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

Abstract

<p><strong>Background:</strong> Despite improved approaches to prognostication in mantle cell lymphoma (MCL), the impact of specific genomic aberrations is not well-described beyond <em>TP53</em>, which is well recognized as a high-risk marker across malignancies and widely assessed at time of diagnosis. However, since outcomes in patients without <em>TP53</em> 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, <em>Blood Adv</em> 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 <em>TP53</em> aberrations.</p><p><strong>Methods:</strong> 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. <em>TP53</em>-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.</p><p><strong>Results:</strong> 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.</p><p>As expected, patients with a confirmed <em>TP53</em> abnormality (n=39) had inferior median OS compared to <em>TP53-</em>WT patients (n=84; 39 months vs 138 months, p<0.001). Recurrent mutations identified in <em>TP53-</em>aberrant and <em>TP53</em>-WT patients are presented in Figure 1. Among <em>TP53</em>-WT patients, the following genes were mutated in ≥10% of cases: <em>ATM</em> (45%), <em>KMT2D</em> (23%), <em>PTPN13</em> (13%), <em>NOTCH1 (</em>13%), <em>NSD2 (</em>11%), and <em>SPEN</em> (10%). Incidence of <em>ATM</em> mutations in <em>TP53-</em>aberrant patients was 21% and was less common in patients with <em>TP53</em> mutations (14%) rather than deletions (30%). Presence of an <em>ATM</em> mutation (median variant allele frequency 43%; range 15-96%) in <em>TP53-</em>WT patients was associated with inferior median PFS (38 months vs 138 months for <em>ATM</em> WT, p=0.023) (Figure 2); median OS was also shorter in patients with <em>ATM</em> mutations (104 vs 138 months, p=0.035). Although the incidence of <em>ATM</em> mutations was lower in <em>TP53</em>-aberrant patients, there was no significant association between <em>ATM</em> mutation and PFS or OS in that subgroup.</p><p><strong>Conclusions:</strong> To our knowledge, this study represents the largest genomic characterization of clinical outcomes in MCL patients. These findings suggest a pathogenic role for <em>ATM</em> mutations in patients with <em>TP53-</em>WT MCL and provide molecular insights into their heterogeneous outcomes. Although <em>ATM</em> mutations have been previously shown to be mutually exclusive with <em>TP53</em> mutations (Mareckova et al, <em>Leukemia & Lymphoma</em> 2019), to our knowledge this is the first study that shows prognostic differences by <em>ATM</em> mutation status among <em>TP53</em>-WT patients. Our data indicate that <em>ATM</em> mutations are a significant prognostic factor and should be assessed at diagnosis along with <em>TP53</em>. Further clinical investigation of <em>ATM</em> mutations in <em>TP53</em>-WT MCL patients will be important to determine how this molecular marker may inform risk stratification and treatment approaches.</p>