Response to: “Refining Combined‐Modality Therapy and Charting the Future of Primary Vitreoretinal Lymphoma”

We read the correspondence by Dr. Gao and colleagues entitled “Refining Combined-modality therapy and charting the future of primary vitreoretinal lymphoma” [1], referred to our recent publication, “Combination of ocular radiation with systemic chemotherapy for treatment of primary vitreoretinal lymphoma: a prospective single center cohort with long follow-up” [2]. We thank the authors for their interest in our manuscript and thoughtful engagement on the future treatments of PVRL. As stated by Gao et al. [1], our study has limitations that were discussed in our manuscript, and are attributed to low incidence of PVRL, impeding execution of phase 2 clinical studies and making phase 3 studies challenging. Because of the rarity of PVRL, such studies will require involvement of multiple institutions and prolonged periods of time to recruit the patients. With rigorous statistical power, recruitment of a sufficient number of patients to reject the null hypothesis may not be feasible. Consequently, our prospectively and uniformly treated currently largest cohort of patients provides valuable information that will help to guide treatment of PVRL. While the major cause of death in PVRL is attributed to parenchymal central nervous system (CNS) involvement occurring frequently in these patients [3], proper local control of the lymphoma localized in the eyes is necessary to prevent CNS dissemination and later relapses. Blood-retinal barrier (BRB) protects the lymphoma cells from systemically administered treatments thus generating a sanctuary with continuous risk for dissemination to brain and CNS [4]. In previous studies, administration of 8 g/m2 of methotrexate (MTX) was needed to achieve MTX vitreous levels considered to be cytotoxic [5]. While systemic Bruton tyrosine kinases inhibitors, lenalidomide and temozolomide may transiently control PVRL, possibly due to initially disturbed BRB, they are not curative as single agents in CNS and systemic lymphomas [6-8]. Similarly, intraocular MTX does not provide complete and long-lasting eradication of PVRL and does not reduce the risk for CNS dissemination. Consequently, despite the side effects, radiotherapy currently remains the most active approach to control intraocular disease, as shown in our and other studies and it improves patients' outcomes when used in combination with systemic MTX-based treatments [2, 9]. We agree with Gao et al. that ocular toxicity is of concern. In our cohort, 80% of patients experience ocular toxicity; however, in most patients it was acute and not lasting. Following treatment, the majority of patients (14/20) retained useful vision, usually in both eyes. Since the combined approach of radiation and systemic chemotherapy led to significant improvement in outcome with long-term remissions and survival, mild to moderate ocular toxicity may be acceptable. However, novel treatments are needed to maintain or improve the results reported by us by using therapeutic modalities associated with reduced general and specifically ocular toxicities. Currently, a randomized phase 3 (NCT07402876) is trying to address the efficacy and dosing intensity schedule of intravitreal treatment. This study will be informative and may become the first randomized study in PVRL. While Gao et al. are very enthusiastic to incorporate BTKi in the treatment of PVRL, we need to remember that they are not curative in primary CNS lymphoma and thus unlikely to be curative in PVRL or replace systemic chemotherapy penetrating to CNS and local control [10, 11]. BTKi are also not useful in systemic diffuse large cell lymphoma, and in a randomized PHOENIX study, ibrutinib with chemotherapy did not improve outcomes [12]. However, BTKi are a valid option for relapsed diseases as opposed to curative-intent, first-line treatment. Overall, until we have prospective studies in PVRL, clinical practice will depend on uniform high-quality case series. The authors have nothing to report. The authors have nothing to report. The authors have nothing to report. I.S.L. research support from Genentech, ADC Therapeutics, and Genmab. A.T. declares no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.