Clinical implications of ctDNA in predicting the genetic subtype, CNS involvement and outcomes of newly diagnosed diffuse large B cell lymphoma

Introduction: Diffuse large B cell lymphoma (DLBCL) is the most common entity of non-Hodgkin lymphoma with high clinical and biological heterogeneity. The value of circulating tumor DNA (ctDNA) in DLBCL need to be further explored. Methods: A total of 128 DLBCL patients (pts) were included in our study. We obtained plasma, tissue and cerebrospinal fluid (CSF) samples before and after first-line therapy for a lymphoma-specific sequencing. Results: The detailed sample collections were shown in Figure 1A. We compared genetic subtypes based on the mutations detected respectively in tissue and plasma, the overall coincidence rate was 77.8%. The characteristics of pts with negative pretreatment ctDNA (pre-ctDNA) burden were shown in Figure 1B. Pts with elevated lactate dehydrogenase (LDH) level (P < 0.001), higher international prognostic index (IPI) score (P < 0.001), advanced stage (P < 0.001), ECOG 2–4 (P < 0.001), multiple extranodal involvement (P < 0.001), non-GCB subtype (P = 0.034) and no surgical excision of the tumor (P < 0.001) had significantly higher pre-ctDNA burden (Figure 1C). However, no significant differences of pre-ctDNA burdens were identified between TP53 mutation and TP53 wild type groups or among different genetic subtype groups (Figure 1D). A significantly high CNS involvement (CNSi) rate (25.8%, 17/66) was detected by pretreatment CSF. Among the 17 pts, only 3 pts (17.6%) had typical radiographic findings or CSF cytomorphology. CNSi was significantly associated with clinical characteristics, including advanced stage (P = 0.046), elevated LDH level (P = 0.016), high IPI (P = 0.004), CNS-IPI score (P = 0.004) and higher pre-ctDNA burden (P = 0.012) (Figure 1E). Among the 17 CNSi pts detected by CSF ctDNA, 15 pts received BTK inhibitor or high-dose methotrexate (HD-MTX) treatment. Six pts achieved CSF clearance among the 8 pts who had CSF ctDNA detection at the end of therapy (EOT). As regard to pretreatment cell free DNA fragmentation patterns, all samples were characterized by a prominent mono-nucleosomal fragments abundance (167 bp), whereas the samples with high IPI scores or non-complete response (CR) at the EOT had a more prominent shift towards shorter cfDNA size (Figure 1H). A significant difference of pre-ctDNA burden existed between CR and non-CR group, and pre-ctDNA burden negative group presented with higher CR rate at the EOT (Figure 1F and 1I). Furthermore, minimal residual disease (MRD) negative (EOT-ctDNA negative) group was associated with higher remission rate (Figure 1G and 1J). Among the 60 pts who had plasma samples at the EOT, all but 1 of the 25 pts with MRD negative achieved CR. All 9 pts who experienced progressive disease (PD) were all MRD positive. However, not all the pts with CR achieved MRD negative (Figure 1K). Keywords: Aggressive B-cell non-Hodgkin lymphoma, Diagnostic and Prognostic Biomarkers No conflicts of interests pertinent to the abstract.