MOLECULAR FEATURES ENCODED IN THE DYNAMIC ctDNA MONITORING REVEAL PROGNOSTIC VALUE, DIFFERENT CLINICAL COURSES AND CLONE EVOLUTION FOR DIFFERENT GENETIC SUBTYPES OF DLBCL

Abstract

Introduction: The ctDNA-based minimal residual disease (MRD) status at the end of treatment (MRD^end) has been demonstrated as even stronger prognostic marker in both clinical trial and the real-world population for DLBCL patients (pts). However, no data has been shown (i) The clinical course embedded in the different genetic subtypes of DLBCL, (ii) Clonal evolution possessed in serial tissue and plasma samples.

Methods: We enrolled 164 DLBCL pts from our center undergoing first line (1L) therapy for ctDNA profiling at 2 pre-defined milestones (matched baseline and end of treatment (EOT) plasma samples) using a 475 gene lymphoma-specific sequencing panel which had been detailed decribed in our previous work (Jinhua Liang, Leukemia). By the last visit in December 2024, the median follow-up duration was 25.4 (range, 14.9−43.7) months. All pts received R-CHOP regimens.

Results: Among the 164 pts, the median age was 57 years, 57.3% had stage III−IV disease and 42.1% had IPI scores 3−5. Among the 164 pts, 46 pts (28.1%) were defined as MRD^end positivity (MRD^end+) (Figure 1A). The LymphGen subtype classification according to plasma and tissue were shown in Figure 1B. The MRD^end− ratio in different genetype was shown in Figure 1C. EOT-MRD status is associated with worse PFS and OS (p < 0.001). Among the EOT-CR patients (N = 131), MRD^end+ pts had trend towards worse PFS (p = 0.069) (Figure 1D-E). After analyzing the disease course of all pts according to the genetic subtypes, we found that the clinical problem for TP53 disruption pts is primary refractory, rather than relapse. However, MCD subtype that has poor prognosis because of a persistent high risk of relapse despite reaching CR while the clinical problem for BN2 pts is primary refractory and high rate of relapse (Figure 1F). MRD^end negativity was unstable and prone to relapse for BN2 and MCD subtype patients (Figure 1G). The EOT top gene alterations (GAs) for MRD^end+ pts was TP53^mut (34.8%) which were significantly different from baseline plasma mutation profiling (Figure 1H). Firstly, we found that most EOT GAs for the MRD^end+ pts were the predominant gene at baseline according the serial plasma samples (Figure 1I). However, 37 pts had additional GAs (Figure 1J) which were enriched in cell differentiation, cell cycle and TP53 disruption pathways (Figure 1L) in PD plasma samples in comparison with pretreatment plasma samples and the detailed number were shown in Figure 1K. Among the 38 pts of TP53^mut, 18 pts were MRD^end+ (47.4%); among these 18 MRD^end+ pts, TP53^mut was not cleared in 11 pts (61.1%) (Figure 1M). 

Conclusions: These data demonstrate that: (i) Different clinical courses were shown in different genetic subtypes for further personalized subtype-specific clinical trial design; (ii) TP53^mut was the first GA which can not be cleared by the 1L induction therapy; (iii) New additional GAs in sequenced PD plasma samples were enriched in cell differentiation, cell cycle and TP53 disruption pathways.

Research funding declaration: No funding disclosure

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Keywords: liquid biopsy; minimal residual disease; aggressive B-cell non-Hodgkin lymphoma

No potential sources of conflict of interest.