THE PROGNOSTIC ROLE OF DEL 9P21.3 (CDKN2A) IN PATIENTS WITH MANTLE CELL LYMPHOMA. RESULTS FROM THE FIL_MANTLE-FIRST BIO STUDY

Mantle Cell Lymphoma (MCL) is an aggressive malignancy with variable clinical behaviour, largely reflecting its molecular heterogeneity. The genomic landscape of MCL encompasses gene mutations with strong prognostic implications (i.e., TP53, NOTCH1/2, KMT2D, etc),and secondary genetic events such as copy number variations (CNVs), which are also implicated in pathogenesis and prognosis. We analyzed genomic DNA (gDNA) extracted from diagnostic formalin-fixed paraf- fin-embedded (FFPE) lymph nodes or extra-nodal biopsies of 81 treat- ment-naïve patients with MCL enrolled in the MANTLE-FIRST BIO study (NCT04882475). We performed targeted sequencing on the Illu- mina platform using a customized panel. The somatic mutations (SNVs) were annotated with MuTect2, while CNVs with CNVkit. To be in- cluded, patients had to have experienced relapse or progression (R/R) after induction therapy and during the observation period, which was held by centres from the Fondazione Italiana Linfomi (FIL). Results were analyzed according to time to first R/R and divided following accepted definition of early versus late progression of disease (POD). Overall, 18 CNVs were identified (11 amplifications and 7 deletions). The oncoprint showed that Del13q14 (RB1, 34%,p=0.02), Del6q (21%, p=0.01), and Del9p21.3 (CDKN2A, 19%, p=0.02) were significantly associated with more frequent early-POD (Figure 1). CNVs’ unbiased clusterization highlighted four different molecular clusters, which could split the cohort into groups with significantly different time to first POD (p=0.01). Specifically, cluster1 was enriched by Del 9p21.3 (CDKN2A). A back- ward multivariate analysis was performed in terms of time to first POD, including all variables that were significant in univariate analysis, as tumor morphology (classic vs blastoid/pleomorphic), MIPI score (high versus others), Ki-67 (≤30% vs >30%), Del 9p21.3 (CDKN2A), Del 13q14 (RB1), mutations of TP53, EZH2, BTK, NFKBIE, and STAT3. Del 9p21.3 (CDKN2A) emerged as the only significant alteration asso- ciated with significantly inferior time to first POD (p=0.01, HR=2.47), together with blastoid/pleomorphic morphology (p=0.14, HR 1.74), and high-risk MIPI (p<0.001, HR 3.72). Our comprehensive analysis shows that CNVs reflect the high heterogeneity of MCL genomic landscape, and reveal a strong and independent association between Del 9p21.3 (CDKN2A) and the occurrence of early POD. We thank FIL for funding support (Premio Giovani Ricercatori, Ed. 2019).