Treatment with obinutuzumab and venetoclax reshapes the TRB repertoire of CLL patients

Anti-leukemic treatment in chronic lymphocytic leukemia (CLL) impacts autologous T cells through various direct and indirect mechanisms. However, how first-line treatment with venetoclax and obinutuzumab impacts the TRB repertoire has not been studied. Here, we have used next-generation sequencing to longitudinally characterize the TRB repertoire of previously untreated CLL patients who received treatment with obinutuzumab and venetoclax in the HOVON-139/ GIVE trial. Following treatment, due to the emergence of a polyclonal population of small-sized, diverse clonotypes, TRB repertoire diversity increased (Shannon’s H; trial entry 5.5 [95%CI 5.2-6.2] vs end of induction treatment [EOiT] 6.2 [95%CI 5.7- 6.7], P=0.001). In contrast, treatment with obinutuzumab and venetoclax did not ameliorate TRB oligoclonality (EOiT, cumulative frequency of top 10 clonotypes 32.5% [95%CI 25.3-39.9], P=0.10; R+12 CF10 31.2% [95%CI 24.3-38.1], P=0.17), due to the persistence of large pre-treatment clonotypes. Patients with IGLV3-21R110 CLL had weaker recovery of TRB repertoire diversity (mean Shannon’s H 5.2 [95%CI 4.0-6.3] vs 6.8 [95%CI 6.3-7.3], P=0.01). TRB clonotypes that were shared among patients could be identified, a minority of which had known pathogenic or auto-antigenic affinity. The concurrent presence or future resurgence of MRD did not impact the TRB repertoire, but low TRB diversity (Poisson regression coefficient -0.32±0.15, P=0.046) and high oligoclonality (Poisson regression coefficient 0.02±0.009, P=0.02) were associated with an increased risk of infection. These data provide the groundwork for the future investigation of the fitness of autologous T cells for T cell-mediated immunotherapy, following treatment with obinutuzumab and venetoclax. TRBV sequences were amplified from PBMC DNA using the EuroClonality TRBV two-step assay on an Illumina Miseq platform. FASTQ files were processed downstream in the Arrest/Interrogate immunoprofiler.