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586 Mutations in BCOR, CCND2, NRAS and XPO1 Predict Clinical Outcomes upon MRD-Guided Venetoclax Plus Ibrutinib in Relapsed and Refractory Chronic Lymphocytic Leukemia

Program: Oral and Poster Abstracts
Type: Oral
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Mutations, Prognosis and MRD in CLL
Hematology Disease Topics & Pathways:
Research, Clinical trials, Lymphoid Leukemias, Combination therapy, Adult, CLL, Clinical Research, Diseases, Treatment Considerations, Lymphoid Malignancies, Technology and Procedures, Human, Measurable Residual Disease , Molecular testing
Sunday, December 8, 2024: 12:45 PM

Christian Brieghel, MD, PhD1*, Julie Dubois, MD, PhD2*, Ida Kappel Buhl, MD, PhD3*, Kazem Nasserinejad, PhD4,5*, Dennis De Rooij6*, Karl Nyrén, PhD7*, Hoa T Tran, MD, PhD8*, Sabina Kersting, MD, PhD9*, Mattias Mattsson, MD10*, Juha Ranti, MD11*, Rogier Mous, MD PhD12*, Gerrit Jan Veldhuis, MD13*, Caspar da Cunha-Bang, MD, PhD1*, Mark-David Levin14, Valtteri Wirta, PhD7*, Richard Rosenquist, MD, PhD15, Arnon P. Kater, MD, PhD16 and Carsten Utoft Niemann, MD, PhD1*

1Department of Hematology, Rigshospitalet, Copenhagen, Denmark
2Department of Hematology, University of Amsterdam, Amsterdam, Netherlands
3Center for Genomic Medicine, Rigshospitalet, Glostrup, Denmark
4Department of Hematology, Erasmus MC, University Medical Center, Rotterdam, Netherlands
5HOVON foundation, Rotterdam, Netherlands
6Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, NLD
7Science for Life Laboratory; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
8Akershus University Hospital, LøRenskog, NOR
9Department of Hematology, Haga Ziekenhuis, Den Haag, Netherlands
10Department of Hematology, Uppsala University Hospital, Uppsala, Sweden
11Department of Hematology, Turku University Central Hospital, Turku, Finland
12Department of Hematology, University Medical Center Utrecht, Utrecht, Netherlands
13Department of Hematology, Antonius Ziekenhuis, Sneek, Netherlands
14Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, Netherlands
15Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
16Amsterdam University Medical Center, Amsterdam, on behalf of HOVON, Netherlands

Introduction

The HOVON141/VISION trial (NCT03226301) randomized patients with relapsed/refractory (RR) chronic lymphocytic leukemia (CLL), who achieved undetectable minimal residual disease (uMRD; <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 > 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 > 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 < 0.0001) and OS (HR 4.1, 95% CI 2.0-8.4; p < 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.

Disclosures: Dubois: Roche Genentech: Research Funding. Buhl: Aida Oncology: Current Employment, Current equity holder in private company, Other: CEO. Tran: Janssen: Consultancy; GSK: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy. Ranti: Astra-Zeneca: Consultancy, Speakers Bureau; Beigene: Consultancy; Janssen-Cilag: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau. Levin: Janssen, AbbVie: Other: Travel. Wirta: Illumina: Other: travel expenses, Speakers Bureau. Rosenquist: Roche: Honoraria; Janssen: Honoraria; Illumina: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria. Kater: Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee, Research Funding; LAVA: Membership on an entity's Board of Directors or advisory committees, Other: Patents planned, issued or pending; Steering Committee; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Patents planned, issued or pending; Steering Committee, Research Funding. Niemann: CSL Behring, Genmab, Takeda, Beigene, MSD, Lilly: Consultancy; Novo Nordisk: Research Funding; AbbVie, Janssen, AstraZeneca, Novo Nordisk Foundation, Octapharma: Consultancy, Research Funding.

*signifies non-member of ASH