2028 - Genomic Alterations and Outcomes with Fixed-duration Ibrutinib + Venetoclax: Results from the Phase 3 GLOW Study in Patients with Previously Untreated CLL

Introduction: IGHV mutation status and specific genomic aberrations are prognostic for chemoimmunotherapy in CLL. We explored the prognostic impact on fixed-duration ibrutinib + venetoclax (Ibr+Ven) in the phase 3 GLOW study.

Methods: The GLOW study aimed to evaluate the impact of baseline (BL) genomic alterations on undetectable minimal residual disease (uMRD) at 3 months after end of treatment (EOT+3) and progression-free survival (PFS) of Ibr+Ven and Clb+O in patients (pts) with previously untreated CLL. Pts aged ≥65 or 18 to 64 years with cumulative illness rating scale score >6 or creatinine clearance < 70 mL/min were randomized 1:1 and stratified by del(11q) and IGHV status. Pts with del(17p) or known TP53 mutation were excluded. Del(11q), trisomy-12 (+12), and del(13q) were assessed by fluorescence in situ hybridization, IGHV mutation status by DNA-based next-generation sequencing (NGS) (98% cutoff), and exome-scale gene mutation analysis by NGS (Personalis ImmunoID NeXT), with genes ≥7% frequency, TP53, and MGA included. Cox proportional hazard models, Kaplan-Meier estimates, and log-rank tests were used to analyze time-to-event variables. Fisher’s Exact test was used for association between binary variables. NGS was used to assess uMRD ( < 10−4) in peripheral blood. Reported p-values are nominal.

Results: Incidences of BL genomic aberrations in both arms based on Dohner hierarchy: 18.5% del(11q), 19.4% +12, and 29.4% del(13q). IGHV was unmutated (uIGHV) in 58.8% and mutated (mIGHV) in 31.8%. Most frequent gene mutations: NOTCH1-ICD (17.5%), SF3B1 (17.5%), ATM (11.8%), XPO1 (7.1%) and RPS15 (7.1%), with TP53mut detected in 4.3%. Mutations in SF3B1, IGLL5* and del(13q) were more frequent in mIGHV, whereas NOTCH1-ICD*, ATM, XPO1*, RPS15*, TP53, MGA*, and del(11q) were more frequent in uIGHV (p < 0.01 denoted by *).
uMRD rates at EOT+3 were 54.7% for Ibr+Ven and 39.0% for Clb+O. For Ibr+Ven, uMRD rates trended higher in pts with del(13q) vs without (66.7% vs 49.3%) and in uIGHV vs mIGHV (59.7% vs 40.6%), and trended lower in pts with +12 (42.1% vs 57.5%) or NOTCH1 (38.9% vs 58.0%) vs without; differences were not significant (NS). For Clb+O, uMRD rates trended higher for pts with +12 (50.0% vs 36.1%), and lower for pts with SF3B1 (26.3% vs 41.9%) or ATM (28.6% vs 40.7%); differences were NS. Except for +12 and IGLL5, Ibr+Ven achieved higher uMRD rates vs Clb+O across major mutations.
With median follow up of 46 months, PFS was significantly improved for Ibr+Ven vs Clb+O (hazard ratio [HR], 0.214 [95% confidence interval [CI], 0.138 to 0.33], p < 0.0001), as was overall survival (HR 0.487 [95% CI, 0.262-0.907]; nominal p=0.0205). For Ibr+Ven, +12 (HR 2.54 [CI, 1.15-5.59]) and uIGHV (HR 3.73 [CI, 1.12-12.43]) were associated with shorter PFS vs wild-type (wt) and mIGHV, respectively (Figure), noting both had an imbalance in non-progression-related on-treatment deaths (3/19 vs 4/87 [+12 vs wt]; 6/67 vs 0/32 [uIGHV vs mIGHV]). PFS was significantly improved with Ibr+Ven vs Clb+O across all genomic subgroups, except +12 (HR 0.58), NOTCH1mut (HR 0.42) and IGLL5mut (HR 0.15), which favored Ibr+Ven but were NS.

Conclusion: With median follow-up of nearly 4 years in GLOW, uIGHV status and presence of +12 were associated with shorter PFS with fixed-duration Ibr+Ven in previously untreated CLL; however, imbalances in early non-progression events and small sample size may limit interpretation of findings. PFS in pts treated with Ibr+Ven was significantly improved vs Clb+O across most genomic subgroups, including mIGHV and uIGHV. Presence of +12 trended in favor of Ibr+Ven that was NS.