C095 | IMPACT OF IGHV REPERTOIRE AFTER IBRUTINIB-CONTAINING REGIMENS IN YOUNGER UNTREATED MANTLE CELL LYMPHOMA PATIENTS: AN ANALYSIS OF THE TRIANGLE DATA EMBEDDED IN THE MULTIPLY PROJECT

Introduction: The TRIANGLE trial (Dreyling et al. 2024) compared three treatment arms (arm I: IR-CHOP/R-DHAP+ ibrutinib maintenance (Im); arm A+I: IR-CHOP/ R-DHAP + ASCT +Im; arm A: previous standard of care R-CHOP/ R-DHAP + ASCT) for younger, untreated mantle cell lymphoma (MCL) patients (pts), demonstrating the superiority of ibrutinib-containing regimens in terms of both failure free (FFS) and overall survival (OS). Previous studies (Hadzidimitriou et al. 2011) identified skewed immunoglobulin (IG) repertoires in MCL, but large, homogeneous cohorts linking IGHV usage to clinical outcomes are lacking. Here, we assess the prognostic impact of IGHV repertoire in TRIANGLE. Methods: IGHV clonal rearrangement analysis was performed for minimal residual disease purposes by Sanger or IG amplicon-based NGS. Data from 7 EuroMRD labs were analyzed by IMGT/V-QUEST or Arrest/Interrogate to determine IGHV rearrangements and identity percentage to germline. Results: Out of the 870 enrolled pts, 600 had an available IGHV sequence for analysis. Baseline characteristics and outcomes were comparable to the full TRIANGLE cohort (3y-FFS: arm A 70% vs arm A+I and I: 85%, P=0.001). Interestingly, pts with IGHV gene identity > 97% (IGHV unmutated) showed a trend towards worse FFS at later follow-up compared to pts with IGHV gene identity ≤ 97% (IGHV mutated) (P=0.056, Fig. 1A). The most common IGHV family was VH 3-21 (22%, Fig 1B). In a univariate analysis, the VH 3-21, 3-30, 3-48, and 3-74 families associated with better FFS and were therefore grouped together, namely VHcomb pts (N=171). VHcomb pts were younger, had lower MIPI scores, and showed superior 3-year FFS compared to other families (VHother) (87% vs. 77%, P=0.002). Stratified by treatment arm, VHcomb had significantly better FFS vs. VHother in arm A (87% vs. 62%, P<0.001, Fig. 1C), but no difference was observed in ibrutinib-containing arms (87% vs. 85%, P=0.2, Fig. 1D). After adjusting for the risk factors MIPI, cytology, and Ki67, VHcomb remained associated with improved FFS in arm A (Hazard ratio [HR] 0.41, P=0.007), while no statistically significant impact was observed in ibrutinib-containing arms (HR 0.77, P=0.3). Conclusions: This is the largest study of IGH repertoire in a phase 3 MCL trial. Specific IGHV rearrangements and IGHV mutation status predict FFS with standard therapy but not with ibrutinib, supporting a potential BCR-driven pathogenesis and an immunological effect of ibrutinib in MCL.