Page 161 - Haematologica Vol. 107 - September 2022

ARTICLE - Use of aqueous humor in VRL management
X. Wang et al.
In addition, we further investigated the mutational sites of IRF4 in VRL patients. Recurrent IRF4 mutations mainly oc- curred in the DNA binding domain with L70V, Q60* and S18R being the most frequent mutations (Figure 4B). Most IRF4 mutation sites were detected in primary and post-treat- ment AH/VF samples (e.g., V1-V3 and V15), while G58S/D, G213D, Y282S, and L358F were acquired after multiple lines of treatment (e.g., V2, V5, and V15).
In the VRL cohort, seven patients received ibrutinib, only one of whom (V2) achieved a partial response and had a significant improvement in visual acuity, leading to an overall response rate of 14% to ibrutinib (Online Supple- mentary Table S5). In contrast, 17 PCNSL patients received systemic treatment containing ibrutinib and the overall response rate was 65%, with nine complete responses and two partial responses. It should be noted that these patients received either ibrutinib monotherapy (PCNSL, 41%; VRL, 29%) or combined therapies (PCNSL, 59%; VRL, 71%); 29% (5/17) of the PCNSL patients and 57% (4/7) of the VRL patients received ibrutinib as first-line treatment. The diverse treatment regimens prevented a direct com- parison of the efficacy of ibrutinib between VRL and PCNSL patients; however, there was a trend to the efficacy of ibrutinib being poorer in VRL patients.
Discussion
To our knowledge, this study was the first to investigate the molecular profiles of AH/VF ctDNA using a large NGS panel covering over 400 lymphoma-related genes in the Chinese population. The findings revealed the potential utility of analyzing AH ctDNA for the diagnosis of VRL, as well as for disease monitoring with serial sampling. The high concordance between AH and VF profiles indicated that AH could serve as a surrogate for VF liquid biopsies, as AH is more easily accessible. We also revealed differ- ences in the molecular landscapes between VRL and PCNSL, and the suboptimal responses to ibrutinib in the VRL cohort.
Due to the low incidence of VRL, our study cohort was relatively small; however, this was a common limitation of other published studies as well.4 For instance, Lee et al. investigated the mutational signatures of primary VRL using whole-exon sequencing in an Asian cohort (n=9), finding that all patients carried MYD88 mutations. The fre- quencies of IRF4 and PIM1 mutations in that cohort were 44.4% and 88.9%, respectively, which were comparable to the frequencies observed in the current study (60% and 80%, respectively).16 However, in another study of 16 pri- mary VRL patients analyzed using targeted NGS, only 18.8% harbored IRF4 mutations, and the frequencies of MYD88 and PIM1 mutations were both 68.8%.15 Notably, that study15 was conducted in a Western population,
which might explain the different mutational frequencies. Bonzheim et al.15 also reported a similar frequency of CD79B mutations (43.8%) as that in our study (53.3%) and in a study by Yonese et al. (35%).23 Another small cohort study (n=8) detected MYD88 L265P in 75% of patients’ AH samples, with a consistency of 87.5% when compared to VF samples using polymerase chain reaction and pyrose- quencing assays.19 Overall, the mutational frequencies re- ported in those studies were comparable to those observed in the current study, although factors including the small cohort sizes and different ethnic populations being studied should be taken into consideration.
IRF4 encodes a transcription factor that controls the dif- ferentiation of B, T, dendritic, and myeloid cells, and regu- lates various aspects of their respective immune responses.24 IRF4 is also an oncogene in some subtypes of diffuse large B-cell lymphoma and a tumor-suppressor in c-Myc-induced malignancies.25-29 IRF4 rearrangement and aberrant hypermutation were commonly character- ized in lymphoproliferative malignancies, especially pedi- atric large B-cell lymphomas.30 In our study, the detected IRF4 mutation sites spanned the complete coding region, and especially affected the DNA-binding domain (DBD) and the IRF association domain (IAD).
CDKN2B (cyclin dependent kinase inhibitor 2B) is a tumor suppressor gene located adjacent to CDKN2A, both of which are frequently deleted in multiple tumors.31,32 In our VRL cohort, 73.3% and 53.3% of patients carried CDKN2A and CDKN2B deletions, respectively. In contrast, PCNSL patients showed much lower frequencies of deletions (CDKN2A: 39% and CDKN2B: 8.7%). These findings revealed the genetic differences between VRL and PCNSL, suggest- ing that more precise clinical management is needed for this rare and unique type of cancer.
There is a limited evidence-base to guide the treatment of VRL. There have been no randomized clinical trials di- rected at the treatment of VRL specifically, although some trials of treatments for PCNSL have included patients with VRL, facilitating limited subset analyses.33 Recently, a phase II clinical trial showed promising efficacy of ibruti- nib monotherapy in relapsed or refractory PCNSL and VRL patients, independently of B-cell antigen receptor path- way alterations, including CD79A/B.34 Conversely, another study suggested that diffuse large B-cell lymphomas with mutated CD79B and MYD88 were more responsive to ibrutinib, while MYD88-only mutant tumors were likely to be ibrutinib-resistant.35 In our study, four PCNSL patients harboring concurrent CD79B and MYD88 mutations all achieved a complete response to ibrutinib treatment (On- line Supplementary Table S5). The efficacy of ibrutinib treatment in our VRL cohort was suboptimal compared to that in PCNSL patients. There are a few possible explana- tions for this observation, including the fact that both ibrutinib monotherapy and combined therapies were in-
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