GENETIC ALTERATIONS AND OUTCOMES WITH FIXED-DURATION IBRUTINIB+VENETOCLAX (IBR+VEN): RESULTS FROM THE PHASE 3 GLOW STUDY IN PATIENTS WITH PREVIOUSLY UNTREATED CLL.
No Thumbnail Available
All Authors
Kater, A.
Hodkinson, B.
Moreno, C.
Munir, T.
Levin, M.
Niemann, C.
Qi, K.
Sinet, P.
Baeten, K.
Caces, B.
LTHT Author
Munir, Talha
LTHT Department
Oncology
Haematology
Haematology
Contributor Profession (Non Medical)
Publication Date
2023
Item Type
Conference Abstract
Language
Subject
Subject Headings
Abstract
Background: IGHV mutation status and specific genomic aberrations are prognostic for chemoimmunotherapy in CLL. We explored the prognostic impact on fixed-duration Ibr+Ven in the phase 3 GLOW study. Aim(s): Evaluate 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 chlorambucil+obinutuzumab (Clb+O). Method(s): GLOW evaluated 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 DNAbased 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 pvalues are nominal. Result(s): 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 (Fig), 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. Summary/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 nonprogression 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.
Journal
HemaSphere