Real world outcomes of intravitreal and systemic therapy in primary and secondary vitreoretinal lymphoma

Abstract

Vitreoretinal large B-cell lymphoma (VR-LBCL) is a rare hematologic malignancy. It is classified as primary (PVR-LBCL) or secondary (SVR-LBCL) based on the initial site of manifestation. Owing to limited prospective data and absent standardized guidelines, treatment remains challenging. This dual-center retrospective study aimed to evaluate outcomes of methotrexate (MTX) intravitreal (itv.), Rituximab itv., or combinatorial itv. therapy (R-MTX) and assess the impact of additional systemic immunochemotherapy. Among 65 patients (median age 72 years) included, 55.4% (n = 36) had PVR-LBCL. The median time to diagnosis was 31 days (1–2805). Over a median follow-up of 23.2 months, 35 patients relapsed. MTX itv. showed a trend toward better ocular relapse-free-survival than Rituximab itv. (P = 0.07). Intriguingly, patients receiving R-MTX itv. experienced no relapses throughout follow-up. In general, addition of systemic therapy was associated with significantly longer relapse-free-survival compared to itv. monotherapy (P = 0.05). Keratopathy and elevated intraocular pressure were common side effects with MTX itv. and Rituximab itv., respectively. Despite compelling findings and being one of the largest cohorts published to date, the heterogeneity of the patient population and small subgroups limit direct clinical translation. Nonetheless, this study provides a strong foundation for the design of future clinical trials.

Supplementary Information: The online version contains supplementary material available at 10.1038/s41598-026-37804-4.

Keywords: Orphan disease; PIOL; PVRL; Relapse-free survival; Vitreoretinal lymphoma.

Fig. 1

Study flow and treatment overview in VR-LBCL patients. Study flow of n = 65 VR-LBCL patients (corresponding to 99 eyes) from Tübingen and Graz, including initial treatments, and follow-up cohort composition.

Fig. 2

Relapse-free survival in PVR-LBCL patients by intravitreal therapy. (A) Relapse-free survival for any site relapse among 22 PVR-LBCL patients showed no significant difference between those treated with Rituximab intravitreal (itv., n = 13) and Methotrexate (MTX) itv. (n = 9) (P = 0.3). (B) Relapse-free survival for eye-confined relapses among 16 PVR-LBCL patients indicated a trend toward improved relapse-free survival with MTX itv. (n = 6) compared to Rituximab itv. (n = 10), though this difference was not statistically significant (P = 0.07).

Fig. 3

Relapse-free survival by combined intravitreal and systemic therapies in PVR-LBCL. (A) For any site relapses, patients receiving both systemic and intravitreal (itv.) therapy (n = 13) demonstrated significantly longer relapse-free survival compared to those treated with itv. monotherapy (n = 13) (P = 0.05). (B) Among different itv. treatment regimens combined with systemic therapy, the Rituximab-Methotrexate (R-MTX) itv. + systemic therapy group (n = 3) showed the most favorable outcomes with no observed relapses, though overall differences did not reach statistical significance (P = 0.1). (C) For eye-confined relapses, significant differences were observed across treatment groups (P = 0.003), with longer relapse-free survival in patients treated with MTX itv. + systemic therapy (n = 3) and R-MTX itv. + systemic therapy (n = 3) compared to other regimens. However, these differences were not significant after adjustment for multiple comparisons (adjusted P = 0.055).

Fig. 4

Relapse-Free survival in PVR-LBCL and SVR-LBCL patients and treatment effects in VR-LBCL. (A) Relapse-free survival for any site relapses showed no significant difference between PVR-LBCL (n = 28) and SVR-LBCL (n = 22) patients (P = 0.8). (B) For eye-confined relapses, no significant difference in relapse-free survival was observed between PVR-LBCL (n = 22) and SVR-LBCL (n = 15) patients (P = 0.7). (C) Relapse-free survival for eye-confined relapses across all VR-LBCL patients (n = 50) showed no significant differences among intravitreal (itv.) treatments (P = 0.2), though a trend toward improved outcomes with R-MTX itv. was observed.