Primary Vitreoretinal Lymphoma Research Articles

Hyper-N-glycosylated SEL1L3 as auto-antigenic B-cell receptor target of primary vitreoretinal lymphomas

Primary vitreoretinal lymphoma (PVRL) is a rare subtype of DLBCL and can progress into primary central nervous system lymphoma (PCNSL). To investigate the role of chronic antigenic stimulation in PVRL, we cloned and expressed B-cell receptors (BCR) from PVRL patients and tested for binding against human auto-antigens. SEL1L3, a protein with multiple glycosylation sites, was identified as the BCR target in 3/20 PVRL cases. SEL1L3 induces proliferation and BCR pathway activation in aggressive lymphoma cell lines. Moreover, SEL1L3 conjugated to a toxin killed exclusively lymphoma cells with respective BCR-reactivity. Western Blot analysis indicates the occurrence of hyper-N-glycosylation of SEL1L3 at aa 527 in PVRL patients with SEL1L3-reactive BCRs. The BCR of a PVRL patient with serum antibodies against SEL1L3 was cloned from a vitreous body biopsy at diagnosis and of a systemic manifestation at relapse. VH4-04*07 was used in both lymphoma manifestations with highly conserved CDR3 regions. Both BCRs showed binding to SEL1L3, suggesting continued dependence of lymphoma cells on antigen stimulation. These results indicate an important role of antigenic stimulation by post-translationally modified auto-antigens in the genesis of PVRL. They also provide the basis for a new treatment approach targeting unique lymphoma BCRs with ultimate specificity.

Case report: Intraretinal hyperflow microinfiltration lesions on swept-source optical coherence tomography angiography as a potential biomarker of primary vitreoretinal lymphoma

Primary vitreoretinal lymphoma (PVRL) is often associated with central nervous system involvement, contributing to a heightened mortality rate, thus imaging features that are characteristic enough to be potential biomarkers of PVRL are important, either in diagnosis or in assessment of disease activity. This report details the case of a 68-year-old male who presented with blurred vision in both eyes persisting for 2 months. Fundus examination demonstrated vitreous opacity and multiple subretinal yellow nodular lesions of varying sizes in the peripheral fundus of both eyes. Multiple vertical hyperreflective lesions in the neural retina of posterior pole, indistinct outer retina borders in the fovea, and hyperreflective lesions in the sub-retinal pigment epithelium (RPE) space of the peripheral retina were demonstrated on swept-source optical coherence tomography (SS-OCT) of the left eye. Hyperflow signals corresponding to the vertical hyperreflective lesions were detected on swept-source optical coherence tomography angiography (SS-OCTA) images of retinal deep capillary plexus (DCP) layer. Notably, the hyperflow signals, precisely located around retinal vessels from the nerve fiber layer to the outer plexiform layer, were postulated to stem from the dilation of infiltrated retinal vessels. Vitreous pathological results of the left eye confirmed the diagnosis of PVRL. Treatments with intravitreal methotrexate injections led to a marked improvement of best-corrected visual acuity (BCVA) and regression of the hyperflow microinfiltration lesions demonstrated on SS-OCTA. In conclusion, SS-OCTA effectively delineated the vertical hyperreflective lesions and corresponding hyperflow signals in the posterior pole macular region of a patient with PVRL. These lesions significantly diminished following intravitreal methotrexate injections. We speculated that the specific hyperflow signals on SS-OCTA could act as a potential biomarker of PVRL, and SS-OCTA holds promise in facilitating early diagnosis and monitoring therapeutic responses in PVRL cases.

Swept-source optical coherence tomography angiography findings in a case of primary vitreoretinal lymphoma over a three-year follow-up

BackgroundVitreoretinal lymphoma (VRL) still represents a diagnostic challenge for retinal specialists. Early diagnosis and treatment are critical for a better prognosis. Several diagnostic tools have proven helpful in the identification of VRL abnormalities. However, swept-source OCT angiography (SS-OCT-A) findings and their long-term follow-up are yet to be explored.Case presentationa 42-year-old man presented with blurred vision in his left eye for 2 weeks. He denied any systemic symptoms. A multimodal imaging examination was performed, raising the clinical suspicion of VRL and guiding the ensuing diagnostic procedures. The patient underwent treatment and at the last FU visit three years later, no disease signs were present on fundus examination, nor on oncologic evaluation. Some novel SS-OCT-A features were identified, and uncommonly reported findings were examined over a long-term follow-up. At baseline multiple hyperreflective alterations were detected on the enface outer retina slabs and choriocapillary analysis revealed low reflectance areas in the foveal and parafoveal areas. One month after the first presentation, multiple hyperreflective retinal lesions in a vertical shape were detected on OCT which appeared on midretinal slabs of enface SS-OCT-A as hyperreflective spots mainly located near second-order retinal vessels. These alterations remarkably reduced after treatment.ConclusionSS-OCT-A may be a useful imaging technique in the detection of VRL, providing ophthalmologists additional findings that assist the diagnosis and follow-up of this disease. This may prove useful for a more timely and precise diagnosis, prompt therapy, and treatment response monitoring. The original aspects found in this case may provide grounds for future studies, ultimately fostering a better understanding of the disease.

Clinical Characteristics and Outcomes of Primary Vitreoretinal Lymphoma in Northern Thailand

OBJECTIVE This study aims to describe clinical characteristics and outcomes after treatment of primary vitreoretinal lymphoma (PVRL). METHODS Fifteen patients with a proven diagnosis of PVRL by histology, cytology and/or flow cytometry were analyzed. RESULTS The median age of the 15 patients was 59 years (range 41-71). Median follow-up time was 37 months (IQR 22.5-80) (range 4-106). Ophthalmic presentations of 25 eyes included vitritis (72%), chorioretinal infiltrations (60%), and retinal vasculitis (20%). Bilateral involvement was observed in 10 patients at presentation and in 4 patients during follow up. Ten patients (67%) developed brain involvement after ocular presentation with a median time of 22.5 months (range 2-84). Treatment modalities were included: 1) isolated intravitreal (IVT) methotrexate (6/15 patients; 40%) with a median number of injections of 4 (IQR 1,6) (range 1-16) 2) combined with IVT metho-trexate and/or rituximab and systemic chemotherapy and/or radiation (8/15; 53%) with a median of 6 injections (IQR 1,11) (range 1-16) and 3) systemic chemotherapy alone (1/15; 7%). Whole brain radiotherapy (WBRT) was performed in 10 of 15 patients (67%). Among the 6 patients who received isolated IVT methotrexate, 3 patients had complete remission (3/6; 50%), one died at 96 months after treatment, and one was lost to follow up after a single injection. Nine of 15 patients who received systemic chemotherapy with or without IVT chemotherapy and/or WBRT had complete remission (8/9; 89%). CONCLUSIONS Vitritis and chorioretinal infiltrations were the main ocular presentations of PVRL. Two-thirds of the patients developed brain involvement which resolved after treatment. Systemic chemotherapy tends to provide a higher rate of complete remission compared to local therapy alone.

Factors related to central nervous system involvement of primary vitreoretinal lymphoma.

This single center retrospective study aimed to investigate the factors associated with central nervous system (CNS) involvement of primary vitreoretinal lymphoma (PVRL). Clinical features of patients with PVRL (Group 1), those diagnosed with vitreoretinal lymphoma (VRL) after primary CNS lymphoma diagnosis (Group 2), and those concurrently diagnosed with CNS lymphoma and VRL (Group 3), were compared. The main outcomes included sex, age, types of treatment, survival, visual acuity, diagnostic methods, VRL recurrence, ocular manifestations, and interleukin levels in the aqueous humor. Groups 1, 2, and 3 included 66 eyes in 38 patients, 29 eyes in 18 patients, and 14 eyes in 8 patients, respectively. Group 3 had shorter overall survival (OS) than Groups 1 and 2 (P = 0.042 and P = 0.009, respectively). The three groups did not differ in progression-free survival (P = 0.060). The 5-year survival rates of Groups 1, 2, and 3 were 56.5%, 44.0%, and 25.0%, respectively (P = 0.001). Patients with CNS involvement in Group 1 exhibited VRL recurrence (P < 0.001), high interleukin-10 (P = 0.024), and sub-retinal pigment epithelium (RPE) infiltration (P = 0.009). Patients experiencing VRL recurrence in Group 1 tended to show CNS involvement (P < 0.001). Patients concurrently diagnosed with CNS lymphoma and VRL had a shorter OS and a lower 5-year survival rate. In patients with PVRL, the recurrence of VRL, high interleukin-10, and sub-RPE infiltration were associated with CNS involvement.

Diagnosis of primary vitreoretinal lymphoma masquerading infectious retinitis by retinal biopsy

PurposeTo report a case of primary vitreoretinal lymphoma masquerading as infectious retinitis that was diagnosed via a retinal biopsy.ObservationsA 72-year-old female patient was referred to our ophthalmology clinic for evaluation of retinitis and vasculitis in the right eye (OD). On examination, best-corrected visual acuities (BCVAs) were hand motions OD and 20/20 in the left eye (OS). Fundus examination revealed optic disc edema and diffuse retinal whitening superior to the superotemporal arcade OD. Given the high suspicion of infectious retinitis, the patient was treated with intravitreal foscarnet, systemic acyclovir, and oral prednisone and underwent a comprehensive uveitis workup, which was unremarkable for viral and autoimmune entities. Given the patient’s history of diffuse large B cell lymphoma with cutaneous involvement, vitreoretinal lymphoma was suspected, prompting pars plana vitrectomy with a retinal biopsy. Biopsy and immunohistochemistry results were consistent with B-cell lymphoma, and the patient was treated with high-dose methotrexate and rituximab. At 5-month follow-up, BCVAs were hand motions OD and 20/30 OS, and fundus examination demonstrated disc edema with resolution of retinal whitening OD. She responded well to the treatment with regression of vitreoretinal lymphoma on examination and is being monitored closely for lymphoma recurrence.Conclusions and importanceAlthough uncommon, patients with vitreoretinal lymphoma may masquerade as infectious retinitis, and vitreoretinal lymphoma should be suspected when refractory to antiviral therapy and in the setting of a negative workup for viral etiologies. Vitrectomy with retinal biopsy may be considered to aid the diagnosis of vitreoretinal lymphoma although careful consideration of the risks and benefits is warranted.

Occlusive retinal vasculitis as a presenting feature of primary vitreoretinal lymphoma relapse.

To report a case of primary vitreoretinal lymphoma (PVRL) relapse presenting as occlusive retinal vasculitis with secondary neovascularization. A retrospective case report. A Forty-year-old woman presented to the clinic with complaints of blurring of vision in the left eye for 4 months. Her best corrected visual acuity (BCVA) was 20/20 and 20/500 in the right and left eye, respectively. Both eyes' vitreous cavities showed vitreous opacities (2+). Both eyes fundus showed multifocal yellowish-white subretinal infiltration. A diagnostic vitreous and subretinal biopsy of the left eye revealed large lymphoid cells with CD20 positivity, confirming the diagnosis of PVRL. The patient received twelve intravitreal methotrexate (MTX) injections in both eyes over a course of 2 months, following which the lesions completely resolved. However, after 5 months, the left eye showed characteristic subretinal lesions along with perivascular exudates and retinal haemorrhages, diagnosed as PVRL relapse presenting as occlusive retinal vasculitis. Fluorescein angiography revealed retinal neovascularization (NVE), for which pan-retinal photocoagulation was performed along with repeated intravitreal MTX injection. PVRL is a great masquerader, and although rare, PVRL relapse can present as occlusive retinal vasculitis with secondary NVE, thereby delaying diagnosis and subsequent treatment.

Cloudy Vitelliform Submaculopathy as an Early Sign of Primary Vitreoretinal Lymphoma.

Cloudy Vitelliform Submaculopathy as an Early Sign of Primary Vitreoretinal Lymphoma.

Clinical factors for central nervous system progression and survival in primary vitreoretinal lymphoma.

Primary vitreoretinal lymphoma (PVRL) is a rare subtype of malignant lymphoma with a poor prognosis because of high frequency of central nervous system (CNS) progression. Identification of factors associated with CNS progression is essential to improve the prognosis of patients with PVRL. We conducted a retrospective study of 54 patients diagnosed with PVRL and treated at our hospital to identify factors associated with CNS progression and prognosis. All patients were treated with intravitreal methotrexate (MTX) injections in the affected eyes until lesion resolution. Twenty-four patients were treated with systemic administration of high-dose MTX (systemic HD-MTX) every other week for a total of five cycles following intravitreal MTX injection. Of 24 patients, 20 completed five cycles of systemic HD-MTX. The 5-year cumulative incidence of CNS progression and overall survival (OS) rate were 78.0% and 69.0% respectively. By univariate and multivariate analyses, bilateral disease and the detection of B-cell clonality confirmed by flow cytometric analysis were risk factors associated with CNS progression. Moreover, systemic HD-MTX completion reduced the risk of CNS progression and was identified as a factor affecting OS. In this study, factors for CNS progression identified may potentially contribute to the optimized therapeutic stratification to improve the survival of patients with PVRL.

An International Multicenter Study of Primary Vitreoretinal Lymphoma from the Australasian Lymphoma Alliance and Collaborators

Background: Primary vitreoretinal lymphoma (PVRL) is a rare high-grade extranodal non-Hodgkin lymphoma characterized by frequent and often fatal central nervous system (CNS) relapse. Despite improved outcomes for patients with primary CNS lymphomas over the last decade, approaches to the diagnosis and management of PVRL remain contentious. Given limited prospective data to date, there is need to better elucidate current international practice in the modern era to optimize outcomes for this patient group. Methods: Patients with pathologically confirmed PVRL diagnosed between January 2010 and December 2022 were identified from ten sites across Australia, Singapore, Canada and the United Kingdom. Patients were aged ≥18 years, with isolated PVRL at diagnosis (i.e. no concomitant CNS involvement at baseline or secondary vitreoretinal involvement). Variables included were baseline demographic data, presenting symptoms, diagnostic procedures undertaken and sample characteristics such as cytological, immunocytochemical and flow cytometric features. Where available, molecular results and biomarkers such as IL-10 and IL-6 were also collected. Treatment approaches including local, systemic and combined local/systemic therapies were captured. Outcomes measured included response rates, patterns of relapse, progression-free (PFS) and overall survival (OS). Results: 36 patients were identified with a median age at diagnosis of 68 years (range 38-89) with a female predominance (58%). Most patients presented with bilateral involvement (72%) with decreased visual acuity being the predominant presenting symptom (53%). Most patients received a PVRL diagnosis within weeks to months of symptom onset, however a third of patients had &amp;gt;12 months delay to diagnosis. Ancillary diagnostic tests such as flow cytometry, molecular and cytokine measurements performed in a minority of patients only, largely due to sample viability and paucity. Concurrent CNS involvement was evaluated by brain MRI in 97% with diagnostic lumbar punctures performed in 64%. Exclusion of systemic disease was predominantly done via PET or PET/CT (69%) with the remainder via CT alone (Table 1). Upfront treatment choices were highly varied across participating sites with incorporation of systemic therapy in the majority (64%) of cases, either alone (25%) or in combination with local therapies (39%). For those who received systemic therapy, all incorporated high-dose methotrexate with the median dose delivered of 3.5g/m 2 per cycle and rituximab was incorporated in 48%. Autologous stem cell transplantation (ASCT) was part of frontline management in 19% of cases, and the median age of those receiving frontline ASCT was 55 years versus 71 years in those who did not. With median follow-up of 57 months (IQR 24-74 months), the median OS was 90 months whilst median PFS was only 23 months (Figures 1 and 2). 18 patients experienced disease relapse during follow up, only 2 of which had received frontline ASCT. The median PFS and OS of those who received frontline ASCT was not reached and 92 months respectively. Patients who had systemic treatment incorporated into frontline management had a trend toward improved OS than those who did not (Figure 3). Of those with relapsing disease, 14 (78%) had CNS involvement, and 29% of these patients experienced concurrent CNS and systemic involvement at relapse. Median OS from time of relapse was 8 months (IQR: 3-89 months). Of the 14 deaths occurring during follow up, 6 (43%) were secondary to lymphoma, 2 (14%) were related to toxicities of treatment and the rest were unknown or related to other co-morbidities. Conclusion: To our knowledge, this is the largest international multicenter cohort of patients with isolated PVRL reported in the modern era. The apparent improvement in OS compared with historical cohorts may reflect improvements in therapy in the recent decade, and incorporation of systemic therapy in frontline management demonstrated a trend to improved OS. However, high rates of CNS relapse continue to be a challenge. Delays in diagnosis and variation in diagnostic and management pathways reflect the need to develop prospective studies and international consensus guidelines for managing this rare lymphoma.

A Phase I/II Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of BTK Inhibitor HZ-a-018 in Adult Patients with Relapsed and/or Refractory Central Nervous System Lymphoma

Background: HZ-A-018 is a highly selective and potent covalent BTK inhibitor with CNS-penetrating profile, which was previously reported (Abstract 5501, ASH 2022). Phase I/II study is ongoing in China, and here we present preliminary results of HZ-A-018 monotherapy of the phase I part in central nervous system lymphoma. Methods: HZ-A-018-102 is an ongoing phase I/II study (CTR20210181) to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of HZ-A-018 in central nervous system lymphoma. The primary objective for phase I monotherapy was to determine the safety and tolerability and the recommended phase 2 dose (RP2D), and secondary objectives included preliminary antitumor activity and pharmacokinetics in patients with relapsed/refractory primary/secondary CNS lymphoma (R/R PCNSL/SCNSL) and primary vitreoretinal lymphoma (PVRL) who had received ≥1 prior therapy. HZ-A-018 was administered orally once daily in 28-day cycles until disease progression or unacceptable toxicity. Results: At the data cutoff date of 30 May 2023, 21 pts from the phase I monotherapy were analyzed, including 18 R/R PCNSL and 3 R/R SCNSL. 3 pts received 300mg/d, 12 pts received 450mg/d and 6 pts received 600mg/d. 600mg was the highest dose pre-defined in the study and MTD was not reached. Pts were with a median age of 62 years (range: 36-80), median KPS 80 (range: 60-90) and a median of 2 prior systemic therapies (range: 1-5). 20 pts (95.2%) presented with brain parenchyma, and 1 pt (4.8%) presented with intraocular (IO) involvement. All patients had received HD-MTX based chemotherapy, 19 pts (90.5%) had received rituximab and 1 pt had received whole brain radiation therapy (WBRT). 16 of 21 pts (76.2%) experienced a treatment related adverse event (TRAE). The most common TRAEs (≥10%) were thrombocytopenia (42.9%), neutropenia (23.8%), leukopenia (23.8%), and hypokalemia (14.3%), majority of which were grade 1 to 2. DLTs occurred in 1 pt at 450 mg/d and 1 pt at 600 mg/d. 4 pts (19.0%) had dose interruption, no pts had dose reductions, and no pts discontinued from the study due to TRAEs. The plasma and cerebrospinal fluid (CSF) pharmacokinetics showed HZ-A-018 was rapidly absorbed and could cross the blood-brain barrier with CSF HZ-A-018 concentration ranged from 5.94 to 17.5 ng/mL two hours post-dose. Of 19 pts available for tumor assessment (16 PCNSL with brain parenchyma, 1 PCNSL with IO and 2 SCNSL with brain parenchyma) and 2 pts not evaluable (1 PCNSL with brain parenchyma, and 1 SCNSL with brain parenchyma), the overall response rate (ORR) was 52.4% (95%CI: 29.8, 74.3), including 23.8% (5 pts) complete response(CR)/unconfirmed complete response(CRu), 28.6% (6 pts) partial response (PR), and 19.0% (4 pts) stable disease (SD), contributing to an 71.4% (95%CI: 47.8, 88.7) disease control rate (DCR). At 600mg/d, all 6 pts had achieved high and deep responses, contributing to 100% ORR and 50% CRR, with the 3-month duration of response (DOR) rate not reached. Dose expansion was ongoing at 600mg QD. Conclusions: These results demonstrated that HZ-A-018 was efficacious and well-tolerated in CNS lymphoma patients with high CNS penetrating profile. The monotherapy RP2D for R/R PCNSL was determined as 600 mg QD and a phase 2 R/R PCNSL registration study in China is currently planned.

Efficacy and Safety of BTK Inhibitors in Vitreoretinal Lymphoma: A Single-Center, Retrospective Analysis of 24 Patients

Background: Vitreoretinal lymphoma (VRL) is a special subtype of rare central nervous system lymphoma (PCNSL). Most of the pathologic types are diffuse large B-cell lymphoma of non-germinal central origin. Currently, the optimal treatment strategy for VRL is not clear, and the traditional treatment usually includes about 20 repeated intravitreal injections of low doses of methotrexate or intraocular local radiotherapy. Eventually, however, 60-90% of VRL will progress to PCNSL. Therefore, CNS prophylaxis of VRL patients is very important. A previous prospective clinical study of our research group (including 10 VRL patients) confirmed that single-drug BTK inhibitors can replace repeated intravitreal injection of low doses of methotrexate, with rapid effect, high safety, and certain value in preventing CNS progression. Methods: In order to further clarify the efficacy and safety of BTK inhibitors in VRL patients, we included 24 VRL patients who were consecutively admitted to the Hematology Department of Beijing Tongren Hospital from May 2020 to December 2022, and retrospectively analyzed their clinical features, treatment methods, treatment outcomes, survival status and treatment-related adverse reactions. Results: Of the 24 patients, 14 were female and 10 were male, with a median age of 62 years old (36-75). There were 18 patients with primary VRL (PVRL) and 6 patients with secondary VRL (SVRL) to PCNSL. The IL-10 in aqueous humor/vitreous fluid at baseline was significantly increased in all patients (362.1±89.5pg/mL), and the IL-10/IL-6 ratio was greater than 1. Except for one patient with both uncontrolled PCNSL and VRL, the other 23 VRL patients showed no evidence of CNS involvement by brain MRI and cerebrospinal fluid detection. All 24 patients were treated with a BTK inhibitor (Zanubrutinib 160mg bid, or Orelabrutinib 150mg qd), of whom, 9 VRL patients were also treated with intravitreal methotrexate injection (0.4mg/ time, weekly ×12 times → monthly ×9 times) concurrently, and the remaining 15 patients did not receive any antitumor therapy other than BTK inhibitors. After 1 month of treatment with BTK inhibitors, the efficacy was evaluated by slit lamp microscope, optical coherence tomography (OCT), and aqueous humor cytokines. 21 patients achieved CR (87.5%), 2 PR (8.3%), and 1 PD (progression of CNS lesion but improvement of intraocular disease). The IL-10/IL-6 levels in aqueous humor were lower than 1 in all 24 patients 1 month after treatment, and the IL-10 levels in aqueous humor were slightly higher than the normal range in two patients. The median duration of BTK inhibitors use was 10 months (1.5-23.0 months). At a median follow-up of 17 months (5.4-31.5 months), 15 patients (62.5%) developed disease progression, including 11 patients (45.8%) with CNS progression and 4 patients (16.7%) with intraocular recurrence. The median progression-free survival (PFS) time was 11.9 months, and the median overall survival (OS) time was not reached. The 1-year and 2-year PFS rates were 34% and 26%, and the 1-year and 2-year OS rates were 96% and 82%, respectively. The recurrence rate was 33.3% in the combined treatment group and 80.0% in the BTK inhibitors monotherapy group. A total of three patients died, all due to CNS progression. BTK inhibitors were generally well tolerated in VRL patients, with no adverse reactions that led to treatment discontinuation. 4 patients had grade 1-2 hypertension (16.7%), 1 patient had grade 1 hypotension (4.2%), 2 patients had grade 1 joint pain (8.5%), and 6 patients had grade 1 subcutaneous hemorrhage and ecchymosis (25.0%). Four patients developed COVID-19 infection while taking the drug and the drug was suspended. All four patients recovered from COVID-19 infection within 2 weeks and did not develop significant pneumonia. Conclusion: This is the largest report regarding the use of BTK inhibitors in VRL patients. BTK inhibitor has a rapid local control effect on VRL and is well tolerated. However, BTK inhibitors monotherapy has unsatisfied preventive effect on the CNS, and it is still necessary to explore the value of combinational therapy, such as combined BTK inhibitors and high-dose methotrexate.

Prognosis, Risk Factors, and Clinical Features of Intraocular Recurrence in Primary Vitreoretinal Lymphoma

PurposeTo investigate the clinical features, risk factors, and prognosis of the intraocular recurrence in primary vitreoretinal lymphoma (PVRL). DesignRetrospective case-control study. Participants97 eyes of 51 patients diagnosed with PVRL between 2011/12 and 2021/1 were enrolled in this study. 14 patients among them had experienced intraocular recurrence. MethodsDate on demographic and ophthalmic characteristics, results of diagnostic tests, treatments, prognosis of intraocular recurrence and non-recurrence PVRL patients were collected and compared. Multivariate logistic regression was used to identify independent risk factors. And receiver operating characteristic curve was conducted to determine the cut-off values. Main Outcome MeasuresClinical features and risk factors. Results14 (19 eyes) of 51 PVRL patients had intraocular recurrences, resulting in a recurrence rate of 27.5% over a mean follow-up period of 42.5 months. No difference was observed in central nervous system lymphoma (CNSL) relapse rate (54.3% vs. 64.3%, p=0.523) and median time to CNSL (36.5 95%CI [24.6-48.3] vs. 37.3 95%CI [24.8-49.8], p=0.777) between intraocular non-recurrence and intraocular recurrence groups. Furthermore, there were no statistically significant difference in the survival outcomes, such as mortality (28.6% vs. 29.7%, p=1.000) and median overall survival (70.8 95%CI [54.0-87.7] vs. 59.2 95%CI [44.8-73.6], p=0.297), between these two groups. Younger onset age (odds ratio [OR] 0.90, 95% confidence intervals [CI] 0.84-0.98, p=0.010), isolated PVRL (OR 35.3, 95%CI 2.08-600.0, p=0.014), and no history of intravitreal chemotherapy (OR 7.72, 95%CI 1.37-43.6, p=0.021) were identified as independent risk factors for intraocular recurrences. Of the patients with intraocular recurrence, 23.6% were asymptomatic and were diagnosed during routine follow-up. The rate of interleukin-10 (IL-10) /IL-6>1 was significantly lower than that at diagnosis (43.8% vs. 92.3%, p=0.008). However, the rate of IL-10≥50 pg/mL was high (81.3%) and not significantly different from that at diagnosis (92.3%, p=0.606). ConclusionsThis study did not identify an impact of intraocular recurrence on CNS manifestations or survival outcomes in patients with PVRL. Younger patients have a higher risk of intraocular recurrence, and combined systemic and intravitreal chemotherapy may reduce intraocular recurrence. Regular ophthalmic follow-up and IL-10 testing are recommended to detect intraocular recurrence.

A novel Finding in the Diagnosis of Primary Vitreoretinal Lymphoma: A Case Report.

Introduce a unique case of primary vitreoretinal lymphoma with a new optical coherence tomography finding. A case report. A 67-year-old healthy man with complaints of blurry vision in his right eye. The patient's visual acuity was 20/60 and 20/20 in the right and left eyes, respectively. Anterior segment exam of the right eye demonstrated mild inflammation. Dilated fundoscopy revealed 2+ vitreous haze and 4+ disc edema. Optical coherence tomography of the macula in the right eye revealed optic nerve head swelling and thickening of the retina. Fluorescein angiography demonstrated mild leakage and staining of vessels along the inferotemporal arcade in the right eye. Labs were within normal limits except positive Herpes simplex virus 1 IgG. Initially, the patient was treated for herpetic panuveitis for three weeks with a favorable response. However, the clinical condition deteriorated as a new abnormality was identified in the macular region of the right eye through optical coherence tomography. Considering intraocular lymphoma as a potential diagnosis, the patient underwent a diagnostic vitrectomy. The vitreous sample analysis confirmed PVRL through immunohistochemistry and flow cytometry. The patient exhibited a rapid response following the initiation of intravenous and intravitreal methotrexate treatment. The presence of subretinal fluid accompanied by suspended hyperreflective lesions originating from the roof of the subretinal fluid pocket on the OCT of macula "stalactite sign" might serve as a characteristic sign indicative of primary vitreoretinal lymphoma; however, further investigation using robust studies is necessary to examine this hypothesis.

Regression of Primary Vitreoretinal Lymphoma (Pvrl) And Perivascular Flower Bud Like Lesions (Pfbls) on Octa After Intravitreal Methotrexate Injection Series

Primary Vitreoretinal Lymphoma (PVRL) is a rare and aggressive type of intraocular lymphoma that affects the eye. PVRL is most commonly diagnosed in individuals in their sixth to eighth decade of life, but it can occur in younger, immunocompromised individuals. PVRL is challenging to diagnose due to its non-specific presentations, and a delay in diagnosis from the onset of symptoms can exceed 12 months. CNS involvement in PVRL is common, and patients may develop CNS involvement within a mean interval of 8-29 months after diagnosis. We present a case of a 73-year-old man who presented to the emergency department with gradual decline in vision in his left eye over the past two years, with acute worsening over the past two weeks. The patient was diagnosed with PVRL with CNS involvement based on exam, imaging and biopsy findings. The patient received intravitreal injection of methotrexate in the left eye and systemic treatment with rituximab and ibrutinib. The patient’s visual acuity improved in the left eye, and regression of tumor size was noted on the fundus exam, OPTOS, and OCTA. Prompt referral to a medical center and early diagnosis are essential in managing PVRL to prevent potential vision loss. Various imaging modalities such as fluorescein angiography, optical coherence tomography, and optical coherence tomography angiography can be helpful in diagnosis and management of PVRL. However, the use of optical coherence tomography angiography has been only described in few case studies. The management of PVRL remains a challenge, with limited treatment options available, including systemic chemotherapy and/or radiation therapy

A case of Epstein-Barr virus-associated primary vitreoretinal lymphoma in an immunosuppressed patient.

To describe a rare case of Epstein-Barr virus (EBV)-positive primary vitreoretinal lymphoma (PVRL) in an immunosuppressed patient. Observational case report. A 64-year-old man under immunosuppressive therapy for rheumatic arthritis was referred for 2-month of blurred vision and decreased visual acuity in the right eye. Only mutton-fat keratic precipitates and mild vitreous opacity were found in the right eye without (sub-)retinal or sub-retinal pigment epithelial lesions. Vitreous biopsy and systemic workup suggested the diagnosis of PVRL of diffuse large B cell lymphoma (DLBCL) subform. Neoplastic cells stained positive for EBV antigens, EBV-encoded small RNA and Epstein-Barr nuclear antigen 2, consistent with EBV-positive DLBCL. Intravitreal methotrexate was effective in improving ocular symptoms. Our case provided evidence on the association of EBV infection with PVRL.

DIAGNOSTIC YIELD OF IN VITRO VITREOUS BIOPSY FOR INTRAOCULAR LYMPHOMA AT VARIABLE VITREOUS CUTTER SPEEDS USING 25-GAUGE VITRECTOMY.

Primary vitreoretinal lymphoma is the most common intraocular lymphoproliferative disorder. We evaluated the diagnostic yield of pars plana vitrectomy, specifically using modern high cut rate dual-cycle cutters, on in vitro cell viability and diagnostic yield. Human Burkitt lymphoma cell line Namalwa at 2 x 10^5 cells/mL was aspirated by 25-gauge dual-blade guillotine-type vitrectomy at five speeds (500, 1,000, 4,000, 7,500, or 15,000 cuts per minute). Cell viability and diagnostic yield in each subtype group were determined using hemocytometry, viable cell count using Cell Counting Kit-8, and pathologist-guided manual count. No significant deviation in cell count was identified in any cut rate by ANOVA ( P = 0.61), and no trends in the number of viable cells were identified across cut rates (R 2 = 0.188, P = 0.47). Among histologic cell counts per cut-rate, neither linear regression (R = 0.531, P = 0.16) nor ANOVA ( P = 0.096) were statistically significant. There was no significant degradation in the number of viable cells with increasing cut speed. These results suggest that in contrast to previous findings using 20g or 23g vitrectomy for diagnostic vitrectomy, modern vitrectomy systems may be used at up to 15,000 cpm without compromising the viability of lymphoma cells.

EFFICACY AND SAFETY OF BTK INHIBITORS IN VITREORETINAL LYMPHOMA: A SINGLE‐CENTER RETROSPECTIVE ANALYSIS OF 24 PATIENTS

Purpose: Vitreoretinal lymphoma (VRL) is a rare subtype of lymphoma. The optimal treatment strategy is not yet defined. 60%–90% of VRL will progress to PCNSL. Therefore, central nervous system (CNS) prophylaxis for VRL patients is critical. Our previous studies have shown that BTK inhibitors monotherapy can replace repeated intravitreal injection of low-dose methotrexate, with rapid effect and a certain preventive value for the CNS. This study aimed to expand the sample size and extend the follow-up time to retrospectively analyze the efficacy and safety of BTK inhibitors in VRL. Method: A total of 24 VRL patients admitted to the Department of Hematology in Beijing Tongren Hospital from May 2020 to December 2022 were included. The clinical characteristics, treatment methods, treatment outcomes, survival status and treatment-related adverse reactions were retrospectively analyzed. Results: The median age was 62 years. There were 18 primary VRLs (PVRLs). The IL-10 in aqueous humor at baseline was significantly increased, and the IL-10/IL-6 ratio was greater than 1. There was no evidence of CNS involvement in 23 patients. All patients were treated with a BTK inhibitors (zanubrutinib 160 mg bid, or orelabrutinib 150 mg qd), and nine of them were also treated with intraocular injection of methotrexate. After 1 month of treatment, 21 patients had CR (87.5%) and 2 patients had PR (8.3%). The IL-10/IL-6 levels of aqueous humor were lower than 1 in all patients. The median duration of BTK inhibitors was 10 months. At a median follow-up of 17 months, 15 patients (62.5%) developed disease progression, including 11 with CNS infiltration and 4 with intraocular recurrence. The median PFS was 11.9 months, and the median OS was not reached. The 1-year PFS rate was 34% and the 1-year OS rate was 96%. The recurrence rate was 33.3% in the combined treatment group and 80.0% in the monotherapy group. Three patients died, all from CNS progression. BTK inhibitors were well tolerated, with grade 1-2 hypertension of 16.7%, grade 1 hypotension of 4.2%, grade 1 joint pain of 8.3%, grade 1 subcutaneous bleeding and ecchymosis of 25.0%. Four patients developed COVID-19 infection and BTK inhibitor medication was suspended. All patients had negative COVID-19 test within 2 weeks and did not develop significant pneumonia. Conclusion: BTK inhibitors showed rapid local control of VRL and were well tolerated. However, monotherapy with BTK inhibitors does not provide adequate central nervous system prophylaxis, and the combination of BTK inhibitors with other drugs, such as high-dose methotrexate, should be explored. The research was funded by: This work was supported by grants from the National Natural Science Foundation of China (grant No. 81873450, 82170181), Beijing Hospitals Authority Youth Programme (code: QML20200201), and Beijing Natural Science Foundation (No.7222027) to Liang Wang. Keywords: aggressive B-cell non-Hodgkin lymphoma, molecular targeted therapies No conflicts of interests pertinent to the abstract.

Diagnosis and management of vitreoretinal lymphoma: present and future treatment perspectives.

Intraocular lymphoma (IOL) is a rare malignant intraocular lymphocytic tumor that mimics uveitis. IOL is anatomically classified into vitreoretinal lymphoma (VRL) and uveal lymphoma; most IOLs are VRLs, while uveal lymphoma is rare. VRL is highly malignant, with 60%-85% of patients developing central nervous system (CNS) lymphoma; primary VRL (PVRL) is an ocular disease with poor prognosis. We aimed to review the management and both current and future treatments for VRL. VRL diagnosis is based on the results of cytopathological examination using vitreous biopsy. However, the positive ratio of vitreous cytology remains 29%-70%. A combination of adjunctive tests may improve diagnostic accuracy, but as yet no gold-standard regimen has been established. Methotrexate intravitreal injections are effective in controlling ocular lesions; however, this treatment allows CNS dissemination. The efficacy of systemic chemotherapy in suppressing CNS dissemination has been recently debated. A multicenter prospective study with a unified treatment protocol is required to clarify this issue. In addition, establishing a treatment protocol for elderly patients and those with poor general health is necessary. Moreover, relapsed/refractory VRL and secondary VRL are more difficult to treat than PVRL because they are prone to recurrence. Ibrutinib, lenalidomide with or without rituximab, and temozolomide are promising treatments for relapsed/refractory VRL. In Japan, Bruton's tyrosine kinase (BTK) inhibitors have been approved for treating refractory CNS lymphoma. Furthermore, a randomized prospective study of tirabrutinib, a highly selective BTK inhibitor, is ongoing for evaluating the suppressing of CNS progression in patients with PVRL.

Primary Vitreoretinal Lymphoma Masquerading as Post-Operative Endophthalmitis in a Pregnant Patient with Longstanding Idiopathic Panuveitis.

To report primary vitreoretinal lymphoma after surgical 0.59 mg fluocinolone acetonide implant (FAi) exchange in a patient treated with adalimumab for idiopathic bilateral panuveitis. Retrospective case review. A 37-year-old woman with bilateral idiopathic panuveitis, who had favorable responses to previous FAi surgical implants, presented with right eye recurrent intraocular inflammation and cystoid macular edema that partially responded to systemic adalimumab. Her FAi was replaced, given her previous favorable response. She developed post-operative ocular inflammation transiently responsive to two serial vitreous taps and injections of intravitreal antimicrobials and then worsening inflammation and new layered flocculant material. Diagnostic vitrectomy showed a few atypical lymphocytes and cultures were negative. At post-diagnostic vitrectomy month 1, flocculant material recurred. Aqueous cytology and flow cytometry revealed large CD45 positive B-cells suspicious for lymphoma. Post-operatively, she revealed that she was pregnant. She was treated with 8 monthly intravitreal methotrexate injections and post-partum consolidation radiotherapy. Subsequent repeat cytology, flow cytometry, and corneal pathology revealed large B-cells that were CD20 positive, and next generation sequencing detected a dominant monoclonal B-cell population, diagnostic of PVRL. 19 months after FAi exchange, she developed an area of enhancement in the lateral aspect of the right frontal lobe on brain MRI, consistent with central nervous system involvement. We present a unique case of PVRL masquerading as post-operative endophthalmitis after FAi exchange in an eye with chronic panuveitis treated with adalimumab immunosuppressive therapy. We hypothesize that there may be a causal relationship between adalimumab and PVRL.