Abstract
Vitreoretinal lymphoma (PCNSL-O) is the most common lymphoma in and around the eye. It is a high-grade B-cell lymphoma and is often associated with central nervous system lymphoma (CNSL). PCNSL-O is the preferred term to emphasize that it is an ocular variant or subset of primary CNS lymphoma (PCNSL). Those with concurrent CNS and ocular disease may be labeled as (PCNSL-CNS/O) in contrast to patients with CNS only involvement (PCNSL-CNS) at presentation. The presence of clumps of lymphoma cells in the vitreous is the hallmark of PCNSL-O, followed by retinal and subretinal infiltrates. Two decades ago, PCNSL-O treatment shifted from radiation and systemic chemotherapy to intravitreal chemotherapy as monotherapy or combined with systemic chemotherapy when the brain is involved (PCNSL-CNS/O). Methotrexate is the most common drug used for intravitreal chemotherapy with a very good response, rare intraocular recurrence of the disease (when following the treatment protocol), and acceptable side effects. In addition, intravitreal injections of rituximab have been used with encouraging results and almost no adverse effects. However, there is limited experience with intravitreal injections of other drugs, and additional drugs are currently tested in animal models and may be used in the future.
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Introduction
PCNSL-O is the most common lymphoma affecting the eye and its surroundings. Still, it is a rare malignancy that almost always involves the vitreous and may additionally involve the retina, subretinal space, retinal pigment epithelium, and the optic nerve [1]. These are high-grade, mostly B-cell malignancies that are associated with a poor prognosis if the patient also develops central nervous system lymphoma (CNSL) [2]. T-cell PCNSL-Os are much less common, constituting only about 10% of the cases [1, 3]. Three other groups of intraocular lymphomas involve various parts of the uvea and are usually low-grade B-cell lymphomas [2].
PCNSL-O is often associated with CNSL and is considered by specialists as a subgroup of CNSL [4, 5], and 9% of the patients initially diagnosed with either PCNSL-O or CNSL are simultaneously diagnosed with lymphoma at the other site as well [1]. It has been reported that 56–90% of PCNSL-O patients ultimately develop CNSL, while 11–54% of patients with CNSL develop PCNSL-O [1, 4, 6,7,8,9]. PCNSL-O is commonly diagnosed in patients over 50 years of age, although younger patients are also diagnosed. There is no clear sex predilection [4, 5], although in several studies, more women were affected than men [1, 10, 11].
The hallmark of PCNSL-O is the presence of cells in the vitreous, mainly in clumps, which is often misdiagnosed as non-responsive uveitis, along with retinal and subretinal infiltrates [12]. In contrast with the reduction in visual acuity in uveitis with similar findings, the visual acuity of PCNSL-O patients is unexpectedly good.
A clinical diagnosis of PCNSL-O often relies on the above-mentioned clinical findings, sometimes assisted by neurological symptoms and CNS MRI findings. However, a biopsy is needed to confirm the diagnosis. Some experts find that a suggestive clinical picture of PCNSL-O with a positive brain biopsy for CNSL is sufficient for the diagnosis of PCNSL-O. Usually, one performs a diagnostic vitrectomy or vitreous tap without or with an anterior chamber tap. The vitreous samples can be analyzed for the presence of malignant cells by cytopathology with possible immunohistochemical staining or flow cytometry to identify the cell type and monoclonality. Other diagnostic methods are the measurement of the levels of interleukins (IL-10 and IL-6) and the ratio between them, which was found to be a very sensitive test, also in aqueous humor samples from the anterior chamber (AC) of the eye; PCR for detection of immunoglobulin heavy chain (IgH) or T-cell receptor (TCR) gene rearrangement which indicates clonality of malignant cells; and a search for an L265P mutation in the myeloid differentiation primary response gene 88 (MYD88) in diffuse large B-cell lymphoma [4, 9, 13,14,15,16,17].
Since intraocular lymphoma was first recognized in 1951 [18, 19], initially as ocular reticulum cell sarcoma, its treatment has evolved from enucleation [19] through radiation therapy, with or without whole-brain radiotherapy, systemic chemotherapy, intrathecal chemotherapy, intravitreal chemotherapy, and biological therapy. All of these modalities have been successful in eradicating intraocular disease.
Failing to treat the eyes will result in blindness, but failing to treat the brain would result in death. There is a years-long debate whether adding systemic treatment to PCNSL-O patients with no clear sign of CNSL can prevent CNSL [4]. So far, there have been no randomized clinical trials that can lead to a consensus recommendation that will solve this debate. In their report, the International CNSL Collaborative Group recommended systemic treatment if the disease involves the CNS and local ocular treatment if the disease involves only the eye, with close follow-up and ongoing collaboration between neuro-oncologists and ophthalmologists [4]. Several other studies presented additional data to support that recommendation [9, 11, 20,21,22,23].
Radiation therapy in doses ranging between 30 and 50 Gy was the gold standard for treating intraocular lymphoma in many institutions. However, because of a high recurrence rate and ocular complications, radiation is less often considered nowadays for therapy of PCNSL-O [8]. Systemic chemotherapy, mainly with high-dose methotrexate (MTX), sometimes combined with rituximab, which is used for treating CNSL, has also been used for treating PCNSL-O. However, the limited penetration of systemic drugs into the vitreous is well known, leading to incomplete response [8]. Therefore, direct intravitreal injection of drugs, including, among others, chemotherapeutic and biological drugs, has become routine in the treatment of various infectious, inflammatory, neovascular, and malignant intraocular diseases. Intravitreal chemotherapy has become the most common method of treating PCNSL-O. In this chapter, we review the current status of intraocular chemotherapy for PCNSL-O.
Intravitreal Chemotherapy
Intravitreal chemotherapy can be given as primary therapy for PCNSL-O or as adjuvant therapy to other treatment methods, although in recent years, the primary intravitreal treatment has become the gold standard.
One of the goals of treating cancer is the localized delivery of therapeutics to the cancer without affecting the rest of the body. Intravitreal injections are therefore an ideal delivery route for treating intraocular malignancies. Ericson and associates [24] had performed trials of intravitreal injections of thiotepa, nitrogen mustard, cyclophosphamide, and methotrexate into rabbits’ eyes, finding no significant intraocular toxicity except in those treated with nitrogen mustard. They even treated several patients with retinoblastoma with intravitreal injections of thiotepa [25]. From 1961 to 1995, it took three decades for another attempt with an intravitreal treatment for retinoblastoma [26]. However, shortly thereafter (1996) intravitreal melphalan for retinoblastoma became a routine practice in Japan [27, 28], while intravitreal methotrexate (MTX) was suggested for the treatment of PCNSL-O in 1997 [29].
In the following paragraphs, we will describe the main drugs currently used in intravitreal injections for treating PCNSL-O.
Intravitreal Methotrexate
Methotrexate (MTX) is currently the most commonly used drug for PCNSL-O. MTX is an anti-metabolite that acts by competitive inhibition of the enzyme dihydrofolate reductase, resulting in reduced thymine synthesis, an essential nuclear base in DNA [30].
Fishburne and associates at the Oregon Health & Science University (OHSU, Portland, Oregon, USA) [29] were the first to report in 1997 on the treatment of PCNSL-O in seven eyes of four patients with intravitreal injections of 400 μg of MTX, injecting 6–11 injections per eye, in conjunction with systemic chemotherapy delivered by hyper-osmotic blood–brain barrier disruption (BBBD). All patients had complete remission without serious ocular toxic effects.
These promising results were repeated by de Smet and associates [22, 23, 31, 32] from the National Eye Institute at the NIH, who reported two successful cases of treating recurrent PCNSL-O with combined intravitreal chemotherapy, one case with intravitreal MTX and thiotepa and one case with intravitreal MTX and dexamethasone, with a full remission.
Following the clinical results, they set out to test the pharmacokinetics of a single dose of intraocular injection of MTX in a blind eye of a patient with recurrent PCNSL-O. Injecting 400 μg resulted in lymphocytotoxic concentrations for 5 days [31]. Next, Velez and associates [33] investigated the pharmacokinetics and toxicity of several intravitreal injections of 400 μg MTX in rabbits’ eyes, together with single injections of fluorouracil and dexamethasone. They found that MTX vitreous levels remain therapeutic (>0.5 μM) in the rabbit eye for 48–72 h without evidence of toxicity.
In 2002 the OHSU group together with the Hadassah Medical Center group reported a larger series of 26 eyes of 16 HIV-negative patients with PCNSL-O from the two centers, treated by intravitreal injections of 400 μg MTX in 0.1 mL [34]. Their protocol included three phases: two injections per week for a month as an induction phase; weekly injection for a month in one center and 2 months in the other center as consolidation phase; and subsequently a maintenance phase of monthly injections to complete a year of treatment. All eyes achieved remission after a maximum of 12 MTX injections (mean of 8.5 injections). Three patients of the center with the shorter consolidation phase had a relapse in the eye and were treated again using the same intravitreal injections protocol with complete remission. Unfortunately, six of the 16 patients died in follow-up as a result of progressive CNSL, but without clinical ocular involvement.
Frenkel and associates at the Hadassah Medical Center (HMC) reported a large series of 44 eyes of 26 patients from a single center, who were treated by the same induction-consolidation-maintenance regimen of intravitreal MTX injections [35] (this group included half of the patients reported by Smith et al. [34]). This HMC group of patients also included several patients with T-cell lymphoma [35]. Clinical remission was reached in all eyes after an average of 6.4 injections, with 95% of the eyes needing 13 injections or less to be cleared of lymphoma cells. None of the patients had a relapse. All patients in these reports who had PCNSL-CNS were also treated for the brain disease by systemic chemotherapy. Sou and colleagues [36] reported similar results in one Japanese center.
The most common side effects of the intravitreal injections are conjunctival hyperemia and transient keratopathy, ranging from diffuse punctate keratopathy to severe epitheliopathy, which usually subside during the maintenance phase [1, 34, 37]. Keratopathy usually leads to a transient decrease in the visual acuity, sometimes even more than expected to that degree of dryness, which usually improves after completion of the consolidation phase. Other complications are acceleration of existing cataract, which could also be due to diagnostic vitrectomy, neovascular glaucoma, which could have occurred because of the PCNSL-O itself, and sterile intraocular inflammation that can be successfully treated by corticosteroids [1, 34, 38]. Patients treated with BBBD for CNSL may develop maculopathy without a significant effect on their visual acuity [34]. None of the patients who were treated with intravitreal injections of MTX but were not treated with BBBD developed maculopathy [39].
There have been some differences in the protocols used in various institutions for intravitreal MTX monotherapy for treating PCNSL-O. Most treating ophthalmologists inject 400 μg in 0.1 mL, as in the first studies. Only a few injected less than 400 μg, and some, like us, reduced the injection volume to 0.05 mL. However, the number of injections varies widely, and some will inject “according to the clinical behavior of the lymphoma” [40]. Reducing the number of injections, especially in the induction and consolidation phase, was attempted to reduce the rate and severity of the keratopathy. However, shorter induction and consolidation phases increased the local recurrence rate from 2.5% [1] to 18–33% [41, 42].
Combined intravitreal injections with systemic chemotherapy, mostly high-dose MTX, have been used in treating PCNSL-O [40,41,42,43]. However, there is no evidence that the systemic MTX improves or shortens the time of treatment or increases the time to relapse and progression of the PCNSL-O. In addition, there is no proof that systemic chemotherapy prevents the development of CNSL in PCNSL-O patients without CNSL [9, 11, 20,21,22,23]. In our experience and that of others, intravitreal MTX injections should be used for treating PCNSL-O and systemic chemotherapy for treating PCNSL-CNS. We recommend avoiding systemic chemotherapy in the treatment of PCNSL-O patients when CNS is not involved. Other combination treatments for PCNSL-O are the use of intravitreal MTX and rituximab, sometimes with the addition of systemic chemotherapy or even radiotherapy [21, 44,45,46].
Intravitreal Rituximab
Rituximab is a humanized monoclonal antibody that targets CD20-positive B-cells in all stages, from a pre-B-cell through a mature B-cell. Thus, CD20 also presents on lymphomatous B-cells in PCNSL-O and CNSL. Rituximab was approved in 1997 by the FDA to be used in B-cell lymphomas of various types. With the vast majority of PCNSL-O and CNSL resulting from malignant B-cells, rituximab seems an ideal, specific drug for intravitreal therapy. The hope was to reach the same tumoricidal effect with milder side effects and fewer injections than the full MTX protocol. Unfortunately, this treatment cannot help the minority of T-cell PCNSL-O patients.
In contrast to the clinical data first and preclinical data later we have seen above for intravitreal melphalan for retinoblastoma and intravitreal MTX for PCNSL-O, Intravitreal rituximab was first tested in animal studies. All these studies tested injection of 1 mg/0.1 mL rituximab. Kim and associates [47], investigating the pharmacokinetics of intravitreal injections of rituximab into rabbit eyes, found a half-life of 4.7 days in both the aqueous and vitreous. Pulido and colleagues [48] found that rituximab penetrated all retinal layers in rabbit eyes, and Kitzmann and associates [49] showed no toxicity to the rabbit eyes. Mineo and colleagues [50] showed eradication of lymphoma in more than half of the animals and significant inhibition of tumor progression in the rest.
Kitzmann and colleagues [49] were the first to report their experience with intravitreal injections of rituximab in treating five eyes of three patients in 2007. They used 3–4 injections of 1 mg/0.1 mL rituximab with a good response, no toxicity, and no evidence of recurrence after a short median follow-up of 3.6 months. Ohguro and associates [51] treated two patients who had PCNSL-O relapse after intravitreal MTX by four weekly injections of 1 mg/0.1 mL rituximab with complete remission and no recurrence after 2 months.
Hashida and associates [52] reported their experience in treating 20 eyes of 13 patients who had discontinued previous intravitreal MTX treatment because of severe corneal epitheliopathy. They used four weekly injections of 1 mg/mL rituximab as a one-course protocol, and additional injections were administered when PCNSL-O recurred in 11 of the eyes. All patients completed 1-year follow-up. Twelve eyes showed transient intraocular pressure elevation. No other significant side effects developed.
In 2014 Larkin and associates [53] presented what is still the largest series of intravitreal rituximab-based treatments for treating PCNSL-O, including 48 eyes of 34 patients in clinics in five countries. The eyes were treated with a median of 3.5 injections; the most common interval was monthly. About two-thirds of the eyes were also injected with MTX, usually on the same day with rituximab. Others were treated with more extensive cytotoxic therapies. Complete remission was achieved in 65% of the eyes, and 23% showed partial remission. Among eyes that were treated only by intraocular chemotherapy, 53% experienced complete remission and 11 partial remissions. However, after a median follow-up of 18 months, PCNSL-O recurred in 23% of the eyes. The main complication in this series was cataract in 19% of eyes.
The use of intravitreal rituximab for PCNSL-O was also reported in other small series and case reports. It was used mainly as a secondary treatment [54,55,56] or in combination with other drugs, mainly MTX [21, 44,45,46]. Unpublished reports from some centers which were discussed in international meetings indicate that fewer than 6 monthly injections are insufficient to prevent local recurrences, and we urge those with experience to publish their results. There is still no significant series of eyes with PCNSL-O treated by rituximab alone as primary treatment. Such a study should be considered.
Other Drugs for Intravitreal Chemotherapy
The experience with using drugs other than MTX and rituximab for the treatment of PCNSL-O is very limited.
Intravitreal injections of melphalan have been often used in recent years for treating retinoblastoma. Melphalan is a phenylalanine derivative of nitrogen mustard and an alkylating agent. Shields and associates [57] reported in 2017 their experience in treating three eyes of two patients with PCNSL-O by intravitreal injections of 10 μg/0.1 mL melphalan. One of the patients with bilateral PCNSL-O showed clinical remission within 3 weeks after a single injection. Recurrence in one of the eyes was treated by additional six bimonthly injections with a good response and no recurrence after 19 months of follow-up. The other patient with bilateral PCNSL-O was treated by intravitreal melphalan in one eye and MTX in the other eye. The PCNSL-O in the eye treated with melphalan was cured by one injection. No toxicity was observed. This group expanded their use of melphalan and reported on 12 more patients with encouraging results [20]. Damato and associates [58] reported their good experience with intravitreal melphalan in treating a single patient with PCNSL-O.
Thiotepa is an organophosphorus alkylating agent, which results in crosslinking of the double-stranded DNA helix and interferes with DNA replication. Ericson and associates reported their results of using intravitreal thiotepa injections for treating intraocular retinoblastoma in 1961 [25] and tested it in rabbits’ eyes in 1964 [24], finding no significant toxicity. de Smet and associates [31, 32] combined thiotepa (2 mg/0.1 mL) with MTX injections in treating a patient with PCNSL-O. However, the thiotepa injection was associated with elevated intraocular pressure and loss of vision. In light of the good results with intravitreal MTX alone, thiotepa is no longer being used.
Corticosteroids have lymphocytotoxic effect; however, the response is usually partial with a high local recurrence rate once the steroids are discontinued. Thus, corticosteroids are not used as a single agent for treating lymphoma. de Smet used a combination of MTX and dexamethasone in treating one patient with PCNSL-O resulting in complete remission. Castellino and associates reported the use of intravitreal corticosteroids injections with other systemic and intravitreal drugs [21]. However, intravitreal injections of corticosteroids did not become part of the standard practice in treating PCNSL-O.
Investigational Drugs for Intravitreal Injections
During the recent two decades, researchers reported their experience using various experimental drugs for intravitreal or intracameral injections in animal models of PCNSL-O. However, none of them has matured for clinical use.
Gregory and associates [59] studied the use of membrane FasL vesicles, the membrane-only form of Fas ligand, to activate innate immunity and terminate the eye’s immune privilege. By a single injection of membrane FasL vesicles into the anterior chamber of mice, they eliminated the lymphoma cells that were previously injected into this site.
Li and associates [60] used recombinant immunotoxin HA22 targeting human B-cell lymphoma via their expression of CD22 in a mouse model of intraocular lymphoma. A single intravitreal injection of immunotoxin HA22 resulted in complete regression of the lymphoma, demonstrating B-cell-specific immunotoxin therapy.
Ublituximab is a glycoengineered anti-human-CD20 monoclonal antibody (similar to rituximab) developed to treat multiple sclerosis. In 2013 Ben-Abdelwahed and associates [61] reported their results in treating the murine model of PCNSL-O by a single intravitreal injection of ublituximab with marked effect against the lymphoma B-cells expressing CD20.
Some other monoclonal antibodies such as daclizumab, efalizumab, and alemtuzumab showed positive results in animal models and have the potential to be a useful adjuvant therapy for intraocular lymphoma [62]. However, as with previous experimental drugs, no further reports are available on their use in treating PCNSL-O.
Summary
Since intraocular lymphoma was first recognized about 70 years ago, its treatment has gradually evolved. Enucleation was often performed in the early years when the disease was diagnosed late. When PCNSL-O was more frequently diagnosed, and its common association with PCNSL-CNS was recognized, other methods of treatments have been used, including radiation therapy, systemic chemotherapy using various drugs, or in a combination of the two. The limited penetration of drugs administered systemically into the eye and their systemic toxicity, and the local side effects of radiation to the eye, paved the way for direct intravitreal chemotherapy to become the popular method of treating PCNSL-O in the last two decades.
Intravitreal injections of MTX as monotherapy were found to be very effective in inducing intraocular tumor remission with acceptable side effects and a rare occurrence of relapse when the entire 16 injections of the induction and consolidation phases are administered. Additional systemic chemotherapy probably neither adds to the cure rate of the PCNSL-O nor does it prevent PCNSL-CNS and should be used only when CNS lymphoma is associated with the PCNSL-O.
In recent years the use of intravitreal injections of rituximab has been carried out in several centers, with or without combining MTX, with encouraging results and no significant adverse effects. However, its use varies markedly among experts and the results are still inferior to MTX. Intravitreal injection of melphalan was also proved to be an effective drug, but at this time has been employed only in one ocular oncology center on a dozen patients.
Because of the rarity of PCNSL-O, international collaboration is needed for defining the role of intravitreal chemotherapy in eradicating this disease. The present drugs used clinically are effective, and probably a consensus on protocols for using them is needed. It seems that in the future, the treatment of PCNSL-O will continue to evolve, new drugs will be introduced, and new methods of intraocular delivery will be developed.
References
Habot-Wilner Z, Frenkel S, Pe’er J. Efficacy and safety of intravitreal methotrexate for vitreo-retinal lymphoma - 20 years of experience. Br J Haematol. 2021;194:92–100.
Coupland SE, Damato B. Understanding intraocular lymphomas. Clin Exp Ophthalmol. 2008;36:564–78.
Chaput F, Amer R, Baglivo E, Touitou V, Kozyreff A, Bron D, et al. Intraocular T-cell lymphoma: clinical presentation, diagnosis, treatment, and outcome. Ocul Immunol Inflamm. 2017;25:639–48.
Chan CC, Rubenstein JL, Coupland SE, Davis JL, Harbour JW, Johnston PB, et al. Primary vitreoretinal lymphoma: a report from an International Primary Central Nervous System Lymphoma Collaborative Group symposium. Oncologist. 2011;16:1589–99.
Kvopka M, Lake SR, Smith JR. Intraocular chemotherapy for vitreoretinal lymphoma: a review. Clin Exp Ophthalmol. 2020;48:240–8.
Hochberg FH, Miller DC. Primary central nervous system lymphoma. J Neurosurg. 1988;68:835–53.
Farrall AL, Smith JR. Eye involvement in primary central nervous system lymphoma. Surv Ophthalmol. 2020;65:548–61.
Pe’er J, Hochberg FH, Foster CS. Clinical review: treatment of vitreoretinal lymphoma. Ocul Immunol Inflamm. 2009;17:299–306.
Grimm SA, Pulido JS, Jahnke K, Schiff D, Hall AJ, Shenkier TN, et al. Primary intraocular lymphoma: an International Primary Central Nervous System Lymphoma Collaborative Group Report. Ann Oncol. 2007;18:1851–5.
Kimura K, Usui Y, Goto H, Japanese Intraocular Lymphoma Study G. Clinical features and diagnostic significance of the intraocular fluid of 217 patients with intraocular lymphoma. Jpn J Ophthalmol. 2012;56:383–9.
Riemens A, Bromberg J, Touitou V, Sobolewska B, Missotten T, Baarsma S, et al. Treatment strategies in primary vitreoretinal lymphoma: a 17-center European collaborative study. JAMA Ophthalmol. 2015;133:191–7.
Coupland SE, Heimann H, Bechrakis NE. Primary intraocular lymphoma: a review of the clinical, histopathological and molecular biological features. Graefes Arch Clin Exp Ophthalmol. 2004;242:901–13.
Fend F, Ferreri AJ, Coupland SE. How we diagnose and treat vitreoretinal lymphoma. Br J Haematol. 2016;173:680–92.
Chan CC, Sen HN. Current concepts in diagnosing and managing primary vitreoretinal (intraocular) lymphoma. Discov Med. 2013;15:93–100.
Reichstein D. Primary vitreoretinal lymphoma: an update on pathogenesis, diagnosis and treatment. Curr Opin Ophthalmol. 2016;27:177–84.
Frenkel S, Pe’er J, Kaufman R, Maly B, Habot-Wilner Z. The importance of cytokines analysis in the diagnosis of vitreoretinal lymphoma. Acta Ophthalmol. 2020;98:e668–73.
Carbonell D, Mahajan S, Chee SP, Sobolewska B, Agrawal R, Bulow T, et al. Consensus recommendations for the diagnosis of vitreoretinal lymphoma. Ocul Immunol Inflamm. 2021;29:1–14.
Cooper EL, Riker JL. Malignant lymphoma of the uveal tract. Am J Ophthalmol. 1951;34:1153–8.
Vogel MH, Font RL, Zimmerman LE, Levine RA. Reticulum cell sarcoma of the retina and uvea. Report of six cases and review of the literature. Am J Ophthalmol. 1968;66:205–15.
Dalvin LA, Lim LS, Ancona-Lezama D, Mazloumi M, Chang M, Mashayekhi A, et al. Tumor control and visual acuity outcomes in vitreoretinal lymphoma with and without sub-retinal pigment epithelium infiltration: analysis of 125 eyes of 70 patients at a single ocular oncology center. Ophthalmol Retina. 2019;3:998–1005.
Castellino A, Pulido JS, Johnston PB, Ristow KM, Nora Bennani N, Inwards DJ, et al. Role of systemic high-dose methotrexate and combined approaches in the management of vitreoretinal lymphoma: a single center experience 1990-2018. Am J Hematol. 2019;94:291–8.
Cho BJ, Kim DY, Park UC, Lee JY, Yoon YH, Yu HG. Clinical features and treatment outcomes of vitreoretinal lymphoma according to its association with CNS lymphoma. Ocul Immunol Inflamm. 2018;26:365–71.
Yonese I, Takase H, Yoshimori M, Onozawa E, Tsuzura A, Miki T, et al. CD79B mutations in primary vitreoretinal lymphoma: diagnostic and prognostic potential. Eur J Haematol. 2019;102:191–6.
Ericson L, Karlberg B, Rosengren BH. Trials of intravitreal injections of chemotherapeutic agents in rabbits. Acta Ophthalmol. 1964;42:721–6.
Ericson LA, Rosengren BH. Present therapeutic resources in retinoblastoma. Acta Ophthalmol. 1961;39:569–76.
Seregard S, Kock E, Af Trampe E. Intravitreal chemotherapy for recurrent retinoblastoma in an only eye. Br J Ophthalmol. 1995;79:194–5.
Kaneko A. Teach us about the current treatments of retinoblastoma. Atarashii Ganka. 1996;13:229–33.
Kaneko A, Suzuki S. Eye-preservation treatment of retinoblastoma with vitreous seeding. Jpn J Clin Oncol. 2003;33:601–7.
Fishburne BC, Wilson DJ, Rosenbaum JT, Neuwelt EA. Intravitreal methotrexate as an adjunctive treatment of intraocular lymphoma. Arch Ophthalmol. 1997;115:1152–6.
Canellos GP, Lister TA, Skarin AT. Chemotherapy of the non-Hodgkin’s lymphomas. Cancer. 1978;42:932–40.
de Smet MD, Vancs VS, Kohler D, Solomon D, Chan CC. Intravitreal chemotherapy for the treatment of recurrent intraocular lymphoma. Br J Ophthalmol. 1999;83:448–51.
de Smet MD. Management of non Hodgkin’s intraocular lymphoma with intravitreal methotrexate. Bull Soc Ophtalmol. 2001:91–5.
Velez G, Yuan P, Sung C, Tansey G, Reed GF, Chan CC, et al. Pharmacokinetics and toxicity of intravitreal chemotherapy for primary intraocular lymphoma. Arch Ophthalmol. 2001;119:1518–24.
Smith JR, Rosenbaum JT, Wilson DJ, Doolittle ND, Siegal T, Neuwelt EA, et al. Role of intravitreal methotrexate in the management of primary central nervous system lymphoma with ocular involvement. Ophthalmology. 2002;109:1709–16.
Frenkel S, Hendler K, Siegal T, Shalom E, Pe’er J. Intravitreal methotrexate for treating vitreoretinal lymphoma: 10 years of experience. Br J Ophthalmol. 2008;92:383–8.
Sou R, Ohguro N, Maeda T, Saishin Y, Tano Y. Treatment of primary intraocular lymphoma with intravitreal methotrexate. Jpn J Ophthalmol. 2008;52:167–74.
Jeong Y, Ryu JS, Park UC, Oh JY. Corneal epithelial toxicity after intravitreal methotrexate injection for vitreoretinal lymphoma: clinical and in vitro studies. J Clin Med. 2020;9:2672.
Goldberg S, Frenkel S, Blumenthal EZ, Solomon A, Pe’er J. Intraocular lymphoma. Ophthalmology. 2007;114:1236–7.
Vicuna-Kojchen J, Frenkel S, Siegal T, Shalom E, Chowers I, Pe’er J. Maculopathy in patients with primary CNS lymphoma treated with chemotherapy in conjunction with blood-brain barrier disruption. Br J Ophthalmol. 2008;92:231–5.
Klimova A, Heissigerova J, Rihova E, Brichova M, Pytlik R, Spicka I, et al. Combined treatment of primary vitreoretinal lymphomas significantly prolongs the time to first relapse. Br J Ophthalmol. 2018;102:1579–85.
Kaburaki T, Taoka K, Matsuda J, Yamashita H, Matsuda I, Tsuji H, et al. Combined intravitreal methotrexate and immunochemotherapy followed by reduced-dose whole-brain radiotherapy for newly diagnosed B-cell primary intraocular lymphoma. Br J Haematol. 2017;179:246–55.
Ma WL, Hou HA, Hsu YJ, Chen YK, Tang JL, Tsay W, et al. Clinical outcomes of primary intraocular lymphoma patients treated with front-line systemic high-dose methotrexate and intravitreal methotrexate injection. Ann Hematol. 2016;95:593–601.
Akiyama H, Takase H, Kubo F, Miki T, Yamamoto M, Tomita M, et al. High-dose methotrexate following intravitreal methotrexate administration in preventing central nervous system involvement of primary intraocular lymphoma. Cancer Sci. 2016;107:1458–64.
Abu Samra K, Oray M, Ebrahimiadib N, Lee S, Anesi S, Foster CS. Intraocular lymphoma: descriptive data of 26 patients including clinico-pathologic features, vitreous findings, and treatment outcomes. Ocul Immunol Inflamm. 2018;26:347–52.
Pulido JS, Johnston PB, Nowakowski GS, Castellino A, Raja H. The diagnosis and treatment of primary vitreoretinal lymphoma: a review. Int J Retina Vitreous. 2018;4:18.
Giuffre C, Cicinelli MV, Marchese A, Modorati GM, Brambati M, Ferreri AJM, et al. Clinical experience in a large cohort of patients with vitreoretinal lymphoma in a single center. Ocul Immunol Inflamm. 2021;29:472–8.
Kim H, Csaky KG, Chan CC, Bungay PM, Lutz RJ, Dedrick RL, et al. The pharmacokinetics of rituximab following an intravitreal injection. Exp Eye Res. 2006;82:760–6.
Pulido JS, Bakri SJ, Valyi-Nagy T, Shukla D. Rituximab penetrates full-thickness retina in contrast to tissue plasminogen activator control. Retina. 2007;27:1071–3.
Kitzmann AS, Pulido JS, Mohney BG, Baratz KH, Grube T, Marler RJ, et al. Intraocular use of rituximab. Eye (Lond). 2007;21:1524–7.
Mineo JF, Scheffer A, Karkoutly C, Nouvel L, Kerdraon O, Trauet J, et al. Using human CD20-transfected murine lymphomatous B cells to evaluate the efficacy of intravitreal and intracerebral rituximab injections in mice. Invest Ophthalmol Vis Sci. 2008;49:4738–45.
Ohguro N, Hashida N, Tano Y. Effect of intravitreous rituximab injections in patients with recurrent ocular lesions associated with central nervous system lymphoma. Arch Ophthalmol. 2008;126:1002–3.
Hashida N, Ohguro N, Nishida K. Efficacy and complications of intravitreal rituximab injection for treating primary vitreoretinal lymphoma. Transl Vis Sci Technol. 2012;1:1.
Larkin KL, Saboo US, Comer GM, Forooghian F, Mackensen F, Merrill P, et al. Use of intravitreal rituximab for treatment of vitreoretinal lymphoma. Br J Ophthalmol. 2014;98:99–103.
Cicinelli MV, Marchese A, Miserocchi E, Giuffre C, Berchicci L, Querques G, et al. Retinal and choroidal changes of vitreoretinal lymphoma from active to remission phase after intravitreal rituximab. Ocul Immunol Inflamm. 2020;28:637–46.
Fernandez Canabate E, Fernandez-Canabate S. [Intravitreal rituximab for the treatment of intraocular relapse of non-Hodgkin’s lymphoma]. Farm Hosp. 2018;42:20–1.
Echegaray JJ, Llop S, Sepulveda M, Velez-Rosario R, Perez N, Oliver AL. Intravitreal rituximab for the treatment of a secondary intraocular relapse of a large B-cell lymphoma. Am J Ophthalmol Case Rep. 2018;9:77–9.
Shields CL, Sioufi K, Mashayekhi A, Shields JA. Intravitreal melphalan for treatment of primary vitreoretinal lymphoma: a new indication for an old drug. JAMA Ophthalmol. 2017;135:815–8.
Damato B, Bever GJ, Kim DJ, Afshar AR, Rubenstein JL. An audit of retinal lymphoma treatment at the University of California San Francisco. Eye (Lond). 2020;34:515–22.
Gregory MS, Koh S, Huang E, Saff RR, Marshak-Rothstein A, Mukai S, et al. A novel treatment for ocular tumors using membrane FasL vesicles to activate innate immunity and terminate immune privilege. Invest Ophthalmol Vis Sci. 2005;46:2495–502.
Li Z, Mahesh SP, Shen DF, Liu B, Siu WO, Hwang FS, et al. Eradication of tumor colonization and invasion by a B cell-specific immunotoxin in a murine model for human primary intraocular lymphoma. Cancer Res. 2006;66:10586–93.
Ben Abdelwahed R, Donnou S, Ouakrim H, Crozet L, Cosette J, Jacquet A, et al. Preclinical study of Ublituximab, a Glycoengineered anti-human CD20 antibody, in murine models of primary cerebral and intraocular B-cell lymphomas. Invest Ophthalmol Vis Sci. 2013;54:3657–65.
Rodrigues EB, Farah ME, Maia M, Penha FM, Regatieri C, Melo GB, et al. Therapeutic monoclonal antibodies in ophthalmology. Prog Retin Eye Res. 2009;28:117–44.
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Pe’er, J., Frenkel, S. (2023). Vitreoretinal Lymphoma: Intraocular Therapy. In: Raval, V.R., Mruthyunjaya, P., Singh, A.D. (eds) Ocular and Adnexal Lymphoma. Essentials in Ophthalmology. Springer, Cham. https://doi.org/10.1007/978-3-031-24595-4_8
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