GENOMIC ANALYSES OF PATIENTS WITH MANTLE CELL LYMPHOMA THAT WERE REFRACTORY OR RELAPSED AFTER INDUCTION THERAPY: RESULTS FROM THE FIL_MANTLE- FIRST BIO STUDY

MANTLE-FIRST BIO retrospective study enrolls mantle cell lym- phoma (MCL) patients, aged 18-80 years, experiencing first relapse or refractoriness (R/R) to frontline chemo-immunotherapy (CIT). Patients with available diagnostic samples other than bone marrow biopsy from 16 centers affiliated with Fondazione Italiana Linfomi (FIL) were en- rolled in this study. We performed a targeted sequencing analysis (Illu- mina platform) on genomic DNA extracted from formalin-fixed paraffin-embedded diagnostic samples (lymph node or extra-nodal tis- sue). A customized panel including 37 genes was used to identify gene mutations associated with different time to first progression of disease (time to POD). Single nucleotide variants (SNVs) calling was performed with MuTect2. The previously defined threshold of 24 months since MCL diagnosis was used to define patients as early- or late-POD. The primary endpoint was to investigate the correlation between time to POD and clinical or molecular features. Eighty-one MCL patients (29 early- and 52 late-POD) were included. Median age was 67 years, 62 were males, median time to POD was 35.3 months (range 3-149.2), and me- dian follow-up from lymphoma diagnosis was 69.9 months. Data anal- ysis identified ATM as the most frequently mutated gene (42%), followed by NOTCH1 (32%), SMARCA4 (30%), TP53 (29%) and KMT2D (26%) (Figure 1). Among mutated genes, TP53 (p=0.0003, HR 2.21), NFKBIE (p=0.01, HR 2.97) and STAT3 (p=0.02, HR 2.78) were significantly as- sociated with shorter time to POD at univariate analysis. Non-negative matrix factorization identified four different clusters with well-defined molecular composition and with significantly different time to POD (p<0.011). Cluster 1 included patients who presented SNVs such as NOTCH1 (40%), TP53 (38%), and KMT2D (20%) that were associated with the shortest time to POD. In multivariate analysis, TP53 (p=0.01, HR 2.15), tumour morphology (classic versus blastoid/pleomorphic, p=0.14, HR 1.74) and MIPI score (high versus others, p<0.001, HR 3.72) were independently associated with shorter time to POD. In conclusion, our MCL cohort showed high genetic complexity that underlies the het- erogeneous clinical behavior. Our findings may contribute to the identi- fication of distinct biological profiles that are associated to significantly different time to POD. We thank FIL for funding support (Premio Giovani Ricercatori, Ed. 2019).