Introduction
Around 5-10% of mantle cell lymphoma (MCL) patients are primary refractory to chemotherapy. They have an extremely dismal prognosis, as do responsive patients that relapsed within 12 months. Despite better understanding of risk factors and evolving classifications, these scores do not predict all high-risk patients and were not designed to guide treatment strategy in newly diagnosed MCL. Optical genome mapping (OGM) is a cutting-edge technology developed for genome-wide detection of structural variants (SVs) including balanced and unbalanced translocations, inversions, insertions, deletions, duplications as well as copy number variations (CNVs).
Methods
High-risk (HR) patients included in the prospective phase III LyMa trial (NCI NCT00921414; Le Gouill et al. NEJM 2017), were identified as patients experiencing early progression of disease (i.e. within 1 year after randomization). We performed OGM in the HR cohort using available frozen tumoral tissue. Low-risk patients (LR) were used as a control. The data were analyzed with the Bionano Solve software.
Results
Among 299 MCL patients included in the LyMa trial, 31 high-risk MCL patients were identified (10.4%). OGM was performed in 15 patients: 8 HR and 7 LR. OGM successfully detected the t(11;14) in all patients. We detected a median of 38 SVs (range, 16-129) and 12 CNVs (range, 1-119) per case, higher in HR patients than in LR patients (median 51 vs. 32, p=0.07 for SVs; and 14 vs. 5, p=0.11 for CNVs). Chromothripsis and chromoplexia occurred in both cohorts, but breakage-fusion-bridge (BFB) cycles was only observed in 2 HR MCL. HR MCL were characterized by frequent loss of 17p/ TP53 (63% vs. 0%, p=0.03), and rare deletions of 11q22-q23/ ATM (13% vs. 57%, p=0.12). Three HR patients had no TP53 deletions, two of whom presented a gain of BCL2. Gain of UBR5, that influence transcription and posttranscription processes, was found in 3/8 HR patients compared to 1/8 LR patients. MTAP deletion that has been recently described as biomarkers predicting refractory MCL was found in 5/8 HR MCL and is associated with CDKN2A/2B deletions, compared to 0/8 LR. MTAP deletion was associated with TP53 deletions in two HR MCL, that is supposed to confer resistance to PRMT5 targeted therapy (Sloan SL et al. Blood 2023). Deletion of the chromatin modifier MEF2B occurred in 3/8 HR MCL and 1/8 LR MCL. Two patients had deletion of SMARCA4 at diagnosis, that confers resistance to the BCL-2 inhibitor venetoclax (Agarwal et al. Nature Med 2018). Mutations in the NF-κB alternative pathway, responsible for resistance to ibrutinib, are found in both LR and HR patients.
Conclusion
In this small cohort of MCL patients included in a trial, complex structural alterations were identified by OGM at the time of diagnosis. OGM is a very promising technology that demonstrated its potential in the cytogenetic prognostic staging of MCL.
Disclosures
Sarkozy:Incyte Bioscience: Consultancy, Other: Travel, Accommodations, Expenses; BMS: Consultancy; Janssen: Consultancy; GSK: Consultancy; AbbVie: Honoraria; Gilead: Other: Congress fees; Roche: Other: Travel, Accommodations, Expenses, Research Funding; Prelude Therapeutics: Consultancy; Beigene: Consultancy; Lilly: Honoraria; Gilead: Other: Travel, Accommodations, Expenses; Takeda: Other: Travel, Accommodations, Expenses. Thieblemont:Paris University, Assistance Publique, hopitaux de Paris (APHP): Current Employment; Bayer: Honoraria; Kyte, Gilead, Novartis, BMS, Abbvie, F. Hoffmann-La Roche Ltd, Amgen: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Hospira: Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Janssen: Honoraria, Other: Travel Expenses. Morschhauser:F. Hoffmann-La Roche Ltd, AbbVie, BMS, Genmab, Gilead, Novartis: Consultancy; F. Hoffmann-La Roche Ltd, Gilead, AbbVie: Membership on an entity's Board of Directors or advisory committees. Safar:janssen: Honoraria. Ghesquieres:Gilead, Roche: Consultancy; Gilead, Roche, Bristol Myers Squibb, AbbVie, Novartis: Honoraria. Cheminant:Amgen: Honoraria; Innate Pharma: Research Funding; AstraZeneca: Other: Travel accomodations and Meeting inscription; Abbvie: Research Funding.
