Cytogenetic Abnormalities In a Cohort of 171 Patients with Waldenström Macroglobulinemia Before Treatment: Clinical and Biological Correlations
Authors: Nguyen-Khac Florence , Lejeune Julie , Chapiro Elise , Grelier Aurore , Mould Sarah , Barin Carole , Daudignon Agnes , Gachard Nathalie , Struski Stephanie , Henry Catherine , Penther Dominique , Mossafa Hossein , Andrieux Joris , Veronese Lauren , Eclache Virginie , Bilhou-Nabera Chrystele , Luquet Isabelle , Terré Christine , Baranger Laurence , Mugneret Francine , Gregoire marie-Jose , Chiesa Jean , Ramond Sylvie , Mozziconacci Marie-Joelle , Callet-Bauchu Evelyne , Merle-Beral Helene , Leblond Véronique 
Published: October 2019

Abstract
Abstract 801
The genetic bases of Waldenström Macroglobulinemia (WM) are poorly understood. Because of the difficulty in obtaining tumor metaphases for karyotype studies, few recurrent chromosomal abnormalities have been reported in WM. We have studied a cohort of 171 untreated WM patients, enrolled in a prospective randomized trial from the French Cooperative Group on Chronic Lymphocytic Leukemia and Waldenstrom Macroglobulinemia (FCG-CLL/WM) comparing the efficacy of fludarabine to that of chlorambucil, by conventional cytogenetic (CC) and Fluorescence in situ hybridization (FISH).
CC was systematically performed on bone marrow or peripheral blood, and FISH analysis carried out using 8 probes CEP4, CEP12, 13q14, 11q22 (ATM), 17p13 (TP53), IGH, BCL2 Abbott, 6q21 Q-Biogene, on metaphases and interphase nuclei. The sex ratio was 2.1M/1F, the average age at inclusion was 66.9 years [40-89]. The mean percentage of lymphoplasmacytic cells was 53% [8-97]. Out of 140/171 successful CC, 65 (46.4%) showed clonal abnormalities. Out of 65 abnormal CC, 19 (29.2%) were complex, with at least 3 chromosomal changes, and 22 (33.8%) showed translocations (balanced and unbalanced). Using CC and FISH, we observed 29/132 (22%) 6q deletion, 18/141 (12.8%) 13q14 deletion, 9/80 (11.2%) trisomy 18, 11/135 (8.1%) TP53 deletion, 10/133 (7.5%) trisomy 4, 10/132 (7.6%) ATM deletion, 4/118(3.4%) IGH rearrangement, and 4/136 (2,9%)trisomy 12.
Chromosomal abnormalities were compared to adverse characteristics described by Morel et al (ISSWM, Blood 2009,113(8),4163-70): advanced age (> 65 years), hemoglobin < 11.5g/dl, platelet count < 100×109/l, b2-microglobulin > 3 mg/l, and serum monoclonal protein concentration > 7g/dl. Patients with 6q deletion had significantly more frequently albumin < 3.5g/dl (15/29 (51.7%) vs 24/103 (23.3%), p=0.005), b2microglobuline > 3 mg/l (20/29 (68.9%) vs 48/103 (46.6%), p=0.04). Similarly, patients with trisomy 4 had significantly more frequently b2microglobuline > 3 mg/l (9/10 (90%) vs 59/123 (47.9%), p=0.02). Of note, all patients with trisomy 4 had M-protein concentration > 2 g/dl (10/10 (100%) vs 73/123 (59.3%), p=0.02). Finally, there were significantly more patients with age > 65 years, when ATM deletion was observed (9/10 (90%) vs 65/122 (53.2%), p=0.04). Cytogenetic abnormalities did not influence the response rate but in multivariate analysis, TP53 deletion was associated with a shorter time to progression (15months (m) versus 35m, p=0.0007) and 6q deletion with a longer time to progression (55m versus 24m, p=0.04) in responding patients.
Cytogenetic abnormalities in WM differ from those commonly reported in other B-cell neoplasms and confirm the originality of this disease. The 6q deletion is frequent compared to chronic lymphocytic leukaemia (CLL) or marginal zone lymphoma (MZL) and 13q14 deletion is rare compared to CLL. In our series trisomy 12 is rare compared to atypical-CLL and MZL. Involvement of the IGH locus, which is frequent in multiple myeloma or lymphoplasmocytic lymphoma, is rare in WM. Finally trisomy 4 is present in WM but not reported in other B-cell malignancies. The 6q deletion is the most frequent reported cytogenetic abnormality in WM. We found 22% cases with deletions of 6q21, a lower percentage compared with the literature [38-54%].Conversely to previous publications, 6q deletion was associated with a longer response duration to treatment and did not influence the overall survival. These discrepancies could be explained by the heterogeneity of the previous published series, mixing untreated patients and treated patients in various ways. In our trial, all patients were analyzed before randomization. As in CLL patients, TP53 deletion seems to be associated with a shorter response duration. However, regarding the small numbers of patients with cytogenetic abnormalities, these results must be confirmed in larger series.

Disclosures:
Leblond: ROCHE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MUNDIPHARMA: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.