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

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.

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:Genmab: Consultancy; Allogene: Research Funding; Amgen: Research Funding; Foresight Diagnostics: Consultancy, Current holder of stock options in a privately-held company; Spectrum: Consultancy; Adaptimmune: Research Funding; EMD: Research Funding; Guardant: Research Funding; Iovance: Research Funding; Kite: Research Funding; Morphosys: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Cellectis: Research Funding; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Takeda: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; Ziopharm: Research Funding; National Cancer Institute: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; NPower: Current holder of stock options in a privately-held company; 4D: Research Funding; SeaGen: Consultancy; Karyopharm: Consultancy; Pharmacyclics/Janssen: Consultancy; Acerta: Research Funding; Janssen Pharmaceutical: Research Funding; Sanofi: Research Funding; V Foundation, Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Celgene: Consultancy, Research Funding; BeiGene: Consultancy; Abbvie: Consultancy, Research Funding; Bayer: Consultancy, 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:Leica Biosystems: Membership on an entity's Board of Directors or advisory committees; USCAP: Honoraria; Lieca Biosystems: Consultancy; U Chicago: Honoraria; NorthShore University HealthSystem (Eavanston IL: 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.