Page 155 - Haematologica Vol. 107 - September 2022

ARTICLE - Non-Hodgkin Lymphoma
A pilot study of the use of dynamic analysis of cell-free DNA from aqueous humor and vitreous fluid for the diagnosis and treatment monitoring of vitreoretinal lymphomas
Xiaoxiao Wang,1,2* Wenru Su,3* Yan Gao,1,2* Yanfen Feng,1,4 Xiaoxia Wang,5 Xiaoqing Chen,3 Yunwei Hu,3 Yutong Ma,5 Qiuxiang Ou,5 Dan Liang3 and Huiqiang Huang1,2
1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou; 2Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou; 3State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou; 4Department of Pathology, Sun Yat- sen University Cancer Center, Guangzhou and 5Geneseeq Research Institute, Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, China
*XW, WS and YG contributed equally as co-first authors.
Abstract
The diagnosis of vitreoretinal lymphoma (VRL), a rare subtype of primary central nervous system lymphoma, is challenging. We aimed to investigate the mutational landscape of VRL by sequencing circulating tumor DNA (ctDNA) from aqueous humor (AH) and/or vitreous fluid (VF), as well as applying ctDNA sequencing to diagnosis and treatment monitoring. Baseline AH and/or VF specimens from 15 VRL patients underwent comprehensive genomic profiling using targeted next-generation sequencing. The molecular profiles of paired baseline AH and VF specimens were highly concordant, with comparable allele frequencies. However, the genetic alterations detected in cerebrospinal fluid ctDNA only partially overlapped with those from simultaneously collected AH/VF samples, with much lower allele frequencies. Serial post-treatment AH or VF samples were available for five patients and their changes in ctDNA allele frequency displayed a similar trend as the changes in interleukin-10 levels; an indicator of response to treatment. A cohort of 23 patients with primary central nervous system lymphoma was included as a comparison group for the genetic landscape and evaluations of the efficacy of ibrutinib. More MYD88 mutations, but fewer IRF4 mutations and CDKN2A/B copy number losses were observed in the baseline samples of primary central nervous system lymphoma than VRL patients. The objective response rate to ibrutinib treatment was much higher for patients with primary central nervous system lymphoma (64.7%, 11/17) than for those with VRL (14.3%, 1/7). In summary, we provide valuable clinical evidence that AH is a good source of tumor genomic information and can substitute VF. Moreover, molecular profiling of AH has clinical utility for the diagnosis of VRL and treatment monitoring.
Correspondence: H. Huang huanghq@sysucc.org.cn
D. Liang
liangdan@gzzoc.com
Received: Accepted: Prepublished:
September 7, 2021. February 2, 2022. February 10, 2022.
https://doi.org/10.3324/haematol.2021.279908
©2022 Ferrata Storti Foundation Published under a CC BY-NC license
Introduction
Vitreoretinal lymphoma (VRL) is a rare type of primary central nervous system lymphoma (PCNSL) which pri- marily involves the retina and vitreous.1-3 Based on the ori- gins of the lymphoma, it can be classified as primary VRL, synchronous VRL with central nervous system or systemic involvement, or secondary VRL, which occurs as a site of relapsed lymphoma.4,5 Approximately 95% of primary VRL are histologically identified as diffuse large B-cell lympho- mas, while at the molecular level, both PCNSL and pri-
mary VRL are classified into MCD/C5 subgroups of diffuse large B-cell lymphoma based on concurrent MYD88 (L265P) and CD79B mutations.6-8 Primary VRL is highly ag- gressive with an elevated mortality rate, and 65% to 90% of patients eventually develop brain parenchymal involve- ment. In contrast, 15% to 25% of patients with PCNSL have vitreoretinal involvement, either as synchronous VRL and PCNSL or secondary VRL.1 The diagnosis of VRL remains a challenge for clinicians as the symptoms of VRL can mimic those of posterior uveitis. Thus, patients are typi- cally diagnosed with intermediate and/or posterior uveitis,
Haematologica | 107 September 2022
2154