OAB-039: Distinct immunoglobulin heavy-chain variable gene repertoire and its clinical relevance in Waldenström macroglobulinemia/lymphoplasmacytic lymphoma

Abstract

<h3>Background</h3> Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) is a heterogeneous disease whose role of immunoglobulin heavy chain variable gene (IGHV) usage remains unknown. <h3>Methods</h3> To determine the clinical relevance of IGHV repertoire in WM/LPL treated with standard immunochemotherapy, we performed the immunoglobulin gene rearrangements and complementarity determining region 3 (CDR3) analysis on 136 patients with WM/LPL. <h3>Results</h3> The IGHV gene repertoire was remarkably biased in WM/LPL. IGHV3-23, IGHV4-34, IGHV3-30, IGHV3-7 and IGHV3-74 accounted for half of the whole cohort. Most of the cases were mutated (97.0%) using a 98% IGHV germline homology cutoff. IGHV3-30 was associated with long heavy chain CDR3, indicating the specific antigen selection in WM/LPL. Patients with IGHV3-7 were significantly more likely to harbor 6q deletion (p<0.001) and complex karyotype (p=0.002). The IGHV hypermutation rate in patients with MYD88 L265P mutation was significantly higher than wildtype patients (p=0.009). IGHV3-23 and IGHV3-74 segments were more frequently detected in MYD88 mutated WM/LPL patients (p=0.025). When we looked into the five predominant IGHV segments mentioned above, we found a trend that IGHV3-23 and IGHV3-74 segments were more frequently detected in MYD88 mutated WM/LPL patients (25.7% vs. 4.3%, p=0.025). Besides, we found IGHV3-7 and IGHV4-59 were represented more in MYD88 wildtype patients compared with MYD88 mutated patients (30.4% vs. 8.9%, p=0,005). IGHV4 segments were higher expressed in MYD88 wildtype patients compared with MYD88 L265P mutated patients (39.1% vs. 21.8%, P=0.083). Moreover, Patients with IGHV4 especially IGHV4-34 had higher level of LDH. IGHV4 was a predictive marker of shorter progression-free-survival. <h3>Conclusion</h3> WM/LPL appears to be composed of different subgroups based on the IGHV repertoire. The mutational status and the IGHV CDR3 length indicated the role for antigen selection in WM/LPL development. The presence of IGHV4 genes proved to be a potential risk factor associated with outcome which deserved further study.