Genomic Profiling of Mantle Cell Lymphoma Suggests Poor-Risk Profile Is Present at Diagnosis and Does Not Arise By Tumor Evolution
Authors: Joffe Erel , Kumar Anita , Zheng Serena , Uppal Manik , Bantilan Kurt S. , Atteberry Preston , Straus David J. , Palomba M. Lia , Noy Ariela , Horwitz Steven M. , Moskowitz Alison J. , Hamlin Paul A. , Matasar Matthew J , Batlevi Connie Lee , von Keudell Gottfried R. , Dogan Ahmet , Younes Anas , Zelenetz Andrew D. 
Published: February 2020

INTRODUCTION
Despite major clinical advancements, mantle cell lymphoma (MCL) remains a therapeutic challenge with a considerable number of patients experiencing a dismal course. We sought to map the genomic landscape of MCL at diagnosis and at disease progression. We aimed to identify genomic drivers of aggressive phenotype, resistance and relapse and to characterize the genomic evolution of this disease.
METHODS
We evaluated the genetic landscape of 210 MCL patients, comparing patients sequenced pretreatment (pre-Tx) to those sequenced at disease progression (POD), including 23 patients with sequential samples. We used CLIA certified targeted sequencing platforms covering 151 genes recognized in lymphoma, including single nucleotide variants (SNV) and copy number alterations (CNA). We compared clinical characteristics, histologic features, IGHV mutational status and genomic profiles between pre-Tx and POD samples. We evaluated the association between genomic features and overall survival (OS) in pre-Tx cases.
RESULTS
Median age was 65 (range 31-92) with a male predominance (75%, n=172). Patients sequenced at POD were characterized by a higher rate of blastoid histology (31% n=20 vs. 10% n=16, p&lt;0.001) and a higher rate of high-proliferation (Ki67≥30% in 79% n=45 vs. 54% n=61, p=0.001), but rates of an 'unmutated' IGHV status were similar (68% n=23 vs. 75% n=57, p=0.6).
The most prevalent genomic abnormalities (mut) seen in the entire cohort were ATM (49%, n=111); TP53 (30%, n=69); KMT2D (22%, n=51); CCND1 (16%, n=37); WHSC1 (14%, n=33); and BIRC3 (14%, n=32). Compared to pre-Tx, POD cases had higher rates of TP53mut (49% n=33 vs. 22% n=36, p&lt;0.001) and a trend towards less ATMmut (38% n=26 vs. 53% n=85, p=0.06) and CCND1mut (7% n=5 vs. 20% n=32, p=0.03). ATMmut and TP53mut were almost completely exclusive (p&lt;0.001) (figure 1).
There were 110 cases with IGHV data (27% n=30 mutated and 73% n=80 unmutated). Mutated IGHV was associated with a higher rate of CCND1mut (37% n=11 vs. 8% n=6, p&lt;0.001) and NOTCH2mut (17% n=5 vs. 3% n=2, p=0.02).
We evaluated pathological characteristics of the sequenced tumor biopsy. Blastoid histology (219 evaluable) observed in 16% (n=36) was associated with TP53mut (61% n=22 vs. 22% n=41, p&lt;0.0001); a lower rate of ATMmut (31% n=11 vs. 53% n=97, p=0.02); and a higher rate of SMARCA4mut (22% n=8 vs. 10% n=17, p=0.04). Similarly, a high Ki67 &gt;=30% (171 evaluable) was associated with TP53mut (38% n=63 vs. 9% n=6, p&lt;0.001) and NOTCH1mut (12% n=13 vs. 2% n=1, p=0.02); with extremely high Ki67 &gt;=60% enriched for CCND1mut (28% n=11 vs. 15% n=10 30%&gt;= Ki67 &lt; 60% and 9% n=6 Ki67&lt;30%, p=0.04) and MED12mut (13% n=5 vs. 3% n=2 30%&gt;= Ki67 &lt; 60% and no cases with Ki67&lt;30%, p=0.006).
There were 23 patients with sequential biopsies with a median time difference of 37m (IQR 18-57) between samples. pre-Tx and POD sequential samples had strikingly similar genomic alterations (figure 2). Furthermore, the mutation landscape of these pre-Tx samples was highly similar to that seen in the overall POD samples. For example, TP53mut were observed in 48% of sequential pre-Tx samples, similar to 49% seen in overall POD samples and not to the 22% seen in overall pre-Tx samples.
Genomic clustering identified four distinct clusters of patients with ATMmut (BIRC3mut; KMT2Dmut; NOTCH1/CCND1 and None) a cluster of WHSC1mut and a cluster of TP53mut associated with SMARCA4mut (figure 3).
Survival analysis was limited to 151 pre-Tx patients and who had completed treatment or managed expectantly (20%, n=30). With a median follow-up of 49m, TP53mut was associated with shorter OS (HR 4.15; 1.9-9.0) corresponding to a 4yOS of 63% vs. 92% in TP53wt (figure 4). In 22 patients (15%) with BIRC3mut, no deaths were observed (p=0.03). Notably, however, the rate of BIRC3mut at POD was similar to pre-Tx and not associated with superior outcomes.
CONCLUSIONS
Our data suggests that the ultimate outcome of MCL is driven by clones present at diagnosis and in most cases is not the result of clonal evolution. As with former studies TP53mut is the strongest driver of poor outcome. Still a considerable subset of patients fares well. BIRC3mut seemed to confer a good prognosis, however this observation needs to be validated in a dedicated study as the rate of BIRC3mut was similar between pre-Tx and POD and not associated with a better prognosis in the latter. We identify several genomic clusters associated with targetable mutations.
Figure

Disclosures
Kumar: Seattle Genetics: Research Funding. Straus:Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria; Elsevier (PracticeUpdate): Consultancy, Honoraria. Palomba:Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights . Noy:Janssen: Consultancy; Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Horwitz:Forty-Seven: Research Funding; Kura: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Astex: Consultancy; Innate Pharma: Consultancy; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Mundipharma: Consultancy; Aileron: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Astex: Consultancy; Astex: Consultancy; Trillium: Research Funding; Trillium: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Innate Pharma: Consultancy; Kura: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Innate Pharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Mundipharma: Consultancy; Aileron: Research Funding; ADCT Therapeutics: Research Funding; Forty-Seven: Research Funding; Affimed: Consultancy; Miragen: Consultancy; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; ADCT Therapeutics: Research Funding; ADCT Therapeutics: Research Funding; Kura: Consultancy; Celgene: Consultancy, Research Funding; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Mundipharma: Consultancy; Miragen: Consultancy; Affimed: Consultancy; Affimed: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Kyowa Hakko Kirin: Consultancy; Miragen: Consultancy; Innate Pharma: Consultancy; Forty-Seven: Research Funding; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy; Forty-Seven: Research Funding; Affimed: Consultancy; Trillium: Research Funding; Portola: Consultancy; Trillium: Research Funding; Portola: Consultancy; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Portola: Consultancy; Portola: Consultancy; Seattle Genetics: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. 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