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1
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Laurent C, Cook JR. Diagnosis and Classification of Follicular Lymphoma and Related Entities. Adv Anat Pathol 2025; 32:195-207. [PMID: 39895407 DOI: 10.1097/pap.0000000000000481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
Follicular lymphoma (FL) is a mature B cell neoplasm classically characterized by B cells harboring the t(14;18) IGH::BCL2 leading to the overexpression of BCL2 in most cases. Conventional FL occurs in lymph nodes and typically shows a follicular B-cell proliferation expressing at least one germinal center marker. Two early lesions closely related to conventional FL are recognized as variants, namely in situ follicular neoplasia (ISFN), and duodenal-type follicular lymphoma (DTFL). FL lacking BCL2 rearrangement ( BCL2 -R negative) accounts for around 10% to 15% of FLs and constitutes a heterogeneous group of FLs. Most of these alternative forms of FL are considered as distinct entities separate from conventional FL in the 2022 International Consensus Classification. This review aims to summarize the key pathologic and diagnostic features of FL conventional and its alternative forms as well as further emphasize the increasing role of molecular studies in the diagnostic work-up.
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Affiliation(s)
- Camille Laurent
- Department of Pathology, Toulouse University Hospital Center, Cancer Institute University of Toulouse-Oncopole, INSERM, France
| | - James R Cook
- Department of Laboratory Medicine, Robert J. Tomsich Institute of Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, OH
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2
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Cheng S, Liu Y. Advances in Personalized Treatment and Prognostic Factors of Follicular Lymphoma. Curr Treat Options Oncol 2025; 26:313-330. [PMID: 40172809 DOI: 10.1007/s11864-025-01297-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/02/2025] [Indexed: 04/04/2025]
Abstract
OPINION STATEMENT Follicular lymphoma is the most prevalent form of indolent B-cell lymphoma, characterized by gradual disease progression and potential survival over several decades. Although the overall prognosis is typically favorable, some patients remain at risk for disease progression or transformation into a more aggressive variant. Recent advancements in the treatment of relapsed or refractory follicular lymphoma include cereblon modulators, kinase inhibitors, chimeric antigen receptor (CAR) T-cell therapies, and antibody-drug conjugates. Ongoing research into novel prognostic markers may improve the identification of patients at high risk for early progression, multiple relapses, or histological transformation, facilitating more precise and individualized treatment strategies.
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Affiliation(s)
- Shijia Cheng
- Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, Henan, China
- Department of Hematology, The Third People'S Hospital of Zhengzhou, Zhengzhou, 450099, Henan, China
| | - Yanyan Liu
- Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, Henan, China.
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3
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Hesius EAM, Stevens WBC, Stewart JP, Kroeze LI, Spek EVD, Issa D, Nooijen P, Luijks J, Gonzalez D, Groenen PJTA, Blijlevens NMA, Spriel ABV, Brand MVD. Mutational profile dynamics in follicular lymphoma and large cell transformation. J Clin Pathol 2025:jcp-2024-209880. [PMID: 39890445 DOI: 10.1136/jcp-2024-209880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 01/06/2025] [Indexed: 02/03/2025]
Abstract
AIMS Follicular lymphoma (FL) is characterised by significant heterogeneity in both the clinical trajectories and the molecular profiles. This study aimed to investigate clonal dynamics in FL by analysing mutation profiles at various time points during the disease course including at histological transformation (HT), to gain insight into the mutational changes over time. METHODS We retrospectively analysed 76 biopsies from 25 patients, including 13 cases with three or more FL biopsies and 12 cases with subsequent HT. Hybrid capture-based Next-Generation Sequencing (NGS) with the EuroClonality-NGS DNA capture (EuroClonality-NDC) assay was used to examine clonal rearrangements and mutations. RESULTS A total of 204 (potentially) pathogenic mutations were identified. Only 40% of mutations remained stably present during a median follow-up period of 139 months (range 9-198). KMT2D and CREBBP were the most frequently mutated genes at diagnosis, exhibiting relative stability in follow-up biopsies. Conversely, EZH2 displayed a dynamic pattern of mutations gained and lost during the disease course. At HT, pathogenic mutations affecting B2M, MYC and TP53 emerged. Changes in mutational burden were observed in both FL-sequential and diagnosis-transformation cohorts, with more pronounced changes in the latter. CONCLUSIONS This real-world study provides insights into the complex molecular pathogenesis of FL and HT. As targeted therapies emerge as treatment modalities, mutational profiles could influence treatment decisions in the future. Therefore, recognising the significant changes occurring in the mutational landscape of FL throughout the disease course is crucial.
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Affiliation(s)
- Eva A M Hesius
- Department of Hematology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Wendy B C Stevens
- Department of Hematology, Radboud University Medical Center, Nijmegen, Netherlands
| | - James P Stewart
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK
| | - Leonie I Kroeze
- Department of Pathology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Ellen van der Spek
- Department of Internal Medicine, Rijnstate Hospital, Arnhem, Netherlands
| | - Djamila Issa
- Department of Internal Medicine, Jeroen Bosch Hospital, 's-Hertogenbosch, Netherlands
| | - Peet Nooijen
- Pathology-DNA, Jeroen Bosch Hospital, 's-Hertogenbosch, Netherlands
| | - Jeroen Luijks
- Department of Pathology, Radboud University Medical Center, Nijmegen, Netherlands
| | - David Gonzalez
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK
| | | | | | - Annemiek B van Spriel
- Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Michiel van den Brand
- Department of Pathology, Radboud University Medical Center, Nijmegen, Netherlands
- Pathology-DNA, Rijnstate Hospital, Arnhem, Netherlands
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Nogueira DS, Lage LADPC, Reichert CO, Culler HF, de Freitas FA, Mendes JAT, Gouveia ACM, Costa RDO, Ferreira CR, Maximino JR, Bydlowski SP, Murga Zamalloa CA, Rocha V, Levy D, Pereira J. Clinical-Demographic Profile, Prognostic Factors and Outcomes in Classic Follicular Lymphoma Stratified by Staging and Tumor Burden: Real-World Evidence from a Large Latin American Cohort. Cancers (Basel) 2024; 16:3914. [PMID: 39682103 DOI: 10.3390/cancers16233914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Revised: 11/18/2024] [Accepted: 11/19/2024] [Indexed: 12/18/2024] Open
Abstract
Background: Clinical staging (CS) and tumor burden (TB) play a significant role in FL prognosis and direct its up-front therapy. The aim of this study is to report prognostic factors and clinical outcomes in newly-diagnosed FL patients stratified according to CS and TB in early-stage (ES) disease, advanced-stage with low tumor burden (AS-LTB) and advanced-stage with high tumor burden (AS-HTB). Methods: Two hundred fourteen patients with FL grades 1-3A had baseline clinical characteristics and outcomes assessed. Survival according to up-front immunochemotherapeutic (ICT) regimens was assessed in the AS-HTB subgroup. Independent predictors for OS, PFS, POD-24, and Histological Transformation (HT) were identified. Results: Seventy-five percent of cases were categorized as AS-HTB, 13.5% as AS-LTB and 11.5% as ES. With a median follow-up of 8.15 years, the estimated 5-year OS and PFS were 75.4% and 57.2%, respectively. OS, but not PFS was markedly decreased in AS-HTB FL patients compared to ES and AS-LTB cases. POD-24 rate was 21.7% and overall mortality rate was 38.7% during the entire follow-up. The annual cumulative rate of HT to high-grade B-cell lymphoma (HGBCL) was 0.5%, and higher in AS-HTB cases, in comparison to ES and AS-LTB. Considering patients with AS-HTB there were no differences in clinical outcomes among cases submitted to ICT based on R-CHOP, R-CVP and regimens containing purine analogs. Additionally, ECOG ≥ 2, hypoalbuminemia, B-symptoms and HT were independently associated with poor survival. High content of centro-blasts (grade 3A), involvement of ≥3 nodal sites by FL and rituximab omission in up-front therapy predicted POD-24. Conclusions: FL has marked clinical-prognostic heterogeneity, translated into diverse CS and TB subcategories. Here, we demonstrated that FL patients classified as AS-HTB demonstrated decreased survival and higher rates of HT to HGBCL compared to ES and AS-LTB cases. Prognostic factors identified in our analysis may help to identify FL patients with higher-risk of HT and early-progression (POD-24).
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Affiliation(s)
- Daniel Silva Nogueira
- Department of Hematology, Hemotherapy and Cell Therapy, Faculty of Medicine, University of Sao Paulo (FM-USP), Sao Paulo 05508-090, Brazil
- Laboratory of Medical Investigation in Pathogenesis and Directed Therapy in Onco-Immuno-Hematology (LIM-31), University of Sao Paulo (FM-USP), Sao Paulo 05508-090, Brazil
| | - Luís Alberto de Pádua Covas Lage
- Department of Hematology, Hemotherapy and Cell Therapy, Faculty of Medicine, University of Sao Paulo (FM-USP), Sao Paulo 05508-090, Brazil
- Laboratory of Medical Investigation in Pathogenesis and Directed Therapy in Onco-Immuno-Hematology (LIM-31), University of Sao Paulo (FM-USP), Sao Paulo 05508-090, Brazil
| | - Cadiele Oliana Reichert
- Department of Hematology, Hemotherapy and Cell Therapy, Faculty of Medicine, University of Sao Paulo (FM-USP), Sao Paulo 05508-090, Brazil
- Laboratory of Medical Investigation in Pathogenesis and Directed Therapy in Onco-Immuno-Hematology (LIM-31), University of Sao Paulo (FM-USP), Sao Paulo 05508-090, Brazil
| | - Hebert Fabrício Culler
- Department of Hematology, Hemotherapy and Cell Therapy, Faculty of Medicine, University of Sao Paulo (FM-USP), Sao Paulo 05508-090, Brazil
- Laboratory of Medical Investigation in Pathogenesis and Directed Therapy in Onco-Immuno-Hematology (LIM-31), University of Sao Paulo (FM-USP), Sao Paulo 05508-090, Brazil
| | - Fábio Alessandro de Freitas
- Department of Hematology, Hemotherapy and Cell Therapy, Faculty of Medicine, University of Sao Paulo (FM-USP), Sao Paulo 05508-090, Brazil
- Laboratory of Medical Investigation in Pathogenesis and Directed Therapy in Onco-Immuno-Hematology (LIM-31), University of Sao Paulo (FM-USP), Sao Paulo 05508-090, Brazil
| | - João Antônio Tavares Mendes
- Laboratory of Medical Investigation in Pathogenesis and Directed Therapy in Onco-Immuno-Hematology (LIM-31), University of Sao Paulo (FM-USP), Sao Paulo 05508-090, Brazil
| | - Ana Carolina Maia Gouveia
- Laboratory of Medical Investigation in Pathogenesis and Directed Therapy in Onco-Immuno-Hematology (LIM-31), University of Sao Paulo (FM-USP), Sao Paulo 05508-090, Brazil
| | - Renata de Oliveira Costa
- Department of Hematology, Faculty of Medicine, Centro Universitário Lusíada (Unilus), Santos 11050-071, Brazil
| | - Cristiane Rúbia Ferreira
- Department of Pathology, University Hospital (HU), University of Sao Paulo (FM-USP), Sao Paulo 05508-090, Brazil
| | - Jéssica Ruivo Maximino
- Laboratory of Translational Neurology (LIM-45), University of Sao Paulo (FM-USP), Sao Paulo 05508-090, Brazil
| | - Sérgio Paulo Bydlowski
- Department of Hematology, Hemotherapy and Cell Therapy, Faculty of Medicine, University of Sao Paulo (FM-USP), Sao Paulo 05508-090, Brazil
- Laboratory of Immunology and Histocompatibility (LIM-19), University of Sao Paulo (FM-USP), Sao Paulo 05508-090, Brazil
| | | | - Vanderson Rocha
- Department of Hematology, Hemotherapy and Cell Therapy, Faculty of Medicine, University of Sao Paulo (FM-USP), Sao Paulo 05508-090, Brazil
- Laboratory of Medical Investigation in Pathogenesis and Directed Therapy in Onco-Immuno-Hematology (LIM-31), University of Sao Paulo (FM-USP), Sao Paulo 05508-090, Brazil
- Fundação Pró-Sangue, Blood Bank of Sao Paulo, Sao Paulo 05468-901, Brazil
- Department of Hematology and Hemotherapy, Churchill Hospital, Oxford University, Oxford OX1 2JD, UK
| | - Débora Levy
- Laboratory of Immunology and Histocompatibility (LIM-19), University of Sao Paulo (FM-USP), Sao Paulo 05508-090, Brazil
| | - Juliana Pereira
- Department of Hematology, Hemotherapy and Cell Therapy, Faculty of Medicine, University of Sao Paulo (FM-USP), Sao Paulo 05508-090, Brazil
- Laboratory of Medical Investigation in Pathogenesis and Directed Therapy in Onco-Immuno-Hematology (LIM-31), University of Sao Paulo (FM-USP), Sao Paulo 05508-090, Brazil
- Department of Hematology and Oncology, Hospital Alemão Oswaldo Cruz (HAOC), Sao Paulo 01323-020, Brazil
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Enemark MH, Hemmingsen JK, Jensen ML, Kridel R, Ludvigsen M. Molecular Biomarkers in Prediction of High-Grade Transformation and Outcome in Patients with Follicular Lymphoma: A Comprehensive Systemic Review. Int J Mol Sci 2024; 25:11179. [PMID: 39456961 PMCID: PMC11508793 DOI: 10.3390/ijms252011179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 10/03/2024] [Accepted: 10/06/2024] [Indexed: 10/28/2024] Open
Abstract
Follicular lymphoma (FL) is the most prevalent indolent B-cell lymphoma entity, often characterized by the t(14;18) BCL2-IGH translocation. The malignancy represents a clinically and biologically highly heterogeneous disease. Most patients have favorable prognoses; however, despite therapeutic advancements, the disease remains incurable, with recurrent relapses or early disease progression. Moreover, transformation to an aggressive histology, most often diffuse large-B-cell lymphoma, remains a critical event in the disease course, which is associated with poor outcomes. Understanding the individual patient's risk of transformation remains challenging, which has motivated much research on novel biomarkers within the past four decades. This review systematically assessed the research on molecular biomarkers in FL transformation and outcome. Following the PRISMA guidelines for systemic reviews, the PubMed database was searched for English articles published from January 1984 through September 2024, yielding 6769 results. The identified publications were carefully screened and reviewed, of which 283 original papers met the inclusion criteria. The included studies focused on investigating molecular biomarkers as predictors of transformation or as prognostic markers of time-related endpoints (survival, progression, etc.). The effects of each biomarker were categorized based on their impact on prognosis or risk of transformation as none, favorable, or inferior. The biomarkers included genetic abnormalities, gene expression, microRNAs, markers of B cells/FL tumor cells, markers of the tumor microenvironment, and soluble biomarkers. This comprehensive review provides an overview of the research conducted in the past four decades, underscoring the persistent challenge in risk anticipation of FL patients.
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Affiliation(s)
- Marie Hairing Enemark
- Department of Hematology, Aarhus University Hospital, 8200 Aarhus N, Denmark; (M.H.E.); (J.K.H.); (M.L.J.)
- Department of Clinical Medicine, Aarhus University, 8000 Aarhus C, Denmark
| | - Jonas Klejs Hemmingsen
- Department of Hematology, Aarhus University Hospital, 8200 Aarhus N, Denmark; (M.H.E.); (J.K.H.); (M.L.J.)
| | - Maja Lund Jensen
- Department of Hematology, Aarhus University Hospital, 8200 Aarhus N, Denmark; (M.H.E.); (J.K.H.); (M.L.J.)
| | - Robert Kridel
- Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2C4, Canada;
| | - Maja Ludvigsen
- Department of Hematology, Aarhus University Hospital, 8200 Aarhus N, Denmark; (M.H.E.); (J.K.H.); (M.L.J.)
- Department of Clinical Medicine, Aarhus University, 8000 Aarhus C, Denmark
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6
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Bai B, Wise JF, Vodák D, Nakken S, Sharma A, Blaker YN, Brodtkorb M, Hilden V, Trøen G, Ren W, Lorenz S, Lawrence MS, Myklebost O, Kimby E, Pan-Hammarström Q, Steen CB, Meza-Zepeda LA, Beiske K, Smeland EB, Hovig E, Lingjærde OC, Holte H, Myklebust JH. Multi-omics profiling of longitudinal samples reveals early genomic changes in follicular lymphoma. Blood Cancer J 2024; 14:147. [PMID: 39191762 PMCID: PMC11350178 DOI: 10.1038/s41408-024-01124-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 08/02/2024] [Accepted: 08/09/2024] [Indexed: 08/29/2024] Open
Abstract
Follicular lymphoma (FL) is the most common indolent type of B-cell non-Hodgkin lymphoma. Advances in treatment have improved overall survival, but early relapse or transformation to aggressive disease is associated with inferior outcome. To identify early genetic events and track tumor clonal evolution, we performed multi-omics analysis of 94 longitudinal biopsies from 44 FL patients; 22 with transformation (tFL) and 22 with relapse without transformation (nFL). Deep whole-exome sequencing confirmed recurrent mutations in genes encoding epigenetic regulators (CREBBP, KMT2D, EZH2, EP300), with similar mutational landscape in nFL and tFL patients. Calculation of genomic distances between longitudinal samples revealed complex evolutionary patterns in both subgroups. CREBBP and KMT2D mutations were identified as genetic events that occur early in the disease course, and cases with CREBBP KAT domain mutations had low risk of transformation. Gains in chromosomes 12 and 18 (TCF4), and loss in 6q were identified as early and stable copy number alterations. Identification of such early and stable genetic events may provide opportunities for early disease detection and disease monitoring. Integrative analysis revealed that tumors with EZH2 mutations exhibited reduced gene expression of numerous histone genes, including histone linker genes. This might contribute to the epigenetic dysregulation in FL.
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Affiliation(s)
- Baoyan Bai
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- KG Jebsen Centre for B-cell malignancies, Institute for Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Clinical Molecular Biology (EpiGen),, Akershus University Hospital, Lørenskog, Norway
| | - Jillian F Wise
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- KG Jebsen Centre for B-cell malignancies, Institute for Clinical Medicine, University of Oslo, Oslo, Norway
- Norwegian Cancer Genomics Consortium, CancerGenomics.no, Oslo, Norway
- Massachusetts General Hospital Cancer Center and Department of Pathology, Harvard Medical School, Charlestown, MA, USA
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Daniel Vodák
- Norwegian Cancer Genomics Consortium, CancerGenomics.no, Oslo, Norway
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Sigve Nakken
- Norwegian Cancer Genomics Consortium, CancerGenomics.no, Oslo, Norway
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Centre for Bioinformatics, University of Oslo, Oslo, Norway
| | - Ankush Sharma
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- KG Jebsen Centre for B-cell malignancies, Institute for Clinical Medicine, University of Oslo, Oslo, Norway
- Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway
| | - Yngvild Nuvin Blaker
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- KG Jebsen Centre for B-cell malignancies, Institute for Clinical Medicine, University of Oslo, Oslo, Norway
| | - Marianne Brodtkorb
- KG Jebsen Centre for B-cell malignancies, Institute for Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Oncology, Division for Cancer Medicine, Oslo University Hospital, Oslo, Norway
| | - Vera Hilden
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- KG Jebsen Centre for B-cell malignancies, Institute for Clinical Medicine, University of Oslo, Oslo, Norway
- Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway
| | - Gunhild Trøen
- Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Weicheng Ren
- Division of Immunology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Susanne Lorenz
- Norwegian Cancer Genomics Consortium, CancerGenomics.no, Oslo, Norway
- Genomics Core Facility, Department of Core Facilities, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Michael S Lawrence
- Massachusetts General Hospital Cancer Center and Department of Pathology, Harvard Medical School, Charlestown, MA, USA
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Ola Myklebost
- Norwegian Cancer Genomics Consortium, CancerGenomics.no, Oslo, Norway
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Department for Clinical Science, University of Bergen, Bergen, Norway
| | - Eva Kimby
- Unit for Hematology and Department of Medicine at Karolinska Institutet, Huddinge, Stockholm, Sweden
| | - Qiang Pan-Hammarström
- Division of Immunology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Chloé B Steen
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- KG Jebsen Centre for B-cell malignancies, Institute for Clinical Medicine, University of Oslo, Oslo, Norway
- Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway
| | - Leonardo A Meza-Zepeda
- Norwegian Cancer Genomics Consortium, CancerGenomics.no, Oslo, Norway
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Genomics Core Facility, Department of Core Facilities, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Klaus Beiske
- Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Erlend B Smeland
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- KG Jebsen Centre for B-cell malignancies, Institute for Clinical Medicine, University of Oslo, Oslo, Norway
| | - Eivind Hovig
- Norwegian Cancer Genomics Consortium, CancerGenomics.no, Oslo, Norway
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Centre for Bioinformatics, University of Oslo, Oslo, Norway
| | - Ole Christian Lingjærde
- KG Jebsen Centre for B-cell malignancies, Institute for Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Informatics, University of Oslo, Oslo, Norway
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Harald Holte
- KG Jebsen Centre for B-cell malignancies, Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
- Norwegian Cancer Genomics Consortium, CancerGenomics.no, Oslo, Norway.
- Department of Oncology, Division for Cancer Medicine, Oslo University Hospital, Oslo, Norway.
| | - June Helen Myklebust
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
- KG Jebsen Centre for B-cell malignancies, Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
- Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway.
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Iwamoto R, Nishikawa T, Musangile FY, Matsuzaki I, Sagan K, Nishikawa M, Mikasa Y, Takahashi Y, Kojima F, Hori Y, Hosoi H, Mori H, Sonoki T, Murata SI. Small sized centroblasts as poor prognostic factor in follicular lymphoma - Based on artificial intelligence analysis. Comput Biol Med 2024; 178:108774. [PMID: 38897149 DOI: 10.1016/j.compbiomed.2024.108774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 05/26/2024] [Accepted: 06/15/2024] [Indexed: 06/21/2024]
Abstract
Histological assessment of centroblasts is an important evaluation in the diagnosis of follicular lymphoma, but there is substantial observer variation in assessment among hematopathologists. We aimed to perform quantitative morphological analysis of centroblasts in follicular lymphoma using new artificial intelligence technology in relation to the clinical prognosis. Hematoxylin and eosin slides of lesions were prepared from 36 cases of follicular lymphoma before initial chemotherapy. Cases were classified into three groups by clinical course after initial treatment. The 'excellent prognosis' group were without recurrence or progression of follicular lymphoma within 60 months, the 'poor prognosis' group were those that had relapse, exacerbation, or who died due to the follicular lymphoma within 60 months, and the 'indeterminate prognosis' group were those without recurrence or progression but before the passage of 60 months. We created whole slide images and image patches of hematoxylin and eosin sections for all cases. We designed an object detection model specialized for centroblasts by fine-tuning YOLOv5 and segmented all centroblasts in whole slide images. The morphological characteristics of centroblasts in relation to the clinical prognosis of follicular lymphoma were analyzed. Centroblasts in follicular lymphoma of the poor prognosis group were significantly smaller in nuclear size than those in follicular lymphoma of the excellent prognosis group in the following points: median of nuclear area (p = 0.013), long length (p = 0.042), short length (p = 0.007), nuclear area of top 10 % cells (p = 0.024) and short length of top 10 % cells (p = 0.020). Cases with a mean nuclear area of <55 μm2 had poorer event-free survival than those with a mean nuclear area of ≥55 μm2 (p < 0.0123). AI methodology is suggested to be able to surpass pathologist's observation in capturing morphological features. Small-sized centroblasts will likely become a new prognostic factor of follicular lymphoma.
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Affiliation(s)
- Ryuta Iwamoto
- Department of Human Pathology, Wakayama Medical University, Wakayama, Japan
| | - Toui Nishikawa
- Department of Human Pathology, Wakayama Medical University, Wakayama, Japan
| | | | - Ibu Matsuzaki
- Department of Human Pathology, Wakayama Medical University, Wakayama, Japan
| | - Kanako Sagan
- Department of Human Pathology, Wakayama Medical University, Wakayama, Japan
| | - Mizuki Nishikawa
- Department of Human Pathology, Wakayama Medical University, Wakayama, Japan
| | - Yurina Mikasa
- Department of Human Pathology, Wakayama Medical University, Wakayama, Japan
| | - Yuichi Takahashi
- Department of Human Pathology, Wakayama Medical University, Wakayama, Japan
| | - Fumiyoshi Kojima
- Department of Human Pathology, Wakayama Medical University, Wakayama, Japan
| | - Yoshikazu Hori
- Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan
| | - Hiroki Hosoi
- Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan
| | - Hideo Mori
- Department of Pathology, Osaka Habikino Medical Center, Osaka, Japan
| | - Takashi Sonoki
- Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan
| | - Shin-Ichi Murata
- Department of Human Pathology, Wakayama Medical University, Wakayama, Japan.
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8
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Fernández-Miranda I, Pedrosa L, González-Rincón J, Espinet B, de la Cruz Vicente F, Climent F, Gómez S, Royuela A, Camacho FI, Martín-Acosta P, Yanguas-Casás N, Domínguez M, Méndez M, Colomo L, Salar A, Horcajo B, Navarro M, García-Cosío M, Piris-Villaespesa M, Llanos M, García JF, Sequero S, Mercadal S, García-Hernández S, Navarro B, Mollejo M, Provencio M, Sánchez-Beato M. Generation and External Validation of a Histologic Transformation Risk Model for Patients with Follicular Lymphoma. Mod Pathol 2024; 37:100516. [PMID: 38763418 DOI: 10.1016/j.modpat.2024.100516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 04/23/2024] [Accepted: 05/04/2024] [Indexed: 05/21/2024]
Abstract
Follicular lymphoma (FL) is the most frequent indolent lymphoma. Some patients (10%-15%) experience histologic transformation (HT) to a more aggressive lymphoma, usually diffuse large B-cell lymphoma (DLBCL). This study aimed to validate and improve a genetic risk model to predict HT at diagnosis.We collected mutational data from diagnosis biopsies of 64 FL patients. We combined them with the data from a previously published cohort (total n = 104; 62 from nontransformed and 42 from patients who did transform to DLBCL). This combined cohort was used to develop a nomogram to estimate the risk of HT. Prognostic mutated genes and clinical variables were assessed using Cox regression analysis to generate a risk model. The model was internally validated by bootstrapping and externally validated in an independent cohort. Its performance was evaluated using a concordance index and a calibration curve. The clinicogenetic nomogram included the mutational status of 3 genes (HIST1HE1, KMT2D, and TNFSR14) and high-risk Follicular Lymphoma International Prognostic Index and predicted HT with a concordance index of 0.746. Patients were classified as being at low or high risk of transformation. The probability HT function at 24 months was 0.90 in the low-risk group vs 0.51 in the high-risk group and, at 60 months, 0.71 vs 0.15, respectively. In the external validation cohort, the probability HT function in the low-risk group was 0.86 vs 0.54 in the high-risk group at 24 months, and 0.71 vs 0.32 at 60 months. The concordance index in the external cohort was 0.552. In conclusion, we propose a clinicogenetic risk model to predict FL HT to DLBLC, combining genetic alterations in HIST1H1E, KMT2D, and TNFRSF14 genes and clinical features (Follicular Lymphoma International Prognostic Index) at diagnosis. This model could improve the management of FL patients and allow treatment strategies that would prevent or delay transformation.
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MESH Headings
- Humans
- Lymphoma, Follicular/genetics
- Lymphoma, Follicular/pathology
- Female
- Male
- Middle Aged
- Aged
- Nomograms
- Adult
- Lymphoma, Large B-Cell, Diffuse/genetics
- Lymphoma, Large B-Cell, Diffuse/pathology
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/pathology
- Risk Assessment
- Aged, 80 and over
- Mutation
- Risk Factors
- Prognosis
- Biomarkers, Tumor/genetics
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Affiliation(s)
- Ismael Fernández-Miranda
- Department of Medical Oncology, Lymphoma Research Group, Hospital Universitario Puerta de Hierro-Majadahonda, IDIPHISA, Madrid, Spain
| | - Lucía Pedrosa
- Department of Medical Oncology, Lymphoma Research Group, Hospital Universitario Puerta de Hierro-Majadahonda, IDIPHISA, Madrid, Spain
| | - Julia González-Rincón
- Department of Medical Oncology, Lymphoma Research Group, Hospital Universitario Puerta de Hierro-Majadahonda, IDIPHISA, Madrid, Spain; CoE Data Intelligence, Fujitsu Technology Solutions S.A., Pozuelo de Alarcón, Madrid, Spain
| | - Blanca Espinet
- Translational Research on Hematological Neoplasms Group, Cancer Research Program, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain; Department of Pathology, Hospital del Mar, Barcelona, Spain
| | - Fátima de la Cruz Vicente
- Department of Hematology, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS)/CSIC/Universidad de Sevilla, Seville, Spain
| | - Fina Climent
- Department of Pathology, Hospital Universitari de Bellvitge-IDIBELL, Barcelona, Spain
| | - Sagrario Gómez
- Department of Medical Oncology, Lymphoma Research Group, Hospital Universitario Puerta de Hierro-Majadahonda, IDIPHISA, Madrid, Spain
| | - Ana Royuela
- Biostatistics Unit, Hospital Universitario Puerta de Hierro-Majadahonda, IDIPHISA. CIBERESP, ISCIII. Madrid, Spain
| | | | - Paloma Martín-Acosta
- Department of Pathology, Cancer Molecular Pathology Group, Hospital Universitario Puerta de Hierro-Majadahonda, IDIPHISA, Madrid, Spain
| | - Natalia Yanguas-Casás
- Department of Medical Oncology, Lymphoma Research Group, Hospital Universitario Puerta de Hierro-Majadahonda, IDIPHISA, Madrid, Spain; Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain
| | - Marina Domínguez
- Department of Medical Oncology, Lymphoma Research Group, Hospital Universitario Puerta de Hierro-Majadahonda, IDIPHISA, Madrid, Spain
| | - Miriam Méndez
- Department of Medical Oncology, Lymphoma Research Group, Hospital Universitario Puerta de Hierro-Majadahonda, IDIPHISA, Madrid, Spain; Department of Medical Oncology, Hospital Universitario Puerta de Hierro-Majadahonda, IDIPHISA, Madrid, Spain
| | - Luis Colomo
- Translational Research on Hematological Neoplasms Group, Cancer Research Program, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain
| | - Antonio Salar
- Department of Hematology, Hospital del Mar, Barcelona, Spain
| | - Beatriz Horcajo
- Department of Medical Oncology, Lymphoma Research Group, Hospital Universitario Puerta de Hierro-Majadahonda, IDIPHISA, Madrid, Spain
| | - Marta Navarro
- Department of Medical Oncology, Lymphoma Research Group, Hospital Universitario Puerta de Hierro-Majadahonda, IDIPHISA, Madrid, Spain
| | - Mónica García-Cosío
- Department of Pathology, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | | | - Marta Llanos
- Department of Oncology, Hospital Universitario de Canarias, Tenerife, Spain
| | - Juan F García
- Department of Pathology, Hospital MD Anderson Cancer Center, Madrid, Spain
| | - Silvia Sequero
- Department of Oncology, Hospital Universitario San Cecilio, Granada, Spain
| | - Santiago Mercadal
- Department of Hematology, ICO-Hospital Duran I Reynals, Barcelona, Spain
| | | | - Belén Navarro
- Department of Hematology, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain
| | - Manuela Mollejo
- Department of Pathology, Complejo Hospitalario de Toledo, Spain
| | - Mariano Provencio
- Department of Medical Oncology, Lymphoma Research Group, Hospital Universitario Puerta de Hierro-Majadahonda, IDIPHISA, Madrid, Spain; Department of Medical Oncology, Hospital Universitario Puerta de Hierro-Majadahonda, Facultad de Medicina, Universidad Autónoma de Madrid, IDIPHISA, Madrid, Spain
| | - Margarita Sánchez-Beato
- Department of Medical Oncology, Lymphoma Research Group, Hospital Universitario Puerta de Hierro-Majadahonda, IDIPHISA, Madrid, Spain.
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9
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Sánchez-Beato M, Méndez M, Guirado M, Pedrosa L, Sequero S, Yanguas-Casás N, de la Cruz-Merino L, Gálvez L, Llanos M, García JF, Provencio M. A genetic profiling guideline to support diagnosis and clinical management of lymphomas. Clin Transl Oncol 2024; 26:1043-1062. [PMID: 37672206 PMCID: PMC11026206 DOI: 10.1007/s12094-023-03307-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 08/09/2023] [Indexed: 09/07/2023]
Abstract
The new lymphoma classifications (International Consensus Classification of Mature Lymphoid Neoplasms, and 5th World Health Organization Classification of Lymphoid Neoplasms) include genetics as an integral part of lymphoma diagnosis, allowing better lymphoma subclassification, patient risk stratification, and prediction of treatment response. Lymphomas are characterized by very few recurrent and disease-specific mutations, and most entities have a heterogenous genetic landscape with a long tail of recurrently mutated genes. Most of these occur at low frequencies, reflecting the clinical heterogeneity of lymphomas. Multiple studies have identified genetic markers that improve diagnostics and prognostication, and next-generation sequencing is becoming an essential tool in the clinical laboratory. This review provides a "next-generation sequencing" guide for lymphomas. It discusses the genetic alterations of the most frequent mature lymphoma entities with diagnostic, prognostic, and predictive potential and proposes targeted sequencing panels to detect mutations and copy-number alterations for B- and NK/T-cell lymphomas.
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Affiliation(s)
- Margarita Sánchez-Beato
- Servicio de Oncología Médica, Grupo de Investigación en Linfomas, Hospital Universitario Puerta de Hierro-Majadahonda, IDIPHISA, Madrid, Spain.
- Grupo Oncológico para el Tratamiento y Estudio de los Linfomas-GOTEL, Madrid, Spain.
| | - Miriam Méndez
- Servicio de Oncología Médica, Grupo de Investigación en Linfomas, Hospital Universitario Puerta de Hierro-Majadahonda, IDIPHISA, Madrid, Spain
- Grupo Oncológico para el Tratamiento y Estudio de los Linfomas-GOTEL, Madrid, Spain
- Servicio de Oncología Médica, Hospital Universitario Puerta de Hierro-Majadahonda, IDIPHISA, Madrid, Spain
| | - María Guirado
- Grupo Oncológico para el Tratamiento y Estudio de los Linfomas-GOTEL, Madrid, Spain
- Servicio de Oncología Médica, Hospital General Universitario de Elche, Alicante, Spain
| | - Lucía Pedrosa
- Servicio de Oncología Médica, Grupo de Investigación en Linfomas, Hospital Universitario Puerta de Hierro-Majadahonda, IDIPHISA, Madrid, Spain
| | - Silvia Sequero
- Grupo Oncológico para el Tratamiento y Estudio de los Linfomas-GOTEL, Madrid, Spain
- Servicio de Oncología Médica, Hospital Universitario San Cecilio, Granada, Spain
| | - Natalia Yanguas-Casás
- Servicio de Oncología Médica, Grupo de Investigación en Linfomas, Hospital Universitario Puerta de Hierro-Majadahonda, IDIPHISA, Madrid, Spain
| | - Luis de la Cruz-Merino
- Grupo Oncológico para el Tratamiento y Estudio de los Linfomas-GOTEL, Madrid, Spain
- Servicio de Oncología Médica, Facultad de Medicina, Hospital Universitario Virgen Macarena, Universidad de Sevilla, Instituto de Biomedicina de Sevilla (IBID)/CSIC, Seville, Spain
| | - Laura Gálvez
- Grupo Oncológico para el Tratamiento y Estudio de los Linfomas-GOTEL, Madrid, Spain
- Unidad de Gestión Clínica Intercentros de Oncología Médica, Hospitales Universitarios Regional y Virgen de la Victoria, Málaga, Spain
| | - Marta Llanos
- Grupo Oncológico para el Tratamiento y Estudio de los Linfomas-GOTEL, Madrid, Spain
- Servicio de Oncología Médica, Hospital Universitario de Canarias, La Laguna, Sta. Cruz de Tenerife, Spain
| | - Juan Fernando García
- Servicio de Anatomía Patológica, Hospital MD Anderson Cancer Center, Madrid, Spain
| | - Mariano Provencio
- Servicio de Oncología Médica, Grupo de Investigación en Linfomas, Hospital Universitario Puerta de Hierro-Majadahonda, IDIPHISA, Madrid, Spain
- Grupo Oncológico para el Tratamiento y Estudio de los Linfomas-GOTEL, Madrid, Spain
- Servicio de Oncología Médica, Departamento de Medicina, Facultad de Medicina, Hospital Universitario Puerta de Hierro-Majadahonda, Universidad Autónoma de Madrid, IDIPHISA, Madrid, Spain
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10
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Leich E, Brodtkorb M, Schmidt T, Altenbuchinger M, Lingjærde OC, Lockmer S, Holte H, Nedeva T, Grieb T, Sander B, Sundström C, Spang R, Kimby E, Rosenwald A. Gene expression and copy number profiling of follicular lymphoma biopsies from patients treated with first-line rituximab without chemotherapy. Leuk Lymphoma 2023; 64:1927-1937. [PMID: 37683053 DOI: 10.1080/10428194.2023.2240462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 07/12/2023] [Accepted: 07/18/2023] [Indexed: 09/10/2023]
Abstract
The Nordic Lymphoma Study Group has performed two randomized clinical trials with chemotherapy-free first-line treatment (rituximab +/- interferon) in follicular lymphoma (FL), with 73% of patients alive and 38% without any need of chemotherapy after 10.6 years median follow-up. In order to identify predictive markers, that may also serve as therapeutic targets, gene expression- and copy number profiles were obtained from 97 FL patients using whole genome microarrays. Copy number alterations (CNAs) were identified, e.g. by GISTIC. Cox Lasso Regression and Lasso logistic regression were used to determine molecular features predictive of time to next therapy (TTNT). A few molecular changes were associated with TTNT (e.g. increased expression of INPP5B, gains in 12q23/q24), but were not significant after adjusting for multiple testing. Our findings suggest that there are no strong determinants of patient outcome with respect to GE data and CNAs in FL patients treated with a chemotherapy-free regimen (i.e. rituximab +/- interferon).
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Affiliation(s)
- E Leich
- Institute of Pathology, University of Würzburg, Comprehensive Cancer Center Mainfranken, Würzburg, Germany
| | | | - T Schmidt
- Statistical Bioinformatics, Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
| | - M Altenbuchinger
- Statistical Bioinformatics, Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
- Department of Medical Bioinformatics, University Medical Center Göttingen, Göttingen, Germany
| | - Ole Christian Lingjærde
- Division of Biomedical Informatics, Department of Computer Science, University of Oslo, Norway
| | - S Lockmer
- Division of Hematology, Department of Medicine at Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - H Holte
- Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - T Nedeva
- Institute of Pathology, University of Würzburg, Comprehensive Cancer Center Mainfranken, Würzburg, Germany
| | - T Grieb
- Institute of Pathology, University of Würzburg, Comprehensive Cancer Center Mainfranken, Würzburg, Germany
| | - B Sander
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden
| | - C Sundström
- Department of Pathology, Uppsala University Hospital, Uppsala University, Uppsala, Sweden
| | - R Spang
- Statistical Bioinformatics, Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
| | - E Kimby
- Division of Hematology, Department of Medicine at Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - A Rosenwald
- Institute of Pathology, University of Würzburg, Comprehensive Cancer Center Mainfranken, Würzburg, Germany
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11
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Tomacinschii V, Mosquera Orgueira A, Santos CA, Robu M, Buruiana S, Fraga Rodriguez MF. The implication of next-generation sequencing in the diagnosis and clinical management of non-Hodgkin lymphomas. Front Oncol 2023; 13:1275327. [PMID: 38023160 PMCID: PMC10663367 DOI: 10.3389/fonc.2023.1275327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 10/27/2023] [Indexed: 12/01/2023] Open
Abstract
Next generation sequencing (NGS) is a technology that broadens the horizon of knowledge of several somatic pathologies, especially in oncological and oncohematological pathology. In the case of NHL, the understanding of the mechanisms of tumorigenesis, tumor proliferation and the identification of genetic markers specific to different lymphoma subtypes led to more accurate classification and diagnosis. Similarly, the data obtained through NGS allowed the identification of recurrent somatic mutations that can serve as therapeutic targets that can be inhibited and thus reducing the rate of resistant cases. The article's purpose is to offer a comprehensive overview of the best ways of integrating of next-generation sequencing technologies for diagnosis, prognosis, classification, and selection of optimal therapy from the perspective of tailor-made medicine.
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Affiliation(s)
- Victor Tomacinschii
- Department of Hematology, Nicolae Testemitanu State University of Medicine and Pharmacy, Chisinau, Moldova
- Department of Hematology, Public Medical Sanitary Institution (PMSI) Institute of Oncology, Chisinau, Moldova
| | - Adrian Mosquera Orgueira
- University Hospital of Santiago de Compostela, Servizo Galego de Saude (SERGAS), Santiago de Compostela, Spain
- Health Research Institute of Santiago de Compostela, Santiago de Compostela, Spain
| | - Carlos Aliste Santos
- University Hospital of Santiago de Compostela, Servizo Galego de Saude (SERGAS), Santiago de Compostela, Spain
| | - Maria Robu
- Department of Hematology, Nicolae Testemitanu State University of Medicine and Pharmacy, Chisinau, Moldova
| | - Sanda Buruiana
- Department of Hematology, Nicolae Testemitanu State University of Medicine and Pharmacy, Chisinau, Moldova
| | - Maximo Francisco Fraga Rodriguez
- University Hospital of Santiago de Compostela, Servizo Galego de Saude (SERGAS), Santiago de Compostela, Spain
- Health Research Institute of Santiago de Compostela, Santiago de Compostela, Spain
- Department of Forensic Sciences, Pathology, Ginecology and Obstetrics and Pediatrics, Faculty of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain
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12
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Russler-Germain DA, Krysiak K, Ramirez C, Mosior M, Watkins MP, Gomez F, Skidmore ZL, Trani L, Gao F, Geyer S, Cashen AF, Mehta-Shah N, Kahl BS, Bartlett NL, Alderuccio JP, Lossos IS, Ondrejka SL, Hsi ED, Martin P, Leonard JP, Griffith M, Griffith OL, Fehniger TA. Mutations associated with progression in follicular lymphoma predict inferior outcomes at diagnosis: Alliance A151303. Blood Adv 2023; 7:5524-5539. [PMID: 37493986 PMCID: PMC10514406 DOI: 10.1182/bloodadvances.2023010779] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 07/17/2023] [Accepted: 07/18/2023] [Indexed: 07/27/2023] Open
Abstract
Follicular lymphoma (FL) is clinically heterogeneous, with select patients tolerating extended watch-and-wait, whereas others require prompt treatment, suffer progression of disease within 24 months of treatment (POD24), and/or experience aggressive histologic transformation (t-FL). Because our understanding of the relationship between genetic alterations in FL and patient outcomes remains limited, we conducted a clinicogenomic analysis of 370 patients with FL or t-FL (from Cancer and Leukemia Group B/Alliance trials 50402/50701/50803, or real-world cohorts from Washington University School of Medicine, Cleveland Clinic, or University of Miami). FL subsets by grade, stage, watch-and-wait, or POD24 status did not differ by mutation burden, whereas mutation burden was significantly higher in relapsed/refractory (rel/ref) FL and t-FL than in newly diagnosed (dx) FL. Nonetheless, mutation burden in dx FL was not associated with frontline progression-free survival (PFS). CREBBP was the only gene more commonly mutated in FL than in t-FL yet mutated CREBBP was associated with shorter frontline PFS in FL. Mutations in 20 genes were more common in rel/ref FL or t-FL than in dx FL, including 6 significantly mutated genes (SMGs): STAT6, TP53, IGLL5, B2M, SOCS1, and MYD88. We defined a mutations associated with progression (MAP) signature as ≥2 mutations in these 7 genes (6 rel/ref FL or t-FL SMGs plus CREBBP). Patients with dx FL possessing a MAP signature had shorter frontline PFS, revealing a 7-gene set offering insight into FL progression risk potentially more generalizable than the m7-Follicular Lymphoma International Prognostic Index (m7-FLIPI), which had modest prognostic value in our cohort. Future studies are warranted to validate the poor prognosis associated with a MAP signature in dx FL, potentially facilitating novel trials specifically in this high-risk subset of patients.
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Affiliation(s)
- David A. Russler-Germain
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Kilannin Krysiak
- Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO
- McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO
| | - Cody Ramirez
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
- McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO
| | - Matthew Mosior
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
- McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO
| | - Marcus P. Watkins
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Felicia Gomez
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
- McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO
| | - Zachary L. Skidmore
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
- McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO
| | - Lee Trani
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
- McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO
| | - Feng Gao
- Public Health Sciences Division, Department of Surgery, Washington University School of Medicine, St. Louis, MO
| | - Susan Geyer
- Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN
| | - Amanda F. Cashen
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO
| | - Neha Mehta-Shah
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO
| | - Brad S. Kahl
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO
| | - Nancy L. Bartlett
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO
| | - Juan P. Alderuccio
- Division of Hematology, Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, FL
| | - Izidore S. Lossos
- Division of Hematology, Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, FL
| | - Sarah L. Ondrejka
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH
| | - Eric D. Hsi
- Department of Pathology, Wake Forest Baptist Medical Center, Winston Salem, NC
| | - Peter Martin
- Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY
| | - John P. Leonard
- Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY
| | - Malachi Griffith
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
- McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO
- Department of Genetics, Washington University School of Medicine, St. Louis, MO
| | - Obi L. Griffith
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
- McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO
- Department of Genetics, Washington University School of Medicine, St. Louis, MO
| | - Todd A. Fehniger
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO
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13
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Thiruvengadam SK, Shouse G, Danilov AV. Thinking "outside the germinal center": Re-educating T cells to combat follicular lymphoma. Blood Rev 2023; 61:101099. [PMID: 37173225 DOI: 10.1016/j.blre.2023.101099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 04/04/2023] [Accepted: 05/08/2023] [Indexed: 05/15/2023]
Abstract
There have been significant advancements in the management of follicular lymphoma (FL), the most common indolent lymphoma. These include immunomodulatory agents such as lenalidomide, epigenetic modifiers (tazemetostat), and phosphoinotiside-3 kinase inhibitors (copanlisib). The focus of this review is T cell-engager therapies, namely chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies, have recently transformed the treatment landscape of FL. Two CAR T cell products, axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), and one bispecific antibody, mosunetuzumab, recently received FDA approvals in FL. Several other new immune effector drugs are being evaluated and will expand the treatment armamentarium. This review focuses on CAR T-cell and bispecific antibody therapies, details their safety and efficacy and considers their evolving role in the current treatment landscape of FL.
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14
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Dreval K, Hilton LK, Cruz M, Shaalan H, Ben-Neriah S, Boyle M, Collinge B, Coyle KM, Duns G, Farinha P, Grande BM, Meissner B, Pararajalingam P, Rushton CK, Slack GW, Wong J, Mungall AJ, Marra MA, Connors JM, Steidl C, Scott DW, Morin RD. Genetic subdivisions of follicular lymphoma defined by distinct coding and noncoding mutation patterns. Blood 2023; 142:561-573. [PMID: 37084389 PMCID: PMC10644066 DOI: 10.1182/blood.2022018719] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 04/06/2023] [Accepted: 04/06/2023] [Indexed: 04/23/2023] Open
Abstract
Follicular lymphoma (FL) accounts for ∼20% of all new lymphoma cases. Increases in cytological grade are a feature of the clinical progression of this malignancy, and eventual histologic transformation (HT) to the aggressive diffuse large B-cell lymphoma (DLBCL) occurs in up to 15% of patients. Clinical or genetic features to predict the risk and timing of HT have not been described comprehensively. In this study, we analyzed whole-genome sequencing data from 423 patients to compare the protein coding and noncoding mutation landscapes of untransformed FL, transformed FL, and de novo DLBCL. This revealed 2 genetically distinct subgroups of FL, which we have named DLBCL-like (dFL) and constrained FL (cFL). Each subgroup has distinguishing mutational patterns, aberrant somatic hypermutation rates, and biological and clinical characteristics. We implemented a machine learning-derived classification approach to stratify patients with FL into cFL and dFL subgroups based on their genomic features. Using separate validation cohorts, we demonstrate that cFL status, whether assigned with this full classifier or a single-gene approximation, is associated with a reduced rate of HT. This implies distinct biological features of cFL that constrain its evolution, and we highlight the potential for this classification to predict HT from genetic features present at diagnosis.
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Affiliation(s)
- Kostiantyn Dreval
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada
| | - Laura K. Hilton
- Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada
| | - Manuela Cruz
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada
| | - Haya Shaalan
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada
| | | | - Merrill Boyle
- Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada
| | - Brett Collinge
- Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada
| | - Krysta M. Coyle
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada
| | - Gerben Duns
- Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada
| | - Pedro Farinha
- Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada
| | | | | | - Prasath Pararajalingam
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada
| | - Christopher K. Rushton
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada
| | - Graham W. Slack
- Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada
| | - Jasper Wong
- Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada
| | - Andrew J. Mungall
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada
| | - Marco A. Marra
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada
| | | | | | - David W. Scott
- Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada
| | - Ryan D. Morin
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada
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15
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Tumedei MM, Piccinini F, Azzali I, Pirini F, Bravaccini S, De Matteis S, Agostinelli C, Castellani G, Zanoni M, Cortesi M, Vergani B, Leone BE, Righi S, Gazzola A, Casadei B, Gentilini D, Calzari L, Limarzi F, Sabattini E, Pession A, Tazzari M, Bertuzzi C. Follicular Lymphoma Microenvironment Traits Associated with Event-Free Survival. Int J Mol Sci 2023; 24:9909. [PMID: 37373066 DOI: 10.3390/ijms24129909] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 05/26/2023] [Accepted: 06/01/2023] [Indexed: 06/29/2023] Open
Abstract
The majority of patients with Follicular Lymphoma (FL) experience subsequent phases of remission and relapse, making the disease "virtually" incurable. To predict the outcome of FL patients at diagnosis, various clinical-based prognostic scores have been proposed; nonetheless, they continue to fail for a subset of patients. Gene expression profiling has highlighted the pivotal role of the tumor microenvironment (TME) in the FL prognosis; nevertheless, there is still a need to standardize the assessment of immune-infiltrating cells for the prognostic classification of patients with early or late progressing disease. We studied a retrospective cohort of 49 FL lymph node biopsies at the time of the initial diagnosis using pathologist-guided analysis on whole slide images, and we characterized the immune repertoire for both quantity and distribution (intrafollicular, IF and extrafollicular, EF) of cell subsets in relation to clinical outcome. We looked for the natural killer (CD56), T lymphocyte (CD8, CD4, PD1) and macrophage (CD68, CD163, MA4A4A)-associated markers. High CD163/CD8 EF ratios and high CD56/MS4A4A EF ratios, according to Kaplan-Meier estimates were linked with shorter EFS (event-free survival), with the former being the only one associated with POD24. In contrast to IF CD68+ cells, which represent a more homogeneous population, higher in non-progressing patients, EF CD68+ macrophages did not stratify according to survival. We also identify distinctive MS4A4A+CD163-macrophage populations with different prognostic weights. Enlarging the macrophage characterization and combining it with a lymphoid marker in the rituximab era, in our opinion, may enable prognostic stratification for low-/high-grade FL patients beyond POD24. These findings warrant validation across larger FL cohorts.
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Affiliation(s)
- Maria Maddalena Tumedei
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", 47014 Meldola, Italy
| | - Filippo Piccinini
- Scientific Directorate, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", 47014 Meldola, Italy
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40126 Bologna, Italy
| | - Irene Azzali
- Biostatistics and Clinical Trials Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", 47014 Meldola, Italy
| | - Francesca Pirini
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", 47014 Meldola, Italy
| | - Sara Bravaccini
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", 47014 Meldola, Italy
| | - Serena De Matteis
- Immunobiology of Transplants and Advanced Cellular Therapies Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Claudio Agostinelli
- Hematopathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Gastone Castellani
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40126 Bologna, Italy
| | - Michele Zanoni
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", 47014 Meldola, Italy
| | - Michela Cortesi
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", 47014 Meldola, Italy
| | - Barbara Vergani
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
| | - Biagio Eugenio Leone
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
| | - Simona Righi
- Hematology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Anna Gazzola
- Hematology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Beatrice Casadei
- Hematology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Davide Gentilini
- Department of Brain and Behavioral Sciences, Università di Pavia, 27100 Pavia, Italy
- Bioinformatics and Statistical Genomics Unit, Istituto Auxologico Italiano IRCCS, 20095 Cusano Milanino, Italy
| | - Luciano Calzari
- Bioinformatics and Statistical Genomics Unit, Istituto Auxologico Italiano IRCCS, 20095 Cusano Milanino, Italy
| | - Francesco Limarzi
- Pathology Unit, Morgagni-Pierantoni Hospital, AUSL Romagna, Via Carlo Forlanini, 34, 47121 Forlì, Italy
| | - Elena Sabattini
- Hematology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Andrea Pession
- Department of Pediatrics, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Marcella Tazzari
- Immunotherapy Cell Therapy and Biobank (ITCB) Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", 47014 Meldola, Italy
| | - Clara Bertuzzi
- Hematopathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
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16
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Correia C, Maurer MJ, McDonough SJ, Schneider PA, Ross PE, Novak AJ, Feldman AL, Cerhan JR, Slager SL, Witzig TE, Eckloff BW, Li H, Nowakowski GS, Kaufmann SH. Relationship between BCL2 mutations and follicular lymphoma outcome in the chemoimmunotherapy era. Blood Cancer J 2023; 13:81. [PMID: 37193683 PMCID: PMC10188323 DOI: 10.1038/s41408-023-00847-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 04/21/2023] [Accepted: 04/27/2023] [Indexed: 05/18/2023] Open
Abstract
How to identify follicular lymphoma (FL) patients with low disease burden but high risk for early progression is unclear. Building on a prior study demonstrating the early transformation of FLs with high variant allele frequency (VAF) BCL2 mutations at activation-induced cytidine deaminase (AICDA) sites, we examined 11 AICDA mutational targets, including BCL2, BCL6, PAX5, PIM1, RHOH, SOCS, and MYC, in 199 newly diagnosed grade 1 and 2 FLs. BCL2 mutations with VAF ≥20% occurred in 52% of cases. Among 97 FL patients who did not initially receive rituximab-containing therapy, nonsynonymous BCL2 mutations at VAF ≥20% were associated with increased transformation risk (HR 3.01, 95% CI 1.04-8.78, p = 0.043) and a trend toward shorter event-free survival (EFS, median 20 months with mutations versus 54 months without, p = 0.052). Other sequenced genes were less frequently mutated and did not increase the prognostic value of the panel. Across the entire population, nonsynonymous BCL2 mutations at VAF ≥20% were associated with decreased EFS (HR 1.55, 95% CI 1.02-2.35, p = 0.043 after correction for FLIPI and treatment) and decreased overall survival after median 14-year follow-up (HR 1.82, 95% CI 1.05-3.17, p = 0.034). Thus, high VAF nonsynonymous BCL2 mutations remain prognostic even in the chemoimmunotherapy era.
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Affiliation(s)
- Cristina Correia
- Division of Oncology Research, Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Matthew J Maurer
- Department of Quantitative Health Sciences, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Samantha J McDonough
- Medical Genome Facility, Mayo Clinic, 200 First Street, S.W., Rochester, MN, 55905, USA
| | - Paula A Schneider
- Division of Oncology Research, Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Paige E Ross
- Genomics Systems Unit, Mayo Clinic, Rochester, MN, 55905, USA
| | - Anne J Novak
- Division of Hematology, Department of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Andrew L Feldman
- Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - James R Cerhan
- Department of Quantitative Health Sciences, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Susan L Slager
- Department of Quantitative Health Sciences, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
- Division of Hematology, Department of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Thomas E Witzig
- Division of Hematology, Department of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Bruce W Eckloff
- Medical Genome Facility, Mayo Clinic, 200 First Street, S.W., Rochester, MN, 55905, USA
| | - Hu Li
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Grzegorz S Nowakowski
- Division of Hematology, Department of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
| | - Scott H Kaufmann
- Division of Oncology Research, Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
- Division of Hematology, Department of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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17
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Stuckey R, Luzardo Henríquez H, de la Nuez Melian H, Rivero Vera JC, Bilbao-Sieyro C, Gómez-Casares MT. Integration of molecular testing for the personalized management of patients with diffuse large B-cell lymphoma and follicular lymphoma. World J Clin Oncol 2023; 14:160-170. [PMID: 37124135 PMCID: PMC10134203 DOI: 10.5306/wjco.v14.i4.160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 03/24/2023] [Accepted: 04/04/2023] [Indexed: 04/21/2023] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the most common forms of aggressive and indolent lymphoma, respectively. The majority of patients are cured by standard R-CHOP immunochemotherapy, but 30%–40% of DLBCL and 20% of FL patients relapse or are refractory (R/R). DLBCL and FL are phenotypically and genetically hereterogenous B-cell neoplasms. To date, the diagnosis of DLBCL and FL has been based on morphology, immunophenotyping and cytogenetics. However, next-generation sequencing (NGS) is widening our understanding of the genetic basis of the B-cell lymphomas. In this review we will discuss how integrating the NGS-based characterization of somatic gene mutations with diagnostic or prognostic value in DLBCL and FL could help refine B-cell lymphoma classification as part of a multidisciplinary pathology work-up. We will also discuss how molecular testing can identify candidates for clinical trials with targeted therapies and help predict therapeutic outcome to currently available treatments, including chimeric antigen receptor T-cell, as well as explore the application of circulating cell-free DNA, a non-invasive method for patient monitoring. We conclude that molecular analyses can drive improvements in patient outcomes due to an increased understanding of the different pathogenic pathways affected by each DLBCL subtype and indolent FL vs R/R FL.
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Affiliation(s)
- Ruth Stuckey
- Department of Hematology, Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas 35019, Spain
| | - Hugo Luzardo Henríquez
- Department of Hematology, Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas 35019, Spain
| | | | - José Carlos Rivero Vera
- Department of Anatomical Pathology, Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas 35019, Spain
| | - Cristina Bilbao-Sieyro
- Department of Hematology, Hospital Universitario de Gran Canaria Dr. Negrin, Las Palmas de Gran Canaria 35019, Las Palmas de Gran Canaria, Spain
- Department of Morphology, Universitario de Las Palmas de Gran Canaria, Las Palmas 35001, Spain
| | - María Teresa Gómez-Casares
- Department of Hematology, Hospital Universitario de Gran Canaria Dr. Negrin, Las Palmas de Gran Canaria 35019, Las Palmas de Gran Canaria, Spain
- Medical Science, Universitario de Las Palmas de Gran Canaria, Las Palmas 35001, Spain
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18
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Laurent C, Cook JR, Yoshino T, Quintanilla-Martinez L, Jaffe ES. Follicular lymphoma and marginal zone lymphoma: how many diseases? Virchows Arch 2023; 482:149-162. [PMID: 36394631 PMCID: PMC9852150 DOI: 10.1007/s00428-022-03432-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 10/04/2022] [Accepted: 10/15/2022] [Indexed: 11/18/2022]
Abstract
Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are indolent mature B-cell neoplasms with variable clinical presentation and distinct histopathologic features. Recent advances in the biology and molecular characteristics of these lymphomas have further expanded our understanding of the heterogeneous nature of these lymphomas, with increasing recognition of specific disease entities within the broader categories of FL and MZL. Here, we discuss the conclusions of the 2022 International Consensus Classification of Mature Lymphoid Neoplasms (2022 ICC) dealing with FL, and review differences with the proposed WHO 5th Edition classification. We review issues related to grading and alternative forms of FL especially those lacking the genetic hallmark of FL, the t(14;18) chromosomal alteration. Among them, t(14;18)-negative CD23+ follicle center lymphoma has been proposed by the 2022 ICC as a provisional entity. Other follicle center-derived lymphomas such as pediatric-type follicular lymphoma, testicular follicular lymphoma, primary cutaneous follicle center lymphoma, and large B-cell lymphoma with IRF4 rearrangement are considered distinct entities separate from conventional FL. Importantly, large B-cell lymphoma with IRF4 rearrangement introduced as a provisional entity in the WHO 2017 is upgraded to a definite entity in the 2022 ICC. We also discuss diagnostic strategies for recognition of MZLs including splenic MZL, extranodal MZL (MALT lymphoma), and primary nodal MZL. The importance of molecular studies in the distinction among marginal zone lymphoma subtypes is emphasized, as well as their value in the differential diagnosis with other B-cell lymphomas.
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Affiliation(s)
- Camille Laurent
- Department of Pathology, Toulouse University Hospital Center, Cancer Institute University of Toulouse-Oncopole, Toulouse, France
| | - James R. Cook
- Department of Laboratory Medicine, Robert J. Tomsich Institute of Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, OH USA
| | - Tadashi Yoshino
- Department of Pathology, Graduate School of Medicine Dentistry and Pharmaceutical Science, Okayama University, Okayama, Japan
| | - Leticia Quintanilla-Martinez
- Institute of Pathology and Neuropathology, Eberhard Karls Univesity of Tübingen and Comprehensive Cancer Center, University Hospital Tübingen, Tuebingen, Germany
| | - Elaine S. Jaffe
- National Cancer Institute, National Institutes of Health, Bethesda, MD USA
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19
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Gordon MJ, Smith MR, Nastoupil LJ. Follicular lymphoma: The long and winding road leading to your cure? Blood Rev 2023; 57:100992. [PMID: 35908982 DOI: 10.1016/j.blre.2022.100992] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 07/18/2022] [Accepted: 07/20/2022] [Indexed: 01/28/2023]
Abstract
Follicular lymphoma, the most common indolent lymphoma, though highly responsive to therapy is coupled with multiple relapses for the majority of patients. Advances in biologic understanding of molecular events in lymphoma cells and the tumor microenvironment, along with novel cellular and targeted therapies, suggest this may soon change. Here we first review the development of the molecular concepts and classification of follicular lymphoma, along with therapeutic development of treatments based on chemotherapy plus monoclonal antibodies targeting CD20. We then focus on developments over the last decade in further defining follicular lymphoma pathophysiology, leading to targeted therapeutics, as well as novel immunotherapeutic strategies effective against B cell lymphomas including follicular, particularly patients with advanced stage disease. Additional alterations beyond the hallmark t(14;18) translocation are necessary for development of follicular lymphoma. Epigenetic mutations are almost universally identified in follicular lymphoma, most commonly involving histone-lysine N-methyltransferase 2D (KMT2D, the histone acetyltransferases, cAMP response element-binding protein binding protein (CREBBP) and E1A binding protein P300 (EP300) and the histone methyltransferase enhancer of zeste homologue 2 (EZH2). Mutations are also commonly identified in other proliferation/survival pathways such as B-cell receptor, RAS, mTOR and JAK-STAT pathways, as well as immune escape mutations. The host immune response plays a key role as well, based on studies correlating various immune cell subsets and gene expression signatures with outcomes. Over the last decade, many therapeutic options beyond the commonly used bendamustine-rituximab induction regimen have become available or are being investigated. We focus on these newer agents in the relapsed setting. New antibody-based agents include the naked CD19 directed antibody tafasitamab, the CD79b directed antibody drug conjugate (ADC) polatuzumab vedotin and the CD47 directed antibody magrolimab that targets macrophages rather than FL cells directly. Immune modulation by lenalidomide has moved to earlier lines of therapy and in combinations. Several small molecule inhibitors of proliferation signal pathways involving PI3kinase and BTK have activity against FL. Apoptotic pathway modulators also have activity. With increasing recognition of the high rate of epigenetic mutations in FL, HDAC inhibition has a role. More importantly, the EZH2 inhibitor tazemetostat is FDA approved for FL after 2 prior lines of therapy. The most exciting data currently involve immune attack against follicular lymphoma by chimeric antigen receptor T-cells (CART) or bispecific antibody constructs. Given these multiple potentially non-crossreactive mechanisms, studies of rationally designed combination strategies hold the promise of improving outcomes and possibly cure of follicular lymphoma.
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Affiliation(s)
- Max J Gordon
- Dept. of Lymphoma & Myeloma, MD Anderson Cancer Center, Houston, TX, USA.
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20
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Crouch S, Painter D, Barrans SL, Roman E, Beer PA, Cooke SL, Glover P, Van Hoppe SJ, Webster N, Lacy SE, Ruiz C, Campbell PJ, Hodson DJ, Patmore R, Burton C, Smith A, Tooze RM. Molecular subclusters of follicular lymphoma: a report from the United Kingdom's Haematological Malignancy Research Network. Blood Adv 2022; 6:5716-5731. [PMID: 35363872 PMCID: PMC9619185 DOI: 10.1182/bloodadvances.2021005284] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 03/06/2022] [Indexed: 11/20/2022] Open
Abstract
Follicular lymphoma (FL) is morphologically and clinically diverse, with mutations in epigenetic regulators alongside t(14;18) identified as disease-initiating events. Identification of additional mutational entities confirms this cancer's heterogeneity, but whether mutational data can be resolved into mechanistically distinct subsets remains an open question. Targeted sequencing was applied to an unselected population-based FL cohort (n = 548) with full clinical follow-up (n = 538), which included 96 diffuse large B-cell lymphoma (DLBCL) transformations. We investigated whether molecular subclusters of FL can be identified and whether mutational data provide predictive information relating to transformation. DNA extracted from FL samples was sequenced with a 293-gene panel representing genes frequently mutated in DLBCL and FL. Three clusters were resolved using mutational data alone, independent of translocation status: FL_aSHM, with high burden of aberrant somatic hypermutation (aSHM) targets; FL_STAT6, with high STAT6 & CREBBP mutation and low aSHM; and FL_Com, with the absence of features of other subtypes and enriched KMT2D mutation. Analysis of mutation signatures demonstrated differential enrichment of predicted mutation signatures between subgroups and a dominant preference in the FL_aSHM subgroup for G(C>T)T and G(C>T)C transitions consistent with previously defined aSHM-like patterns. Of transformed cases with paired samples, 17 of 26 had evidence of branching evolution. Poorer overall survival (OS) in the aSHM group (P = .04) was associated with older age; however, overall tumor genetics provided limited information to predict individual patient risk. Our approach identifies 3 molecular subclusters of FL linked to differences in underlying mechanistic pathways. These clusters, which may be further resolved by the inclusion of translocation status and wider mutation profiles, have implications for understanding pathogenesis as well as improving treatment strategies in the future.
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Affiliation(s)
- Simon Crouch
- Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York, United Kingdom
| | - Daniel Painter
- Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York, United Kingdom
| | - Sharon L. Barrans
- Haematological Malignancy Diagnostic Service, St. James’s Institute of Oncology, Leeds, United Kingdom
| | - Eve Roman
- Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York, United Kingdom
| | - Philip A. Beer
- Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom
| | - Susanna L. Cooke
- Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Paul Glover
- Haematological Malignancy Diagnostic Service, St. James’s Institute of Oncology, Leeds, United Kingdom
| | - Suzan J.L. Van Hoppe
- Haematological Malignancy Diagnostic Service, St. James’s Institute of Oncology, Leeds, United Kingdom
| | - Nichola Webster
- Haematological Malignancy Diagnostic Service, St. James’s Institute of Oncology, Leeds, United Kingdom
| | - Stuart E. Lacy
- Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York, United Kingdom
| | - Camilo Ruiz
- Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom
| | | | - Daniel J. Hodson
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
| | - Russell Patmore
- Queen’s Centre for Oncology and Haematology, Castle Hill Hospital, Cottingham, United Kingdom
| | - Cathy Burton
- Haematological Malignancy Diagnostic Service, St. James’s Institute of Oncology, Leeds, United Kingdom
| | - Alexandra Smith
- Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York, United Kingdom
| | - Reuben M. Tooze
- Section of Experimental Haematology, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, United Kingdom
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21
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Ennishi D. Biological and clinical significance of epigenetic alterations in B-cell lymphomas. Int J Hematol 2022; 116:821-827. [PMID: 36208393 DOI: 10.1007/s12185-022-03461-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 09/21/2022] [Accepted: 09/21/2022] [Indexed: 10/10/2022]
Abstract
Recent advances in genetic analysis of hematopoietic tumors have led to the discovery of enzyme abnormalities that control epigenetic changes. Notably, genetic mutations associated with DNA methylation and histone modifications have been identified in B-cell malignant lymphomas, including diffuse large B-cell lymphoma and follicular lymphoma. Gene expression involved in B lymphocyte differentiation and maturation within the germinal center (GC) is regulated epigenetically in these lymphomas, and epigenetic alterations play critical roles in the pathogenesis of GC-driven lymphomas. Recent studies also indicate the importance of epigenetic alterations as biomarkers and therapeutic targets, suggesting that they will have a central role in developing precision medicine for patients with GC-driven lymphomas.
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Affiliation(s)
- Daisuke Ennishi
- Center for Comprehensive Genomic Medicine, Okayama University Hospital, 2-5-1 Shikata-Cho, Kita-ku, Okayama, 700-8558, Japan.
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22
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Wästerlid T, Cavelier L, Haferlach C, Konopleva M, Fröhling S, Östling P, Bullinger L, Fioretos T, Smedby KE. Application of precision medicine in clinical routine in haematology-Challenges and opportunities. J Intern Med 2022; 292:243-261. [PMID: 35599019 PMCID: PMC9546002 DOI: 10.1111/joim.13508] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Precision medicine is revolutionising patient care in cancer. As more knowledge is gained about the impact of specific genetic lesions on diagnosis, prognosis and treatment response, diagnostic precision and the possibility for optimal individual treatment choice have improved. Identification of hallmark genetic aberrations such as the BCR::ABL1 gene fusion in chronic myeloid leukaemia (CML) led to the rapid development of efficient targeted therapy and molecular follow-up, vastly improving survival for patients with CML during recent decades. The assessment of translocations, copy number changes and point mutations are crucial for the diagnosis and risk stratification of acute myeloid leukaemia and myelodysplastic syndromes. Still, the often heterogeneous and complex genetic landscape of haematological malignancies presents several challenges for the implementation of precision medicine to guide diagnosis, prognosis and treatment choice. This review provides an introduction and overview of the important molecular characteristics and methods currently applied in clinical practice to guide clinical decision making in haematological malignancies of myeloid and lymphoid origin. Further, experimental ways to guide the choice of targeted therapy for refractory patients are reviewed, such as functional precision medicine using drug profiling. An example of the use of pipeline studies where the treatment is chosen according to the molecular characteristics in rare solid malignancies is also provided. Finally, the future opportunities and remaining challenges of precision medicine in the real world are discussed.
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Affiliation(s)
- Tove Wästerlid
- Department of Medicine Solna, Division of Clinical Epidemiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.,Department of Hematology, Karolinska University Hospital, Stockholm, Sweden
| | - Lucia Cavelier
- Department of Immunology, Genetics and Pathology, Clinical Genomics Uppsala, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | | | - Marina Konopleva
- Department of Leukemia, M.D. Anderson Cancer Center, Houston, Texas, USA
| | - Stefan Fröhling
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Päivi Östling
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Lars Bullinger
- Department of Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.,German Cancer Consortium (DKTK) Berlin Site, and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Thoas Fioretos
- Division of Clinical Genetics, Department of Laboratory Medicine, Science for Life Laboratory, Lund University and Clinical Genomics Lund, Lund, Sweden
| | - Karin E Smedby
- Department of Medicine Solna, Division of Clinical Epidemiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.,Department of Hematology, Karolinska University Hospital, Stockholm, Sweden
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23
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Hatipoğlu T, Esmeray Sönmez E, Hu X, Yuan H, Danyeli AE, Şeyhanlı A, Önal-Süzek T, Zhang W, Akman B, Olgun A, Özkal S, Alacacıoğlu İ, Özcan MA, You H, Küçük C. Plasma Concentrations and Cancer-Associated Mutations in Cell-Free Circulating DNA of Treatment-Naive Follicular Lymphoma for Improved Non-Invasive Diagnosis and Prognosis. Front Oncol 2022; 12:870487. [PMID: 35795062 PMCID: PMC9252432 DOI: 10.3389/fonc.2022.870487] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Accepted: 05/02/2022] [Indexed: 12/14/2022] Open
Abstract
Follicular lymphoma (FL) is the second most frequent non-Hodgkin lymphoma accounting for 10-20% of all lymphomas in western countries. As a clinically heterogeneous cancer, FL occasionally undergoes histological transformation to more aggressive B cell lymphoma types that are associated with poor prognosis. Here we evaluated the potential of circulating cell-free DNA (cfDNA) to improve the diagnosis and prognosis of follicular lymphoma patients. Twenty well-characterized FL cases (13 symptomatic and 7 asymptomatic) were prospectively included in this study. Plasma cfDNA, formalin-fixed paraffin-embedded (FFPE) tumor tissue DNA, and patient-matched granulocyte genomic DNA samples were obtained from 20 treatment-naive FL cases. Ultra-deep targeted next-generation sequencing was performed with these DNA samples by using a custom-designed platform including exons and exon-intron boundaries of 110 FL related genes. Using a strict computational bioinformatics pipeline, we identified 91 somatic variants in 31 genes in treatment-naive FL cases. Selected variants were cross-validated by using PCR-Sanger sequencing. We observed higher concentrations of cfDNA and a higher overlap of somatic variants present both in cfDNA and tumor tissue DNA in symptomatic FL cases compared to asymptomatic ones. Variants known to be associated with FL pathogenesis such as STAT6 p.D419 or EZH2 p.Y646 were observed in patient-matched cfDNA and tumor tissue samples. Consistent with previous observations, high Ki-67 staining, elevated LDH levels, FDG PET/CT positivity were associated with poor survival. High plasma cfDNA concentrations or the presence of BCL2 mutations in cfDNA showed significant association with poor survival in treatment-naive patients. BCL2 mutation evaluations in cfDNA improved the prognostic utility of previously established variables. In addition, we observed that a FL patient who had progressive disease contained histological transformation-associated gene (i.e. B2M and BTG1) mutations only in cfDNA. Pre-treatment concentrations and genotype of plasma cfDNA may be used as a liquid biopsy to improve diagnosis, risk stratification, and prediction of histological transformation. Targeted therapies related to oncogenic mutations may be applied based on cfDNA genotyping results. However, the results of this study need to be validated in a larger cohort of FL patients as the analyses conducted in this study have an exploratory nature.
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Affiliation(s)
- Tevfik Hatipoğlu
- İzmir Biomedicine and Genome Center, İzmir, Turkey
- İzmir International Biomedicine and Genome Institute, Dokuz Eylül University, İzmir, Turkey
| | - Esra Esmeray Sönmez
- İzmir Biomedicine and Genome Center, İzmir, Turkey
- İzmir International Biomedicine and Genome Institute, Dokuz Eylül University, İzmir, Turkey
| | - Xiaozhou Hu
- İzmir Biomedicine and Genome Center, İzmir, Turkey
- İzmir International Biomedicine and Genome Institute, Dokuz Eylül University, İzmir, Turkey
| | - Hongling Yuan
- İzmir International Biomedicine and Genome Institute, Dokuz Eylül University, İzmir, Turkey
| | - Ayça Erşen Danyeli
- Department of Pathology, Faculty of Medicine, Dokuz Eylül University, İzmir, Turkey
| | - Ahmet Şeyhanlı
- Department of Hematology, Faculty of Medicine, Dokuz Eylül University, İzmir, Turkey
| | - Tuğba Önal-Süzek
- Department of Bioinformatics, Graduate School of Natural and Applied Sciences, Muğla Sıtkı Koçman University, Muğla, Turkey
| | - Weiwei Zhang
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Burcu Akman
- İzmir Biomedicine and Genome Center, İzmir, Turkey
- İzmir International Biomedicine and Genome Institute, Dokuz Eylül University, İzmir, Turkey
| | - Aybüke Olgun
- Department of Hematology, Faculty of Medicine, Dokuz Eylül University, İzmir, Turkey
| | - Sermin Özkal
- Department of Pathology, Faculty of Medicine, Dokuz Eylül University, İzmir, Turkey
| | - İnci Alacacıoğlu
- Department of Hematology, Faculty of Medicine, Dokuz Eylül University, İzmir, Turkey
| | - Mehmet Ali Özcan
- Department of Hematology, Faculty of Medicine, Dokuz Eylül University, İzmir, Turkey
| | - Hua You
- Department of Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
- *Correspondence: Can Küçük, ; Hua You,
| | - Can Küçük
- İzmir Biomedicine and Genome Center, İzmir, Turkey
- İzmir International Biomedicine and Genome Institute, Dokuz Eylül University, İzmir, Turkey
- Department of Medical Biology, Faculty of Medicine, Dokuz Eylül University, İzmir, Turkey
- *Correspondence: Can Küçük, ; Hua You,
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Zhao F, Cheng LL, Zheng Z, Zhang MC, Cheng S, Xu PP, Wang L, Zhao WL. [Analysis of clinical factors of bendamustine combined with rituximab in the treatment of recurrent follicular lymphoma]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2022; 43:513-517. [PMID: 35968596 PMCID: PMC9800227 DOI: 10.3760/cma.j.issn.0253-2727.2022.06.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Indexed: 12/24/2022]
Affiliation(s)
- F Zhao
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China Zhao Fang is working at the Hematology Center, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Institute of Hematology, Urumqi 830054, China
| | - L L Cheng
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Z Zheng
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - M C Zhang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - S Cheng
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - P P Xu
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - L Wang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - W L Zhao
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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25
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Ren W, Wang X, Yang M, Wan H, Li X, Ye X, Meng B, Li W, Yu J, Lei M, Xie F, Jiang W, Kimby E, Huang H, Liu D, Li ZM, Wu K, Zhang H, Pan-Hammarström Q. Distinct clinical and genetic features of hepatitis B virus-associated follicular lymphoma in Chinese patients. Blood Adv 2022; 6:2731-2744. [PMID: 35030632 PMCID: PMC9092402 DOI: 10.1182/bloodadvances.2021006410] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 12/19/2021] [Indexed: 12/15/2022] Open
Abstract
Hepatitis B virus (HBV) infection has been associated with an increased risk for B-cell lymphomas. We previously showed that 20% of diffuse large B-cell lymphoma (DLBCL) patients from China, an endemic area of HBV infection, have chronic HBV infection (surface antigen-positive, HBsAg+) and are characterized by distinct clinical and genetic features. Here, we showed that 24% of follicular lymphoma (FL) Chinese patients are HBsAg+. Compared with the HBsAg- FL patients, HBsAg+ patients are younger, have a higher histological grade at diagnosis, and have a higher incidence of disease progression within 24 months. Moreover, by sequencing the genomes of 109 FL tumors, we observed enhanced mutagenesis and distinct genetic profile in HBsAg+ FLs, with a unique set of preferentially mutated genes (TNFAIP3, FAS, HIST1H1C, KLF2, TP53, PIM1, TMSB4X, DUSP2, TAGAP, LYN, and SETD2) but lack of the hallmark of HBsAg- FLs (ie, IGH/BCL2 translocations and CREBBP mutations). Transcriptomic analyses further showed that HBsAg+ FLs displayed gene-expression signatures resembling the activated B-cell-like subtype of diffuse large B-cell lymphoma, involving IRF4-targeted genes and NF-κB/MYD88 signaling pathways. Finally, we identified an increased infiltration of CD8+ memory T cells, CD4+ Th1 cells, and M1 macrophages and higher T-cell exhaustion gene signature in HBsAg+ FL samples. Taken together, we present new genetic/epigenetic evidence that links chronic HBV infection to B-cell lymphomagenesis, and HBV-associated FL is likely to have a distinct cell-of-origin and represent as a separate subtype of FL. Targetable genetic/epigenetic alterations identified in tumors and their associated tumor microenvironment may provide potential novel therapeutic approaches for this subgroup of patients.
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Affiliation(s)
- Weicheng Ren
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Xianhuo Wang
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Mingyu Yang
- BGI-Shenzhen, Shenzhen, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, Shenzhen, China
| | - Hui Wan
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
| | - Xiaobo Li
- BGI-Shenzhen, Shenzhen, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, Shenzhen, China
| | - Xiaofei Ye
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
| | - Bing Meng
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Wei Li
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Jingwei Yu
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Mengyue Lei
- BGI-Shenzhen, Shenzhen, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, Shenzhen, China
| | - Fanfan Xie
- BGI-Shenzhen, Shenzhen, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, Shenzhen, China
| | - Wenqi Jiang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Eva Kimby
- Unit of Hematology, Department of Medicine at Huddinge, Karolinska Institutet, Stockholm, Sweden; and
| | - Huiqiang Huang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Dongbing Liu
- BGI-Shenzhen, Shenzhen, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, Shenzhen, China
| | - Zhi-Ming Li
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Kui Wu
- BGI-Shenzhen, Shenzhen, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, Shenzhen, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Huilai Zhang
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Qiang Pan-Hammarström
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- BGI-Shenzhen, Shenzhen, China
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26
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Mondello P, Ansell SM, Nowakowski GS. Immune Epigenetic Crosstalk Between Malignant B Cells and the Tumor Microenvironment in B Cell Lymphoma. Front Genet 2022; 13:826594. [PMID: 35237302 PMCID: PMC8883034 DOI: 10.3389/fgene.2022.826594] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 01/24/2022] [Indexed: 12/22/2022] Open
Abstract
Epigenetic reprogramming is a hallmark of lymphomagenesis, however its role in reshaping the tumor microenvironment is still not well understood. Here we review the most common chromatin modifier mutations in B cell lymphoma and their effect on B cells as well as on T cell landscape. We will also discuss precision therapy strategies to reverse their aberrant signaling by targeting mutated proteins or counterbalance epigenetic mechanisms.
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27
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Mondello P, Ansell SM. Tazemetostat: a treatment option for relapsed/refractory follicular lymphoma. Expert Opin Pharmacother 2021; 23:295-301. [PMID: 34904909 DOI: 10.1080/14656566.2021.2014815] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
INTRODUCTION Follicular lymphoma (FL) is the second most common form of B cell lymphoma and generally presents as an indolent and relatively slow-growing tumor. However, most FLs are incurable with a shortening of subsequent responses. Therefore, novel and more effective treatments are desperately needed. Tazemetostat is a first-in-class, selective, oral inhibitor of EZH2, a lysine methyltransferase that is mutated in about 25% of FL. Tazemetostat has been recently approved for relapsed/refractory FL after two or more lines of therapy in the presence of an EZH2 mutation or independent of an EZH2 mutation in the absence of other options. AREAS COVERED Here, the authors provide a review focusing on the molecular mechanisms of EZH2, clinical development of tazemetostat and other EZH2 inhibitors (EZH2i), as single-agent therapy and in combinatorial regimens. Finally, they provide a futuristic look at therapeutic approaches for this disease. EXPERT OPINION Tazemetostat monotherapy showed clinically meaningful and durable responses with a favorable toxicity profile, especially in EZH2 mutant lymphoma. Future studies should explore mechanism-based combinatorial regimens to maximize and prolong the anti-lymphoma effect.
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Affiliation(s)
- Patrizia Mondello
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Stephen M Ansell
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA
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28
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Follicular lymphoma: is there an optimal way to define risk? Hematology 2021; 2021:313-319. [DOI: 10.1182/hematology.2021000264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Follicular lymphoma (FL) has a long natural history and typically indolent behavior. In the present era, there are a plethora of prognostic factors combining clinical, biological, and genetic data to determine patient prognosis and help develop treatment strategies over the course of a patient's lifetime. The rapid pace of tumor-specific and clinical advances in FL has created a challenge in the prioritization and implementation of these factors into clinical practice. Developing a comprehensive understanding of existing prognostic markers in FL will help select optimal ways of utilization in the clinical setting and investigate opportunities to define and intervene upon risk at FL diagnosis and disease recurrence.
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29
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Early Progressing Follicular Lymphoma. Curr Oncol Rep 2021; 23:149. [PMID: 34797453 DOI: 10.1007/s11912-021-01126-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/29/2021] [Indexed: 10/19/2022]
Abstract
PURPOSE OF REVIEW Follicular lymphoma is an indolent lymphoma which does not limit life expectancy in most patients; however, approximately 20% of patients will experience progression of disease within 24 months (POD24) of diagnosis and have inferior survival outcomes. To date, no clinical, genetic, or tumor microenvironment prediction models have been able to definitively predict which patients will experience POD24 which limits the ability to alter frontline management of patients suspected to be at high risk of early progression. Here, we review recent literature regarding novel prediction models and management recommendations for POD24 patients. RECENT FINDINGS Recent studies have revealed novel clinicopathologic prediction models which may be closer to identifying patients at risk of POD24. In addition, several clinical trials utilizing novel therapies such as tazemetostat, obinutuzumab, PI3K inhibitors, and lenalidomide have been performed which help further guide treatment. Ongoing trials seek to identify the optimal management of these patients, and data from bispecific antibodies and CAR T cell therapies is forthcoming. With ongoing research efforts, hope remains that we are closer to being able to predict which patients will experience early progressing follicular lymphoma and have an improved management plan for those who do in order to improve survival outcomes.
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30
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Leslie LA. Novel Therapies for Follicular Lymphoma and Other Indolent Non-Hodgkin Lymphomas. Curr Treat Options Oncol 2021; 22:111. [PMID: 34694508 PMCID: PMC8543415 DOI: 10.1007/s11864-021-00909-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/25/2021] [Indexed: 01/22/2023]
Abstract
OPINION STATEMENT When selecting therapy for patients with indolent non-Hodgkin lymphoma (iNHL) including follicular (FL), marginal zone (MZL), small lymphocytic (SLL), and lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM), there are several factors to consider. With a median age around 70 at diagnosis, many patients have accumulated comorbid conditions that may limit treatment options. Although incurable for most, iNHL is a chronic disease with a median overall survival measured in years to decades. This long natural history changes the risk-to-benefit balance with a lower acceptance of toxicity early in the treatment course compared to that of aggressive lymphomas. Despite a recent rapid increase in available therapies, overall progress in iNHL has been slow for several reasons. Initial trials grouped iNHLs together making it challenging to appreciate the differential activity among subtypes. We have not been able to develop prognostic models that maintain validity in the era of chemotherapy-free options. Predictive markers have been elusive and without identified molecular signatures, it is challenging to select and sequence therapy. With these clinical factors in mind, in addition to the heterogeneity among and within iNHLs, I do not have a standard treatment algorithm and feel each patient should have an individualized treatment approach. This review focuses on recent updates and controversies in the management of iNHL with a focus on FL and MZL.
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MESH Headings
- Antineoplastic Agents, Immunological/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Bendamustine Hydrochloride/administration & dosage
- Cyclophosphamide
- Doxorubicin
- Humans
- Immunotherapy, Adoptive
- Leukemia, Lymphocytic, Chronic, B-Cell/therapy
- Lymphoma, B-Cell, Marginal Zone/therapy
- Lymphoma, Follicular/therapy
- Lymphoma, Non-Hodgkin/therapy
- Prednisone
- Receptors, Chimeric Antigen
- Risk Assessment
- Rituximab/administration & dosage
- Stem Cell Transplantation
- Vincristine
- Waldenstrom Macroglobulinemia/therapy
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Affiliation(s)
- Lori A Leslie
- John Theurer Cancer Center, Hackensack Meridian Health, Hackensack, NJ, 07601, USA.
- Hackensack Meridian School of Medicine, Nutley, NJ, USA.
- Mountainside Medical Center, Montclair, NJ, USA.
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31
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Nogueira DS, Lage LADPC, Culler HF, Pereira J. Follicular Lymphoma: Refining Prognostic Models and Impact of Pod-24 in Clinical Outcomes. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2021; 22:67-75. [PMID: 34580043 DOI: 10.1016/j.clml.2021.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/03/2021] [Accepted: 08/22/2021] [Indexed: 11/28/2022]
Abstract
Follicular lymphoma (FL) is the most common indolent lymphoma, accounting for 20%-25% of all non-Hodgkin's lymphomas (NHLs). It is a malignancy with variable biologic presentation and heterogeneous clinical outcomes. Several models incorporating clinical laboratory variables and molecular biomarkers are able to predict its prognosis, allowing to stratify patients into different risk groups. However, these prognostic scores should not be used to indicate first-line treatment or risk-adapted therapeutic recommendations. Over the past 5 years, progression of disease within 24 months (POD-24) of first-line chemo-immunotherapy has emerged as a robust adverse prognostic factor, capable of assessing overall survival and identifying high-risk patients with indication for more aggressive therapeutic approaches, such as consolidation based in autologous stem cell transplantation. It should be reinforced that POD-24 is not a baseline measurement, it is based on a post-treatment strategy, and is usually applied to patients with a high tumor burden. The identification of newly diagnosed patients at high risk for disease progression, particularly those with low tumor volume is still a challenge in the context of FL. Therefore, the primary purpose of this review is to provide an overview of the main prognostic models validated to date for FL. Moreover, using these scores, which incorporate clinical and genetic variables, we aim to identify individuals with newly diagnosed FL, advanced disease, and low tumor burden with a high probability of progression or relapse within 24 months of first treatment. Thus, a decision regarding risk-adapted induction therapy could be better stablished for these subset of patients.
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Affiliation(s)
- Daniel Silva Nogueira
- Department of Hematology, Hemotherapy & Cell Therapy, Faculty of Medicine, University of Sao Paulo (FM-USP), Sao Paulo, Brazil.
| | - Luís Alberto de Pádua Covas Lage
- Department of Hematology, Hemotherapy & Cell Therapy, Faculty of Medicine, University of Sao Paulo (FM-USP), Sao Paulo, Brazil; Laboratory of Medical Investigation in Pathogenesis and Directed Therapy in Onco-Immuno-Hematology (LIM-31), University of Sao Paulo (FM-USP), Sao Paulo, Brazil
| | - Hebert Fabrício Culler
- Department of Hematology, Hemotherapy & Cell Therapy, Faculty of Medicine, University of Sao Paulo (FM-USP), Sao Paulo, Brazil; Laboratory of Medical Investigation in Pathogenesis and Directed Therapy in Onco-Immuno-Hematology (LIM-31), University of Sao Paulo (FM-USP), Sao Paulo, Brazil
| | - Juliana Pereira
- Department of Hematology, Hemotherapy & Cell Therapy, Faculty of Medicine, University of Sao Paulo (FM-USP), Sao Paulo, Brazil; Laboratory of Medical Investigation in Pathogenesis and Directed Therapy in Onco-Immuno-Hematology (LIM-31), University of Sao Paulo (FM-USP), Sao Paulo, Brazil
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32
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Early Relapse in First-Line Follicular Lymphoma: A Review of the Clinical Implications and Available Mitigation and Management Strategies. Oncol Ther 2021; 9:329-346. [PMID: 34319556 PMCID: PMC8594248 DOI: 10.1007/s40487-021-00161-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 06/21/2021] [Indexed: 10/25/2022] Open
Abstract
Chemoimmunotherapy with rituximab (R-chemo) or obinutuzumab (G-chemo) is standard of care for patients with previously untreated symptomatic or high-tumor-burden follicular lymphoma. Median progression-free survival (PFS) with R-chemo plus R maintenance exceeds 10 years, and G-chemo plus G maintenance improves PFS relative to the corresponding R-containing regimen. Despite these positive results, a sizable proportion of patients continue to progress during or shortly after initial treatment. While no single definition of early relapse has been established, progression of disease within 24 months of initial treatment (POD24) is now widely accepted as a critical adverse prognostic factor. Multiple studies have shown increased mortality risk in patients with POD24 versus those without POD24. Unfortunately, tools for the assessment of POD24 risk are suboptimal, and it is not currently possible in clinical practice to identify individual patients who are at increased risk for early relapse. Treatment strategies for patients with POD24 are not well defined. G-chemo regimens appear to reduce the risk of POD24 relative to R-chemo regimens, although the impact on survival outcomes remains unclear. Beyond standard therapy, autologous stem cell transplant and emerging treatment modalities, such as bispecific antibodies and chimeric antigen receptor T-cells, may have a role in future management. Until standard treatments are defined, mitigating the risk of early relapse with effective up-front treatment remains the priority.
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33
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Jelicic J, Stauffer Larsen T, Bukumiric Z, Andjelic B. The clinical applicability of current prognostic models in follicular lymphoma: A systematic review. Crit Rev Oncol Hematol 2021; 164:103418. [PMID: 34246773 DOI: 10.1016/j.critrevonc.2021.103418] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 06/18/2021] [Accepted: 07/04/2021] [Indexed: 12/29/2022] Open
Abstract
The Follicular Lymphoma International Prognostic Index (FLIPI) is widely used for risk stratification of patients with follicular lymphoma (FL). Motivated by evolvement in treatment modalities, several prognostic models for FL have been proposed recently. This systematic review aimed to identify available prognostic models for newly diagnosed FL and discuss their potential limitations. A total of ten studies fulfilled the inclusion criteria. Different clinical, laboratory, radiological, and histopathological findings were combined in prognostic models. The majority of studies developed models from clinical trial cohorts, and most lacked validation in populations treated with current treatment options. Although the FLIPI is the most widely used model for prognostication in FL patients, current prognostic models, including FLIPI, are rarely used in clinical practice for treatment decision-making. Future studies should validate the existing, or develop new prognostic models, to identify which of the current standard treatment options benefit high-risk FL patients the most.
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Affiliation(s)
- Jelena Jelicic
- Department of Hematology, Odense University Hospital, Odense, Denmark
| | - Thomas Stauffer Larsen
- Department of Hematology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
| | - Zoran Bukumiric
- Department of Statistics, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Bosko Andjelic
- Department of Haematology, Blackpool Victoria Hospital, Lancashire Haematology Centre, Blackpool, United Kingdom
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34
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Julia E, Salles G. EZH2 inhibition by tazemetostat: mechanisms of action, safety and efficacy in relapsed/refractory follicular lymphoma. Future Oncol 2021; 17:2127-2140. [PMID: 33709777 PMCID: PMC9892962 DOI: 10.2217/fon-2020-1244] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Epigenetic alterations are major drivers of follicular lymphomagenesis, and these alterations are frequently caused by mutations in or upregulation of EZH2, a histone methyltransferase responsible for PRC2-mediated gene repression. EZH2 hyperactivation increases proliferation of B cells and prevents them from exiting the germinal center, favoring lymphomagenesis. The first FDA-approved EZH2 inhibitor is tazemetostat, which is orally available and targets both mutant and wild-type forms of the protein to induce cell cycle arrest and apoptosis of lymphoma cells in preclinical models. Phase II trials have shown objective response rates of 69% for patients with lymphoma-carrying EZH2 mutations and 35% for those with wild-type EZH2 without major toxicity, leading to tazemetostat approval for this cancer by the US FDA in June 2020.
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Affiliation(s)
- Edith Julia
- Department of Hematology, Hospices Civils de Lyon, Hôpital Lyon-Sud, Pierre-Bénite, 69310, France,Faculté de Médecine Lyon-Sud, Université de Lyon, Université Claude Bernard, 165, Chemin du Grand Revoyet, Cedex, Oullins, 69495, France
| | - Gilles Salles
- Faculté de Médecine Lyon-Sud, Université de Lyon, Université Claude Bernard, 165, Chemin du Grand Revoyet, Cedex, Oullins, 69495, France,Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA,Author for correspondence:
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35
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von Keudell G, Salles G. The role of tazemetostat in relapsed/refractory follicular lymphoma. Ther Adv Hematol 2021; 12:20406207211015882. [PMID: 34104370 PMCID: PMC8165870 DOI: 10.1177/20406207211015882] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 04/19/2021] [Indexed: 12/28/2022] Open
Abstract
Large strides have been made in the treatment of follicular lymphoma (FL) over the last few years. Although the majority of patients respond to upfront therapy, many experience disease progression with a progressive shortening of subsequent treatment free intervals. New treatment options are therefore crucial for such patients. Tazemetostat is a first-in-class, selective, oral inhibitor of enhancer of zester homolog 2 (EZH2), a histone methyltransferase that is mutated in about a quarter of FL cases. Tazemetostat was recently approved for the treatment of patients with relapsed FL after 2 or more prior lines of therapy in the presence of an EZH2 mutation and for those without any other available therapeutic option, independently of EZH2 mutation status. In this review, we will summarize the background and key data that led to the development of tazemetostat, and, ultimately, to its approval for this indication.
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Affiliation(s)
- Gottfried von Keudell
- Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Gilles Salles
- Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
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Khanlari M, Wang SA, Fowler NH, Tang G, Saluja K, Muzzafar T, Medeiros LJ, Thakral B. Concurrent TP53 Mutation and Deletion in Refractory Low-grade Follicular Lymphoma. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2021; 21:e626-e629. [PMID: 33867306 DOI: 10.1016/j.clml.2021.03.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/08/2021] [Accepted: 03/14/2021] [Indexed: 11/30/2022]
Affiliation(s)
- Mahsa Khanlari
- Department of Hematopathology, MD Anderson Cancer Center, Houston, TX
| | - Sa A Wang
- Department of Hematopathology, MD Anderson Cancer Center, Houston, TX
| | - Nathan H Fowler
- Department of Lymphoma and Myeloma Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX
| | - Guilin Tang
- Department of Hematopathology, MD Anderson Cancer Center, Houston, TX
| | - Karan Saluja
- Department of Pathology and Laboratory Medicine, McGovern Medical School, The University of Texas Health Science Center, Houston, TX
| | - Tariq Muzzafar
- Department of Hematopathology, MD Anderson Cancer Center, Houston, TX
| | | | - Beenu Thakral
- Department of Hematopathology, MD Anderson Cancer Center, Houston, TX.
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Chauhan AF, Cheson BD. Copanlisib in the Treatment of Relapsed Follicular Lymphoma: Utility and Experience from the Clinic. Cancer Manag Res 2021; 13:677-692. [PMID: 33531838 PMCID: PMC7846853 DOI: 10.2147/cmar.s201024] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Accepted: 12/30/2020] [Indexed: 12/25/2022] Open
Abstract
The phosphatidylinositol-3-kinase (PI3K) pathway is ubiquitous to multiple cellular processes and is intricately implicated in lymphomagenesis. The development of PI3K inhibitors has broadened treatment options for relapsed and/or refractory follicular lymphoma (FL) and currently three PI3K inhibitors have been approved in the third-line setting for FL, including idelalisib (oral), duvelisib (oral), and copanlisib (intravenous), with other agents under investigation. In this review, we discuss the clinical advance of copanlisib through preclinical to Phase III trials, its unique cellular targets and side effect profile that have poised it as a safer and equally efficacious option when compared to the older-generation oral PI3Kis, and its utility to the clinician as part of the therapeutic armamentarium for relapsed and/or refractory FL.
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Affiliation(s)
- Ayushi F Chauhan
- Department of Hematology and Oncology, Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington DC, USA
| | - Bruce D Cheson
- Scientific Advisory Board, Lymphoma Research Foundation, Washington, DC, USA
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Genetic complexity impacts the clinical outcome of follicular lymphoma patients. Blood Cancer J 2021; 11:11. [PMID: 33431798 PMCID: PMC7801414 DOI: 10.1038/s41408-020-00395-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 11/19/2020] [Accepted: 11/27/2020] [Indexed: 11/13/2022] Open
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Lumish M, Falchi L, Imber BS, Scordo M, von Keudell G, Joffe E. How we treat mature B-cell neoplasms (indolent B-cell lymphomas). J Hematol Oncol 2021; 14:5. [PMID: 33407745 PMCID: PMC7789477 DOI: 10.1186/s13045-020-01018-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 12/02/2020] [Indexed: 12/30/2022] Open
Abstract
Mature B cell neoplasms, previously indolent non-Hodgkin lymphomas (iNHLs), are a heterogeneous group of malignancies sharing similar disease courses and treatment paradigms. Most patients with iNHL have an excellent prognosis, and in many, treatment can be deferred for years. However, some patients will have an accelerated course and may experience transformation into aggressive lymphomas. In this review, we focus on management concepts shared across iNHLs, as well as histology-specific strategies. We address open questions in the field, including the influence of genomics and molecular pathway alterations on treatment decisions. In addition, we review the management of uncommon clinical entities including nodular lymphocyte-predominant Hodgkin lymphoma, hairy cell leukemia, splenic lymphoma and primary lymphoma of extranodal sites. Finally, we include a perspective on novel targeted therapies, antibodies, antibody-drug conjugates, bispecific T cell engagers and chimeric antigen receptor T cell therapy.
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Affiliation(s)
- Melissa Lumish
- Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, SR-441B, New York, NY, 10065, USA
| | - Lorenzo Falchi
- Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, SR-441B, New York, NY, 10065, USA
| | - Brandon S Imber
- Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, SR-441B, New York, NY, 10065, USA
| | - Michael Scordo
- Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, SR-441B, New York, NY, 10065, USA
| | - Gottfried von Keudell
- Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, SR-441B, New York, NY, 10065, USA
| | - Erel Joffe
- Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, SR-441B, New York, NY, 10065, USA.
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Sorigue M, Cañamero E, Sancho JM. Precision medicine in follicular lymphoma: Focus on predictive biomarkers. Hematol Oncol 2020; 38:625-639. [PMID: 32700331 DOI: 10.1002/hon.2781] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 07/16/2020] [Accepted: 07/16/2020] [Indexed: 02/06/2023]
Abstract
Current care for patients with follicular lymphoma (FL) offers most of them long-term survival. Improving it further will require careful patient selection. This review focuses on predictive biomarkers (ie, those whose outcome correlations depend on the treatment strategy) in FL, because awareness of what patient subsets benefit most or least from each therapy will help in this task. The first part of this review aims to summarize what biomarkers are predictive in FL, the magnitude of the effect and the quality of the evidence. We find predictive biomarkers in the setting of (a) indication of active treatment, (b) front-line induction (use of anthracyline-based regimens, CHOP vs bendamustine, addition of rituximab), (c) post-(front-line)induction (rituximab maintenance, radioimmunotherapy), and (d) relapse (hematopoietic stem cell transplant) and targeted agents. The second part of this review discusses the challenges of precision medicine in FL, including (a) cost, (b) clinical relevance considerations, and (c) difficulties over the broad implementation of biomarkers. We then provide our view on what biomarkers may become used in the next few years. We conclude by underscoring the importance of assessing the potential predictiveness of available biomarkers to improve patient care but also that there is a long road ahead before reaching their broad implementation due to remaining scientific, technological, and economic hurdles.
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Affiliation(s)
- Marc Sorigue
- Department of Hematology, ICO-Hospital Germans Trias i Pujol, Institut de Recerca Josep Carreras, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Eloi Cañamero
- Department of Hematology, ICO-Hospital Germans Trias i Pujol, Institut de Recerca Josep Carreras, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Juan-Manuel Sancho
- Department of Hematology, ICO-Hospital Germans Trias i Pujol, Institut de Recerca Josep Carreras, Universitat Autònoma de Barcelona, Badalona, Spain
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Abstract
Although outcomes for follicular lymphoma (FL) continue to improve, it remains incurable for the majority of patients. Through next generation sequencing (NGS) studies, we now recognize that the genomic landscape of FL is skewed toward highly recurrent mutations in genes that encode epigenetic regulators co-occurring with the pathognomonic t(14;18) translocation. Adopting these technologies to study longitudinal and spatially-derived lymphomas has provided unique insights into the tumoral heterogeneity, clonal evolution of the disease and supports the existence of a tumor-repopulating population, considered the Achilles' heel of this lymphoma. An in-depth understanding of the genomics and its contribution to the disease pathogenesis is identifying new biomarkers and therapeutic targets that can be translated into clinical practice and, in the not too distant future, enable us to start considering precision-based approaches to the management of FL.
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Affiliation(s)
- Lucy Pickard
- Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Giuseppe Palladino
- Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Jessica Okosun
- Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK
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Kimby E, Lockmer S, Holte H, Hagberg H, Wahlin BE, Brown P, Østenstad B. The simplified follicular lymphoma PRIMA‐prognostic index is useful in patients with first‐line chemo‐free rituximab‐based therapy. Br J Haematol 2020; 191:738-747. [DOI: 10.1111/bjh.16692] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Accepted: 04/05/2020] [Indexed: 12/12/2022]
Affiliation(s)
- Eva Kimby
- Unit of Hematology Department of Medicine at Huddinge Karolinska Institutet Stockholm Sweden
| | - Sandra Lockmer
- Unit of Hematology Department of Medicine at Huddinge Karolinska Institutet Stockholm Sweden
- Unit of Hematology Karolinska University Hospital Stockholm Sweden
| | - Harald Holte
- Department of Oncology Oslo University Hospital Oslo Norway
- KG Jebsen Center for B‐Cell Malignancies Oslo Norway
| | - Hans Hagberg
- Department of Oncology Academic Hospital Uppsala Sweden
| | - Björn E. Wahlin
- Unit of Hematology Department of Medicine at Huddinge Karolinska Institutet Stockholm Sweden
- Unit of Hematology Karolinska University Hospital Stockholm Sweden
| | - Peter Brown
- Department of Hematology Rigshospitalet Copenhagen Denmark
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[Progress in the research of gene mutations in follicular lymphoma]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2020; 41:172-176. [PMID: 32135639 PMCID: PMC7357952 DOI: 10.3760/cma.j.issn.0253-2727.2020.02.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Bishton MJ, Rule S, Wilson W, Turner D, Patmore R, Clifton-Hadley L, McMillan A, Lush R, Haynes A. The UK NCRI study of chlorambucil, mitoxantrone and dexamethasone (CMD) versus fludarabine, mitoxantrone and dexamethasone (FMD) for untreated advanced stage follicular lymphoma: molecular response strongly predicts prolonged overall survival. Br J Haematol 2020; 190:545-554. [PMID: 32150649 DOI: 10.1111/bjh.16555] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Accepted: 02/05/2020] [Indexed: 11/28/2022]
Abstract
We present a long-term follow-up of the UK chlorambucil, mitoxantrone and dexamethasone (CMD) versus fludarabine, mitoxantrone and dexamethasone (FMD) for untreated advanced, symptomatic follicular lymphoma (FL). This trial was the first to prospectively assess molecular response and the impact on outcomes for 400 patients. The median progression-free survival (PFS) and overall survival (OS) for CMD were 3·6 and 14·6 years vs. 3·0 and 15·7 years for FMD, respectively. Estimates for Restricted Mean Survival Time (RMST) suggested no difference in PFS or OS. For the whole cohort there was a highly significant difference in survival by POD24, with a median OS from a risk-defining event of 3·9 years compared to 13·7 years for all others (RMST P < 0·001). Molecular remission was achieved in 25/46 patients (54·3%) in the CMD arm and 20/41 (48·8%) in the FMD arm (P = 0·6). Molecular negativity resulted in median PFS of 5·6 years vs. 2·3 years for molecularly positive (log-rank P < 0·001) and median OS not reached versus 12·5 years (log-rank P < 0·01). No cases of progression occurred in minimal residual disease (MRD) negative patients after six years of follow-up. Although there was no difference in outcomes between arms, this is the first prospective study to report MRD negativity resulting in significantly improved OS.
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Affiliation(s)
- Mark J Bishton
- Clinical Haematology, Nottingham City Hospital, Nottingham, UK
| | - Simon Rule
- Department of Haematology, University of Plymouth Medical School, Plymouth, UK
| | - William Wilson
- CRUK and UCL Cancer Trials Centre, University College London, London, UK
| | - Deborah Turner
- Department of Haematology, Torbay and South Devon NHS Trust, Torquay, UK
| | - Russell Patmore
- Queen's Centre for Oncology and Haematology, Hull and East Yorkshire Hospitals, Cottingham, UK
| | | | - Andrew McMillan
- Centre for Clinical Haematology, Nottingham University Hospitals, Nottingham, UK
| | - Richard Lush
- Department of Haematology, Gloucestershire Hospitals NHS Foundation Trust, Cheltenham, UK
| | - Andrew Haynes
- Sherwood Forest Hospitals NHS Foundation Trust, Sutton-In-Ashfield, UK
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