MEK Inhibitor-Associated Central Retinal Vein Occlusion Associated with Hyperhomocysteinemia and MTHFR Variants

Background: Central retinal vein occlusion (CRVO) is a visually threatening event that has rarely been observed in patients taking MEK1/2 inhibitors and that may necessitate permanent discontinuation of a potentially efficacious therapy. We investigated the clinical characteristics of CRVO in patients on mitogen-activated protein kinase kinase (MEK) inhibition to better understand their predisposing factors and clinical course. Case Series: This was a single-center, retrospective cohort study (between December 2006 and September 2018). Three of 546 patients enrolled in 46 prospective trials involving treatment with MEK inhibitors at Memorial Sloan Kettering Cancer Center were identified as having CRVO. Clinical examination and course, multimodal ophthalmic imaging, and serum laboratory results (including homocysteine levels and genetic variants of methylene tetrahydrofolate reductase [MTHFR]) were reviewed for the 3 affected patients. All 3 patients with MEK inhibitor-associated CRVO had elevated serum homocysteine and gene variants of MTHFR (1 homozygous for A1298C, 1 heterozygous for A1298C, and 1 homozygous for C677T). Following intravitreous injections of anti-VEGF and discontinuation of drug, all patients regained vision to their baseline. Discussion: MEK inhibitor-associated CRVO is a rare event which can exhibit visual recovery after drug cessation and intravitreous anti-VEGF injections. In this cohort, it was associated with hyperhomocysteinemia and genetic mutations in MTHFR, suggesting a potential role for hyperhomocysteinemia screening prior to initiation of MEK inhibitor therapy.