Diffuse-Large-B-Cell Lymphoma Patients with Secretory IgM Monoclonal Component Are A Very Poor Prognostic Subset.
Authors: Cox M. Christina , Napoli Arianna Di , Scarpino Stefania , Cavalieri Elena , Naso Virginia , Talerico Caterina , Salerno Gerardo , Tatarelli Caterina , Spiriti Maria Antonietta Aloe , Monarca Bruno , Amadori Sergio , Ruco Luigi 
Published: October 2019

Abstract
Abstract 2659

Background:
Gene-expression-profiling defined at least two main groups within Diffuse-large-B-cell Lymphoma (DLBCL) patients who have substantially different outcomes: Activated-B-cell (ABC-type) and Germinal-Center-B-cell (GCB-type). The translation of gene-expression-profiling arrays into robust algorithm useful for clinical purposes is still in progress. The detection of IgM monoclonal component (IgM MC) in DLBCL has been previously described in a few reports, mainly because it was associated with autoimmune hemolytic anaemia. To our knowledge this is the first report describing the incidence and prognosis of a series of DLBCL with IgM MC.

Aims:
In this report we compared clinical and biological features of DLBCL patients with and without secretory IgM MC .

Patients & Methods:
Within a consecutive series of 132 patients, diagnosed between September 2004 and April 2012 with conventional DLBCL, 16 cases (12%) with a IgM MC were identified. We selected a set of 95 consecutive DLBCL patients, treated with 6–8 cycles of RCHOP-like for comparison of histological features and survival. Only cases with a follow up time >24 months were included, unless a DLBCL–related event (i.e. primary refractoriness or relapse) had occurred earlier. Biological material was obtained after receiving patient's consent. This study was approved by our Institutional-Review-Board.

Immunohistochemistry and FISH:
Paraffin sections were immunostained for CD3, CD5, CD20, CD10, CD30, CD79a, CD138, ALK-1, MUM1, BCL2, BCL6, IgM, Kappa and Lambda immunoglobulin light chains, using an automated immunostainer (DAKO, Denmark). The Hans algorithm was used in order to classify cases as GCB-type and non GCB-type. FISH with Vysis break-apart probe was used to assess c-MYC gene abnormalities in tissue sections (Abbott Molecular Inc. US).

Statistics:
univariate comparisons between groups were carried out with appropriate non parametric test. Survival analyses were done by the Kaplan-Meier method, the analyses of factor predicting survival were carried out by the log-rank test. Cox's regression was used for multivariate analyses. The SPSS19 package (SPSS Inc.Chicago IL) was used for elaborations.

Histology, immunohistochemistry and FISH Results:
In 14 out of 16 cases (87.5%) the IgM MC was related to the DLBCL clone. This was ascertained by immunostaining of cytoplasm for IgM, Kappa and Lambda immunoglobulin light chains. All the 14 cases were classified as non GCB-type. FISH analysis detected no c-MYC gene rearrangements in all the cases.

Clinical Results:
The incidence of bone marrow involvement, two or more extranodal sites, female sex, IPI score 3–5 and failure to achieve CR on RCHOP treatment were significantly more frequent in the IgM MC group. Noteworthy four out of 14 patients had central nervous system involvement at diagnosis or at relapse. All but one, with a previous diagnosis of marginal zone lymphoma, were de novo DLBCL. Twelve patients (85.7%) presented a DLBCL related event compared to 35 patients (37%) without IgM MC (p=.001). Seven patients (50%) died with primary refractory or relapsed-chemoresistant disease, another one died of an adverse event during chemotherapy. Two are alive on salvage treatment, two are in PFS at +30 and +13 months after salvage treatment with Bortezomib-RDHAP followed by high dose therapy. Only two patients are in PFS after first line RCHOP at +56 and +29 months respectively.

Survival analysis:
The estimated two-year EFS, PFS and OS were significantly worst for IgM MC group (22% Vs 70%, p<.0001; 22% Vs 75%, p<.0001; 50% Vs 85%, p=.011, respectively). In multivariate analysis IgM MC was the only significant factor for EFS (p=.001; 0.194 CI:0.089–0.57) while for PFS were both significant the IgM-MC (p=0.014; 0.360; 5%CI: 0,159–0,815) and the IPI-score 3–5 (p=.002; 0.186; 95% CI 0.063–0.552).

Conclusions:
A secretory IgM MC related to the neoplastic clone, was detected in more than 10% of newly diagnosed DLBCL. IgM MC in DLBCL might be easily missed, given its negligible entity, the rarity of associated clinical signs and the rapid MC fading during treatment. This group showed homogeneous morphologic and immunohistochemical features consistent with the non GCB-type. FISH analysis was negative for c-MYC gene rearrangements. IgM MC in DLBCL patients, might be related to a very poor non GCB-type subset who should be given upfront intensified therapies.

Disclosures:
No relevant conflicts of interest to declare.