Introduction: Genomic alterations, including IGHV mutation status, are predictive for outcomes on chemoimmunotherapy in CLL. Here we report outcomes in subgroups by genomic alterations in patients (pts) treated with fixed-duration (FD) ibrutinib (Ibr) + venetoclax (Ven) in the phase 2 CAPTIVATE study and in those treated with FD Ibr+Ven or chlorambucil (Clb) + obinutuzumab (Obi) in the phase 3 GLOW study. The impact of the 4-gene signature (BCOR, CCND2, NRAS, and XPO1; BCNX), which was found to be predictive of PFS and OS with MRD-guided Ibr+Ven in pts with relapsed/refractory CLL in the VISION study (Brieghel et al, ASH 2024), was also assessed in pts with previously untreated CLL who were treated with FD Ibr+Ven in the CAPTIVATE FD cohort and with MRD-guided Ibr+Ven in the CAPTIVATE MRD cohort.

Methods: Efficacy outcomes were complete response (CR) rate, overall response rate (ORR), undetectable MRD (uMRD) in peripheral blood at 3 months after end of treatment (EOT+3), PFS, and OS. uMRD (<10−4) was assessed by flow cytometry in CAPTIVATE and by next-generation sequencing (NGS) in GLOW. In CAPTIVATE, mutational analysis was performed using targeted NGS covering >1400 genes (Personalis ACE panel) in CD19+-enriched peripheral blood mononuclear cells (PBMCs) collected at baseline from 322 pts treated with Ibr+Ven (FD cohort, n=158; MRD cohort, n=164). In GLOW, mutational analysis was performed using whole exome sequencing (Personalis ImmunoID NeXT) in PBMCs collected at baseline from 211 pts (Ibr+Ven, n=106; Clb+Obi, n=105). Time-to-event end points were analyzed using Cox proportional hazards models, Kaplan-Meier estimates, and log-rank tests. Fisher exact test was used to test for associations between binary variables. Nominal P values are reported.

Results: Incidence of baseline genomic aberrations (except for del(17p) or known TP53 mutations, which were an exclusion for GLOW) were similar in pts treated with FD Ibr+Ven in CAPTIVATE and GLOW, respectively, with del(17p) in 12.8% (CAPTIVATE only), del(11q) in 17.7% and 18%, trisomy 12 in 14.6% and 19.4%, and del(13q) in 34.2% and 29.4%, per Dohner hierarchy. IGHV was unmutated (uIGHV) in 41.8% and 58.8% and mutated (mIGHV) in 56.3% and 31.8%. The most frequently mutated genes were SF3B1 (16.5% and 17.5%), PCLO (13.3% and 7.1%), NOTCH1-ICD (12.7% and 17.5%), ATM (9.5% and 11.8%), IGLL5 (8.2% and 7.1%), and TP53 (10.3% vs 4.3%). Mutations in NOTCH1-ICD, XPO1, MGA (CAPTIVATE and GLOW), TP53 (CAPTIVATE only), and RPS15 (GLOW only) were more frequent in pts with uIGHV (P<0.05), whereas mutations in IGLL5 (CAPTIVATE and GLOW) andMYD88_L265P (CAPTIVATE only) were more frequent in pts with mIGHV (P<0.05).

CR rates were higher with Ibr+Ven vs Clb+Obi across all genomic subgroups in GLOW (P<0.05). In pts treated with FD Ibr+Ven in both CAPTIVATE and GLOW, CR, ORR, and uMRD rates at EOT+3 across genomic subgroups were generally similar to those observed in all pts treated with FD Ibr+Ven. There were no statistically significant differences in PFS between mutant vs wild-type subgroups, except for lower PFS in pts with uIGHV vs mIGHV (CAPTIVATE and GLOW, P<0.05) and lower PFS in pts with TP53 mutant vs wild type (CAPTIVATE, P<0.05). Similarly, there were no statistically significant differences in OS between mutant vs wild-type subgroups, except for IGHV and TP53 (CAPTIVATE).

At baseline, BCNX mutations were found in 13.9% of pts in the CAPTIVATE FD cohort and 13.4% of pts in the MRD cohort. There were no statistically significant differences in PFS or OS between BCNX mutant vs wild-type subgroups in the FD cohort, but PFS and OS were significantly longer in the BCNX wild-type vs mutant subgroup (both P<0.05) in the MRD cohort.

Conclusion: These robust analyses from CAPTIVATE and GLOW showed that FD Ibr+Ven provided clinical benefit across almost all subgroups of pts with and without genomic alterations. Ibr+Ven provided clinical benefit compared with Clb+Obi across all genomic subgroups in GLOW. The proposed BCNX mutation signature had no impact on PFS and OS in pts treated with FD Ibr+Ven in CAPTIVATE; the impact of BCNX mutations on PFS and OS seen with MRD-guided Ibr+Ven in the MRD cohort appeared to be in MRD-positive arms only, and interpretation is limited by small sample sizes.

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2025
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