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

Abstract

Abstract

We commend Trabolsi et al. for presenting the largest prospectively treated, uniformly managed cohort of primary vitreoretinal lymphoma (PVRL) to date [1]. By combining bilateral ocular radiation therapy (BORT) with high-dose methotrexate (HD-MTX)-based systemic chemotherapy, the authors achieved an impressive 95% complete response (CR) rate and a median overall survival (OS) of 15 years, with only one ocular relapse observed throughout the follow-up period. These data strongly support the value of combined-modality treatment in achieving durable local control and prolonging survival without consolidation autologous stem cell transplantation. In an era where PVRL management remains largely empirical, this single-center experience offers a meaningful benchmark for both local and systemic disease eradication. Nevertheless, several limitations warrant cautious interpretation. First, although treatment was administered prospectively, data collection was retrospective, which may introduce ascertainment and reporting bias. Second, the cohort remains small (n = 20), reflecting the rarity of PVRL and constraining the generalizability of the findings. Third, and most clinically relevant, the high rate of radiation-induced ocular complications (80%) and visual impairment raises important concerns about long-term quality of life, particularly given that PVRL predominantly affects elderly patients. As previously pointed out by Soussain et al., the progression of the central nervous system (CNS) remains the primary determinant of the mortality rate in PVRL [2]. In the present study, although CNS progression remained the dominant failure pattern (seven of eight relapses), it is noteworthy that the median disease-free survival reached 13.1 years, indicating that HD-MTX-based approaches afford substantial intracranial disease control. In the French LOC network study of 59 isolated PVRL patients uniformly treated with first-line intravenous HD-MTX based therapy, Lam et al. reported a median brain-free survival of 73 months [3]. Taken together, these findings suggest that meaningful CNS control can be achieved with HD-MTX–based therapy; however, given the excellent ocular control already observed, the burden of radiation-induced toxicity now shifts attention toward refining local therapeutic strategies to preserve vision while maintaining disease control. Our recent PRISMA-compliant meta-analysis of 37 studies comprising 801 patients provides additional context [4]. The pooled CR rate across all treatment modalities was 85% and the overall response rate was 93%; however, the 2-year progression-free survival (PFS) was only 58%, underscoring the suboptimal durability of current therapies. Intriguingly, combined intravitreal MTX plus systemic HD-MTX achieved a pooled CR of 98%, whereas BTK inhibitor monotherapy yielded only 79%, highlighting the necessity of multi-modality approaches. Yet, the pooled median PFS of intravitreal MTX plus systemic HD-MTX was merely 19.89 months, without clear advantage over single-modality strategies, echoing the findings of Riemens et al. and suggesting that simply layering local and systemic cytotoxics is insufficient to prevent CNS sanctuary failure [5]. In our retrospective cohort of 56 vitreoretinal lymphoma patients, HD-MTX significantly prolonged median PFS compared with non-HD-MTX regimens (1287 vs. 376 days; p = 0.003) and markedly reduced CNS progression rates (17.2% vs. 62.5%; p = 0.001) [6]. However, BTK inhibitor monotherapy did not significantly improve PFS, and its combination with HD-MTX showed no additive PFS benefit in this setting, consistent with our earlier meta-analysis showing inferior CR rates with BTKi monotherapy [7]. These data suggest that while HD-MTX remains the cornerstone of CNS prophylaxis, BTK inhibitors alone are insufficient for durable disease control in unselected populations. Encouragingly, emerging prospective data point toward more effective chemo-sparing or chemo-integrated regimens. In a recent prospective cohort study comparing systemic chemo-free inductions for isolated PVRL, the zanubrutinib-plus-rituximab (ZR) regimen demonstrated significantly superior PFS compared with lenalidomide-plus-rituximab (R2) [8]. Looking forward, we believe the future of PVRL management lies in three strategic pillars. First, precision risk stratification using molecular profiling—such as MYD88^L265P, CD79B, ETV6 loss, and PRDM1 alterations—should guide the intensity of CNS prophylaxis [9]. Second, vision-sparing de-escalation should be prioritized; given the 80% ocular toxicity rate reported by Trabolsi et al., replacing radiotherapy with BTKi-containing systemic regimens in selected patients could preserve visual function without compromising CNS control [1]. Third, liquid biopsy surveillance utilizing aqueous humor IL-10/IL-6 ratios and cell-free DNA should be incorporated for real-time monitoring of minimal residual disease and early detection of CNS progression. Ultimately, international multicenter randomized trials comparing radiation-chemotherapy combinations with novel BTKi-based systemic regimens are urgently needed to redefine the standard of care for this challenging disease. In summary, Trabolsi et al. provide valuable long-term evidence that combined-modality therapy achieves excellent local control and prolonged survival [1]. However, the persistently high rate of CNS progression and radiation-related morbidity underscore the need for a paradigm shift—one that integrates targeted agents, refined CNS prophylaxis, and molecular biomarkers to deliver personalized, vision-preserving treatment strategies for patients with PVRL. This work was supported by grants from Noncommunicable Chronic Diseases-National Science and Technology Major Project (2025ZD0544300) to L.W. This work was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2025ZD0544300). The authors have nothing to report. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.