Efficacy and safety of first-line combination therapy versus monotherapy for vitreoretinal lymphoma: a systematic review and meta-analysis

Vitreoretinal lymphoma (VRL), also known as intraocular lymphoma (IOL), is a rare variant of central nervous system lymphoma (CNSL). It is a extranodal, non-Hodgkin's lymphoma, typically of the B-cell type, which predominantly affects the vitreous and retina of the eye, while also potentially involving the optic nerve without any infiltration of the brain parenchyma. It is important to note that VRL is an exceptionally aggressive lymphoma subtype, often posing significant challenges for diagnosis and treatment.

VRL is a very rare disease, with only approximately 50 new cases reported annually in the United States, mostly affecting elderly patients. Additionally, women appear to be more susceptible than men [1]. Nonetheless, there exists a close association between VRL and CNSL, as some CNSL may ultimately develop an ocular manifestation, while most VRL-origin lymphomas may eventually progress to CNSL. Hence, despite its low prevalence, the severity of VRL should not be underestimated, making it crucial to find an appropriate treatment strategy that can minimize the risk of CNS recurrence while alleviating ocular symptoms.

The first-line treatment for VRL typically includes both local treatment, such as intravitreal injection of chemotherapy, ocular radiotherapy, and systemic therapy based on high-dose (HD) methotrexate (MTX). Nevertheless, the contribution of the combination of these two first-line treatments to improved outcomes remains controversial [2]. In addition to local and systemic treatments, there are currently several other therapeutic modalities that have gained widespread attention in research. Various single agents, including temozolomide, and targeted agents such as Bruton tyrosine kinase inhibitors (BTKi), are also emerging as potential treatment options for VRL [3, 4]. However, the specific advantages and disadvantages between the two first-line therapy modalities and monotherapy remain unclear. Thus, the objective of this study is to conduct a systematic review and meta-analysis comparing the efficacy and safety of first-line combination therapy versus monotherapy, in order to provide recommendations for future clinical management.

Intraocular lymphoma, being an uncommon ailment, can be mistakenly identified as uveitis during diagnosis. Additionally, a treatment approach that achieves both effectiveness and safety remains elusive. Moreover, the long-term prognosis for PVRL patients is bleak, as around 60%-80% of them eventually develop PCNSL, as reported in 1999 by Akpek [29]. Treatment modalities for PVRL are variable and include methotrexate-based local/systemic therapy, local/whole-brain radiation therapy, various monotherapy and intensive chemotherapy plus hematopoietic stem cell transplantation (IC + ASCT), the optimal treatment modality has not yet been identified.

Intravitreal methotrexate (ioMTX) is an early proposed local treatment with a high remission rate but usually a poor prognosis, with most patients experiencing CNS progression within a short period of time (2004 Coupland) [30]. Anthony et al. designed a small sample single-center retrospective study to investigate the efficacy of ioMTX alone in the treatment of PVRL [11]. Although all achieved CR or PR, their time until disease recurrence was not promising (mean time to first recurrence was 6.5 months). Based on the anatomical and functional similarities of PVRL to PCNSL at the blood–brain barrier (BBB) and blood-retinal barrier (BRB), intravenous high-dose methotrexate injection (IV HD-MTX) has also been used as an empirical agent for PVRL treatment and is often combined with ioMTX and local radiotherapy to improve efficacy (Akiyama, de la Fuente) [19, 22].

Lam et al. gathered data pertaining to 59 patients who were diagnosed with isolated primary vitreoretinal lymphoma (PVRL) from the French LOC network database, in order to examine the effectiveness and adverse effects of intravenous high-dose methotrexate (HD-MTX)-based systemic chemotherapy in treating PVRL patients [8]. Despite the fact that 70% of patients attained a complete response (CR) or unconfirmed complete response (uCR), the relapse rate was not insignificant (with a median follow-up of 61 months, 37% of patients experienced central nervous system recurrence and 58% had ocular recurrence), and the occurrence of grade 3/4 toxicity in 53% of patients implied poor tolerability. Furthermore, there are instances of using more than two regimens for treating PVRL. Kaburaki et al.'s R-MTX + ioMTX + rdWBRT (reduced-dose whole brain radiation therapy) regimen for PVRL resulted in long-term progression-free survival (PFS) and overall survival (OS) (with a 4-year PFS of 74.9% and a 4-year OS of 86.3%), as well as a low overall relapse rate (23.5%) [26]. However, it is important to note that this regimen was associated with significant grade 3/4 hematologic toxicity.

In addition, intraocular injection of rituximab as another intravitreal treatment for VRL, usually at a dose of 1 mg/0.1 mL, was first used by Kitzmann et al. in 2007 and achieved rapid remission in 8 eyes of 5 patients, demonstrating good tolerability [31]. Subsequently, Hashida et al. included 13 patients' 20 eyes in their 2012 study, all of whom exhibited severe corneal epithelial lesions or were unresponsive to repeated ioMTX injections. Following a course of intraocular rituximab therapy, initial control of retinal lesions was achieved. However, within three months, 11 eyes (55%) of nine patients experienced ocular relapse, and 9 cases (69%) eventually progressed to central nervous system involvement [32]. In 2014, Larkin et al. designed a multinational, multicenter study with a larger cohort, consisting of 48 eyes from 34 patients. The treatment was based on intravitreal injection of rituximab. Ultimately, complete and partial remission were observed in 31 eyes (64.6%) and 11 eyes (22.9%), respectively, while 12 eyes (25%) suffered complications, potentially due to rituximab [33]. To assess the therapeutic response and safety of intravitreal rituximab in PVRL patients, Kakkassery et al. conducted a study in 2021, enrolling 20 eyes from 15 consecutively diagnosed PVRL patients. No other intravitreal or systemic injections were given during treatment. Following therapy, there was a significant reduction in vitreous haze scores, marked improvement in best-corrected visual acuity, and no manifestation of severe adverse effects [34].

In recent times, various monotherapy regimens have been investigated to identify an effective and safe treatment combination. Temozolomide (TMZ), a second-generation alkylating agent that is well-tolerated, has been found to have good penetrative capacity into the central nervous system and cerebrospinal fluid (CSF) (Reni, 2007) [35]. Baron et al. conducted a retrospective study using TMZ for the treatment of PVRL, which produced encouraging results (with an ORR of 81%, mPFS of 12 months, and a central nervous system [CNS] relapse rate of 23.8%) [3]. Bruton tyrosine kinase (BTK) is a crucial mediator molecule in B-cell proliferation, and its inhibitors have the potential to serve as therapeutic agents in various B-cell malignancies. However, it is yet to be determined whether such inhibitors can offer therapeutic benefit to patients with primary vitreoretinal lymphoma (PVRL). To address this, Soussain et al. designed a multicenter, open-label phase II clinical trial aimed at evaluating the efficacy of Ibrutinib as a single agent in patients with both primary central nervous system lymphoma (PCNSL) and PVRL [23]. Of the 14 patients with PVRL included in the study, 86% achieved remission after 2 months of treatment, with a median progression-free survival (PFS) value of 22.7 months. Moreover, single-agent combination intraocular methotrexate (ioMTX) regimens have also been investigated. Zhang et al. sequentially tried a regimen of R2 (lenalidomide plus rituximab) + ioMTX induction, lenalidomide maintenance therapy, and ZR (zanubrutinib plus rituximab) + ioMTX to further investigate the optimal treatment strategy for PVRL [24, 27].

Moreover, a prospective study designed by Soussain et al. evaluating the feasibility of intensive chemotherapy (consisting of high-dose thiotepa, busulfan and cyclophosphamide) plus hematopoietic stem cell transplantation as a treatment modality for relapsed or refractory CNS lymphoma and intraocular lymphoma with an ultimate 3-year overall survival rate of 63.7%. demonstrating the benefit of IC + ASCT in patients with relapsed PVRL, but this modality is only indicated for younger relapsed patients younger than 60 years of age who are well tolerated, and its safety is difficult to guarantee in patients older than 60 years of age [36].

In this meta-analysis, we compared the efficacy and safety of combination therapy versus monotherapy regimens for the treatment of VRL. In the combination therapy group, specific interventions included ioMTX + chemotherapy (in 4 studies), RT + chemotherapy (in 2 studies), ioMTX/HD-MTX based regimen (in 2 studies), ioMTX + RT + chemotherapy (in 2 studies), ioMTX + lenalidomide/BTKi (in 2 studies) and combination of multiple therapies (in 7 studies). In the monotherapy group included in our study, interventions included Pomalidomide, Temozolomide, and BTKi.

We found that patients receiving combination therapy demonstrated a higher ORR and CRR as well as a relatively longer median progression-free survival (PFS) compared to those receiving monotherapy. BTKi, as a single agent, achieved an ORR that approximated that of the combination group, suggesting a strong potential for the treatment of VRL. The analysis also explored whether the number of treatment approaches in the combination group had an impact on survival time. Interestingly, the results showed that there were no significant survival differences between treatment regimens combining three approaches versus those combining two or less approaches. This suggests that the number of treatment approaches may not be the primary factor influencing survival time in patients receiving combination therapy for the condition under study. Moreover, this study investigated the potential influence of demographic and clinical characteristics on survival time, including age, gender, and whether the onset of the condition was bilateral. The study results indicated that none of these factors demonstrated a significant association with survival time. In further subgroup analysis, we found that ioMTX plus monotherapy did not show superior survival compared to other combination therapies, suggesting that MTX-based systemic chemotherapy regimens may be more effective when combined with ioMTX compared to lenalidomide and BTKi, but the data on ioMTX plus monotherapy is limited and requires more data to confirm its true benefits.

In addition, we also observed that the combination therapy group exhibited a higher incidence of grade 3/4 toxicities. Grade 3/4 toxicities mainly included ocular and systemic toxicities, with ocular toxicities mainly consisting of cataracts and keratitis, and systemic toxicities mainly consisting of neutropenia and anemia. We found that the combination therapy group had more significant grade 3/4 toxicities than the monotherapy group, suggesting that the safety of monotherapy may be better than that of combination therapy. Furthermore, we observed similar recurrence rates between the two groups. Whether it was a combination therapy or monotherapy, the CNS recurrence rate was approximately 30%. However, the ocular recurrence rate appeared to be relatively higher in the combination therapy group, but the number of studies included in the monotherapy treatment group was limited, and further research is needed to better understand the potential differences between the two treatment methods in terms of ocular recurrence.

In general, these results suggest that a treatment approach that combines efficacy and safety still needs to be explored to achieve better management of intraocular lymphoma. The long-term efficacy of systemic therapy with one drug alone is not satisfactory, and the combination of systemic and local therapy for intraocular lymphoma is the future trend. The use of single drugs such as BTK inhibitors and temozolomide in combination with high-dose systemic MTX chemotherapy regimens may also be a potential new research direction. Future research may focus on identifying the optimal treatment combination that can provide VRL patients with a longer period of remission, extended survival time, and prevention of recurrence in the central nervous system and ocular region.

The limitations of this article stem from the rarity of VRL, which results in a relatively small sample size. Additionally, the diverse treatment methods employed across various studies introduce significant heterogeneity, leading to some conclusions drawn from the combined data lacking statistical support. Moreover, the average follow-up time in the literature involving the use of new BTKi-like drugs is not yet long and may lead to some uncertainty in the results. Furthermore, the number of studies on oral monotherapy for VRL is small and more prospective studies are needed to facilitate a more robust comparison between the two groups. Nonetheless, our analysis provides a comprehensive summary of the efficacy and safety of various VRL treatment methods and serves as a valuable reference for further exploration of more optimal solutions.

Based on the available evidence, first-line combination therapy for VRL appears to be more effective than monotherapy, with higher OR and CR rates and longer median progression-free survival. However, combination therapy also has higher rates of grade 3/4 toxicity compared to monotherapy. While BTK inhibitors as monotherapy for VRL appear to be well tolerated, further studies are needed to confirm their long-term efficacy. Prospective studies are necessary to evaluate the optimal treatment approach for VRL.