Mutations in BCOR, CCND2, NRAS and XPO1 Predict Clinical Outcomes upon MRD-Guided Venetoclax Plus Ibrutinib in Relapsed and Refractory Chronic Lymphocytic Leukemia
Authors: Brieghel Christian , Dubois Julie , Buhl Ida Kappel , Nasserinejad Kazem , De Rooij Dennis , Nyrén Karl , Tran Hoa T , Kersting Sabina , Mattsson Mattias , Ranti Juha , Mous Rogier , Veldhuis Gerrit Jan , da Cunha-Bang Caspar , Levin Mark-David , Wirta Valtteri , Rosenquist Richard , Kater Arnon P. , Niemann Carsten Utoft 
Published: December 2024

Introduction
The HOVON141/VISION trial (NCT03226301) randomized patients with relapsed/refractory (RR) chronic lymphocytic leukemia (CLL), who achieved undetectable minimal residual disease (uMRD; &lt;10-4) after 15 cycles (C15) of ibrutinib plus venetoclax (I+V), to either continued ibrutinib (arm A) or treatment cessation (arm B); patients with detectable MRD (dMRD; ≥10-4) at C15 could not be randomized and continued ibrutinib (non-randomized). Patients, who converted to dMRD during treatment cessation (arm B), re-initiated I+V. Previously reporting a 12-month progression-free survival (PFS) of 98% after treatment cessation, time-limited and MRD guided I+V is feasible and attractive in RR CLL (Kater 2022). So far, however, classic CLL biomarkers have failed to predict outcomes on I+V. In this study, we investigated whether CLL gene mutations may predict clinical outcomes on MRD-guided I+V.
Methods
Baseline samples underwent capture-based sequencing using the Genomic Medicine Sweden Lymphoid Gene Panel (GMS-LGP); covering 252 genes and applying unique duals indices and unique molecular identifiers. Single-nucleotide variants and small indels in 25 known CLL driver genes (Brieghel et al, Clin Cancer Res 2020) were called down to 1% variant allele frequency using BALSAMIC pipeline (SciLifeLab), and variants were manually curated in VarSeq 2.5.0 (Golden Helix) excluding variants with a frequency &gt; 1% in GnomAD and those classified as benign and likely benign according to the ACMG.
Results
For this study, baseline samples were available in 176 of 225 included patients: 19/24 (79%) in arm A, 36/48 (75%) in arm B and 121/153 (79%) non-randomized patients; including 89/116 (77%) with dMRD at C15 continuing ibrutinib.
We identified a total of 397 mutations (mean 2.3 mutation per patient) most commonly identified in SF3B1 (27%), TP53 (20%), ATM (20%), NOTCH1 (19%), BIRC3 (17%), BCOR (9%), NFKBIE (7%), XPO1 (7%), MGA (7%), DDX3X (6%), MED12 (6%), BRAF (6%), FBXW7 (6%), POT1 (5%), and ZMYM3 (5%). IGHV status was unmutated in 113 of 163 (69.3%) patients. No particular mutated gene was significantly enriched in patients with IGHV unmutated status (pairwise Fisher's exact tests; p = 0.076 for NOTCH1, but otherwise p &gt; 0.32).
Harboring NRAS and XPO1 mutations correlated with high MRD levels at C15 (p = 0.025 and p = 0.0050, respectively), whereas the number of mutated drivers and mutated pathways did not. No associations between mutations in specific genes and PFS were observed in arms A and B (uMRD) or in non-randomized patients (dMRD). In arm B (uMRD; treatment cessation), no specific gene mutation was associated with re-initiating I+V during treatment cessation. Of note, the I+V re-initiation rate was 100% for patients with TP53 mutations.
For the entire cohort, BCOR (hazard ratio [HR] 2.8, 95% confidence interval [CI] 1.2-7.0), CCND2 (HR 5.9, 95% CI 1.4-25.0), and XPO1 (HR 3.2, 95% CI 1.2-8.3) mutations were associated with shorter overall survival (OS). NRAS (HR 7.7 95% CI 1.0-58.2) and XPO1 (HR 5.7 95% CI 2.2-14.6) mutations were associated with shorter PFS.
A combined BCOR, CCND2, NRAS and XPO1 (BCNX) mutation-status correlated with significantly higher MRD levels at C15 (p = 0.011), significantly shorter PFS (HR 4.1, 95% CI 2.2-7.8; p &lt; 0.0001) and OS (HR 4.1, 95% CI 2.0-8.4; p &lt; 0.0001) as compared to patients without BCNX mutations (median OS 60.8 months vs not reached [NR] and median PFS 51.7 months vs NR, respectively). Thus, impairment of different signaling pathways engaging the BCNX genes (i.e. NF-κB, DNA damage, MAPK-ERK, and RNA processing, respectively) seems to impact outcome upon I+V treatment for RR CLL.
Conclusion
BCNX (BCOR, CCND2, NRAS and XPO1) mutations at baseline predict poor MRD response, PFS, and OS on MRD guided I+V in RR CLL. An updated analysis on all 252 sequenced lymphoma-associated genes will be presented at the meeting.