Bertrand Coiffier

Next-Generation Sequencing in Diffuse Large B-Cell Lymphoma Highlights Molecular Divergence and Therapeutic Opportunities: a LYSA Study.

Purpose: Next-generation sequencing (NGS) has detailed the genomic characterization of diffuse large B-cell lymphoma (DLBCL) by identifying recurrent somatic mutations. We set out to design a clinically feasible NGS panel focusing on genes whose mutations hold potential therapeutic impact. Furthermore, for the first time, we evaluated the prognostic value of these mutations in prospective clinical trials. Experimental Design: A Lymphopanel was designed to identify mutations in 34 genes, selected according to literature and a whole exome sequencing study of relapsed/refractory DLBCL patients. The tumor DNA of 215 patients with CD20+de novo DLBCL in the prospective, multicenter, and randomized LNH-03B LYSA clinical trials was sequenced to deep, uniform coverage with the Lymphopanel. Cell-of-origin molecular classification was obtained through gene expression profiling with HGU133+2.0 Affymetrix GeneChip arrays. Results: The Lymphopanel was informative for 96% of patients. A clear depiction of DLBCL subtype molecular heterogeneity was uncovered with the Lymphopanel, confirming that activated B-cell–like (ABC), germinal center B-cell like (GCB), and primary mediastinal B-cell lymphoma (PMBL) are frequently affected by mutations in NF-κB, epigenetic, and JAK–STAT pathways, respectively. Novel truncating immunity pathway, ITPKB, MFHAS1, and XPO1 mutations were identified as highly enriched in PMBL. Notably, TNFAIP3 and GNA13 mutations in ABC patients treated with R-CHOP were associated with significantly less favorable prognoses. Conclusions: This study demonstrates the contribution of NGS with a consensus gene panel to personalized therapy in DLBCL, highlighting the molecular heterogeneity of subtypes and identifying somatic mutations with therapeutic and prognostic impact. Clin Cancer Res; 22(12); 2919–28. ©2016 AACR. See related commentary by Lim and Elenitoba-Johnson, p. 2829

Immunoglobulin heavy chain/light chain pair measurement is associated with survival in diffuse large B-cell lymphoma

Abstract Elevated serum free light chains (FLCs) have been associated with an unfavorable prognosis in diffuse large B-cell lymphoma (DLBCL). The aim of this study was to determine the clinical relevance of a quantitative assessment of intact circulating immunoglobulin (Ig), using serum Ig heavy chain/light chain pair (HLC) measurements in patients with DLBCL. FLC and HLC were measured in 409 serum samples of patients with DLBCL included in the LNH03-B clinical trial program of the Groupe d’Etudes des Lymphomes de l’Adulte (GELA). Patients with an abnormal IgMκ/IgMλ ratio or an abnormal FLC ratio more frequently displayed adverse clinical characteristics. Patients with abnormal IgMκ/IgMλ ratios had inferior progression-free survival (PFS) and overall survival (OS) as compared to patients with a normal ratio in the overall cohort (5-year PFS 44.9% vs. 69.3%, p = 0.0003 and 5-year OS 50.8% vs. 78.1%, p = 0.0003) and in the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) cohort (5-year OS 43.5% vs. 70.3%, p = 0.003). In multivariate analysis, including elevated FLC/HLC and International Prognostic Index (IPI), an abnormal IgMκ/IgMλ ratio (hazard ratio [HR] = 1.54, 95% confidence interval [CI] 1.03–2.3, p = 0.03) remained predictive of shorter progression-free survival. Gene expression profile experiments and immunohistochemistry indicate that this measurement is at least partially related to tumor cell secretion. Both elevated serum FLCs and an abnormal IgMκ/IgMλ ratio are associated with unfavorable outcomes in patients with DLBCL treated by R-CHOP.

Immunoarchitectural patterns in splenic marginal zone lymphoma: correlations with chromosomal aberrations, IGHV mutations, and survival. A study of 76 cases

To describe 76 cases of splenic marginal zone lymphoma (SMZL), including correlations with clinical and other characteristics.

Impact of BMI and Gender on Outcomes in DLBCL Patients Treated with R-CHOP: A Pooled Study from the LYSA

In diffuse large B-cell lymphoma (DLBCL), the age-adjusted International Prognostic Index (aaIPI) score is currently used to predict patient outcomes and to choose the best therapeutic treatment. Body mass index (BMI) and gender are occasionally sited as prognostic factors; however, their value has never been studied in a large series of patients included in prospective clinical trials in the rituximab era. To assess the impact of BMI and gender on OS and PFS independently of the aaIPI score, we pooled 985 patients that were prospectively included in GELA studies and uniformly treated with R-CHOP. Univariate analysis indicated that high aaIPI and male gender were associated with a worse PFS, whereas high (>25) or low (<18.5) BMI scores were not. High aaIPI score was the only factor predictive for OS. In a multivariate analysis, including aaIPI score, gender, BMI, and interaction between BMI and gender, aaIPI remained the strongest predictive factor, and BMI < 18.5 was significantly associated with a worse OS but not PFS. In conclusion, in the rituximab era, the aaIPI score remains the major predictor of outcome in DLBCL patients; however, male gender and low BMI seem to impact outcome.

Treatment of Non-Hodgkin’s Diffuse Large Cell Lymphomas

In the past 20 years, the advent of intensive combination chemotherapy has transformed non-Hodgkin’s diffuse large cell lymphoma (DLCL) from a disease that was very often fatal to one that is often curable [1]. In the last decade, multi-agent regimens have been developed in an attempt to increase both the complete response rate and long-term survival [2–5]. This improvement in complete response and survival rates has been associated with an increase in the treatment toxicity and it is not yet formally established that these new regimens are truly improving overall long-term survival. More recently, intensified therapy in the form of high-dose chemotherapy with bone marrow transplantation (BMT) has been utilized in patients who either failed initial or salvage treatment or have a high risk of relapse [6–8]. The definition of the optimal strategy for a specific patient is complicated by the multiplicity of potentially active combination regimens and the diversity of strategic approaches. Clinical and biological parameters have also been identified that stratify patients into subgroups with markedly different prognoses, facilitating the individualization of therapy for patients in different risk groups and the comparison of therapeutic approaches in similar groups of patients [9]. However, randomized trials are still needed to resolve many questions regarding the ideal treatment for several subgroups of aggressive malignant lymphomas. Although in this review we will address the treatment of diffuse large cell lymphomas (groups F, G and H), the therapeutic approaches are similar in all aggressive histological subtypes [10,11].

Management of Non-Hodgkin’s Lymphomas: Conclusions of the First Intercity Meeting, 1986

On 15 December 1986 in Strasbourg (France) the first Intercity Meeting of the European School of Oncology was held with a survey of the current status of non-Hodgkin’s lymphoma (NHL) management. The conclusions of this meeting are presented here. The Working Formulation for clinical use [1] (Table 1) is used throughout this paper.