Targeting Bruton Tyrosine Kinase for the Treatment of Vitreoretinal Lymphoma: Report of 11 Consecutive Patients

Abstract

Background:Vitreoretinal lymphoma (VRL) is a rare intraocular malignancy, which is regarded as a part of the central nervous system lymphoma (CNSL) and shows a close relationship with CNS progression. Currently, no standard treatment approaches have been defined yet, although intravitreal methotrexate with or without systemic chemotherapy are generally used. Bruton tyrosine kinase (BTK) is a vital effector molecule in the progress of B-cell proliferation. VRL, as well as PCNSL, display typically an activated B cell-like (ABC) phenotype of diffuse large B-cell lymphoma (DLBCL), with frequent CD79B and MYD88 mutations, which may represent a strong biological rationale for the use of BTK inhibitors. Previous studies have demonstrated that BTK inhibitors could penetrate the blood-brain barrier, and achieve 70-90% response rate in patients with PCNSL. However, whether BTK inhibitors could penetrate the blood-eye barrier and provide benefits to patients with VRL remains unknown.Methods:In this retrospective study, 11 consecutive patients with VRL were treated with BTK inhibitors monotherapy (zanubrutinib 160mg orally twice daily, or orelabrutinib 150mg orally daily), and they were intended to be treated for 2 years, or till disease progression, or unacceptable toxicity, whichever occurs first. All enrolled patients were pathologically confirmed as vitreoretinal DLBCL using vitreous biopsy, and PET-CT scan were performed to rule out the systemic involvement of lymphoma. Patients with pretreated or concurrent CNSL were allowed in this study. Cytokine analysis (including IL-10 and IL-6) in the anterior chamber of the eye was done using Cytometric Bead Array (CBA) at one month after initiation of treatment, and every three months thereafter or as symptom indicated. Fundus photograph and optical coherence tomography (OCT) were done at each follow-up. Magnetic resonance imaging (MRI) of brain was done every three months. This study was approved by the Ethic Committee of Beijing Tongren Hospital and written informed consent was provided by all patients.Results:11 consecutive patients with VRL were treated since May 2020, among whom 5 patients were enrolled in our prospective study evaluating the efficacy and safety of zanubrutinib in the treatment of VRL (ChiCTR2000037921), and the other 6 patients were treated with off-label use of BTK inhibitors, and those 11 patients were analyzed combined in this report. The female to male ratio was 7:4, with a median of 61 years old (41-73). 3 patients had pretreated PCNSL and were in complete remission at the time of VRL relapse, and one patient (YSX2) had concurrent PCNSL and VRL. All the other 7 patients had isolated VRL, among whom 3 patients were diagnosed as de novo VRL and the other 4 patients were previously treated with repeated intravitreal methotrexate and had disease relapse at the time of BTK inhibitor treatment. The detailed efficacy information was shown in Figure 1. All but one patients achieved complete remission (CR) after one months of BTK inhibitor treatment, with symptoms resolved, disappearance of infiltration lesions in OCT, and IL-10 levels returned to normal. One patient (YSX2) suffered from disease progression in the brain and withdrew from the study after 2 months of treatment, while the eye symptoms were significantly improved. At a median follow up of 7.5 months (4-15), 4 patients were confirmed to have disease progression, with a progression-free survival (PFS) of 2, 7, 7.5, and 9 months, respectively. All the other 7 patients have durable CR. 4 patients treated with off-label use of zanubrutinib discontinued BTKi due to economic reasons, and remained in CR till the last follow-up. One patient (YSX1) stopped BTK inhibitor after 2 months, and suffered from disease relapse 5.5 months later without any other treatments. BTK inhibitors were well-tolerated, with grade 1 ecchymosis in 3/11 patients, grade 3 hypertension in 1/11 patients, grade 2 arthralgia in 1/11 patients, and grade 1 liver dysfunction in 2/11 patients. No patients stopped the drug due to adverse events, and one patient reduced the dosage due to uncontrolled hypertension. All patients were alive at the time of this report.Conclusions:In conclusion, targeting BTK in VRL is feasible and our findings can be a foundation for a paradigm shift in treatment options for this rare disease. A well-designed prospective study in a larger cohort of patients is needed to validate our findings. [Display omitted] DisclosuresNo relevant conflicts of interest to declare. OffLabel Disclosure:USE OF ZANUBRUTINIB FOR THE TREATMENT OF DIFFUSE LARGE B CELL LYMPHOMA