IgM-Secreting Diffuse Large B-Cell Lymphoma (DLBCL) Is a Poor Prognostic Subset within the Non-Germinal-Centre-Type (GC-type): An Italian Multicentre Study
Authors: Cox M. Christina , Marcheselli Luigi , Musuraca Gerardo , Cantonetti Maria , Visco Carlo , Hohaus Stefan , Annibali Ombretta , Fabbri Alberto , Tani Monica , Luminari Stefano , Battistini Roberta , Petrucci Luigi , Re Francesca , Marchesi Francesco , Anticoli Borza Paola , Natalino Fiammetta , Abruzzese Elisabetta , Pelliccia Sabrina , Mammoli Fabiana , Pupo Livio , Carli Giuseppe , Alma Eleonora , Tomarchio Valeria , Cencini Emanuele , Fabbri Francesca , Meconi Federico , D'Amore Emanuele , Larocca Luigi Maria , Asioli Silvia , Scafetta Giorgia , Tesei Cristiano , Ruco Luigi , Di Napoli Arianna 
Published: November 2020

BACKGROUND: In 2014 we identified a new subset of DLBCL, defined as "IgM-secreting" (Cox MC & Di Napoli A , PLOS One 2014). This was characterised by poor prognostic features and outcome as well as frequent central nervous (CNS) system localizations. Furthermore, IgM-secretion, was an independent prognostic factor in multivariate analysis. Here we report on the largest series of IgM-secreting-DLBCL, from a multicentre Italian study.
METHODS: The observational and biological study was approved by the Ethical Committee of the AUO Sant'Andrea, Italy. Enrolment criteria were: DLBCL with an associated IgM paraprotein diagnosed between 1st January 2010 and 31st December 2018 (IgM-secreting). Data were collected both prospectively and retrospectively from 17 Centres participating in the study. In addition, histopathology samples were centrally revised for immunohistochemistry (IHC) and FISH analyses. The control group (CTRL) consisted in a series of consecutive DLBCL, without an associated IgM-paraprotein (diagnosed between 01/01/2013 and 30/06/2016, enrolled in the Lymphoma Registry of the Lazio region (ReLLi Network). Last follow-up was carried out on 31st December 2019.
RESULTS: 569 DLBCL cases were enrolled: 102 (17.9%) were IgM-secreting; 48 (8.4%) had a non-IgM paraprotein (IgA, IgG, or other), and 414 (72.7%) had no associated paraprotein (CTRL). IgM-secreting cases within the consecutive DLBCL patients enrolled in the ReLLi Registry were 41/466 (8.8%, 95CI 6.4-11.7%) while non IgM-paraprotein DLBCL cases were 11/466 (2.4%, 95CI 1.2-4.2%). The median level of IgM paraprotein was 17gr/L (range: &lt;1-84gr/L); 83/102 (81.3%) were IgMk and 23/102 (22.5%) IgML respectively. The IgM-secreting group differed from the CTRL because the following characteristics were significantly more frequent: 1] age&gt;60 (p=.001); 2] advanced stage (p&lt;.001); 3] PS≥2 (p=.001); 4] LDH&gt;UNL (p=.008) ; 5] ≥2 Extra-nodal sites involved (p&lt;.001) ; 6] IPI 3-5 (p&lt;.001); 7] central nervous system (CNS) involvement at diagnosis or relapse (p&lt;.001); 8] lower rate of complete remission(CR) at the end of induction immunochemotherapy (p&lt;.001). Conversely, no differences were observed for: sex, B-symptoms, HCV and HBV status, bulky disease, age≥80 years, and for transformation from low-grade lymphoma. PATHOLOGICAL AND MOLECULAR FEATURES: Paraffin tissue from 74 CTRL and 69 IgM-secreting was suitable for immunohistochemistry (IHC). The non-GCB subtype, based on Hans algorithm, was prevalent in the IgM-secreting (p=.005). No difference in BCL2 expression alone or in MYC and BCL2 double expression was observed within groups. In 48/63(76%; 95CI: 64-86%) IgM-secreting cases, both the IgM heavy and the corresponding kappa or lambda light chain protein expression were detected in the cytoplasm of the neoplastic clone. FISH analyses for MYC, BCL2 and BCL6 genes rearrangements performed in 25 IgM-secreting cases with either expression of MYC protein or a GC-phenotype showed no evidence of double or triple hits (DH/TH). TREATMENT: in the IgM-secreting group more patients were treated with RCOMP and with less intensive approach than the CTRL (p&lt;.001). SURVIVAL: The median follow-up time was 46 months (95CI= 44-49; range 18-101) with 130 events and an incidence rate x100 person/year of 7.22 (95%CI 6.08-8.58) and a 5-yr OS of 76% (95CI 72-79%). The 5-PFS was 61% (95CI 57-65%). In univariable analysis age&gt;60, B-symptoms, bulky disease, IPI &gt;low risk and IgM-secreting IgM showed a worse survival (all with p&lt;0.001). Also, the IgM-secreting group, showed a worse survival compared to the DLBCL with an associated IgG/IgA paraprotein (p&lt;0.001). Adjusting in multiple Cox regression, IgM-secreting with IPI, gender, bulky and B-symptoms, maintain a higher risk of death either in the all cohort (HR 1.93, 95CI 1.34-2.78, p&lt;0.001) or in patients with age&lt;80 (HR 1.71, 95CI 1.16-2.54, p=0.007). Noteworthy, a survival sub-analysis showed that the 12/69 (17.4%) IgM-secreting with a GC-type had a better OS (9=0.008) and PFS (p=0.002) compared to the 57/69 (82.6%) IgM-secreting with a non-GC-type.
CONCLUSION: Our data confirm that IgM-secreting DLBCL: 1) represents a sizable proportion of non-DH DLBCL; 2) have poor prognostic features and 3) have mostly a non-GC phenotype. Furthermore, IgM secretion appears to be an independent prognostic factor for both PFS and OS. Studies to define the biological features of this new subset are ongoing.

Disclosures
Cantonetti: Mundipharma: Consultancy; Takeda: Consultancy; Vifor: Consultancy; Roche: Consultancy. Re:BerGenBio ASA: Research Funding. Abruzzese:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bms: Honoraria.