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1.
Ann Oncol ; 34(2): 186-199, 2023 02.
Article in English | MEDLINE | ID: mdl-36402300

ABSTRACT

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare and distinct entity within diffuse large B-cell lymphoma presenting with variable response rates probably to underlying molecular heterogeneity. PATIENTS AND METHODS: To identify and characterize PCNSL heterogeneity and facilitate clinical translation, we carried out a comprehensive multi-omic analysis [whole-exome sequencing, RNA sequencing (RNA-seq), methylation sequencing, and clinical features] in a discovery cohort of 147 fresh-frozen (FF) immunocompetent PCNSLs and a validation cohort of formalin-fixed, paraffin-embedded (FFPE) 93 PCNSLs with RNA-seq and clinico-radiological data. RESULTS: Consensus clustering of multi-omic data uncovered concordant classification of four robust, non-overlapping, prognostically significant clusters (CS). The CS1 and CS2 groups presented an immune-cold hypermethylated profile but a distinct clinical behavior. The 'immune-hot' CS4 group, enriched with mutations increasing the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and nuclear factor-κB activity, had the most favorable clinical outcome, while the heterogeneous-immune CS3 group had the worse prognosis probably due to its association with meningeal infiltration and enriched HIST1H1E mutations. CS1 was characterized by high Polycomb repressive complex 2 activity and CDKN2A/B loss leading to higher proliferation activity. Integrated analysis on proposed targets suggests potential use of immune checkpoint inhibitors/JAK1 inhibitors for CS4, cyclin D-Cdk4,6 plus phosphoinositide 3-kinase (PI3K) inhibitors for CS1, lenalidomide/demethylating drugs for CS2, and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) inhibitors for CS3. We developed an algorithm to identify the PCNSL subtypes using RNA-seq data from either FFPE or FF tissue. CONCLUSIONS: The integration of genome-wide data from multi-omic data revealed four molecular patterns in PCNSL with a distinctive prognostic impact that provides a basis for future clinical stratification and subtype-based targeted interventions.


Subject(s)
Central Nervous System Neoplasms , Lymphoma, Large B-Cell, Diffuse , Humans , Phosphatidylinositol 3-Kinases/genetics , Lymphoma, Large B-Cell, Diffuse/pathology , Mutation , Polycomb Repressive Complex 2/genetics , Central Nervous System/pathology , Central Nervous System Neoplasms/genetics , Central Nervous System Neoplasms/pathology
4.
Bone Marrow Transplant ; 51(9): 1184-90, 2016 Sep.
Article in English | MEDLINE | ID: mdl-27111043

ABSTRACT

Poly-chemotherapy plus rituximab followed by autologous stem cell transplantation (auto-SCT) is standard care for untreated young patients with mantle cell lymphoma (MCL). Despite this intensive treatment, transplant patients remain highly susceptible to relapse over time. The French SFGM-TC performed a national survey on reduced-intensity conditioning allogeneic stem cell transplantation (RIC-allo-SCT) for fit relapsed/refractory patients who failed after auto-SCT (n=106). Median times of relapse after auto-SCT, and from auto-SCT to RIC-allo-SCT were 28 months and 3.6 years, respectively. Sixty per cent of patients received at least three lines of treatment before RIC-allo-SCT. Conditioning regimens for RIC-allo-SCT were heterogeneous. Twenty patients experienced grade III/IV aGvHD, extensive cGvHD was reported in 28 cases. Median follow-up after RIC-allo-SCT was 45 months. Median PFS after RIC-allo-SCT was 30.1 months and median overall survival was 62 months. Treatment-related mortality (TRM) at 1 year and 3 years were estimated at 28% and 32%, respectively. A total of 52 patients died; major causes of death were related to toxicity (n=34) and MCL (n=11). Patients in good response before RIC-allo-SCT experienced a better PFS and OS. Our work highlights the need for new RIC-allo-SCT MCL-tailored approaches to reduce TRM, and early and late relapse.


Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Lymphoma, Mantle-Cell/therapy , Salvage Therapy/methods , Transplantation, Homologous , Adult , Aged , Female , France , Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/mortality , Humans , Lymphoma, Mantle-Cell/complications , Lymphoma, Mantle-Cell/mortality , Male , Middle Aged , Salvage Therapy/mortality , Surveys and Questionnaires , Survival Analysis , Transplantation Conditioning/methods , Transplantation, Autologous/adverse effects , Transplantation, Autologous/mortality , Transplantation, Homologous/adverse effects , Transplantation, Homologous/methods , Transplantation, Homologous/mortality
5.
Leukemia ; 25(3): 473-8, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21127498

ABSTRACT

We report our experience on rituximab-cyclophosphamide-dexamethasone (RCD) combination therapy for the treatment of autoimmune disorders (AIDs) in 48 chronic lymphocytic leukemia (CLL) patients. Overall, 81% of patients were relapsing for AID after previous treatment with corticosteroids, splenectomy, rituximab or alemtuzumab. Diagnosis of AID was autoimmune hemolytic anemia (AIHA) in 26 (54%), autoimmune thrombocytopenia (AITP) in 9 (18.8%), Evan's syndrome in 8 (16.7%) and pure red cell aplasia (PRCA) in 5 patients (10.5%). Median time of autoimmune disorder (AID) onset from CLL diagnosis was 60 months (range: 0-240), and CLL was considered progressive in 40% of subjects upon AID diagnosis (complex AID). Median hemoglobin pre-treatment was 7.7 g/100 ml, and median platelet count 36.5 × 10(9)/l, returning to a median of 12.5 /100ml and 37.5 × 10(9)/l, respectively. Overall, an 89.5% response rate was obtained with this combination, irrespective of the AID type. Relapse occurred in 19 patients (39.6%). Median duration of response for autoimmunity (DR-AI) was 24 months, but DR-AI was higher for patients presenting: (1) AID early during CLL course (<3 years), or (2) both PRCA and AIHA. Median time to CLL progression in 48 patients was 16 months, but this time was statistically shorter for Evan's syndrome and AITP patients as compared with AIHA and PRCA patients. This study emphasizes the relevance of CLL-directed immune chemotherapy in the management of CLL-associated AID.


Subject(s)
Anemia, Hemolytic, Autoimmune/drug therapy , Antibodies, Monoclonal, Murine-Derived/therapeutic use , Cyclophosphamide/therapeutic use , Dexamethasone/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/complications , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Adult , Aged , Aged, 80 and over , Anemia, Hemolytic, Autoimmune/etiology , Anemia, Hemolytic, Autoimmune/mortality , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Antibodies, Monoclonal, Murine-Derived/adverse effects , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Dexamethasone/administration & dosage , Dexamethasone/adverse effects , Drug Therapy, Combination , Female , Humans , Male , Middle Aged , Purpura, Thrombocytopenic, Idiopathic/mortality , Recurrence , Red-Cell Aplasia, Pure/drug therapy , Red-Cell Aplasia, Pure/mortality , Retrospective Studies , Rituximab , Thrombocytopenia/drug therapy , Thrombocytopenia/mortality
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