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Summary: Mantle cell lymphoma (MCL) is clinically and biologically heterogeneous. While various prognostic features have been proposed, none currently impact therapy selection, particularly in older patients, for whom treatment is primarily dictated by age and comorbidities. Herein, we undertook a comprehensive comparison of clinicopathological features in a cohort of patients 60 years and older, uniformly treated with bendamustine and rituximab, with a median survival of >8 years. The strongest prognostic indicators in this cohort were a high‐risk call by a simplified MCL international prognostic index (s‐MIPI) (HR: 3.32, 95% CI: 1.65–6.68 compared to low risk), a high‐risk call by MCL35 (HR: 10.34, 95% CI: 2.37–45.20 compared to low risk) and blastoid cytology (HR: 4.21, 95% CR: 1.92–9.22 compared to classic). Patients called high risk by both the s‐MIPI and MCL35 had the most dismal prognosis (HR: 11.58, 95% CI: 4.10–32.72), while those with high risk by either had a moderate but clinically relevant prognosis (HR: 2.95, 95% CI: 1.49–5.82). A robust assay to assess proliferation, such as MCL35, along with stringent guidelines for cytological evaluation of MCL, in combination with MIPI, may be a strong path to risk‐stratify older MCL patients in future clinical trials. [ABSTRACT FROM AUTHOR]

While some follicular lymphoma (FL) patients do not require treatment or experience prolonged responses, others relapse early, and little is known about genetic alterations specific to patients with a particular clinical behavior. We selected 56 grade 1–3A FL patients according to their need of treatment or timing of relapse: never treated (n = 7), non‐relapsed (19), late relapse (14), early relapse or POD24 (11), and primary refractory (5). We analyzed 56 diagnostic and 12 paired relapse lymphoid tissue biopsies and performed copy number alteration (CNA) analysis and next generation sequencing (NGS). We identified six focal driver losses (1p36.32, 6p21.32, 6q14.1, 6q23.3, 9p21.3, 10q23.33) and 1p36.33 copy‐neutral loss of heterozygosity (CN‐LOH). By integrating CNA and NGS results, the most frequently altered genes/regions were KMT2D (79%), CREBBP (67%), TNFRSF14 (46%) and BCL2 (40%). Although we found that mutations in PIM1, FOXO1 and TMEM30A were associated with an adverse clinical behavior, definitive conclusions cannot be drawn, due to the small sample size. We identified common precursor cells harboring early oncogenic alterations of the KMT2D, CREBBP, TNFRSF14 and EP300 genes and 16p13.3‐p13.2 CN‐LOH. Finally, we established the functional consequences of mutations by means of protein modeling (CD79B, PLCG2, PIM1, MCL1 and IRF8). These data expand the knowledge on the genomics behind the heterogeneous FL population and, upon replication in larger cohorts, could contribute to risk stratification and the development of targeted therapies. [ABSTRACT FROM AUTHOR]

The lymphocyte-to-monocyte ratio (LMR) is a prognostic factor in different neoplasms, but its potential importance in follicular lymphoma (FL) is not well defined. We studied 384 FL patients for which the LMR was available at diagnosis. Baseline features and outcomes were compared between patients with an LMR ≤/>2.5. The 76 patients (20%) who had an LMR ≤2.5 were older and had a higher tumor burden. A low LMR was predictive of a lower 10-y progression-free survival (32 vs. 55%, p =.001) and overall survival (35 vs. 78%, p <.0001; HR = 2.3, p =.003 in a 6-element multivariable model). A low LMR was also an independent risk factor for histological transformation (11 vs. 6% at 10 years, p =.01). Likewise, patients with a low LMR had a higher rate of second malignancies. The potential utility of this widely available parameter and its contribution to well-established prognostic scores need to be explored in independent, prospective series. [ABSTRACT FROM AUTHOR]

Aims: Mantle cell lymphoma (MCL) is a heterogeneous disease with an aggressive behaviour in most cases, which is associated with expression of sex determining region‐Y‐box11 (SOX11). Experimental studies have shown that SOX11 expression is associated with an angiogenic switch characterised by increased expression of angiogenic‐related signatures and vascularisation of murine tumours. However, the relationship between angiogenesis and SOX11 expression in primary tumours is not well understood. Therefore, the aim of this study was to evaluate the development of microvascular angiogenesis in primary MCL in relation to SOX11 expression and its potential prognostic value. Methods and results: Fifty‐six patients diagnosed with MCL, 38 SOX11‐positive and 18 SOX11‐negative, were studied. The relative intratumoral microvascular area (MVA) and microvessel density (MVD) (number of intratumoral microvessels/μm2) were measured on CD34‐stained slides using a computerised image analysis system. SOX11‐positive MCL showed a significant higher microvascular development than negative tumours (median MVA = 14.5 × 10−3 versus 5.0 × 10−3P < 0.001; median MVD = 18.6/μm2 versus 14.2/μm2, P = 0.021). Analysing the MVA and MVD as continuous variables, a high MVD was associated with shorter overall survival (P = 0.004), and a similar tendency was observed for high MVA (P = 0.064). The microvascular development was not related to the Ki‐67 proliferative index or 17p/TP53, 9p or 11q alterations. Conclusions: These findings suggest that SOX11 promotes an angiogenic phenotype in primary MCL, which may contribute to the more aggressive behaviour of these tumours. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is a phenotypically and genetically heterogeneous malignancy in which the genetic alterations determining clinical indications are not fully understood. Here, we performed a comprehensive whole-exome sequencing analysis of 152 primary samples derived from 134 MCL patients, including longitudinal samples from 16 patients and matched RNA-Seq data from 48 samples. We classified MCL into 4 robust clusters (C1-C4). C1 featured mutated immunoglobulin heavy variable (IGHV), CCND1 mutation, amp(11q13), and active B cell receptor (BCR) signaling. C2 was enriched with del(11q)/ATM mutations and upregulation of NF-κB and DNA repair pathways. C3 was characterized by mutations in SP140, NOTCH1, and NSD2, with downregulation of BCR signaling and MYC targets. C4 harbored del(17p)/TP53 mutations, del(13q), and del(9p), and active MYC pathway and hyperproliferation signatures. Patients in these 4 clusters had distinct outcomes (5-year overall survival [OS] rates for C1-C4 were 100%, 56.7%, 48.7%, and 14.2%, respectively). We also inferred the temporal order of genetic events and studied clonal evolution of 16 patients before treatment and at progression/relapse. Eleven of these samples showed drastic clonal evolution that was associated with inferior survival, while the other samples showed modest or no evolution. Our study thus identifies genetic subsets that clinically define this malignancy and delineates clonal evolution patterns and their impact on clinical outcomes. [ABSTRACT FROM AUTHOR]