Clinicobiological characteristics and treatment efficacy of novel agents in chronic lymphocytic leukemia with IGLV3-21 R110

Background: The composition of the clonotypic B cell receptor (BCR) is of key importance in chronic lymphocytic leukemia (CLL). Recently, a novel immunogenetically defined CLL subset was described, characterized by a clonotypic BCR using the immunoglobulin lambda (IGL) IGLV3-21*01/IGLV3-21*04 gene with a distinctive G110R somatic hypermutation (IGLV3-21R110). IGLV3-21R110 CLL accounts for approximately 20% of all CLL and is associated with an adverse prognosis. However, the clinicobiological profile and predictive impact of IGLV3-21R110 CLL in the context of novel therapies remains incompletely characterized. Aims: To characterize the cytogenetic, immunogenetic and mutational landscape of IGLV3-21R110 CLL and to assess the predictive impact of this genotype in the context of novel therapies. Methods: We characterized the light chain genotype, clinicobiological features and response to therapy of patients enrolled in the HOVON-139/GIVE trial and the Dutch sub-cohort of the HOVON-141/VIsion trial. The HOVON-139/GIVE phase-II trial evaluated first-line minimal residual disease (MRD)-guided duration of treatment with obinutuzumab and venetoclax in CLL patients unfit for treatment with chemoimmunotherapy. The HOVON-141/VIsion phase-II trial evaluated MRD-guided ibrutinib and venetoclax combination treatment in relapsed or refractory (R/R) CLL patients. Results: The IGLV3-21R110 genotype was present in 16/65 patients (25%) in the first-line cohort and in 32/129 patients (25%) in the R/R cohort. Loss of 13q14 and 11q22 were enriched in IGLV3-21R110 patients, compared to other patients (del13q14: 79% vs. 57%, P=0.009; del11q22: 34% vs. 18%, P=0.03). In contrast, the IGLV3-21R110 genotype and trisomy 12 or loss of 17p13 were mutually exclusive (trisomy 12: 0% vs. 12%, P=0.008; del17p13: 0% vs. 12%, P=0.01). Mutations in the SF3B1 and ATM genes were significantly more common in IGLV3-21R110 patients, compared to other patients (SF3B1: 49% vs. 21%, P=0.0008; ATM: 36% vs. 18%, P=0.02). IGHV and IGHD gene usage of IGLV3-21R110 patients was markedly skewed. The IG heavy-chain complementarity determining region 3 (HCDR3) was shorter in IGLV3-21R110 patients, compared to other patients (median HCDR3 aa length 13 [range: 9-17] vs. 19 [range 8-30], P<0.0001). Whereas the IGHV SHM imprint of IGLV3-21R110 patients was centered around the 98% cutoff between unmutated and mutated IGHV, the range was wider in other patients (range 95.1%-99.7% vs. 85%-100%, P=0.01). When comparing patients with IGLV3-21R110 CLL versus all other light chains, were no differences regarding MRD (%uMRD<10-4 in peripheral blood, HOVON-139/GIVE after 12 cycles: 87% vs. 98%, P=0.15; HOVON-141/VIsion after 15 cycles: 52% vs. 61%, P=0.11) and progression-free survival (24-month PFS, HOVON-139/GIVE: 100% vs. 94%, P=0.52; HOVON-141/VIsion: 91% vs. 92%, P=0.74) in either trial. Summary/Conclusion: We have characterized the clinicobiological features of the largest cohort of IGLV3-21R110 patients reported thus far. We demonstrate that CLL with IGLV3-21R110 is typified by a distinct cytogenetic, mutational and immunogenetic profile. There was no evidence for a predictive impact of the IGLV3-21R110 genotype on the efficacy of the novel therapies with venetoclax and ibrutinib employed in the HOVON-139/GIVE and HOVON-141/VIsion trials. Our results suggest that novel targeted therapies may mitigate the adverse risk profile of IGLV3-21R110 CLL. To determine whether these patients should preferentially receive novel therapies, characterization of the predictive impact of IGLV3-21R110 in the setting of chemoimmunotherapy is warranted.