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3233 The Impact of Therapeutic Selective Pressure on the Evolutionary Landscape of Chronic Lymphocytic Leukemia

Program: Oral and Poster Abstracts
Session: 641. Chronic Lymphocytic Leukemia: Basic and Translational: Poster II
Hematology Disease Topics & Pathways:
Research, Translational Research
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Negin Karisani, PhD1,2*, Amit Sud, MD, PhD, FRCPath, MRCP3,4,5*, Liang Li, MS1*, Satyen Gohil, MD PhD3,6*, Kristy Schlueter-Kuck, PhD1*, Laura Rassenti, PhD7*, Tuan N. Tran7*, Leo Wang-Kit Cheung, PhD, MSc, BS8*, Iliana Edith Szafer-Glusman, PhD8*, James P. Dean, MD, PhD8*, Guang Chen1*, Junko Tsuji, PhD1*, Neil E. Kay, MD9,10, Kanti R. Rai11,12, Jennifer R. Brown, MD, PhD4,13, John G. Gribben, MD14, John C. Byrd, MD15, Donna S. Neuberg, ScD16, Chip Stewart, PhD1*, Ivana Bozic, PhD17*, Thomas J. Kipps, MD18,19,20, Gad Getz, PhD1,4,21* and Catherine J. Wu, MD1,3,4*

1Broad Institute of MIT and Harvard, Cambridge, MA
2Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA
3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
4Harvard Medical School, Boston, MA
5Centre for Immuno-Oncology, University of Oxford, Oxford, United Kingdom
6University College London Hospitals NHS Foundation Trust, London, United Kingdom
7Center for Novel Therapeutics, University of California, La Jolla, CA
8Pharmacyclics LLC, an AbbVie Company, South San Francisco, CA
9Department of Immunology, Mayo Clinic, Rochester, MN
10Division of Hematology, Mayo Clinic, Rochester, MN
11Department of Medicine, Northwell Health, Manhasset, NY
12Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY
13Department of Medical Oncology, Dana-Farber Cancer Institute, Newton, MA
14Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
15Department of Internal Medicine, University of Cincinnati, Cincinnati, OH
16Department of Data Science, Dana-Farber Cancer Institute, Boston, MA
17Department of Applied Mathematics, University of Washington, Seatlle, WA
18Center for Novel Therapeutics, University of California, San Diego, La Jolla, CA
19Division of Hematology Oncology, Department of Medicine, University of California, San Diego, La Jolla, CA
20Moores Cancer Center, University of California, San Diego, La Jolla, CA
21Department of Pathology, Massachusetts General Hospital, Boston, MA

BACKGROUND

Our knowledge of how the genomic landscape of chronic lymphocytic leukemia (CLL) is impacted by the selective pressure imposed by chemotherapy and targeted agents remains incomplete. We hypothesize that the extent of clonal evolution, baseline transcriptional state, and the overall and clone-specific growth kinetics of CLL will vary under native conditions or following exposure to chemotherapy and targeted therapy.

METHODS

We report the systematic genomic analysis of leukemia-normal whole-exome sequencing (WES) of 420 samples collected from 170 patients who were >65 years of age with treatment-naïve CLL. The treatment-cohort consisted of 83 patients who received ibrutinib (420mg daily) and 40 patients who received chlorambucil (0.5 mg/kg up to maximum 0.8 mg/kg, on days 1 and 15 of a 28-day cycle, up to 12 cycles) as part of the RESONATE-2 trial (NCT01722487). The ‘watch and wait’ (WW) cohort comprised 47 age-matched patients whose samples originated from the CLL Research Consortium and were untreated for their CLL during sampling. Sampling occurred at baseline and at day 300, and/or day 600, following initiation of therapy or following a diagnosis of CLL for those in the WW cohort. The WW cohort had more cases with a mutated IGHV (72% vs 40%), del17p (14% vs 0%), and del13q (72% vs 45%) when compared to the treatment cohort. Baseline CLL RNA-seq data were available for 150 patients.

We used PhylogicNDT to reconstruct the clonal architecture from WES. By determining the fraction of cancer cells with each mutation (cancer cell fraction [CCF]) and their multiplicities (number of DNA molecules carrying a mutation per cancer cell), subclones were identified through clustering of CCFs of mutational events across samples from each patient. This allowed us to estimate the phylogenetic relationships and significant clonal shifts (defined as a distribution shift of CCF in a subclone of >95% between two timepoints, corresponding to a median ΔCCF of 18%) for each patient’s CLL and to relate these shifts to somatic and clinical features.

RESULTS

In total, we identified 791 subclonal clusters across the three patient cohorts (ibrutinib = 406, chlorambucil = 189, WW = 196). We observed higher rates of significant clonal shifts between any two time points in patients exposed to chlorambucil (68%, q=0.008) and ibrutinib (77%, q<0.0001) when compared to patients on WW (36%). There was no significant difference in the number of patients exhibiting a clonal shift between those receiving ibrutinib and chlorambucil (q=0.3). More patients treated with ibrutinib (54%, q=0.0002) and chlorambucil (50%, q=0.004) harbored a clone that reduced in size than those on WW (17%). More patients treated with ibrutinib (71%, q<0.0002) and chlorambucil (55%, q=0.12) possessed at least one clone that increased in size during therapy than patients receiving WW (34%). In ibrutinib-treated patients, SF3B1 mutations (q=0.13, 14% vs 5%) and XPO1 mutations (q=0.13, 5% vs 0.3%) were enriched in subclones that significantly reduced over the complete time period. We also observed more BIRC3 mutations in subclones that had a significant shift in CCF when compared to subclones that remained stable over time (q=0.2, 5% vs 2%).

Consistent with the overall study, with 8 years of follow-up in this patient subset, long-term progression-free survival (PFS) was significantly higher in the patients treated with ibrutinib when compared to chlorambucil (P<0.0001). This PFS benefit was also seen regardless of subclonal growth patterns. Using baseline RNA-seq data, we identified 7 of the 8 recently defined CLL expression clusters (EC), that were identified in the context of chemoimmunotherapy for CLL (Knisbacher et al. Nat Gen 2022), and could recapitulate the relationship to outcomes in individuals treated with chlorambucil. However, despite the larger cohort, no significant relationship between EC clusters and PFS were observed in ibrutinib-treated patients, suggesting that a distinct predictive baseline transcriptional signature may be present in ibrutinib-treated patients.

CONCLUSION

Our analyses highlight the need to interrogate the molecular features of CLL in relation to the impact of therapeutic selective pressure imposed by BTK inhibition, which appear distinct from exposure to chemotherapy. Ongoing analyses aim to identify relationships between patterns of growth and subclonal growth rates molecular and clinical features.

Disclosures: Gohil: EUSA/Recordati: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Takeda: Other: Travel and conference support; Gilead: Speakers Bureau; Novalgen​: Consultancy, Patents & Royalties; UCL Business: Patents & Royalties; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Abbvie: Honoraria, Other: travel support; Janssen: Speakers Bureau; Electra Pharma: Membership on an entity's Board of Directors or advisory committees. Cheung: AbbVie Inc.: Current Employment, Current equity holder in publicly-traded company. Szafer-Glusman: AbbVie Inc.: Current Employment, Current equity holder in publicly-traded company. Dean: AbbVie Inc.: Current Employment, Current holder of stock options in a privately-held company. Kay: Agios Pharma: Other: data safety monitoring committee; BMS –Celgene: Other: data safety monitoring committee; Vincerx: Research Funding; Sunesis: Research Funding; Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: data safety monitoring committee and advisory board; BeiGene: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Other: data safety monitoring committee and advisory board; Behring: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Dren Bio: Other: data safety monitoring committee; Bristol Meyer Squibb: Research Funding; Acerta Pharma: Research Funding; Dava Oncology: Membership on an entity's Board of Directors or advisory committees. Brown: UpToDate: Patents & Royalties: Author Royalties; TG Therapeutics: Research Funding; MEI Pharma: Research Funding; Gilead: Research Funding; Grifols Therapeutics: Other: Data Safety Monitoring Board Member; iOnctura: Consultancy, Research Funding; Pfizer: Consultancy; Pharmacyclics: Consultancy; Numab Therapeutics: Consultancy; InnoCare Pharma Inc: Consultancy; Grifols Worldwide Operations: Consultancy; Genentech/Roche: Consultancy; Bristol-Myers Squibb: Consultancy; Kite: Consultancy; Loxo/Lilly: Consultancy, Research Funding; Merck: Consultancy; AbbVie: Consultancy; Acerta/AstraZeneca: Consultancy; Alloplex Biotherapeutics: Consultancy; BeiGene: Consultancy, Research Funding. Gribben: Kite/Gilead: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Byrd: Vincerx Pharma, Eilean Therapeutics, and Kurome Therapeutics: Current equity holder in private company; Abbvie, AstraZeneca, and Syndax: Consultancy. Neuberg: Madrigal Pharmaceutical: Current equity holder in publicly-traded company. Kipps: Oncternal Therapeutics: Current equity holder in private company; Abbvie/Janssen/Pharmacyclics/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Lymphoma and Leukemia Society: Research Funding. Getz: Broad Institute: Patents & Royalties: MSMuTect, MSMutSig, POLYSOLVER, SignatureAnalyzer-GPU, MSEye, and MinimuMM-seq; Scorpion Therapeutics: Consultancy, Current equity holder in private company, Other: Founder; IBM, Pharmacyclics/Abbvie, Bayer, Genentech, Calico, and Ultima Genomics: Research Funding; PreDICTA Biosciences: Consultancy, Current equity holder in private company, Other: Founder. Wu: Aethon Therapeutics: Membership on an entity's Board of Directors or advisory committees; BioNtech, Inc: Current equity holder in publicly-traded company; Pharmacyclics: Research Funding; Adventris: Membership on an entity's Board of Directors or advisory committees; Repertoire: Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH