PS1124 IBRUTINIB TREATMENT ALTERS ENHANCER ACTIVITY PATTERNS IN CHRONIC LYMPHOCYTIC LEUKEMIA
Authors: A. Lambe, N. Papakonstantinou, M. Gounari, K. Stamatopoulos, E. Kostareli
Journal: HemaSphere (2019)

Background: We reported superior efficacy for venetoclax + rituximab (VenR) vs bendamustine + rituximab (BR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) in the MURANO study (NCT02005471), with a significant progression-free survival (PFS) benefit and sustained undetectable minimal residual disease (uMRD), irrespective of historical risk factors for poor response to chemoimmunotherapy, e.g., unmutated IGHV and del(17p) and/or TP53 mutation. However, the impact of other recurrent somatic mutations and of cytogenetic alterations on outcome of R/R patients (pts) treated with fixed-duration VenR has not been examined. Aims: To interrogate clinical impact of the major somatic mutations, and of cytogenetic high-risk features defined by array-based analysis of genomic complexity (aGC), on outcome in pts treated with VenR and BR in MURANO. Methods: Whole exome sequencing (WES) and aGC by high-density array-comparative genomic hybridization were performed on baseline DNA specimens, available from 313/389 enrolled pts. Array-based genomic complexity was defined as having ≥3 or ≥5 genetic aberrations. Kaplan–Meier estimates and Cox proportional-hazards models were used to analyze PFS. uMRD was defined as <1 CLL cell in 10,000 leukocytes in peripheral blood (PB). Results: At least one of the 9 mutated driver genes examined here was identified in 234/313 (74.8%) pts from both arms; clonal mutations of ATM occurred in 30.7% of pts, TP53 in 25.6%, SF3B1 in 22.0%, NOTCH1 in 13.7%, BRAF in 8.3%, BIRC3 in 8.0%, and NRAS/KRAS/MYD88 in 1.6% each. Mutation frequency was equally distributed between treatment arms. Prevalence of all CLL key mutated genes will be presented. After 36.0 months’ median follow-up, a PFS benefit was observed consistently with VenR over BR across mutated (mut) and wildtype (WT) subgroups for ATM, TP53, SF3B1, NOTCH1, (Figure 1) and BIRC3. Median PFS for VenR was not reached in TP53mut or WT pts, compared with medians of 12.2 months (mo; HR 0.11, 95% CI 0.055–0.24) and 21.6 mo (HR 0.16, 95% CI 0.098–0.25), respectively, for BR. Mutation frequency was too low for assessment in the other subgroups. Within treatment arm, inferior PFS was observed with both VenR and BR for TP53mut pts, but only with VenR for NOTCH1mut pts, representing a significant treatment-dependent prognostic effect (interaction p = 0.007). Two-year PFS with VenR was 76% for NOTCH1mut pts vs 89% for WT. The negative impact on PFS in NOTCH1mut VenR pts was further confirmed by multivariate analysis (MVA) with IGHV, del(17p)/TP53, B2 M, stage, and age as covariates (HR 0.54, 95% CI 0.22–1.30). NOTCH1 mutation was enriched in pts with disease progression (47.1%) vs those without (13.9%) in VenR but not BR (69.2% vs 70.8%, respectively). The PFS observations were consistent with PB uMRD rates; the PB uMRD rate was lower in NOTCH1mut pts (23.5% vs 49.3% in WT pts) at the end of Ven treatment visit (∼24 mo from start of treatment). Assessments of aGC are ongoing and impact on clinical outcomes will be presented.Summary/Conclusion: We assessed the mutational landscape of R/R CLL by WES and confirmed prior mutation frequency reports. A superior PFS benefit was observed for VenR vs BR in all clinical and molecular subgroups assessed, including the key CLL driver mutations reported here. NOTCH1 mutations may define a new high-risk pt subgroup for VenR. MVA, further validation and deep sequencing for subclones are needed, given the small size of the mutated cohort, and to address the biological basis of the findings.