003cp\u003e17/19 (90%)\u003c/p\u003e \u003cp\u003e1/19 (5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRelapse rate after HCT-ASCT according to the HCT-ASCT treatment line (N, %)\u003c/p\u003e \u003cp\u003e1st line\u003c/p\u003e \u003cp\u003e2nd line\u003c/p\u003e \u003cp\u003e\u0026gt; 2nd line\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1/3 (33%)\u003c/p\u003e \u003cp\u003e12/24 (50%)\u003c/p\u003e \u003cp\u003e6/11 (55%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRelapse rate after HCT-ASCT according to the type of HCT (N, %)\u003c/p\u003e \u003cp\u003eTBC or TTP-Bu\u003c/p\u003e \u003cp\u003eTTP-BCNU\u003c/p\u003e \u003cp\u003eBEAM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11/25 (44%)\u003c/p\u003e \u003cp\u003e4/7 (57%)\u003c/p\u003e \u003cp\u003e4/6 (67%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrain relapse rate after HCT-ASCT according to the initial localization of the disease (N, %)\u003c/p\u003e \u003cp\u003ePVRL\u003c/p\u003e \u003cp\u003ePCNSL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9/20 (45%)\u003c/p\u003e \u003cp\u003e8/18 (44%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eN: number of patients, %: proportion of patients. TBC: Thiotepa-busulfan-cyclophosphamide; TTP-BCNU: Thiotepa-carmustine; BEAM: Carmustine, etoposide, cytarabine, melphalan; TTP-Bu: Thiotepa, busulfan. HCT-ASCT: high-dose chemotherapy with autologous haematopoietic stem cell transplantation; PVRL: primary vitreoretinal lymphoma; PCNSL: primary central nervous system lymphoma *Paired Student\u0026rsquo;s t test comparing the mean best corrected visual acuity before and after HCT-ASCT\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThirty-two of 38 patients (84%) received thiotepa-based HCT, 23/32 patients (72%) received thiotepa-busulfan-cyclophosphamide (TBC), 7/32 patients (22%) received thiotepa-carmustine (TTP-BCNU), and 2/32 patients (6%) received thiotepa-busulfan (TTP-Bu). Six of 38 patients (16%) received carmustine-etoposide-cytarabine-melphalan (BEAM)-based HCT. Thirty-three of 38 patients (87%) achieved CR after HCT-ASCT. Among the 33 patients who achieved CR, 10 patients (30%) had aqueous-humour IL-10 levels available after HCT-ASCT, with a median IL-10 level of 2.5 pg/ml (range: 0\u0026ndash;7). Two patients (5%) experienced progressive disease with active vitritis after HCT-ASCT (one who was in CR with a normal IL-10 level in the aqueous humour before HCT-ASCT and one with SD and increased IL-10 levels before HCT-ASCT).\u003c/p\u003e \u003cp\u003eThe median follow-up from HCT-ASCT was 79 months (95% CI: 64\u0026ndash;111). Nineteen of the 38 patients (50%) experienced relapse during the follow-up after HCT-ASCT. There was brain involvement in 10/19 (53%) patients at the 1st relapse following HCT-ASCT. A total of 17/38 (45%) patients (including 9/20 patients (45%) with initial PVRL and 8/18 patients (44%) with initial PCNSL) experienced brain relapse during follow-up, while one patient experienced only one isolated vitreoretinal relapse, and one patient experienced lumboaortic relapse followed by ocular and meningeal relapse. Of the 3 patients who received HCT-ASCT in first-line treatment, one experienced relapse (ocular relapse 56.8 months after HCT-ASCT with BEAM, followed by cerebral relapse 72 months after HCT-ASCT and death at 83 months), while the other 2 patients who received TBC were still disease free at 60 and 109 months. Among the five patients with persistent increased IL-10 levels in the aqueous humour at the time of HCT-ASCT, three relapsed, one died from HCT-ASCT toxicity, and only one did not relapse. The median PFS was 96 months (95% CI: 34-NA). The 2-year and 5-year PFS rates were 68% (95% CI: 59\u0026ndash;88) and 50.2% (95% CI: 36\u0026ndash;74), respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). In the 35 patients who underwent HCT-ASCT in the setting of relapse, the PFS from HCT-ASCT (2-year PFS: 66% (95% CI: 52\u0026ndash;83%)) was significantly longer than the PFS between initial diagnosis and first relapse (2-year PFS: 29% (17\u0026ndash;48%)) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The median BFS was 113 months (95% CI: 45-NA). The 2-year and 5-year BFS rates were 75% (95% CI: 59\u0026ndash;88) and 57% (95% CI: 36\u0026ndash;74), respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFifteen patients (40%) died during follow-up. One patient (3%) died from HCT-ASCT toxicity, and the other 14 (37%) died from cerebral progression of lymphoma. The median OS from HCT-ASCT was 92 months (95% CI: 77-NA). The 2-year and 5-year OS rates were 87% (95% CI: 72\u0026ndash;96) and 71% (95% CI: 46\u0026ndash;82), respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC). The median OS from initial diagnosis was 185 months (95% CI: 83-NA), with a 5-year OS rate of 79% (95% CI: 67\u0026ndash;94).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eToxicity\u003c/h2\u003e \u003cp\u003eThe grade 3\u0026ndash;4 adverse events related to HCT-ASCT are represented in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. One hundred percent and 88% of patients experienced grade 4 neutropenia and thrombocytopenia, respectively. The median duration of grade 4 neutropenia was 9 days (range: 3\u0026ndash;18). The median duration of grade 4 thrombocytopenia was 4 days (range: 0\u0026ndash;83). The median hospitalization duration for patients who underwent HCT-ASCT was 21 days (range: 13\u0026ndash;129). One patient died from HCT-ASCT toxicity following acute respiratory distress syndrome after pneumonitis in the context of grade 4 neutropenia. He was a 62-year-old patient with a KPS of 80 who received HCT-ASCT (TBC) as a consolidation of 2nd -line treatment for ocular relapse of a PCNSL.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003ePrognostic factors\u003c/h2\u003e \u003cp\u003eNo factors, most notably age, KPS, initial diagnosis (PVRL vs. PCSNL) (Supplemental Fig.\u0026nbsp;1) and line of treatment with HCT-ASCT (Supplementary Fig.\u0026nbsp;2), were significantly associated with OS according to univariate analysis (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePrognostic factors for overall survival (univariate analysis)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c6\" namest=\"c3\"\u003e \u003cp\u003eUnivariate analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMedian OS\u003c/p\u003e \u003cp\u003e(months)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHazard Ratio\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at HCT-ASCT\u0026thinsp;\u0026le;\u0026thinsp;60 years\u003c/p\u003e \u003cp\u003eAge at HCT-ASCT\u0026thinsp;\u0026gt;\u0026thinsp;60 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e18\u003c/p\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e92.2\u003c/p\u003e \u003cp\u003e158\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.39\u0026ndash;3.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.79\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale sex\u003c/p\u003e \u003cp\u003eMale sex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76.8\u003c/p\u003e \u003cp\u003e158\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e(0.12\u0026ndash;1.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKPS at HCT-ASCT\u0026thinsp;\u0026le;\u0026thinsp;80\u003c/p\u003e \u003cp\u003eKPS at HCT-ASCT\u0026thinsp;\u0026gt;\u0026thinsp;80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e92.2\u003c/p\u003e \u003cp\u003e158\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.21\u0026ndash;1.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.38\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo initial cerebral involvement\u003c/p\u003e \u003cp\u003eInitial cerebral involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e92.2\u003c/p\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.45\u0026ndash;3.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHCT-ASCT in the first line\u003c/p\u003e \u003cp\u003eHCT-ASCT in the 2nd line\u003c/p\u003e \u003cp\u003eHCT-ASCT in the \u0026gt;\u0026thinsp;2nd line\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003cp\u003e24\u003c/p\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e83.1\u003c/p\u003e \u003cp\u003e92.2\u003c/p\u003e \u003cp\u003e158\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.10\u003c/p\u003e \u003cp\u003e1\u0026nbsp;.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.26\u0026ndash;16.6)\u003c/p\u003e \u003cp\u003e(0.12\u0026ndash;10.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.48\u003c/p\u003e \u003cp\u003e0.92\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnilateral ocular involvement before HCT-ASCT\u003c/p\u003e \u003cp\u003eBilateral ocular involvement before HCT-ASCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e158\u003c/p\u003e \u003cp\u003e92.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.62\u0026ndash;17.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTBC or TTP-BU conditioning\u003c/p\u003e \u003cp\u003eTTP-BCNU conditioning\u003c/p\u003e \u003cp\u003eBEAM conditioning\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003cp\u003e7\u003c/p\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e158\u003c/p\u003e \u003cp\u003e53.6\u003c/p\u003e \u003cp\u003e61.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.87\u003c/p\u003e \u003cp\u003e2.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.82-10.0)\u003c/p\u003e \u003cp\u003e(0.53\u0026ndash;8.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003cp\u003e0.29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIn CR after salvage chemotherapy\u003c/p\u003e \u003cp\u003eNot in CR after salvage chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e29\u003c/p\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e92.2\u003c/p\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.26\u0026ndash;3.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.96\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElevated IL-10 level before HCT-ASCT\u003c/p\u003e \u003cp\u003eNormal IL-10 level before HCT-ASCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53.6\u003c/p\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e(0.46\u0026ndash;42.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eN: number of patients. KPS: Karnofsky Performance Status. TBC: Thiotepa-busulfan-cyclophosphamide; TTP-BCNU: Thiotepa-carmustine; BEAM: Carmustine, etoposide, cytarabine, melphalan; TTP-Bu: Thiotepa, busulfan. HCT-ASCT: high-dose chemotherapy with autologous haematopoietic stem cell transplantation. CR: complete remission.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThere was no significant difference in terms of BFS between patients with PVRL (median: 113 months) and patients with PCNSL at initial diagnosis (median: not reached) (p\u0026thinsp;=\u0026thinsp;0.3).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge, this work represents the first large study with a long follow-up dedicated to HCT-ASCT in patients with isolated VRL. Autologous stem cell transplantation with a thiotepa-based conditioning regimen has been the standard first-line consolidation treatment for PCNSL, according to two major randomized phase II studies (\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). However, this treatment is still underutilized in PVRL, with limited data available in the literature. However, several studies from our team since the 2000s have shown the feasibility and effectiveness of HCT-ASCT for the treatment of VRL. Soussain et al. conducted a pilot study in 1996 involving five patients with refractory PVRL who underwent HCT, demonstrating its feasibility and showing encouraging results, with no cerebral relapse observed during the follow-up period (between 16 and 26 months) (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Soussain et al. conducted another study in 2001, which further demonstrated the feasibility of this treatment and revealed promising outcomes (3-year overall survival of 63.7% in 22 patients, including 3 with relapsed VRL and 6 with isolated vitreoretinal relapse of PCNSL) (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Subsequently, two additional studies were conducted: there was a 2-year OS rate of 69% after HCT-ASCT in a study of 43 relapsed patients including 5 with VRL (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e), and a median OS of 86 months after HCT-ASCT in 19 patients with relapsed VRL (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). More recently, Lee et al. described two patients with VRL treated with first-line HCT-ASCT who achieved long-term survival with follow-up durations of 7 and 8 years, respectively(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe results observed in our study were generally favourable (median OS, BFS, and PFS from HCT-ASCT of 92, 113 and 96 months, respectively). The PFS from HCT-ASCT was much longer than the PFS from initial diagnosis. These results represent a better prognosis than that usually described in the literature for PVRL (median overall survival from initial diagnosis ranging from 37 to 75 months in the main studies, with heterogeneous treatments ranging from local treatments to systemic treatment mainly based on high-dose methotrexate or to combined systemic and local treatments) (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) as well as for isolated ocular relapses of PCNSL (median overall survival from the date of isolated ocular relapse: 57.1 months) (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). We can reasonably imagine that most of the patients who were still disease-free 5 years after HCT-ASCT were definitely cured with this strategy. However, these results must be interpreted cautiously, especially given the retrospective nature of this study, with a high proportion of young patients having a good KPS, which is a factor well known to be associated with a better prognosis in PCNSL (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMost of the patients in our study received a thiotepa-based HCT. Due to the limited number of patients, it was difficult to compare the effectiveness of the various regimens or of thiotepa-based HCT versus BEAM. However, with 4 of 6 patients who relapsed following BEAM and given the poor results of this regimen in PCNSL cases (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e), our recommendation would be to prefer thiotepa-based regimens.\u003c/p\u003e \u003cp\u003eDespite the favourable survival outcomes, the post-HCT-ASCT relapse rate, particularly the cerebral relapse rate, remains high, both in patients with PVRL and in patients with PCNSL at initial diagnosis (45% at 5 years, 45% in patients with initial PVRL, 44% in patients with initial PCNSL). An important issue that could partly explain this high rate of relapse is the difficulty in adequately evaluating the quality of response in VRL patients. Currently, according to the IPCG criteria (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e), the response to treatment is assessed by a rather subjective clinical ophthalmological evaluation. There is no measurable mass in VRL, and many patients maintain residual abnormalities that may be either only a scar or the persistence of an active disease (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). We could therefore hypothesize that some patients from our cohort did not exhibit a good response at the time of HCT-ASCT, which is a well-known adverse prognostic factor regarding the efficacy of HCT-ASCT in PCNSL (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). The systematic assessment of IL-10 in the aqueous humour might be an interesting tool (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). This marker may have a greater sensitivity than clinical examination in detecting relapses early, although further research is needed to confirm this issue. In our cohort, we had limited data, with only 13 patients whose IL-10 levels were measured prior to HCT-ACST. However, three of five patients with elevated IL-10 levels at the time of HCT-ASCT subsequently relapsed.\u003c/p\u003e \u003cp\u003eThe majority of the patients in our series received HCT-ASCT in second line or subsequent lines of treatment. In PCNSL patients, the relapse rate is low following HCT-ASCT performed as a 1st-line treatment (5-year PFS of approximately 75%) (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) but is significantly higher in the setting of relapse, with rates close to those observed in our series (2nd -line treatment: 5-year PFS of 48% in PCNSL patients (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) vs. 44% in VRL patients in our series). In our cohort, only three patients received first-line HCT-ASCT, two of whom never relapsed after 5 and 9 years of follow-up. However, this represents a cohort that was too small to draw any adequate conclusions. Considering the similarity of the results observed in PCNSL and in PVRL, we could hypothesize that the results of HCT-ASCT in the 1st-line treatment of PVRL would be better than those in the setting of relapse. In light of the poor long-term prognosis of this disease, the use of HCT-ASCT as a 1st-line treatment for VRL should be discussed, especially considering the fact that most PVRL patients experience relapse after \"conventional\" first-line treatments (with a 5-year PFS of approximately 25% (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)). Given the good KPS of most PVRL patients, this strategy could be used in many of these individuals up to a fairly advanced age, as is done in select elderly patients with PCNSL (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe toxicity profile observed was close to what is usually observed in other studies involving HCT-ASCT (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). There was a 3% rate of toxicity-related mortality, which is slightly lower than the 5 to 10% range reported for PCNSL (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). Even if this toxic mortality rate appears to be acceptable, HCT-ASCT remains a toxic treatment that is difficult for many patients to tolerate, and patients should be aware of the limited but real risk of toxic death. Optimizing induction treatments for PVRL, potentially through the incorporation of novel drugs (imids, iBTK, etc.) (\u003cspan additionalcitationids=\"CR37\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e), could limit the need for HCT-ASCT by increasing the rate of complete response. We also currently lack molecular prognostic factors that could indicate whether patients belong to a group with a higher or a lower risk of relapse. Several recent studies have revealed promising prognostic molecular factors in PCNSL cases (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e), but reliable tools for identifying these factors in patients with VRLs are lacking. There might also be a role for the use of CAR T-cells, which has yet to be determined. Indeed, in systemic lymphomas, therapeutic strategies using CAR T-cells compare favourably to standard strategies, including HCT-ASCT (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e). Promising preliminary data on CNS lymphoma treated with CAR T-cells have been published in recent years, but there are limited data regarding ophthalmological involvement (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e).\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIntensive chemotherapy followed by autologous stem cell transplantation is an aggressive therapeutic approach for VRL but appears to provide interesting efficacy results for select patients, with a tolerable safety profile. However, the relapse rate, notably in the brain, following such a strategy remained high in a cohort of patients who mainly received 2nd or subsequent lines of treatment with HCT-ASCT. Several options might improve the prognosis: using HCT-ASCT in 1st -line treatment, as in PCNSL, improving the quality of the response prior to HCT-ASCT by incorporating new drugs into the induction chemotherapy regimen or using new strategies such as treatment with CART-cells.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFinancial support\u003c/strong\u003e: None\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest statement:\u003c/strong\u003e The authors have no proprietary interest in the materials used in this study and declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eAcknowledgments:\u003c/u\u003e\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe French National Institute of Cancer (INCa : Institut National du Cancer).\u003c/p\u003e\n\u003cp\u003ePhilippe Agapé\u003csup\u003e1\u003c/sup\u003e, Jérôme Paillassa\u003csup\u003e2\u003c/sup\u003e, Eve Rousseau\u003csup\u003e3\u003c/sup\u003e Ibrahim Jdid\u003csup\u003e4\u0026nbsp;\u003c/sup\u003eand all the members of the LOC network.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u0026nbsp;\u003c/sup\u003eDepartment of Medical Oncology,\u0026nbsp;Institut de Cancérologie de l’Ouest, Saint Herblain, France\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e2\u0026nbsp;\u003c/sup\u003eDepartment of Hematology, Angers University Hospital, Angers University, Angers, France\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e3\u0026nbsp;\u003c/sup\u003eDepartment of Ophthalmology, Clermont Ferrand University Hospital, France\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e4\u0026nbsp;\u003c/sup\u003eDepartment of Hematology, Orleans Hospital, France\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eAuthorship statement:\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCaroline Houillier, Carole Soussain and Valérie Touitou designed the research study; Adam Mainguy and\u0026nbsp;Caroline Houillier wrote the paper, acquired, analysed and interprated data\u003cstrong\u003e;\u0026nbsp;\u003c/strong\u003eCarole Soussain, Sylvain Choquet,Sara Touhami, Amin Bennedjai, Jean-Baptiste Ducloyer, Denis Malaise, Valérie Touitou, Laurent Kodjikian, Hervé Ghesquières, Gandhi Damaj, Rémy Gressin, Olivier Chinot, Anaïs Vautier, Cécile Moluçon-Chabrot, Guido Ahle, Luc Taillandier, Jean Pierre Marolleau, Adrien Chauchet, Fabrice Jardin,\u0026nbsp;Nathalie Cassoux, Adélaïde Toutée, Magali Le Garff-Tavernier and Khê\u0026nbsp;Hoang-Xuan\u0026nbsp;provided data, assisted in the preparation of the paper, and made significant contributions to the critical revision of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eCompeting Interests: \u0026nbsp;\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors confirm that there are no competing financial interests associated with the work described herein.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMalaise D, Houillier C, Touitou V, Choquet S, Maloum K, Le Garff-Tavernier M, et al. Primary vitreoretinal lymphoma: short review of the literature, results of a European survey and French guidelines of the LOC network for diagnosis, treatment and follow-up. Curr Opin Oncol. sept 2021;33(5):420\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLam M, Touitou V, Choquet S, Cassoux N, Ghesqui\u0026egrave;res H, Kodjikian L, et al. Intravenous high-dose methotrexate based systemic therapy in the treatment of isolated primary vitreoretinal lymphoma: An LOC network study. Am J Hematol. juill 2021;96(7):823\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCoupland SE, Damato B. Understanding intraocular lymphomas. Clin Experiment Ophthalmol. ao\u0026ucirc;t 2008;36(6):564\u0026ndash;78.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHong JT, Chae JB, Lee JY, Kim JG, Yoon YH. Ocular involvement in patients with primary CNS lymphoma. 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J Clin Oncol Off J Am Soc Clin Oncol. 10 nov 2022;40(32):3692\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchorb E, Kasenda B, Ihorst G, Scherer F, Wendler J, Isbell L, et al. High-dose chemotherapy and autologous stem cell transplant in elderly patients with primary CNS lymphoma: a pilot study. Blood Adv. 28 juill 2020;4(14):3378\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchorb E, Isbell LK, Kerkhoff A, Mathas S, Braulke F, Egerer G, et al. High-dose chemotherapy and autologous haematopoietic stem-cell transplantation in older, fit patients with primary diffuse large B-cell CNS lymphoma (MARTA): a single-arm, phase 2 trial. Lancet Haematol. 29 janv 2024;S2352-3026(23)00371-X.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKasenda B, Ihorst G, Schroers R, Korfel A, Schmidt-Wolf I, Egerer G, et al. 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Am J Hematol. 8 avr 2024;\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Supplementary Figures","content":"\u003cp\u003eSupplementary Figures are not available with this version\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bone-marrow-transplantation","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"bmt","sideBox":"Learn more about [Bone Marrow Transplantation](http://www.nature.com/bmt/)","snPcode":"41409","submissionUrl":"https://mts-bmt.nature.com/cgi-bin/main.plex","title":"Bone Marrow Transplantation","twitterHandle":"@bmtjournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Vitreoretinal Lymphoma, Autologous Haematopoietic Stem Cell Transplantation, High-dose Chemotherapy, CNS Lymphoma","lastPublishedDoi":"10.21203/rs.3.rs-4730575/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4730575/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eDespite its indolent evolution, vitreoretinal lymphoma (VRL) has a poor prognosis due to a major risk of relapse in the central nervous system (CNS) and may necessitate aggressive therapy. However, the use of high-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) is poorly documented. We retrospectively analysed from the French LOC network database the adult immunocompetent patients treated with HCT-ASCT for isolated VRL. Thirty-eight patients underwent consolidation with HCT-ASCT for isolated VRL between 2008 and 2019 after induction chemotherapy. Twenty patients had primary VRL, and 18 had an isolated VRL relapse of a primary CNS lymphoma. Three patients underwent HCT-ASCT in first-line treatment, 24 in second-line treatment, and 11 in subsequent lines. At HCT-ASCT, the median age was 61 years, and the median KPSwas 90. Thirty-two patients (84%) received high-dose thiotepa-based HCT. One patient (3%) died from HCT-ASCT toxicity. Nineteen (50%) patients relapsed after HCT-ASCT, including 17 cases occurring in the brain. The median progression-free survival, brain-free survival and overall survival from HCT-ASCT were 96, 113 and 92 months, respectively. HCT-ASCT represents an effective therapeutic strategy for select VRL patients, with a tolerable safety profile. However, the risk of subsequent brain relapse remains significant.\u003c/p\u003e","manuscriptTitle":"High-dose chemotherapy with autologous haematopoietic stem cell transplantation in patients with isolated vitreoretinal lymphoma: A LOC network study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-08 19:41:51","doi":"10.21203/rs.3.rs-4730575/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-08-06T15:01:35+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-08-04T13:02:53+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-07-15T15:03:49+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-15T10:29:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-12T13:16:11+00:00","index":"","fulltext":""},{"type":"submitted","content":"Bone Marrow Transplantation","date":"2024-07-12T13:16:10+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bone-marrow-transplantation","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"bmt","sideBox":"Learn more about [Bone Marrow Transplantation](http://www.nature.com/bmt/)","snPcode":"41409","submissionUrl":"https://mts-bmt.nature.com/cgi-bin/main.plex","title":"Bone Marrow Transplantation","twitterHandle":"@bmtjournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"ed73f435-6333-4f91-b969-c8f7a265f70e","owner":[],"postedDate":"August 8th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":34629200,"name":"Health sciences/Health care/Therapeutics/Stem-cell therapies"},{"id":34629201,"name":"Health sciences/Health care/Prognosis/Disease-free survival"}],"tags":[],"updatedAt":"2024-11-20T08:07:46+00:00","versionOfRecord":{"articleIdentity":"rs-4730575","link":"https://doi.org/10.1038/s41409-024-02477-y","journal":{"identity":"bone-marrow-transplantation","isVorOnly":false,"title":"Bone Marrow Transplantation"},"publishedOn":"2024-11-19 05:00:00","publishedOnDateReadable":"November 19th, 2024"},"versionCreatedAt":"2024-08-08 19:41:51","video":"","vorDoi":"10.1038/s41409-024-02477-y","vorDoiUrl":"https://doi.org/10.1038/s41409-024-02477-y","workflowStages":[]},"version":"v1","identity":"rs-4730575","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4730575","identity":"rs-4730575","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}