5 research outputs found
Lymphomes B inclassables avec des caractéristiques intermédiaires entre le lymphome B diffus à grandes cellules et le lymphome de Burkitt (évaluation rétrospective des caractéristiques cliniques et impact de l'intensification thérapeutique)
TOURS-BU MĂ©decine (372612103) / SudocSudocFranceF
No survival improvement in patients with highârisk multiple myeloma harbouring del(17p) and/or t(4;14) over the two past decades
International audienceNo abstract availabl
Efficacy of ruxolitinib in the treatment of relapsed/refractory large granular lymphocytic leukaemia
International audienceLarge granular lymphocytic (LGL) leukaemia is a rare chronic lymphoproliferative disorder characterized by an expansion of cytotoxic T or NK cells. Despite a usually indolent evolution, most patients will require a treatment over the course of the disease because of cytopenia or symptomatic associated autoimmune disorders. First-line treatment is based on immunosuppressive agents, namely cyclophosphamide, methotrexate and ciclosporin. However, relapses are frequent, and there is no consensus on the management of relapsed/refractory patients. The implication of the JAK/STAT pathway in the pathogenesis of this disease has prompted our group to propose treatment with ruxolitinib. A series of 21 patients who received this regimen is reported here. Ten patients (47.6%) were refractory to the three main immunosuppressive drugs at the time of ruxolitinib initiation. Ruxolitinib yielded an overall response rate of 86% (n = 18/21), including 3 complete responses and 15 partial responses. With a median follow-up of 9 months, the median response duration was 4 months. One-year event-free survival and 1-year overall survival were 57% and 83% respectively. Mild side effects were observed. Biological parameters, notably neutropenia and anaemia, improved significantly, and complete molecular responses were evidenced. This study supports ruxolitinib as a valid option for the treatment of relapsed/refractory LGL leukaemia
Whole Exome Sequencing of refractory aggressive B-cell lymphomas identified recurrent mutations of the exportin 1 gene (XPO1) in Primary Mediastinal B-cell Lymphoma subtype. A LYSA study.
International audienceIntroduction: Although diffuse large Bâcell lymphoma (DLBCL) has largely benefited from immunochemotherapy combinations in the past decade, 30% to 40% of patients still do not respond to treatment or relapse rapidly, underlying the need for understanding the mechanisms involved and identifying predictive biomarkers. To address this issue, we performed whole exome sequencing (WES) in a cohort of refractory/relapsed (RR) DLBCLs included in the LYSA clinical trial program. Methods: Fourteen normal/tumoural pairs of exomes from patients who progressed or relapsed within 12âmonths were sequenced on a HiSeq2000 platform. These cases had been classified as GCB (nâ=â4), ABC (nâ=â4), primary mediastinal Bâcell lymphoma (PMBL) (nâ=â4) subtypes or unclassified (nâ=â2), using Affymetrix U133â+â2 arrays. To refine the results obtained with WES, we performed highâthroughput targeted resequencing in 216 patients enroled in the LNH03 LYSA (LYmphoma Study Association) clinical trial programme and sequenced additional cohorts by Sanger method to assess the frequency and specificity of the candidate mutations. Results: WES identified several recurrent somatic mutations that are under investigation. Among candidate mutations, we identified a recurrent point mutation (p.E571K) targeting the Exportin 1 gene (XPO1) in 2/4 RR PMBL. XPO1 encodes a cargo protein mediating the nuclear export of multiple tumour suppressor proteins, including p53. Targeted resequencing was performed in four cohorts including GEPâdefined PMBLs (nâ=â36, cohort 1), PMBLs defined by histological criteria (nâ=â81, cohort 2), Hodgkin lymphoma (HL) cases and grayâzone lymphomas (GZL) (22 HLs and 19 ReedâSternberg microâdissected HLs, 20 GZLs, cohort 3) and DLBCLâNOS (nâ=â194, 81 ABC, 81 GCB, 32 unclassified, cohort 4). XPO1 mutations were observed in 16/36 (44%) cases of PMBL cohort 1 and 10/81cases (12%) of cohort 2. By contrast, no mutation was observed in cohort 3, and only 3 cases (1.5%) were mutated in cohort 4. Copy number gains of XPO1 were observed in 8/22 PMBL cases (3 to 7 copies). In cohort 1, XPO1 mutation was significantly associated with a decreased PFS and OS [3y OSâ=â74% CI95% (55â100) as compared to 3y OSâ=â95% (86â100), logârank test pâ=â0.04]. The highly recurrent E571K variant (27/29 mutations) is located in the NES binding groove related to the cargo function. The effects of KPTâ185, a small inhibitor of nuclear export (SINE) that blocks XPO1âdependent nuclear export, were assessed in 3 PMBL cell lines (MedBâ1, Karpas1106 and U2940) using cell proliferation and apoptosis assays. The XPO1 E571K mutated MedBâ1 cells showed a decreased response to the compound compared to the 2 other cell lines which are XPO1 wild type. Conclusions: XPO1 mutations represent a new distinctive genetic feature of the PMBL subtype and could be a biomarker with prognostic impact. The effect of the recurrent E571K variant on the cargo function of XPO1 is currently investigated
Recurrent mutations of the exportin 1 gene (XPO1) and their impact on selective inhibitor of nuclear export compounds sensitivity in primary mediastinal B-cell lymphoma
International audiencePrimary mediastinal B-cell lymphoma (PMBL) is an entity of B-cell lymphoma distinct from the other molecular subtypes of diffuse large B-cell lymphoma (DLBCL). We investigated the prevalence, specificity, and clinical relevance of mutations of XPO1, which encodes a member of the karyopherin-ÎČ nuclear transporters, in a large cohort of PMBL. PMBL cases defined histologically or by gene expression profiling (GEP) were sequenced and the XPO1 mutational status was correlated to genetic and clinical characteristics. The XPO1 mutational status was also assessed in DLBCL, Hodgkin lymphoma (HL) and mediastinal gray-zone lymphoma (MGZL).The biological impact of the mutation on Selective Inhibitor of Nuclear Export (SINE) compounds (KPT-185/330) sensitivity was investigated in vitro. XPO1 mutations were present in 28/117 (24%) PMBL cases and in 5/19 (26%) HL cases but absent/rare in MGZL (0/20) or DLBCL (3/197). A higher prevalence (50%) of the recurrent codon 571 variant (p.E571K) was observed in GEP-defined PMBL and was associated with shorter PFS. Age, International Prognostic Index and bulky mass were similar in XPO1 mutant and wild-type cases. KPT-185 induced a dose-dependent decrease in cell proliferation and increased cell-death in PMBL cell lines harboring wild type or XPO1 E571K mutant alleles. Experiments in transfected U2OS cells further confirmed that the XPO1 E571K mutation does not have a drastic impact on KPT-330 binding. To conclude the XPO1 E571K mutation represents a genetic hallmark of the PMBL subtype and serves as a new relevant PMBL biomarker. SINE compounds appear active for both mutated and wild-type protein