Current state and progress of intravitreal injection of chemotherapeutic agents for the treatment of vitreoretinal lymphoma_Chinese Journal of Ocular Fundus Diseases

Authors：

Zheng Chuanzhen , Ren Xinjun ,  Zhang Xiaomin

Tianjin Medical University Eye Hospital, Eye Institute and School of Optometry, Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin International Joint Research and Development Centre of Ophthalmology and Vision Science, Tianjin 300384, China;

Corresponding author：

Zhang Xiaomin, Email: xzhang08@tmu.edu.cn

Keywords：

Lymphoma; non-Hodgkin; Methotrexate; Review

DOI：

10.3760/cma.j.cn511434-20200826-00414

Video：

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Primary vitreoretinal lymphoma (PVRL) is one of the most common type of primary intraocular lymphoma. The current treatment options include local ocular radiotherapy (radiotherapy), systemic chemotherapy (chemotherapy), local ocular chemotherapy, and combination therapy. The treatment options are different at different stages of PVRL, however, there is no uniform treatment guideline. Local ocular chemotherapy can make the drug reach effective therapeutic concentration in the eye, and it can be repeated many times. At the same time, it can avoid the adverse reactions caused by systemic medication or radiotherapy. It is an ideal choice for relieving ocular symptoms. At present, the mainstream ocular local chemotherapeutics are methotrexate (MTX) and rituximab (RTX). The basic consensus about the intravitreal injection of MTX (IVM) is the induction-consolidation-maintenance model, however, the time of each stage and frequency of IVM are diverse. The time interval of intravitreal injection of RTX is also variable, ranging from 1 time/week to 1 time/months and so on. Corneal epithelial lesions caused by frequent MTX injections and the higher recurrence rate after RTX treatment are the main reasons for changing the treatment plan. For patients with primary central nervous system lymphoma and PVRL, combined treatment with neurology department is necessary to save patient's lives, ophthalmology treatment relieves ocular symptoms and improves the patient's quality of life. For patients with PVRL alone without central nervous system involvement, ophthalmology treatment is necessary to control patient's eye symptoms, and close follow-up should be followed to find the involvement of the central nervous system in time, and then combined with neurological treatment to save patient’s lives.

Citation： Zheng Chuanzhen, Ren Xinjun, Zhang Xiaomin. Current state and progress of intravitreal injection of chemotherapeutic agents for the treatment of vitreoretinal lymphoma. Chinese Journal of Ocular Fundus Diseases, 2021, 37(9): 731-736. doi: 10.3760/cma.j.cn511434-20200826-00414 Copy

1.	Sagoo MS, Mehta H, Swampillai AJ, et al. Primary intraocular lymphoma[J]. Surv Ophthalmol, 2014, 59(5): 503-516. DOI: 10.1016/j.survophthal.2013.12.001.
2.	Kvopka M, Lake SR, Smith JR. Intraocular chemotherapy for vitreoretinal lymphoma: a review[J]. Clin Exp Ophthalmol, 2020, 48(2): 240-248. DOI: 10.1111/ceo.13668.
3.	Fend F, Ferreri AJ, Coupland SE. How we diagnose and treat vitreoretinal lymphoma[J]. Br J Haematol, 2016, 173(5): 680-692. DOI: 10.1111/bjh.14025.
4.	Pe'er J, Hochberg FH, Foster CS. Clinical review: treatment of vitreoretinal lymphoma[J]. Ocul Immunol Inflamm, 2009, 17(5): 299-306. DOI: 10.3109/09273940903370755.
5.	Preisz Z, Kunsági-Máté S. Effect of methotrexate and its photodegradation products on the temperature induced denaturation of human serum albumin[J/OL]. Spectrochim Acta A Mol Biomol Spectrosc, 2021, 245: 118905[2021-01-15]. https://pubmed.ncbi.nlm.nih.gov/32927299/. DOI: 10.1016/j.saa.2020.118905.
6.	de Smet MD, Stark-Vancs V, Kohler DR, et al. Intraocular levels of methotrexate after intravenous administration[J]. Am J Ophthalmol, 1996, 121(4): 442-444. DOI: 10.1016/s0002-9394(14)70444-1.
7.	Velez G, Yuan P, Sung C, et al. Pharmacokinetics and toxicity of intravitreal chemotherapy for primary intraocular lymphoma[J]. Arch Ophthalmol, 2001, 119(10): 1518-1524. DOI: 10.1001/archopht.119.10.1518.
8.	de Smet MD, Vancs VS, Kohler D, et al. Intravitreal chemotherapy for the treatment of recurrent intraocular lymphoma[J]. Br J Ophthalmol, 1999, 83(4): 448-451. DOI: 10.1136/bjo.83.4.448.
9.	Fishburne BC, Wilson DJ, Rosenbaum JT, et al. Intravitreal methotrexate as an adjunctive treatment of intraocular lymphoma[J]. Arch Ophthalmol, 1997, 115(9): 1152-1156. DOI: 10.1001/archopht.1997.01100160322009.
10.	Kuijpers TW, Bende RJ, Baars PA, et al. CD20 deficiency in humans results in impaired T cell-independent antibody responses[J]. J Clin Invest, 2010, 120(1): 214-222. DOI: 10.1172/JCI40231.
11.	Plosker GL, Figgitt DP. Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia[J]. Drugs, 2003, 63(8): 803-843. DOI: 10.2165/00003495-200363080-00005.
12.	Kim H, Csaky KG, Chan CC, et al. The pharmacokinetics of rituximab following an intravitreal injection[J]. Exp Eye Res, 2006, 82(5): 760-766. DOI: 10.1016/j.exer.2005.09.018.
13.	Pulido JS, Bakri SJ, Valyi-Nagy T, et al. Rituximab penetrates full-thickness retina in contrast to tissue plasminogen activator control[J]. Retina, 2007, 27(8): 1071-1073. DOI: 10.1097/IAE.0b013e31804ac032.
14.	Kitzmann AS, Pulido JS, Mohney BG, et al. Intraocular use of rituximab[J]. Eye (Lond), 2007, 21(12): 1524-1527. DOI: 10.1038/sj.eye.6702804.
15.	Smith JR, Rosenbaum JT, Wilson DJ, et al. Role of intravitreal methotrexate in the management of primary central nervous system lymphoma with ocular involvement[J]. Ophthalmology, 2002, 109(9): 1709-1716. DOI: 10.1016/s0161-6420(02)01125-9.
16.	Frenkel S, Hendler K, Siegal T, et al. Intravitreal methotrexate for treating vitreoretinal lymphoma: 10 years of experience[J]. Br J Ophthalmol, 2008, 92(3): 383-388. DOI: 10.1136/bjo.2007.127928.
17.	Smith JR, Pe'er J, Belfort RN, et al. Proceedings of the association for research in vision and ophthalmology and champalimaud foundation ocular oncogenesis and oncology conference[J/OL]. Transl Vis Sci Technol, 2019, 8(1): 9[2018-01-09]. https://pubmed.ncbi.nlm.nih.gov/30652059/. DOI: 10.1167/tvst.8.1.9.
18.	Sou R, Ohguro N, Maeda T, et al. Treatment of primary intraocular lymphoma with intravitreal methotrexate[J]. Jpn J Ophthalmol, 2008, 52(3): 167-174. DOI: 10.1007/s10384-008-0519-9.
19.	Akiyama H, Takase H, Kubo F, et al. High-dose methotrexate following intravitreal methotrexate administration in preventing central nervous system involvement of primary intraocular lymphoma[J]. Cancer Sci, 2016, 107(10): 1458-1464. DOI: 10.1111/cas.13012.
20.	Ma WL, Hou HA, Hsu YJ, et al. Clinical outcomes of primary intraocular lymphoma patients treated with front-line systemic high-dose methotrexate and intravitreal methotrexate injection[J]. Ann Hematol, 2016, 95(4): 593-601. DOI: 10.1007/s00277-015-2582-x.
21.	Kaburaki T, Taoka K, Matsuda J, et al. Combined intravitreal methotrexate and immunochemotherapy followed by reduced-dose whole-brain radiotherapy for newly diagnosed B-cell primary intraocular lymphoma[J]. Br J Haematol, 2017, 179(2): 246-255. DOI: 10.1111/bjh.14848.
22.	Zhou X, Zhou X, Shi H, et al. Reduced frequency of intravitreal methotrexate injection lowers the risk of keratopathy in vitreoretinal lymphoma patients[J/OL]. BMC Ophthalmol, 2020, 20(1): 189[2020-05-12]. https://pubmed.ncbi.nlm.nih.gov/32397978/. DOI: 10.1186/s12886-020-01464-3.
23.	Ohguro N, Hashida N, Tano Y. Effect of intravitreous rituximab injections in patients with recurrent ocular lesions associated with central nervous system lymphoma[J]. Arch Ophthalmol, 2008, 126(7): 1002-1003. DOI: 10.1001/archopht.126.7.1002.
24.	Hashida N, Ohguro N, Nishida K. Efficacy and complications of intravitreal rituximab injection for treating primary vitreoretinal lymphoma[J/OL]. Transl Vis Sci Technol, 2012, 1(3): 1[2012-10-22]. https://pubmed.ncbi.nlm.nih.gov/24049708/. DOI: 10.1167/tvst.1.3.1.
25.	Fernández Cañabate E, Fernández-Cañabate S. Intravitreal rituximab for the treatment of intraocular relapse of non-Hodgkin's lymphoma[J]. Farm Hosp, 2018, 42(1): 20-21. DOI: 10.7399/fh.10830.
26.	Echegaray JJ, Llop S, Sepulveda M, et al. Intravitreal rituximab for the treatment of a secondary intraocular relapse of a large B-cell lymphoma[J]. Am J Ophthalmol Case Rep, 2018, 9: 77-79. DOI: 10.1016/j.ajoc.2018.01.032.
27.	Cicinelli MV, Marchese A, Miserocchi E, et al. Retinal and choroidal changes of vitreoretinal lymphoma from active to remission phase after intravitreal rituximab[J]. Ocul Immunol Inflamm, 2020, 28(4): 637-646. DOI: 10.1080/09273948.2019.1616769.
28.	Larkin KL, Saboo US, Comer GM, et al. Use of intravitreal rituximab for treatment of vitreoretinal lymphoma[J]. Br J Ophthalmol, 2014, 98(1): 99-103. DOI: 10.1136/bjophthalmol-2013-304043.
29.	Gorovoy I, Prechanond T, Abia M, et al. Toxic corneal epitheliopathy after intravitreal methotrexate and its treatment with oral folic acid[J]. Cornea, 2013, 32(8): 1171-1173. DOI: 10.1097/ICO.0b013e3182910106.
30.	Goldberg S, Frenkel S, Blumenthal EZ, et al. Intraocular lymphoma[J]. Ophthalmology, 2007, 114(6): 1236-1237. DOI: 10.1016/j.ophtha.2007.03.040.
31.	Coupland SE, Heimann H, Bechrakis NE. Primary intraocular lymphoma: a review of the clinical, histopathological and molecular biological features[J]. Graefe's Arch Clin Exp Ophthalmol, 2004, 242(11): 901-913. DOI: 10.1007/s00417-004-0973-0.
32.	Klimova A, Heissigerova J, Rihova E, et al. Combined treatment of primary vitreoretinal lymphomas significantly prolongs the time to first relapse[J]. Br J Ophthalmol, 2018, 102(11): 1579-1585. DOI: 10.1136/bjophthalmol-2017-311574.
33.	Saito T, Ohguro N, Iwahashi C, et al. Optical coherence tomography manifestations of primary vitreoretinal lymphoma[J]. Graefe's Arch Clin Exp Ophthalmol, 2016, 254(12): 2319-2326. DOI: 10.1007/s00417-016-3395-x.
34.	Conrady CD, Shakoor A. Rituximab-associated retinal occlusive vasculopathy: a case report and literature review[J]. Ocul Immunol Inflamm, 2020, 28(4): 622-625. DOI: 10.1080/09273948.2019.1611874.
35.	Coupland SE, Damato B. Understanding intraocular lymphomas[J]. Clin Exp Ophthalmol, 2008, 36(6): 564-578. DOI: 10.1111/j.1442-9071.2008.01843.x.
36.	Chan CC, Sen HN. Current concepts in diagnosing and managing primary vitreoretinal (intraocular) lymphoma[J]. Discov Med, 2013, 15(81): 93-100. DOI: 10.1590/1414-431X20122397.
37.	Riemens A, Bromberg J, Touitou V, et al. Treatment strategies in primary vitreoretinal lymphoma: a 17-center European collaborative study[J]. JAMA Ophthalmol, 2015, 133(2): 191-197. DOI: 10.1001/jamaophthalmol.2014.4755.
38.	Grimm SA, McCannel CA, Omuro AM, et al. Primary CNS lymphoma with intraocular involvement: international PCNSL collaborative group report[J]. Neurology, 2008, 71(17): 1355-1360. DOI: 10.1212/01.wnl.0000327672.04729.8c.
39.	Gote V, Sikder S, Sicotte J, et al. Ocular drug delivery: present innovations and future challenges[J]. J Pharmacol Exp Ther, 2019, 370(3): 602-624. DOI: 10.1124/jpet.119.256933.

1. Sagoo MS, Mehta H, Swampillai AJ, et al. Primary intraocular lymphoma[J]. Surv Ophthalmol, 2014, 59(5): 503-516. DOI: 10.1016/j.survophthal.2013.12.001.
2. Kvopka M, Lake SR, Smith JR. Intraocular chemotherapy for vitreoretinal lymphoma: a review[J]. Clin Exp Ophthalmol, 2020, 48(2): 240-248. DOI: 10.1111/ceo.13668.
3. Fend F, Ferreri AJ, Coupland SE. How we diagnose and treat vitreoretinal lymphoma[J]. Br J Haematol, 2016, 173(5): 680-692. DOI: 10.1111/bjh.14025.
4. Pe'er J, Hochberg FH, Foster CS. Clinical review: treatment of vitreoretinal lymphoma[J]. Ocul Immunol Inflamm, 2009, 17(5): 299-306. DOI: 10.3109/09273940903370755.
5. Preisz Z, Kunsági-Máté S. Effect of methotrexate and its photodegradation products on the temperature induced denaturation of human serum albumin[J/OL]. Spectrochim Acta A Mol Biomol Spectrosc, 2021, 245: 118905[2021-01-15]. https://pubmed.ncbi.nlm.nih.gov/32927299/. DOI: 10.1016/j.saa.2020.118905.
6. de Smet MD, Stark-Vancs V, Kohler DR, et al. Intraocular levels of methotrexate after intravenous administration[J]. Am J Ophthalmol, 1996, 121(4): 442-444. DOI: 10.1016/s0002-9394(14)70444-1.
7. Velez G, Yuan P, Sung C, et al. Pharmacokinetics and toxicity of intravitreal chemotherapy for primary intraocular lymphoma[J]. Arch Ophthalmol, 2001, 119(10): 1518-1524. DOI: 10.1001/archopht.119.10.1518.
8. de Smet MD, Vancs VS, Kohler D, et al. Intravitreal chemotherapy for the treatment of recurrent intraocular lymphoma[J]. Br J Ophthalmol, 1999, 83(4): 448-451. DOI: 10.1136/bjo.83.4.448.
9. Fishburne BC, Wilson DJ, Rosenbaum JT, et al. Intravitreal methotrexate as an adjunctive treatment of intraocular lymphoma[J]. Arch Ophthalmol, 1997, 115(9): 1152-1156. DOI: 10.1001/archopht.1997.01100160322009.
10. Kuijpers TW, Bende RJ, Baars PA, et al. CD20 deficiency in humans results in impaired T cell-independent antibody responses[J]. J Clin Invest, 2010, 120(1): 214-222. DOI: 10.1172/JCI40231.
11. Plosker GL, Figgitt DP. Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia[J]. Drugs, 2003, 63(8): 803-843. DOI: 10.2165/00003495-200363080-00005.
12. Kim H, Csaky KG, Chan CC, et al. The pharmacokinetics of rituximab following an intravitreal injection[J]. Exp Eye Res, 2006, 82(5): 760-766. DOI: 10.1016/j.exer.2005.09.018.
13. Pulido JS, Bakri SJ, Valyi-Nagy T, et al. Rituximab penetrates full-thickness retina in contrast to tissue plasminogen activator control[J]. Retina, 2007, 27(8): 1071-1073. DOI: 10.1097/IAE.0b013e31804ac032.
14. Kitzmann AS, Pulido JS, Mohney BG, et al. Intraocular use of rituximab[J]. Eye (Lond), 2007, 21(12): 1524-1527. DOI: 10.1038/sj.eye.6702804.
15. Smith JR, Rosenbaum JT, Wilson DJ, et al. Role of intravitreal methotrexate in the management of primary central nervous system lymphoma with ocular involvement[J]. Ophthalmology, 2002, 109(9): 1709-1716. DOI: 10.1016/s0161-6420(02)01125-9.
16. Frenkel S, Hendler K, Siegal T, et al. Intravitreal methotrexate for treating vitreoretinal lymphoma: 10 years of experience[J]. Br J Ophthalmol, 2008, 92(3): 383-388. DOI: 10.1136/bjo.2007.127928.
17. Smith JR, Pe'er J, Belfort RN, et al. Proceedings of the association for research in vision and ophthalmology and champalimaud foundation ocular oncogenesis and oncology conference[J/OL]. Transl Vis Sci Technol, 2019, 8(1): 9[2018-01-09]. https://pubmed.ncbi.nlm.nih.gov/30652059/. DOI: 10.1167/tvst.8.1.9.
18. Sou R, Ohguro N, Maeda T, et al. Treatment of primary intraocular lymphoma with intravitreal methotrexate[J]. Jpn J Ophthalmol, 2008, 52(3): 167-174. DOI: 10.1007/s10384-008-0519-9.
19. Akiyama H, Takase H, Kubo F, et al. High-dose methotrexate following intravitreal methotrexate administration in preventing central nervous system involvement of primary intraocular lymphoma[J]. Cancer Sci, 2016, 107(10): 1458-1464. DOI: 10.1111/cas.13012.
20. Ma WL, Hou HA, Hsu YJ, et al. Clinical outcomes of primary intraocular lymphoma patients treated with front-line systemic high-dose methotrexate and intravitreal methotrexate injection[J]. Ann Hematol, 2016, 95(4): 593-601. DOI: 10.1007/s00277-015-2582-x.
21. Kaburaki T, Taoka K, Matsuda J, et al. Combined intravitreal methotrexate and immunochemotherapy followed by reduced-dose whole-brain radiotherapy for newly diagnosed B-cell primary intraocular lymphoma[J]. Br J Haematol, 2017, 179(2): 246-255. DOI: 10.1111/bjh.14848.
22. Zhou X, Zhou X, Shi H, et al. Reduced frequency of intravitreal methotrexate injection lowers the risk of keratopathy in vitreoretinal lymphoma patients[J/OL]. BMC Ophthalmol, 2020, 20(1): 189[2020-05-12]. https://pubmed.ncbi.nlm.nih.gov/32397978/. DOI: 10.1186/s12886-020-01464-3.
23. Ohguro N, Hashida N, Tano Y. Effect of intravitreous rituximab injections in patients with recurrent ocular lesions associated with central nervous system lymphoma[J]. Arch Ophthalmol, 2008, 126(7): 1002-1003. DOI: 10.1001/archopht.126.7.1002.
24. Hashida N, Ohguro N, Nishida K. Efficacy and complications of intravitreal rituximab injection for treating primary vitreoretinal lymphoma[J/OL]. Transl Vis Sci Technol, 2012, 1(3): 1[2012-10-22]. https://pubmed.ncbi.nlm.nih.gov/24049708/. DOI: 10.1167/tvst.1.3.1.
25. Fernández Cañabate E, Fernández-Cañabate S. Intravitreal rituximab for the treatment of intraocular relapse of non-Hodgkin's lymphoma[J]. Farm Hosp, 2018, 42(1): 20-21. DOI: 10.7399/fh.10830.
26. Echegaray JJ, Llop S, Sepulveda M, et al. Intravitreal rituximab for the treatment of a secondary intraocular relapse of a large B-cell lymphoma[J]. Am J Ophthalmol Case Rep, 2018, 9: 77-79. DOI: 10.1016/j.ajoc.2018.01.032.
27. Cicinelli MV, Marchese A, Miserocchi E, et al. Retinal and choroidal changes of vitreoretinal lymphoma from active to remission phase after intravitreal rituximab[J]. Ocul Immunol Inflamm, 2020, 28(4): 637-646. DOI: 10.1080/09273948.2019.1616769.
28. Larkin KL, Saboo US, Comer GM, et al. Use of intravitreal rituximab for treatment of vitreoretinal lymphoma[J]. Br J Ophthalmol, 2014, 98(1): 99-103. DOI: 10.1136/bjophthalmol-2013-304043.
29. Gorovoy I, Prechanond T, Abia M, et al. Toxic corneal epitheliopathy after intravitreal methotrexate and its treatment with oral folic acid[J]. Cornea, 2013, 32(8): 1171-1173. DOI: 10.1097/ICO.0b013e3182910106.
30. Goldberg S, Frenkel S, Blumenthal EZ, et al. Intraocular lymphoma[J]. Ophthalmology, 2007, 114(6): 1236-1237. DOI: 10.1016/j.ophtha.2007.03.040.
31. Coupland SE, Heimann H, Bechrakis NE. Primary intraocular lymphoma: a review of the clinical, histopathological and molecular biological features[J]. Graefe's Arch Clin Exp Ophthalmol, 2004, 242(11): 901-913. DOI: 10.1007/s00417-004-0973-0.
32. Klimova A, Heissigerova J, Rihova E, et al. Combined treatment of primary vitreoretinal lymphomas significantly prolongs the time to first relapse[J]. Br J Ophthalmol, 2018, 102(11): 1579-1585. DOI: 10.1136/bjophthalmol-2017-311574.
33. Saito T, Ohguro N, Iwahashi C, et al. Optical coherence tomography manifestations of primary vitreoretinal lymphoma[J]. Graefe's Arch Clin Exp Ophthalmol, 2016, 254(12): 2319-2326. DOI: 10.1007/s00417-016-3395-x.
34. Conrady CD, Shakoor A. Rituximab-associated retinal occlusive vasculopathy: a case report and literature review[J]. Ocul Immunol Inflamm, 2020, 28(4): 622-625. DOI: 10.1080/09273948.2019.1611874.
35. Coupland SE, Damato B. Understanding intraocular lymphomas[J]. Clin Exp Ophthalmol, 2008, 36(6): 564-578. DOI: 10.1111/j.1442-9071.2008.01843.x.
36. Chan CC, Sen HN. Current concepts in diagnosing and managing primary vitreoretinal (intraocular) lymphoma[J]. Discov Med, 2013, 15(81): 93-100. DOI: 10.1590/1414-431X20122397.
37. Riemens A, Bromberg J, Touitou V, et al. Treatment strategies in primary vitreoretinal lymphoma: a 17-center European collaborative study[J]. JAMA Ophthalmol, 2015, 133(2): 191-197. DOI: 10.1001/jamaophthalmol.2014.4755.
38. Grimm SA, McCannel CA, Omuro AM, et al. Primary CNS lymphoma with intraocular involvement: international PCNSL collaborative group report[J]. Neurology, 2008, 71(17): 1355-1360. DOI: 10.1212/01.wnl.0000327672.04729.8c.
39. Gote V, Sikder S, Sicotte J, et al. Ocular drug delivery: present innovations and future challenges[J]. J Pharmacol Exp Ther, 2019, 370(3): 602-624. DOI: 10.1124/jpet.119.256933.

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Current state and progress of intravitreal injection of chemotherapeutic agents for the treatment of vitreoretinal lymphoma

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