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1520 Mutations of ATM Confer a Risk of Inferior Survival in Patients with TP53-wild Type Mantle Cell Lymphoma

Program: Oral and Poster Abstracts
Session: 621. Lymphomas: Translational—Molecular and Genetic: Poster I
Hematology Disease Topics & Pathways:
Research, Lymphomas, Translational Research, non-Hodgkin lymphoma, B Cell lymphoma, Diseases, Lymphoid Malignancies
Saturday, December 10, 2022, 5:30 PM-7:30 PM

Jean L. Koff, MD, MSc1, Rachel Kositsky, BS2*, David L. Jaye, MD3, Michael C. Churnetski4*, Katelin Baird, BS5*, Colin B. O'Leary, MA6*, Christopher R. Flowers, MD7,8, Sirpa Leppa, MD, PhD9, Marja-Liisa Karjalainen-Lindsberg, MD, PhD10*, Shaoying Li11*, Jie Xu, MD12*, Mette Ø Pedersen, MD PhD13*, Anne Ortved Gang, MD PhD13*, Kikkeri N Naresh, MD, MBBS14, Rebecca J Leeman-Neill, MD, PhD15, Kwok Him Rex Au Yeung, FRCPath16, Hina Naushad Qureishi17*, Javeed Iqbal, Ph.D.18*, Jennifer R Chapman-Fredricks, MD19*, Chad M. McCall, MD, PhD2*, Michael Crump20, Amy Chadburn, MD21, Erin C. Mulvey, MD22*, Izidore S. Lossos, MD23, Sandra L. Ondrejka, DO24, Eric D. Hsi, MD25, Abner Louissaint Jr., MD, PhD26, Haley Martin26*, Eric Tse, MBBS, PhD, FRCP, FRCPath27, Cassandra Love2, Tushar Dave, MS2*, Clay Parker28*, Choon Kiat Ong, PhD29, Andrew G Evans, MD, PhD30, Amir Behdad, MD31*, Lixin Yang, PhD32*, Nishitha Reddy, MD33, Mary Ann Arildsen, MD, PHD33*, Ridas Juskevicius34*, Jiong Yan35*, Magdalena Czader, MD, PhD36, Andrew M. Evens, DO, MBA, MMSc37, Dina Sameh Soliman, MD, PhD, MBBS, MSc38, Yuri Fedoriw, MD39*, Sandeep S. Dave, MD, MS40 and Jonathon B. Cohen, MD, MS41

1Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA
2Duke University Medical Center, Durham, NC
3Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Dunwoody, GA
4Winship Cancer Institute, Emory University Medical Center, Atlanta, GA
5Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA
6Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA
7The Winship Cancer Institute of Emory University, Atlanta, GA
8Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, TX
9Department of Oncology, Helsinki University Central Hosp., Helsinki, Finland
10Helsinki University Hospital, Helsinki, Finland
11Department of Hematopathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
12Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
13Copenhagen University Hospital, Herlev, Denmark
14Department of Pathology, University of Washington, Seattle, WA
15Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY
16Department of Pathology, Queen Mary Hospital, Pokfulam, HK Island, Hong Kong
17University of Nebraska, Omaha
18Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
19University of Miami Miller School of Medicine, Miami, FL
20Princess Margaret Hospital, Toronto, ON, Canada
21Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY
22Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY
23Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, FL
24Department of Laboratory Medicine, Cleveland Clinic, Cleveland, OH
25Wake Forest Baptist Medical Center, Winston Salem, NC
26Massachusetts General Hospital, Boston, MA
27Queen Mary Hospital, University of Hong Kong, Pokfulam, Hong Kong
28Data Driven Bioscience, Durham, NC
29Lymphoma Genomic Translational Research Laboratory, Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore, Singapore
30University of Rochester Medical Center, Rochester, NY
31Northwestern University Feinberg School of Medicine, Chicago, IL
32Department of Pathology, City of Hope National Medical Center, Duarte, CA
33Vanderbilt University Medical Center, Nashville, TN
34Vanderbilt University Medical Center, Nashville
35University of Toronto, Toronto, ON, Canada
36Indiana University School of Medicine, Indianapolis, IN
37Rutgers Cancer Institute of New Jersey, Warren, NJ
38Department of Laboratory Medicine and Pathology, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
39Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
40Duke Cancer Institute, Duke University, Durham, NC
41Department of Hematology and Medical Oncology, Emory University, Atlanta, GA

Background: Despite improved approaches to prognostication in mantle cell lymphoma (MCL), the impact of specific genomic aberrations is not well-described beyond TP53, which is well recognized as a high-risk marker across malignancies and widely assessed at time of diagnosis. However, since outcomes in patients without TP53 aberrations can be highly variable and difficult to predict, additional molecular markers are needed to identify patients who are at high risk for early relapse and inferior OS (Bond et al, Blood Adv 2021). In this study, we used comprehensive whole exome and transcriptome sequencing to genomically assess the prognostic impact of recurrent abnormalities in patients with MCL with and without TP53 aberrations.

Methods: The Atlas of Blood Cancer Genomes (ABCG) project is a worldwide effort to systematically profile the genetic alterations and expression changes in all blood cancers. We recruited MCL patients with detailed clinical data available and subjected their tumors to whole exome and transcriptome sequencing. TP53-aberrant cases were identified from the genomic and diagnostic data. Progression-free survival (PFS) and overall survival (OS) were measured from the date of diagnosis until date of progression/relapse or death (PFS) or death (OS) using the Kaplan-Meier method and statistical comparisons by the logrank test.

Results: Whole exome and whole transcriptome sequencing was performed successfully for 252 patients with MCL. Consistent with previous descriptions of the disease, median age at diagnosis was 65 years (range: 32-96), and 73% of patients were male. Seventy-five percent of patients had stage IV disease, and MIPI score was high, intermediate, or low in 34%, 34%, and 32% of patients, respectively. Ki67 proliferative index was ≥30% in 48% of patients with available data (n=115). Most patients received commonly used MCL therapies. Of the 185 patients for whom first-line treatment was known, 28% received bendamustine-containing regimens, 42% received cytarabine-containing regimens, and the remaining 30% received other regimens. Twenty-one percent of patients underwent autologous stem cell transplant consolidation as part of first-line therapy. Seventeen percent of patients had blastoid or pleomorphic histology, and 3% had leukemic non-nodal type MCL. Median PFS for the entire cohort was 41 months, and median OS was 138 months.

As expected, patients with a confirmed TP53 abnormality (n=39) had inferior median OS compared to TP53-WT patients (n=84; 39 months vs 138 months, p<0.001). Recurrent mutations identified in TP53-aberrant and TP53-WT patients are presented in Figure 1. Among TP53-WT patients, the following genes were mutated in ≥10% of cases: ATM (45%), KMT2D (23%), PTPN13 (13%), NOTCH1 (13%), NSD2 (11%), and SPEN (10%). Incidence of ATM mutations in TP53-aberrant patients was 21% and was less common in patients with TP53 mutations (14%) rather than deletions (30%). Presence of an ATM mutation (median variant allele frequency 43%; range 15-96%) in TP53-WT patients was associated with inferior median PFS (38 months vs 138 months for ATM WT, p=0.023) (Figure 2); median OS was also shorter in patients with ATM mutations (104 vs 138 months, p=0.035). Although the incidence of ATM mutations was lower in TP53-aberrant patients, there was no significant association between ATM mutation and PFS or OS in that subgroup.

Conclusions: To our knowledge, this study represents the largest genomic characterization of clinical outcomes in MCL patients. These findings suggest a pathogenic role for ATM mutations in patients with TP53-WT MCL and provide molecular insights into their heterogeneous outcomes. Although ATM mutations have been previously shown to be mutually exclusive with TP53 mutations (Mareckova et al, Leukemia & Lymphoma 2019), to our knowledge this is the first study that shows prognostic differences by ATM mutation status among TP53-WT patients. Our data indicate that ATM mutations are a significant prognostic factor and should be assessed at diagnosis along with TP53. Further clinical investigation of ATM mutations in TP53-WT MCL patients will be important to determine how this molecular marker may inform risk stratification and treatment approaches.

Disclosures: Koff: Atara BioTherapeutics: Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Oncternal Therapeutics: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Viracta Therapeutics: Research Funding. Flowers: TG Therapeutics: Research Funding; EMD: Research Funding; Ziopharm: Research Funding; Pfizer: Research Funding; Iovance: Research Funding; Amgen: Research Funding; Allogene: Research Funding; Adaptimmune: Research Funding; NPower: Current holder of stock options in a privately-held company; 4D: Research Funding; Spectrum: Consultancy; SeaGen: Consultancy; Pharmacyclics/Janssen: Consultancy; Bayer: Consultancy, Research Funding; Cellectis: Research Funding; Guardant: Research Funding; Takeda: Research Funding; Xencor: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; Gilead: Consultancy, Research Funding; Genmab: Consultancy; Genentech/Roche: Consultancy, Research Funding; BeiGene: Consultancy; Foresight Diagnostics: Consultancy, Current holder of stock options in a privately-held company; Denovo Biopharma: Consultancy; Celgene: Consultancy, Research Funding; Pharmacyclics: Research Funding; Kite: Research Funding; Morphosys: Research Funding; Sanofi: Research Funding; Janssen Pharmaceutical: Research Funding; Acerta: Research Funding; Karyopharm: Consultancy; Abbvie: Consultancy, Research Funding; National Cancer Institute: Research Funding; V Foundation, Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding. Leppa: Beigene: Consultancy; Pfizer: Consultancy; Orion Pharma: Consultancy; Bayer: Research Funding; BMS: Consultancy, Research Funding; Gilead Sciences: Consultancy, Honoraria; Roche: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria; Genmab: Research Funding; Nordic Nanovector: Research Funding. Crump: Kyte-Gilead, Novartis: Honoraria; Roche: Research Funding. Chadburn: U Chicago: Honoraria; NorthShore University HealthSystem (Eavanston IL: Honoraria; Lieca Biosystems: Consultancy; Leica Biosystems: Membership on an entity's Board of Directors or advisory committees; USCAP: Honoraria. Lossos: LRF: Membership on an entity's Board of Directors or advisory committees; NCI: Research Funding; Adaptive: Honoraria. Hsi: Cytomx: Consultancy; Novartis: Consultancy; Virtuoso: Research Funding; Abcon: Consultancy; Eli Lilly: Research Funding; Abcon: Current holder of stock options in a privately-held company; Astellas: Consultancy; Abbvie: Research Funding. Louissaint: Lymphoma Research Foundation: Research Funding. Tse: MSD: Research Funding. Love: Data Driven Biosciences: Consultancy, Current holder of stock options in a privately-held company. Ong: SymBio Pharmaceuticals Limited: Research Funding. Behdad: Lilly: Honoraria; Foundation Medicine/Roche China: Honoraria; Leica: Honoraria; Leica: Membership on an entity's Board of Directors or advisory committees; Thermofisher scientific: Honoraria; advisory committee: Membership on an entity's Board of Directors or advisory committees. Czader: Beckman Coulter: Membership on an entity's Board of Directors or advisory committees. Dave: Data Driven Biosciences: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months; Lantern Pharma Inc.: Other: Data Driven Biosciences conducted some of Lantern Pharma's pre-clinical studies. Cohen: Takeda: Research Funding; Lilly Oncology/Eli Lilly: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Astrazeneca: Consultancy, Research Funding; HutchMed: Consultancy, Research Funding; Kite Pharma/Gilead: Consultancy; Novartis: Research Funding; Aptitude Health: Consultancy; Janssen: Consultancy; Genentech: Research Funding; BMS/Celgene: Research Funding.

*signifies non-member of ASH