RARE DISEASE
Primary intraocular lymphoma
Primary intraocular lymphoma
Primary intraocular lymphoma
Synonyms: PIOL, Primary intraocular non-Hodgkin lymphoma
Synonyms: PIOL, Primary intraocular non-Hodgkin lymphoma
Synonyms: PIOL, Primary intraocular non-Hodgkin lymphoma
Drug discovery
1
drug
With orphan designation
Overview
Primary intraocular lymphoma (PIOL), a rare subtype of primary central nervous system lymphoma (PCNSL), is an aggressive diffuse large B-cell lymphoma affecting the retina, vitreous, and/or optic nerve. It often mimics chronic uveitis, delaying diagnosis. Definitive diagnosis requires invasive techniques, including cytokine analysis (IL-10:IL-6 >1) and vitreous biopsy. Treatment combines intravitreal methotrexate/rituximab with systemic high-dose methotrexate-based chemotherapy. Despite initial remission, CNS relapse occurs in up to 90% of patients, resulting in poor prognosis (median survival <3 years) [1][4][7][12].
Therapies
Local control: Intravitreal methotrexate (400 µg) or rituximab (1 mg) injections (induction, consolidation, maintenance phases) [3][12][16].
Systemic therapy: High-dose methotrexate (≥8 g/m²) ± rituximab for CNS prophylaxis [2][3][7].
Radiation: Low-dose ocular radiotherapy (20–40 Gy) for refractory cases; combined neuro-ophthalmic management is critical [3][12][16].
Categories: rare hematological diseases, rare neoplastic diseases, rare ophthalmic disorders, rare transplant-related disorders
Research Papers
335 drug discovery papers about Primary intraocular lymphoma, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
335 drug discovery papers about Primary intraocular lymphoma, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-10 | Diagnostic and therapeutic challenges in primary vitreoretinal lymphoma: a practical clinical approach.
Primary vitreoretinal lymphoma (PVRL) is a rare but aggressive subtype of extranodal diffuse large B-cell lymphoma and is closely related to primary central nervous system lymphoma (PCNSL). Its ability to masquerade as chronic posterior uveitis frequently leads to delayed diagnosis and inappropriate treatment, with significant prognostic implications. A narrative review was performed following a comprehensive search of the PubMed/MEDLINE and Cochrane Library databases, encompassing publications from 2000 through 2025 and including randomized controlled trials, observational studies, prospective and retrospective studies, and systematic reviews. The search strategy incorporated the following keywords: "primary vitreoretinal lymphoma", "intraocular lymphoma", "diagnostic vitrectomy", "MYD88 mutation", "IL-10/IL-6 ratio", "intravitreal methotrexate", "rituximab", "CNS involvement", "optical coherence tomography". Two authors independently conducted study selection and eligibility assessment. Heightened clinical awareness remains pivotal for diagnosing PVRL, particularly when vitritis is partially responsive to steroids, when involvement is bilateral or asymmetric, and when subretinal pigment epithelial infiltrates are present. Multimodal imaging - including optical coherence tomography (OCT), fundus autofluorescence (FAF), and fluorescein angiography (FA) - facilitates early recognition and supports clinical suspicion. Diagnostic vitrectomy with cytology, immunohistochemistry, cytokine analysis (IL-10/IL-6 ratio), and molecular testing (IgH rearrangement, MYD88 L265P mutation) significantly increases diagnostic accuracy. Due to the strong association with central nervous system (CNS) involvement, neuroimaging is mandatory at diagnosis and during follow-up. Treatment options include intravitreal methotrexate and/or rituximab, systemic high-dose methotrexate-based chemotherapy, and radiotherapy. Emerging therapies in PVRL focus on targeted agents, including intravitreal biologics, BTK inhibitors, and personalized molecular-based treatments. The optimal strategy remains controversial and should be individualized based on CNS status and patient characteristics. Primary vitreoretinal lymphoma remains a diagnostic challenge due to its ability to mimic chronic inflammatory eye disorders and the frequent delay in establishing a definitive diagnosis. The integration of multimodal imaging, vitreous cytology, immunohistochemistry, cytokine profiling, and molecular testing has significantly improved diagnostic accuracy. However, management remains complex because of the close association with CNS involvement and the absence of universally accepted treatment protocols. Current therapeutic approaches, including intravitreal chemotherapy, systemic methotrexate-based regimens, and targeted therapies, require individualized selection based on disease extension and patient characteristics. Future advances in molecular diagnostics and personalized treatment strategies may contribute to earlier detection, improved disease control, and better long-term outcomes. Prompt diagnosis, combined with a structured diagnostic approach, is essential to improving outcomes in PVRL. Close collaboration among ophthalmologists, hematologists, neurologists, and pathologists is mandatory for optimal patient management.
2026-07-16 | Expanding the Horizon of CAR-T Cell Therapy: Present Obstacles and New Strategies for Future CARs in Solid Tumors.
Chimeric antigen receptor (CAR)-T cells are synthetic receptors used for the recognition of specific antigens expressed by reprogrammed T cells for targeting tumors. CAR-T cell therapy has gained remarkable clinical success for the treatment of hematological malignancies such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), lymphoplasmacytic lymphoma (LPL), and primary intraocular lymphoma (PIL). The increasing number of preclinical investigations and clinical trials is focusing on extending CAR-T cell therapy to solid tumors due to its remarkable success in leukemia and lymphoma cancers. However, some limitations of CAR-T therapy still exist, including a lack of targetable antigen diversity, heterogeneous antigen expression, insufficient T-cell trafficking efficiency, and an immunosuppressive tumor microenvironment. This review explores the role of CAR-T cell therapy, current challenges, and emerging solutions for solid tumor malignancies. To overcome the existing limitations of CAR-T cell therapy, innovative strategies, including the optimization of novel CAR vectors with checkpoint inhibitors, have been designed to enhance the antitumor activity of CAR-T cells against solid tumors. It also explores the design of novel CAR-T cells and strategies for improving antitumor activity against solid tumors. Among the emerging strategies, universal CARs and combination approaches with checkpoint inhibitors are especially promising for extending CAR-T therapy to solid tumors.
2026-07-16 | Long-term observation of treatment strategies for primary vitreoretinal lymphoma in a multicenter Chinese cohort.
To compare outcomes of different treatment regimens for primary vitreoretinal lymphoma (PVRL) without central nervous system (CNS) involvement, specifically assessing their association with subsequent onset of central nervous system lymphoma (CNSL). This retrospective study collected data from 64 PVRL patients (118 eyes) from January 2015 to June 2023 at 4 ophthalmologic centers in China. Clinical, laboratory, and imaging data of these patients has been reviewed, focusing on the incidence of CNS manifestations during follow-up. Among the 64 patients with PVRL, 26 patients received only intravitreal injection of methotrexate (group A), and 38 patients received combined intraocular and systemic treatment (group B). The median follow-up time was 36.1 months, the median CNS progression-free survival (PFS) was 23.5 months, and the median overall survival (OS) was not-reached. CNSL developed in 44 of the 64 patients (68.8%) during the follow-up, including 19 of the 26 patients (73.1%) in group A, and 25 of the 38 (65.8%) in group B. Increased cerebrospinal fluid IL-10 levels (range: 2.2-472 pg/ml, mean 63.715 pg/ml) were significantly correlated with the progression of CNSL (P < 0.001). In this observational cohort, combined therapeutic approach of systemic and intraocular therapy was associated with higher OS (P = 0.002). No significant differences in CNS-PFS was observed between the two treatment groups (P = 0.095). In this cohort of patients with PVRL, combined intraocular and systemic therapy may be associated with longer OS, while no significant difference in CNS-PFS was observed.
2026-06-26 | Case Report: Longitudinal analysis of local immunoregulatory mediators in a DLBCL vitreoretinal lymphoma receiving local chemotherapy.
Vitreoretinal lymphoma (VRL) is a rare, high-grade B-cell lymphoma that affects immune-privileged sites and is classified as a variant of primary central nervous system lymphoma (PCNSL). The pathogenesis of VRL, including the origin of malignant B-cells, remains poorly understood. Cytokines, chemokines, and growth factors are thought to play critical roles in both the homing and autocrine proliferation of lymphomatous B-cells. In this study, we present the first longitudinal analysis of the dynamic interplay of vitreous immune mediators during intravitreal (IVT) methotrexate and dexamethasone therapy in a patient with VRL. A patient in their 70s with unilateral VRL underwent nine serial vitreous samplings over 12 weeks of IVT therapy with methotrexate (460 μg/injection) and dexamethasone (0.4 mg/injection). Each 0.2 mL vitreous sample was analyzed using a multiplex panel assessing 58 cytokines, chemokines, and growth factors. Vitreous levels were monitored longitudinally and correlated with clinical responses and optical coherence tomography. During therapy, key cytokines, including IL-10, IL-6, IL-16, IL-1RA, and sIL-2R, decreased progressively, with IL-10 becoming undetectable by day 22. Chemokines CXCL12 and CXCL13, involved in malignant B-cell homing, declined more slowly than IL-10, suggesting persistent microenvironmental support for tumor cells. MCP-1 remained elevated, whereas hepatocyte growth factor (HGF) was consistently high, indicating potentially aggressive behavior. Other immune mediators, including MIP-1α, MIP-1β, Mig (CXCL9), and IP-10 (CXCL10), showed variable kinetics, reflecting a dynamic interplay between the tumor and host immune response. Notably, certain cytokines previously reported in VRL cohorts, such as FGF2, IFN-γ, TNF-α, and IL-17, were not elevated, highlighting patient-specific variability in the immunological profile. This case represents the first longitudinal characterization of vitreous immune mediators during IVT MTX/dexamethasone therapy for VRL. Dynamic changes in soluble mediators mirrored clinical tumor regression and suggested potential biomarkers for disease activity, therapeutic response, and prognosis. Persistent chemokines, such as CXCL12 and CXCL13, may indicate the optimal treatment duration, whereas high HGF levels may identify patients with aggressive disease. These findings propose a novel framework for integrating intraocular immunomonitoring into personalized therapeutic strategies and deepen our understanding of the complex tumor-immune microenvironment in vitreoretinal lymphoma. As derived from a single case, these observations are hypothesis-generating and require confirmation in larger cohorts.
2026-06-12 | Vitreoretinal Lymphoma: a clinical case highlighting the diagnostic and therapeutic challenge and the need for a multidisciplinary management.
Vitreoretinal Lymphoma (VRL) is a rare ocular malignancy often presenting with atypical retinal findings, which can lead to misdiagnosis. We report the case of a patient with bilateral intraocular lesions and reduced visual acuity. Diagnosis was confirmed by multimodal imaging and molecular analysis of aqueous humor. Treatment consisted of intravitreal methotrexate and rituximab, followed by systemic chemotherapy, achieving partial resolution of the ocular lesions but subsequent ocular and systemic recurrence. After rescue treatment, patient achieved sustained complete remission. Early diagnosis and a multidisciplinary approach are essential, and multimodal imaging combined with molecular diagnostics is key in confirming the diagnosis.
2026-08-10 | Diagnostic and therapeutic challenges in primary vitreoretinal lymphoma: a practical clinical approach.
Primary vitreoretinal lymphoma (PVRL) is a rare but aggressive subtype of extranodal diffuse large B-cell lymphoma and is closely related to primary central nervous system lymphoma (PCNSL). Its ability to masquerade as chronic posterior uveitis frequently leads to delayed diagnosis and inappropriate treatment, with significant prognostic implications. A narrative review was performed following a comprehensive search of the PubMed/MEDLINE and Cochrane Library databases, encompassing publications from 2000 through 2025 and including randomized controlled trials, observational studies, prospective and retrospective studies, and systematic reviews. The search strategy incorporated the following keywords: "primary vitreoretinal lymphoma", "intraocular lymphoma", "diagnostic vitrectomy", "MYD88 mutation", "IL-10/IL-6 ratio", "intravitreal methotrexate", "rituximab", "CNS involvement", "optical coherence tomography". Two authors independently conducted study selection and eligibility assessment. Heightened clinical awareness remains pivotal for diagnosing PVRL, particularly when vitritis is partially responsive to steroids, when involvement is bilateral or asymmetric, and when subretinal pigment epithelial infiltrates are present. Multimodal imaging - including optical coherence tomography (OCT), fundus autofluorescence (FAF), and fluorescein angiography (FA) - facilitates early recognition and supports clinical suspicion. Diagnostic vitrectomy with cytology, immunohistochemistry, cytokine analysis (IL-10/IL-6 ratio), and molecular testing (IgH rearrangement, MYD88 L265P mutation) significantly increases diagnostic accuracy. Due to the strong association with central nervous system (CNS) involvement, neuroimaging is mandatory at diagnosis and during follow-up. Treatment options include intravitreal methotrexate and/or rituximab, systemic high-dose methotrexate-based chemotherapy, and radiotherapy. Emerging therapies in PVRL focus on targeted agents, including intravitreal biologics, BTK inhibitors, and personalized molecular-based treatments. The optimal strategy remains controversial and should be individualized based on CNS status and patient characteristics. Primary vitreoretinal lymphoma remains a diagnostic challenge due to its ability to mimic chronic inflammatory eye disorders and the frequent delay in establishing a definitive diagnosis. The integration of multimodal imaging, vitreous cytology, immunohistochemistry, cytokine profiling, and molecular testing has significantly improved diagnostic accuracy. However, management remains complex because of the close association with CNS involvement and the absence of universally accepted treatment protocols. Current therapeutic approaches, including intravitreal chemotherapy, systemic methotrexate-based regimens, and targeted therapies, require individualized selection based on disease extension and patient characteristics. Future advances in molecular diagnostics and personalized treatment strategies may contribute to earlier detection, improved disease control, and better long-term outcomes. Prompt diagnosis, combined with a structured diagnostic approach, is essential to improving outcomes in PVRL. Close collaboration among ophthalmologists, hematologists, neurologists, and pathologists is mandatory for optimal patient management.
2026-07-16 | Expanding the Horizon of CAR-T Cell Therapy: Present Obstacles and New Strategies for Future CARs in Solid Tumors.
Chimeric antigen receptor (CAR)-T cells are synthetic receptors used for the recognition of specific antigens expressed by reprogrammed T cells for targeting tumors. CAR-T cell therapy has gained remarkable clinical success for the treatment of hematological malignancies such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), lymphoplasmacytic lymphoma (LPL), and primary intraocular lymphoma (PIL). The increasing number of preclinical investigations and clinical trials is focusing on extending CAR-T cell therapy to solid tumors due to its remarkable success in leukemia and lymphoma cancers. However, some limitations of CAR-T therapy still exist, including a lack of targetable antigen diversity, heterogeneous antigen expression, insufficient T-cell trafficking efficiency, and an immunosuppressive tumor microenvironment. This review explores the role of CAR-T cell therapy, current challenges, and emerging solutions for solid tumor malignancies. To overcome the existing limitations of CAR-T cell therapy, innovative strategies, including the optimization of novel CAR vectors with checkpoint inhibitors, have been designed to enhance the antitumor activity of CAR-T cells against solid tumors. It also explores the design of novel CAR-T cells and strategies for improving antitumor activity against solid tumors. Among the emerging strategies, universal CARs and combination approaches with checkpoint inhibitors are especially promising for extending CAR-T therapy to solid tumors.
2026-07-16 | Long-term observation of treatment strategies for primary vitreoretinal lymphoma in a multicenter Chinese cohort.
To compare outcomes of different treatment regimens for primary vitreoretinal lymphoma (PVRL) without central nervous system (CNS) involvement, specifically assessing their association with subsequent onset of central nervous system lymphoma (CNSL). This retrospective study collected data from 64 PVRL patients (118 eyes) from January 2015 to June 2023 at 4 ophthalmologic centers in China. Clinical, laboratory, and imaging data of these patients has been reviewed, focusing on the incidence of CNS manifestations during follow-up. Among the 64 patients with PVRL, 26 patients received only intravitreal injection of methotrexate (group A), and 38 patients received combined intraocular and systemic treatment (group B). The median follow-up time was 36.1 months, the median CNS progression-free survival (PFS) was 23.5 months, and the median overall survival (OS) was not-reached. CNSL developed in 44 of the 64 patients (68.8%) during the follow-up, including 19 of the 26 patients (73.1%) in group A, and 25 of the 38 (65.8%) in group B. Increased cerebrospinal fluid IL-10 levels (range: 2.2-472 pg/ml, mean 63.715 pg/ml) were significantly correlated with the progression of CNSL (P < 0.001). In this observational cohort, combined therapeutic approach of systemic and intraocular therapy was associated with higher OS (P = 0.002). No significant differences in CNS-PFS was observed between the two treatment groups (P = 0.095). In this cohort of patients with PVRL, combined intraocular and systemic therapy may be associated with longer OS, while no significant difference in CNS-PFS was observed.
2026-06-26 | Case Report: Longitudinal analysis of local immunoregulatory mediators in a DLBCL vitreoretinal lymphoma receiving local chemotherapy.
Vitreoretinal lymphoma (VRL) is a rare, high-grade B-cell lymphoma that affects immune-privileged sites and is classified as a variant of primary central nervous system lymphoma (PCNSL). The pathogenesis of VRL, including the origin of malignant B-cells, remains poorly understood. Cytokines, chemokines, and growth factors are thought to play critical roles in both the homing and autocrine proliferation of lymphomatous B-cells. In this study, we present the first longitudinal analysis of the dynamic interplay of vitreous immune mediators during intravitreal (IVT) methotrexate and dexamethasone therapy in a patient with VRL. A patient in their 70s with unilateral VRL underwent nine serial vitreous samplings over 12 weeks of IVT therapy with methotrexate (460 μg/injection) and dexamethasone (0.4 mg/injection). Each 0.2 mL vitreous sample was analyzed using a multiplex panel assessing 58 cytokines, chemokines, and growth factors. Vitreous levels were monitored longitudinally and correlated with clinical responses and optical coherence tomography. During therapy, key cytokines, including IL-10, IL-6, IL-16, IL-1RA, and sIL-2R, decreased progressively, with IL-10 becoming undetectable by day 22. Chemokines CXCL12 and CXCL13, involved in malignant B-cell homing, declined more slowly than IL-10, suggesting persistent microenvironmental support for tumor cells. MCP-1 remained elevated, whereas hepatocyte growth factor (HGF) was consistently high, indicating potentially aggressive behavior. Other immune mediators, including MIP-1α, MIP-1β, Mig (CXCL9), and IP-10 (CXCL10), showed variable kinetics, reflecting a dynamic interplay between the tumor and host immune response. Notably, certain cytokines previously reported in VRL cohorts, such as FGF2, IFN-γ, TNF-α, and IL-17, were not elevated, highlighting patient-specific variability in the immunological profile. This case represents the first longitudinal characterization of vitreous immune mediators during IVT MTX/dexamethasone therapy for VRL. Dynamic changes in soluble mediators mirrored clinical tumor regression and suggested potential biomarkers for disease activity, therapeutic response, and prognosis. Persistent chemokines, such as CXCL12 and CXCL13, may indicate the optimal treatment duration, whereas high HGF levels may identify patients with aggressive disease. These findings propose a novel framework for integrating intraocular immunomonitoring into personalized therapeutic strategies and deepen our understanding of the complex tumor-immune microenvironment in vitreoretinal lymphoma. As derived from a single case, these observations are hypothesis-generating and require confirmation in larger cohorts.
2026-06-12 | Vitreoretinal Lymphoma: a clinical case highlighting the diagnostic and therapeutic challenge and the need for a multidisciplinary management.
Vitreoretinal Lymphoma (VRL) is a rare ocular malignancy often presenting with atypical retinal findings, which can lead to misdiagnosis. We report the case of a patient with bilateral intraocular lesions and reduced visual acuity. Diagnosis was confirmed by multimodal imaging and molecular analysis of aqueous humor. Treatment consisted of intravitreal methotrexate and rituximab, followed by systemic chemotherapy, achieving partial resolution of the ocular lesions but subsequent ocular and systemic recurrence. After rescue treatment, patient achieved sustained complete remission. Early diagnosis and a multidisciplinary approach are essential, and multimodal imaging combined with molecular diagnostics is key in confirming the diagnosis.
Access all drug discovery papers and probability of success in trials forecasts:
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Drug Discovery Landscape
1 orphan drug designation for Primary intraocular lymphoma.
1 orphan drug designation for Primary intraocular lymphoma.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
methotrexate (intravitreal) | small molecules | FDA | 2021-07-19 | — | Aldeyra Therapeutics, Inc. |
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