Clinico‐biological features and outcome of patients with splenic marginal zone lymphoma with histological transformation

BACKGROUND: The clinical course of splenic marginal zone lymphoma (SMZL) is usually indolent, but development of transformation to aggressive lymphoma (SMZL-T) is seen in 10 to 15% of the cases. Risk factors to predict SMZL-T are poorly defined. AIM: The aims of our study were: 1.- to assess the risk of transformation in a large series of SMZL patients; 2.- to analyze the prognostic factors for this event and 3.- to analyze clinical and biological features of SMZL-T. PATIENT AND METHODS: We identified 84 SMZL diagnosed at the HCB between 1994 and 2017 and 15 of them (18%) had developed histological transformation (SMZL-T). In addition, we reviewed 21 SMZL with transformation referred to HCB from other centers. Median age at diagnosis of low-grade SMZL in the 84 patients was 63 years (range, 32-91), and male/female ratio was 34/50. Complex karyotype (CK) defined as ≥3 chromosomal aberrations by conventional cytogenetics was observed in 22% and del(7q) in 59% of cases. The risk distribution according to the Splenic Marginal Zone Lymphoma Study Group simplified score HPLL/ABC was: low: 34, intermediate: 51 and high: 15. After a median follow-up of 80 months (range, 1-265), 37 of 84 (44%) patients have died, with a median overall survival (OS) of 146 months. To assess the risk of transformation and to identify predictive factors for such event, we exclusively evaluated the cohort of 84 patients from HCB. RESULTS: Fifteen of the 84 patients in the HCB cohort (18%) developed histological transformation. The cumulative incidence of transformation at 60 months from diagnosis was 15% (95% CI: 7 - 23) (Figure). In univariate analysis, variables predicting transformation were anemia, lymphopenia, thrombocytopenia, hypoalbuminemia, CK and high-risk scores of Intergruppo Italiano Linfomi (IIL) and HPLL (p<0.05 for all variables). In addition, lack of response to front-line treatment, relapse, and an early relapse at 12 and 24 months from treatment (p<0.05 for all variables) predicted for a higher risk of transformation. In multivariate analysis, only CK maintained significance to predict transformation (HR 4.85 (CI 95%: 1.15-20.56) p=0.03). Main clinico-biological features of all 36 SMZL-T patients (including HCB patients and those referred from other centers) are described in the Table. Thirty-five patients transformed to diffuse large B-cell lymphoma (DLCBL) and 1 to Hodgkin lymphoma. Treatment at transformation is detailed in Table. Response was assessable in 34 cases: 21 (62%) achieved a complete response (CR), and 13 patients did not respond. Among responders, 11 continue in CR, 9 relapsed during the follow-up and 1 patient died from therapy related acute myeloid leukemia (AML) when still in CR. Twenty SMZL-T patients (56%) eventually died, 19 related to lymphoma and 1 from AML. The median survival of the 36 SMZL-T patients from the time of transformation (SFT) was 59 months; with 60-months SFT of 46% (95% CI: 28-64) (Figure). Variables at the time of transformation predicting survival were age >60 years, thrombocytopenia and renal impairment. In addition, patients not achieving a CR, those not receiving an ASCT, and those who relapsed had a poorer SFT (p<0.05 for all variables). In multivariate analysis the independent variables predicting a worse SFT were: age > 60 years (HR 6.28 (95% CI: 1.55-25.39), p=0.01), thrombocytopenia (HR 32.77 (95% CI: 1.97-546.06), p=0.01), and response < CR (HR 8.75 (95% CI: 2.76-27.72), p<0.0001). Finally, SMZL-T was analyzed as a time-dependent variable for OS, showing that patients who eventually developed transformation had a significant higher risk of death (HR 3.894 (95% IC: 1.816-8.350), p<0.001). CONCLUSION: The risk of SMZL-T in our series of HCB was 15% at 60 months. The only factor that significatively predicted risk of SMZL-T in a multivariant analysis was the presence of complex karyotype. SMZL-T patients had a significative shorter survival compared to not transformed patients. Disclosures Gine: Roche: Other: Travel expenses, Research Funding; Gilead: Other: Travel expenses, Research Funding; Janssen: Other: Travel expenses, Research Funding. Lopez-Guillermo:Celgene: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Janssen: Research Funding.

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DNA methylation profiling identifies two splenic marginal zone lymphoma subgroups with different clinical and genetic features

Blood ◽

10.1182/blood-2014-08-596247 ◽

2015 ◽

Vol 125 (12) ◽

pp. 1922-1931 ◽

Cited By ~ 25

Author(s):

Alberto J. Arribas ◽

Andrea Rinaldi ◽

Afua A. Mensah ◽

Ivo Kwee ◽

Luciano Cascione ◽

...

Keyword(s):

Dna Methylation ◽

Marginal Zone ◽

Marginal Zone Lymphoma ◽

Splenic Marginal Zone Lymphoma ◽

Epigenetic Alterations ◽

Biological Features ◽

Key Points ◽

Dna Methylation Profiling ◽

Genetic Features ◽

Methylation Profiling

Key Points Methylation profiling identifies subgroups of SMZL with distinct biological features. Demethylating agents can reverse some of the adverse epigenetic alterations.

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Gene Expression Profiling Analysis in Splenic Marginal Zone Lymphoma Allows To Predict Survival and Histological Transformation.

Blood ◽

10.1182/blood.v104.11.1125.1125 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1125-1125

Author(s):

C. Thieblemont ◽

B. Ballester ◽

V. Nasser ◽

S. Gazzo ◽

G. Doucet ◽

...

Keyword(s):

Gene Expression ◽

Cell Proliferation ◽

Prognostic Factors ◽

Marginal Zone ◽

Marginal Zone Lymphoma ◽

Matched Pair ◽

Splenic Marginal Zone Lymphoma ◽

Term Survival ◽

Disease Evolution ◽

Histological Transformation

Abstract Splenic Marginal Zone Lymphoma (MZL) is described as an indolent lymphoma with a long term survival. However classical prognostic factors can not distinguish between patients who are likely to have good or poor outcomes. Moreover histological progression occurs in 10–20% of cases at the time of recurrence, but may be present at diagnosis, inducing a shorter survival with a median around 2 years. New model based on molecular understanding are needed to better discriminate these patients for their prognosis and disease evolution. Biopsy samples of splenic MZL from 43 patients treated in one institution and 8 with transformed splenic MZL were examined for gene expression using a nylon cDNA microarray consisting of 7, 000 human genes. Two of them came from a group of matched pair of splenic MZL and the transformed counterpart. An additional group comprising 4 transformed follicular lymphomas and 1 transformed small lymphocytic lymphoma were also analysed. Hierarchical clustering realized with all samples allowed to visualized patterns of gene expression already described in our previous work1 and corresponding to precise functions (proliferation, early response...), cell or tissue subtype (T cells, stroma …) or lymphoma subtype (MZL, MCL, SLL). The ability of individual genes to distinguish 1/ MZL and transformed-MZL subtypes, and 2/ alive patients and dead patients was calculated using a supervised method (discriminating score and bootstrap resampling). This allowed us to construct molecular predictors of survival and histological transformation. Transformation discriminating genes regrouped 73 genes related to cell proliferation such as CDC10, CDK4, PRKDC, PLCG2, LDHA, MCL2, and NPM1. P53 was down-expressed in all the transformed samples. Survival discriminating genes regrouped 26 genes from a unique cluster related to cell proliferation such as LDHA, NME1, MYC, ENO1. Although these genes seem to participate to the same function, only one gene was found discriminating the 2 parameters (LDHA). Gene ontology analysis using GOminer showed that the histological transformation was more related to cyclin-dependent protein kinase and that the survival was more related to metabolism. We used 26 genes to construct a predictor for survival in MZL patients. This gene-based predictor allowed predicting survival (p <0.00001) in MZL patients better than with classical prognostic factors (age, performance status, stage, LDH, monoclonal component, IPI…), but also in transformed MZL patients. In conclusion, genes involved in histological transformation and survival in MZL patients are implicated in independent but complementary functions leading to cell proliferation.

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Prognostic Impact Of Somatic NOTCH2 Mutation In Splenic Marginal Zone Lymphoma

Blood ◽

10.1182/blood.v122.21.4247.4247 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4247-4247 ◽

Cited By ~ 1

Author(s):

Caroline Algrin ◽

Gabriel Brisou ◽

Kheira Beldjord ◽

Nicolas Mounier ◽

Francoise Berger ◽

...

Keyword(s):

Marginal Zone ◽

Cox Model ◽

International Prognostic Index ◽

Marginal Zone Lymphoma ◽

Coagulation Disorder ◽

Splenic Marginal Zone Lymphoma ◽

Prognostic Impact ◽

Mutational Status ◽

Histological Transformation ◽

Recurrent Mutations

Abstract Introduction New insights in the pathogenesis of the splenic marginal zone lymphoma (SMZL) has been recently enlightened by next generation sequencing technology discovering recurrent mutations in several genes implicated in major signalling pathways. In 2 recent reports (JEM 2012), mutations in NOTCH2, a gene encoding a protein required for marginal zone B-cell development, were identified in nearly 25% of the patients, with controversial impact on clinical outcome. The aim of our analysis was to analyse the incidence and the prognostic impact of somatic NOTCH2 mutations in a large cohort of patients with SMZL homogeneously treated. Methods A series of 105 consecutive SMZL patients requiring treatment and referred in 2 expert centers was analysed. Genomic DNA was extracted from frozen tumor samples of involved spleen or blood or bone marrow obtained at diagnosis. Tumor cell clonality was established by amplification of the rearranged IGH genes. Targeted sequencing of the NOTCH2 C-terminal coding exons 26, 27 and 34 was performed using Sanger sequencing and primers described by Kiel MJ et al (J.Exp.Med.209:9,2012). All mutations were verified in at least two independent PCR amplification and sequencing reactions. Log-rank tests were used to compare survival times -overall survival (OS) and progression-free survival (PFS)- between patients with mutated NOTCH2 and patient with wild-type NOTCH2. We controlled the effects of prognostic factors on outcome using multivariate Cox model analysis. Results The median follow-up was 7 years. At diagnosis, median age was 63 years. Sex ratio was M/F 1:1.35. Nearly all patients presented with a disseminated disease and a good performance status. Forty-four percent of the patients had a high LDH level. A monoclonal component was detected in 31% of the patients. An immunological event such as haemolytic anemia, thrombocytopenia, neutropenia, coagulation disorder, and cryoglobulinemia, was observed in 27% of the patients. None of the patients was infected with hepatitis C virus. Patients were scored according to the age-adjusted International Prognostic Index (n=95), and to the IIL score system (n=76). Splenectomy was realized in 97% of the patients. Three patients were treated with R-Bendamusine without splenectomy. Adjuvant treatment after splenectomy was proposed for 24% of the patients, and included CHOP+/-R (n=16), HLX-VP16 (n=1), chlorambucil (n=4), and rituximab alone (n=1). Five and 10-year OS was estimated at 82% and 69%, respectively. Five and 10-year PFS was estimated at 61% and 46%, respectively. Age>60 was significantly associated to a shorter OS (p=0.0135). We identified NOTCH2 mutations in 10 (10%) of the patients. The detected mutations occurred only within the exon 34 (TAD and PEST domains) and represented mostly truncating or insertional events leading to frameshift mutations (8 of the 10 cases) (also 1 nonsense and 1 missense mutations). Comparison of the clinical characteristics at diagnosis between patients with or without NOTCH2 mutations did not show any significant differences. Patients with NOTCH2 mutations were characterized by a significantly worse OS (at 5 years, 32% vs 87%, p<0.0001). Presence of NOTCH2 mutations was also significantly associated with a shorter PFS (at 5-years, 16% vs 66%; p=.0008), and with a shorter time to histological transformation (at 5 years, 26% vs 6%; p=0.0051). NOTCH2 mutational status did not influence the time to first treatment. Multivariate analysis showed an independent prognostic impact of NOTCH2 mutational status on OS (RR 4.7, p=0.02). Conclusion NOTCH2 mutation was identified in 10% of the SMZL patients in our series. Our data demonstrate also, as described, than patients with NOTCH2 mutations have a significant poorer prognosis than patients without NOTCH2 mutations, with a shorter PFS and a shorter OS. NOTCH2 mutational status seems to be an independent prognostic factor. This needs to be confirmed in prospective trials in the context of new therapeutics. CA and GB equally contributed Disclosures: Coiffier: Millennium Pharmaceuticals : Consultancy.

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Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma

Journal of Experimental Medicine ◽

10.1084/jem.20120910 ◽

2012 ◽

Vol 209 (9) ◽

pp. 1553-1565 ◽

Cited By ~ 196

Author(s):

Mark J. Kiel ◽

Thirunavukkarasu Velusamy ◽

Bryan L. Betz ◽

Lili Zhao ◽

Helmut G. Weigelin ◽

...

Keyword(s):

B Cell ◽

Marginal Zone ◽

Marginal Zone Lymphoma ◽

Lymphocytic Leukemia ◽

Primary Lymphoma ◽

Reactive Lymphoid Hyperplasia ◽

Low Grade ◽

Splenic Marginal Zone Lymphoma ◽

Whole Genome ◽

Histological Transformation

Splenic marginal zone lymphoma (SMZL), the most common primary lymphoma of spleen, is poorly understood at the genetic level. In this study, using whole-genome DNA sequencing (WGS) and confirmation by Sanger sequencing, we observed mutations identified in several genes not previously known to be recurrently altered in SMZL. In particular, we identified recurrent somatic gain-of-function mutations in NOTCH2, a gene encoding a protein required for marginal zone B cell development, in 25 of 99 (∼25%) cases of SMZL and in 1 of 19 (∼5%) cases of nonsplenic MZLs. These mutations clustered near the C-terminal proline/glutamate/serine/threonine (PEST)-rich domain, resulting in protein truncation or, rarely, were nonsynonymous substitutions affecting the extracellular heterodimerization domain (HD). NOTCH2 mutations were not present in other B cell lymphomas and leukemias, such as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 15), mantle cell lymphoma (MCL; n = 15), low-grade follicular lymphoma (FL; n = 44), hairy cell leukemia (HCL; n = 15), and reactive lymphoid hyperplasia (n = 14). NOTCH2 mutations were associated with adverse clinical outcomes (relapse, histological transformation, and/or death) among SMZL patients (P = 0.002). These results suggest that NOTCH2 mutations play a role in the pathogenesis and progression of SMZL and are associated with a poor prognosis.

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