bims-hodlyp Biomed News
on Hodgkin lymphoma: Pathology and Biology
Issue of 2023–10–22
eleven papers selected by
Old Bear
  1. Microenvironmental immune cell alterations across the spectrum of nodular lymphocyte predominant Hodgkin lymphoma and T-cell/histiocyte-rich large B-cell lymphoma.
  2. Tackling PD1i resistance in Hodgkin lymphoma.
  3. EBV-induced T-cell responses in EBV-specific and nonspecific cancers.
  4. Epstein-Barr virus encoded EBNA2 downregulates ICOSL by inducing miR-24 in B-cell lymphoma.
  5. The impact of hepatitis B virus and hepatitis C virus infections in patients with Hodgkin's and non-Hodgkin's lymphoma.
  6. Physiologic 18F-FDG Uptake in Brown Adipose Tissue and Lactating Breast in a Patient with Hodgkin Lymphoma.
  7. Lymphoma In Patients With Inflammatory Bowel Disease: A Multicenter Collaborative Study Between Getaid And Lysa.
  8. Characteristics and predictors of infusion-related reactions to rituximab in patients with B-cell non-Hodgkin lymphoma.
  9. Baseline circulating tumour DNA and interim PET predict response in relapsed/refractory classical Hodgkin lymphoma.
  10. Follow-up of the GHSG HD16 trial of PET-guided treatment in early-stage favorable Hodgkin lymphoma.
  11. Efficacy and Safety of Immune Checkpoint Inhibitors in Hematologic Malignancies.
  1. Front Oncol. 2023 ;13 1267604
    Microenvironmental immune cell alterations across the spectrum of nodular lymphocyte predominant Hodgkin lymphoma and T-cell/histiocyte-rich large B-cell lymphoma.
    Christos Panayi, Ayse U Akarca, Alan D Ramsay, Ananth G Shankar, Brunangelo Falini, Miguel A Piris, David Linch, Teresa Marafioti.
       Background: The clinicopathological spectrum of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), also known as nodular lymphocyte predominant B-cell lymphoma, partially overlaps with T-cell/histiocyte-rich large B-cell lymphoma (THRLCBL). NLPHL histology may vary in architecture and B-cell/T-cell composition of the tumour microenvironment. However, the immune cell phenotypes accompanying different histological patterns remain poorly characterised.
    Methods: We applied a multiplexed immunofluorescence workflow to identify differential expansion/depletion of multiple microenvironmental immune cell phenotypes between cases of NLPHL showing different histological patterns (as described by Fan et al, 2003) and cases of THRLBCL.
    Results: FOXP3-expressing T-regulatory cells were conspicuously depleted across all NLPHL cases. As histology progressed to variant Fan patterns C and E of NLPHL and to THRLBCL, there were progressive expansions of cytotoxic granzyme-B-expressing natural killer and CD8-positive T-cells, PD1-expressing CD8-positive T-cells, and CD163-positive macrophages including a PDL1-expressing subset. These occurred in parallel to depletion of NKG2A-expressing natural killer and CD8-positive T-cells.
    Discussion: These findings provide new insights on the immunoregulatory mechanisms involved in NLPHL and THLRBCL pathogenesis, and are supportive of an increasingly proposed biological continuum between these two lymphomas. Additionally, the findings may help establish new biomarkers of high-risk disease, which could support a novel therapeutic program of immune checkpoint interruption targeting the PD1:PDL1 and/or NKG2A:HLA-E axes in the management of high-risk NLPHL and THRLBCL.
    Keywords:  T-cell/histiocyte-rich large B-cell lymphoma; immune checkpoints; lymphoma biology; multispectral immunofluorescence; nodular lymphocyte predominant Hodgkin lymphoma (NLPHL); tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2023.1267604
  2. Blood. 2023 Oct 19. 142(16): 1333-1334
    Tackling PD1i resistance in Hodgkin lymphoma.
    Graham P Collins.
      
    DOI:  https://doi.org/10.1182/blood.2023021283
  3. Front Immunol. 2023 ;14 1250946
    EBV-induced T-cell responses in EBV-specific and nonspecific cancers.
    Qiuting Zhang, Miao Xu.
      Epstein-Barr virus (EBV) is a ubiquitous human tumor virus associated with various malignancies, including B-lymphoma, NK and T-lymphoma, and epithelial carcinoma. It infects B lymphocytes and epithelial cells within the oropharynx and establishes persistent infection in memory B cells. With a balanced virus-host interaction, most individuals carry EBV asymptomatically because of the lifelong surveillance by T cell immunity against EBV. A stable anti-EBV T cell repertoire is maintained in memory at high frequency in the blood throughout persistent EBV infection. Patients with impaired T cell immunity are more likely to develop life-threatening lymphoproliferative disorders, highlighting the critical role of T cells in achieving the EBV-host balance. Recent studies reveal that the EBV protein, LMP1, triggers robust T-cell responses against multiple tumor-associated antigens (TAAs) in B cells. Additionally, EBV-specific T cells have been identified in EBV-unrelated cancers, raising questions about their role in antitumor immunity. Herein, we summarize T-cell responses in EBV-related cancers, considering latency patterns, host immune status, and factors like human leukocyte antigen (HLA) susceptibility, which may affect immune outcomes. We discuss EBV-induced TAA-specific T cell responses and explore the potential roles of EBV-specific T cell subsets in tumor microenvironments. We also describe T-cell immunotherapy strategies that harness EBV antigens, ranging from EBV-specific T cells to T cell receptor-engineered T cells. Lastly, we discuss the involvement of γδ T-cells in EBV infection and associated diseases, aiming to elucidate the comprehensive interplay between EBV and T-cell immunity.
    Keywords:  CAR-T; EBV-associated cancer; EBV-specific T cells; Epstein-Barr virus; T-cell immunity; tumor-associated antigens (TAAs); γδ T-cells
    DOI:  https://doi.org/10.3389/fimmu.2023.1250946
  4. Blood. 2023 Oct 17. pii: blood.2023021346. [Epub ahead of print]
    Epstein-Barr virus encoded EBNA2 downregulates ICOSL by inducing miR-24 in B-cell lymphoma.
    Martina Leopizzi, Lucia Mundo, Elena Messina, Federica Campolo, Stefano Lazzi, Antonio Angeloni, Cinzia Marchese, Lorenzo Leoncini, Carla Giordano, Frank Slack, Pankaj Trivedi, Eleni Anastasiadou.
      Hematological malignancies like Burkitt lymphoma (BL), Hodgkin's lymphoma (HL) and diffuse large B cell lymphoma (DLBCL) cause significant morbidity in humans. A substantial number of these lymphomas, particularly, HL and DLBCLs have poorer prognosis due to their association with Epstein-Barr virus (EBV). Our earlier studies have shown that EBV encoded nuclear antigen EBNA2 upregulates PD-L1 in DLBCL and BLs by downregulating miR-34a. Here, we investigated whether EBNA2 affects the inducible co-stimulator ligand, ICOSL, a molecule required for efficient recognition of tumor cells by T cells through the engagement of ICOS on the latter. In virus-infected and EBNA2-transfected B-lymphoma cells, ICOSL expression was reduced. Our investigation of the molecular mechanisms revealed that this was due to an increase in miR-24 by EBNA2. By using ICOSL 3'UTR-Luc reporter system, we validated that ICOSL is an authentic miR-24 target. Transfection of anti-miR-24 molecules in EBNA2 expressing lymphoma cells reconstituted ICOSL expression and increased tumor immunogenicity in mixed lymphocyte reactions. Since miR-24 is known to target c-MYC, an oncoprotein positively regulated by EBNA2, we analyzed its expression in anti-miR-24 transfected lymphoma cells. Indeed, the reduction of miR-24 in EBNA2 expressing DLBCL further elevated c-MYC and increased apoptosis. Consistent with the in vitro data, EBNA2 positive DLBCL biopsies expressed low ICOSL and high miR-24. We suggest that EBV evades host immune responses through EBNA2 by inducing miR-24 to reduce ICOSL expression and for simultaneous rheostatic maintenance of pro-proliferative c-MYC levels. Overall, these data identify miR-24 as potential therapeutically relevant target in EBV associated lymphomas.
    DOI:  https://doi.org/10.1182/blood.2023021346
  5. Int J Immunopathol Pharmacol. 2023 Jan-Dec;37:37 3946320231207342
    The impact of hepatitis B virus and hepatitis C virus infections in patients with Hodgkin's and non-Hodgkin's lymphoma.
    Dalia Y Kadry, Mostafa A Elbahnasawy, Mohamed Tm Mansour, Omnia K El Gebaly, Hala Aziz, Mahmoud M Kamel, Ahmed S Abdel-Moneim, Samah Radwan.
       BACKGROUND: This study aimed to determine the prevalence of HCV and occult HBV among newly diagnosed pre-treatment Egyptian lymphoma patients and evaluate patients' outcomes based on the presence of the viral infections.
    METHODS: The study included 80 therapy-naïve lymphoma patients including 71 non-Hodgkin lymphoma (NHL) and 9 Hodgkin lymphoma disease (HD) in addition to 100 healthy volunteers. HBV screening using HBsAg and anti-HBc IgM and HCV using AB/Ag ELISA and real-time RT-PCR were screened in tested and control groups. The diagnosis was confirmed by histopathology. Overall survival (OS) and progression-free survival (PFS) were conducted to diseased patients.
    RESULTS: Healthy patients showed 4/100, (4%) active HCV infection and 1/100, (1%) active HBV infection and no occult HBV infection. Among NHL patients, 28 were positive for HBV (6 active and 22 occult HBV infection). Occult HBV was also detected in 5/9 HD patients. HCV was detected in (30/71, 42.3%) of NHL patients and in a single HD patient. Ten occult HBV NHL patients showed a mixed infection with HCV. The incidence of both HCV and HBV are higher in NHL than HL patients. After antitumor treatment, complete remission for lymphoma was achieved in 45% of patients. Both overall survival (OS) and progression-free survival (PFS) were correlated and significantly associated with patients' LDH levels.
    CONCLUSIONS: Our findings claim the suggestive role of HCV and occult HBV infections in NHL but not HL patients in comparison to healthy control, suggesting pre-screening of related factors including occult HBV in for potential better therapy response.
    Keywords:  co-infection; lymphoma; occult HBV; overall survival; progression-free survival
    DOI:  https://doi.org/10.1177/03946320231207342
  6. J Nucl Med Technol. 2023 Oct 18. pii: jnmt.123.266472. [Epub ahead of print]
    Physiologic 18F-FDG Uptake in Brown Adipose Tissue and Lactating Breast in a Patient with Hodgkin Lymphoma.
    Lulu Bi, Allison C Rosenthal, Phillip H Kuo, Ming Yang.
      We present the case of a young woman with Hodgkin lymphoma exhibiting physiologic 18F-FDG uptake in brown adipose tissue and lactating breast on consecutive 18F-FDG PET/CT scans. Both entities are common imaging interpretation pitfalls and should be recognized in oncologic 18F-FDG PET/CT practice. We review the imaging features and differential diagnosis of these 2 entities and discuss the radiation safety precautions during breastfeeding.
    Keywords:  FDG; PET; breast; brown adipose tissue; lactating
    DOI:  https://doi.org/10.2967/jnmt.123.266472
  7. J Crohns Colitis. 2023 Oct 18. pii: jjad177. [Epub ahead of print]
    Lymphoma In Patients With Inflammatory Bowel Disease: A Multicenter Collaborative Study Between Getaid And Lysa.
    Marie Muller, Julien Broséus, Adrien Guilloteau, Stéphane Wasse, Catherine Thiéblemont, Stéphane Nancey, Guillaume Cadiot, Aurélien Amiot, David Laharie, Sophie Vieujean, Yoram Bouhnik, Chloé Martineau, Christophe Michiels, Xavier Hebuterne, Guillaume Savoye, Denis Franchimont, Philippe Seksik, Laurent Beaugerie, Marc Maynadié, Pierre Feugier, Laurent Peyrin-Biroulet.
       BACKGROUND: IBD is associated with an increased risk of developing lymphoma. Although recent data clarifies lymphoma epidemiology in IBD patients, clinical and pathological characteristics of lymphoma occurring in IBD remain ill-known.
    METHODS: Patients with IBD and lymphoma were retrospectively identified in the framework of a national collaborative study including the Groupe d'Étude Thérapeutique des Affections Inflammatoires du Tube Digestif (GETAID) and the Lymphoma Study Association (LYSA). We characterized clinical and prognostic features for the 3 most frequent lymphoma subtypes occurring in IBD. We performed a multicentric case-control study. Controls (lymphoma de novo) were matched (5:1) to cases on gender, age at diagnosis, lymphoma subtype, year of diagnosis, IPI/FLIPI indexes. Overall survival (OS) and progression free survival were compared between cases and controls.
    RESULTS: 133 IBD patients with lymphoma were included (males = 62.4 %, median age at lymphoma diagnosis = 49 years in males ; 42 in females). Most had Crohn's disease (73.7 %) and were exposed to thiopurines (59.4 %). The most frequent lymphoma subtypes were diffuse large B cell lymphoma (DLBCL, 45.1 %), Hodgkin lymphoma (HL, 18.8 %), and follicular lymphoma (FL, 10.5 %). When matched with 365 controls, prognosis was improved in IBD patients with DLBCL compared to controls (p = 0.0064, hazard ratio = 0.36) or similar (HL and FL).
    CONCLUSION: Lymphomas occurring in IBD patients do not seem to have a worse outcome than in patients without IBD. Due to the scarcity of this situation, those patients should be managed in expert centers.
    Keywords:  Crohn’s disease; inflammatory bowel disease; lymphoma; prognosis; ulcerative colitis
    DOI:  https://doi.org/10.1093/ecco-jcc/jjad177
  8. J Chemother. 2023 Oct 20. 1-8
    Characteristics and predictors of infusion-related reactions to rituximab in patients with B-cell non-Hodgkin lymphoma.
    Nour Faqeer, Rawaa Alrabie, Rand Al-Haddadin, Mohammad Ma'koseh.
      This retrospective study aimed to assess the characteristics and predictors of infusion-related reactions (IRRs) to rituximab in patients with B-cell non-Hodgkin lymphoma (B-NHL). The medical records of adult patients with B-NHL who received their first cycle of rituximab from August 2020 to August 2022 were reviewed. IRRs were defined as any signs experienced by patients during rituximab infusion and graded according to the Common Terminology Criteria for Adverse Events. During the study period, 334 patients were included; among them, 100 patients (30%) developed IRRs (mean age 54.7 (SD 13.2) years). Of the reported IRRs, 90% were grade II reactions, and 10% were grade III reactions. The multivariate analysis identified indolent lymphoma [OR 1.90, p = 0.025], no hydrocortisone as premedication [OR 3.03, p = 0.029], thrombocytopenia [OR 2.55, p = 0.009], and absolute lymphocyte count ≥ 2000 lymphocytes/microL [OR 1.74, p = 0.045] as independent predictors for IRRs.
    Keywords:  B-cell lymphoma; Rituximab; adverse reactions; infusion-related reactions; non-Hodgkin lymphoma
    DOI:  https://doi.org/10.1080/1120009X.2023.2270833
  9. Br J Haematol. 2023 Oct 18.
    Baseline circulating tumour DNA and interim PET predict response in relapsed/refractory classical Hodgkin lymphoma.
    Eleonora Calabretta, Martina di Trani, Francesco Corrado, Martina Sollini, Vanessa Cristaldi, Fabrizio Marino, Lodovico Terzi di Bergamo, Alessio Bruscaggin, Maria Cristina Pirosa, Stefania Bramanti, Arturo Chiti, Davide Rossi, Carmelo Carlo-Stella.
      Reliable biomarkers for early identification of treatment failure in relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL) are lacking. Circulating tumour DNA (ctDNA) profiling has emerged as a powerful predictive and prognostic tool in several haemopoietic and non-haemopoietic malignancies and may guide rational treatment choices in r/r cHL. To assess the predictive and prognostic value of ctDNA, we performed a retrospective analysis on 55 r/r cHL patients treated with the bendamustine, gemcitabine and vinorelbine (BEGEV) regimen and additionally evaluated the potential utility of integrating ctDNA with interim [18 F]-FDG positron emission tomography (iPET). Baseline ctDNA genotyping in r/r cHL mirrored gene mutations and pathways involved in newly diagnosed cHL. We found that baseline ctDNA quantification and serial ctDNA monitoring have prognostic value in r/r cHL receiving salvage chemotherapy. Lastly, integrating ctDNA quantification with iPET evaluation may improve the early identification of patients at high risk of failing standard salvage therapy, who may benefit from an early switch to immunotherapeutic agents. Collectively, our results support the implementation of non-invasive methods to detect minimal residual disease in recurrent cHL and justify its prospective evaluation in appropriately designed clinical trials.
    Keywords:  Hodgkin lymphoma; PET; circulating tumour DNA; prognostic factors
    DOI:  https://doi.org/10.1111/bjh.19162
  10. Leukemia. 2023 Oct 16.
    Follow-up of the GHSG HD16 trial of PET-guided treatment in early-stage favorable Hodgkin lymphoma.
    Michael Fuchs, Anne Sophie Jacob, Helen Kaul, Carsten Kobe, Georg Kuhnert, Thomas Pabst, Richard Greil, Paul J Bröckelmann, Max S Topp, Marianne Just, Bernd Hertenstein, Martin Soekler, Martin Vogelhuber, Josée M Zijlstra, Ulrich Bernd Keller, Stefan W Krause, Ulrich Dührsen, Julia Meissner, Andreas Viardot, Hans-Theodor Eich, Christian Baues, Volker Diehl, Andreas Rosenwald, Ina Buehnen, Bastian von Tresckow, Markus Dietlein, Peter Borchmann, Andreas Engert, Dennis A Eichenauer.
      The primary analysis of the GHSG HD16 trial indicated a significant loss of tumor control with PET-guided omission of radiotherapy (RT) in patients with early-stage favorable Hodgkin lymphoma (HL). This analysis reports long-term outcomes. Overall, 1150 patients aged 18-75 years with newly diagnosed early-stage favorable HL were randomized between standard combined-modality treatment (CMT) (2x ABVD followed by PET/CT [PET-2] and 20 Gy involved-field RT) and PET-2-guided treatment omitting RT in case of PET-2 negativity (Deauville score [DS] < 3). The study aimed at excluding inferiority of PET-2-guided treatment and assessing the prognostic impact of PET-2 in patients receiving CMT. At a median follow-up of 64 months, PET-2-negative patients had a 5-year progression-free survival (PFS) of 94.2% after CMT (n = 328) and 86.7% after ABVD alone (n = 300; HR = 2.05 [1.20-3.51]; p = 0.0072). 5-year OS was 98.3% and 98.8%, respectively (p = 0.14); 4/12 documented deaths were caused by second primary malignancies and only one by HL. Among patients assigned to CMT, 5-year PFS was better in PET-2-negative (n = 353; 94.0%) than in PET-2-positive patients (n = 340; 90.3%; p = 0.012). The difference was more pronounced when using DS4 as cut-off (DS 1-3: n = 571; 94.0% vs. DS ≥ 4: n = 122; 83.6%; p < 0.0001). Taken together, CMT should be considered standard treatment for early-stage favorable HL irrespective of the PET-2-result.
    DOI:  https://doi.org/10.1038/s41375-023-02064-y
  11. Clin Lymphoma Myeloma Leuk. 2023 Sep 19. pii: S2152-2650(23)01549-5. [Epub ahead of print]
    Efficacy and Safety of Immune Checkpoint Inhibitors in Hematologic Malignancies.
    Muhammed Talha Bilgihan, Ayse Nur Eryigit, Rafiye Ciftciler.
      The emergence of immune checkpoint inhibitors (ICIs) has led to a dramatic paradigm shift within the landscape of cancer treatment, igniting significant interest in their potential application in treating hematologic malignancies. This comprehensive review critically has examined the existing body of literature to shed light on the evolving understanding of the efficacy and safety of ICIs, both as a single agent and in combination regimens in hematologic malignancies. Across distinct lymphoma subtypes, the observed treatment responses exhibit diversity, and conflicts. Notably, Hodgkin lymphoma and certain non-Hodgkin lymphomas such as primary mediastinal B-cell lymphoma, emerge as remarkable cases, showing encouraging response rates and outcomes. However, the efficacy of ICIs reveals variations among subtypes such as chronic lymphocytic leukemia and multiple myeloma. Combination therapies consistently demonstrated superior outcomes compared to monotherapy in several malignancies. While the potential benefits of ICIs in hematologic malignancies are evident, the safety profile warrants careful consideration. Immune-related and other adverse events, though generally tolerable and manageable, highlight the necessity of meticulous monitoring and appropriate intervention. The discussions prompted by these findings underscore the need for tailored treatment approaches, driven by disease subtype, patient characteristics, and potential biomarkers. Moreover, the emerging realm of combination therapies involving immune checkpoint inhibitors holds promise for enhanced treatment outcomes, and ongoing research endeavors aim to unravel the optimal strategies.
    Keywords:  Hematologic malignancy; Immune checkpoint inhibitors; Leukemia; Lymphoma; Multiple myeloma
    DOI:  https://doi.org/10.1016/j.clml.2023.09.002
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