bims-hodlyp 2023-11-19 papers

bims-hodlyp

Biomed News

on Hodgkin lymphoma: Pathology and Biology

Issue of 2023–11–19
eleven papers selected by

Genetic abnormalities assist in pathological diagnosis and EBV-positive cell density impact survival in Chinese angioimmunoblastic T-cell lymphoma patients.
Viral and host factors drive a type 1 Epstein-Barr virus spontaneous lytic phenotype.
Prognostic Markers within the Tumour Microenvironment in Classical Hodgkin Lymphoma.
Whole slide imaging of tumour microenvironment in classical Hodgkin's lymphoma: development of a clinical prediction model based on programmed death-ligand 1 and tumorous Reed-Sternberg cells.
A rare presentation of vanishing bile duct syndrome in Hodgkin lymphoma: Case report.
Does discontinuing bleomycin due to toxicity increase the risk of lymphoma progression? Real-life data from a homogeneous population of advanced stage Hodgkin lymphoma.
Tislelizumab monotherapy in patients with previously untreated early-stage classical Hodgkin lymphoma: a real-world study.
"Wandering Spleen" With Lymphomatous Involvement.
A different perspective on PET/CT before treatment in patients with Hodgkin lymphoma: importance of volumetric and dissemination parameters.
Analysis of redox status and HDL subclasses in patients with lymphoma and the associations with FDG-PET/CT findings.
Phase 2 LYSA study of prednisone, vinblastine, doxorubicin, bendamustine for untreated older Hodgkin lymphoma patients.

Chin J Cancer Res. 2023 Oct 30. 35(5): 536-549

Genetic abnormalities assist in pathological diagnosis and EBV-positive cell density impact survival in Chinese angioimmunoblastic T-cell lymphoma patients.

Yunfei Shi, Haojie Wang, Yanfei Liu, Mengping Long, Ning Ding, Lan Mi, Yumei Lai, Lixin Zhou, Xinting Diao, Xianghong Li, Weiping Liu, Jun Zhu.

   Objective: To explore the application of genetic abnormalities in the diagnosis of angioimmunoblastic T-cell lymphoma (AITL) and the reliable pathological prognostic factors.
Methods: This study included 53 AITL cases, which were reviewed for morphological patterns, immunophenotypes, presence of Hodgkin and Reed-Sternberg (HRS)-like cells, and co-occurrence of B cell proliferation. The Epstein-Barr virus (EBV)-positive cells in tissues were counted, and cases were classified into "EBV encoded RNA (EBER) high-density" group if >50/HPF. Targeted exome sequencing was performed.
Results: Mutation data can assist AITL diagnosis: 1) with considerable HRS-like cells (20 cases): RHOA mutated in 14 cases (IDH2 co-mutated in 3 cases, 4 cases with rare RHOA mutation), TET2 was mutated in 5 cases (1 case co-mutated with DNMT3A), and DNMT3A mutated in 1 case; 2) accompanied with B cell lymphoma (7 cases): RHOA mutated in 4 cases (1 case had IDH2 mutation), TET2 mutated in 2 cases and DNMT3A mutated in 1 case; 3) mimic peripheral T cell lymphoma, not otherwise specified (5 cases): RHOA mutated in 2 cases (IDH2 co-mutated in 1 case), TET2 mutated in 3 cases, and DNMT3A mutated in 1 case; 4) pattern 1 (1 case), RHOA and TET2 co-mutated. Besides RHOAG17V (30/35), rare variant included RHOAK18N, RHOAR68H, RHOAC83Y, RHOAD120G and RHOAG17del, IDH2R172 co-mutated with IDH2M397V in one case. There were recurrent mutations of FAT3, PCLO and PIEZO1 and genes of epigenetic remodeling, T-cell activation, APC and PI3K/AKT pathway. EBER high-density independently indicated adverse overall survival and progression-free survival (P=0.046 and P=0.008, Kaplan-Meier/log-rank).
Conclusions: Over half AITL cases might be confused in diagnosis for certain conditions without mutation data. Targeted exome sequencing with a comprehensive panel is crucial to detect both hot-spot and rare mutation variants for RHOA and IDH2 and other recurrent mutated genes in addition to TET2 and DNMT3A. EBER high-density independently indicated adverse survival.

Keywords:  T cell; lymphoma; mutation; pathology; prognosis

DOI:  https://doi.org/10.21147/j.issn.1000-9604.2023.05.10
mBio. 2023 Nov 16. e0220423

Viral and host factors drive a type 1 Epstein-Barr virus spontaneous lytic phenotype.

Katherine A Willard, Ashley P Barry, Cliff I Oduor, John Michael Ong'echa, Jeffrey A Bailey, Ann M Moormann, Micah A Luftig.

   IMPORTANCE: Epstein-Barr virus (EBV) infects over 95% of adults worldwide. Given its connection to various cancers and autoimmune disorders, it is important to understand the mechanisms by which infection with EBV can lead to these diseases. In this study, we describe an unusual spontaneous lytic phenotype in EBV strains isolated from Kenyan endemic Burkitt lymphoma patients. Because lytic replication of EBV has been linked to the pathogenesis of various diseases, these data could illuminate viral and host factors involved in this process.

Keywords:  Epstein–Barr virus; burkitt lymphoma; herpesvirus; lytic replication

DOI:  https://doi.org/10.1128/mbio.02204-23
Cancers (Basel). 2023 Oct 30. pii: 5217. [Epub ahead of print]15(21):

Prognostic Markers within the Tumour Microenvironment in Classical Hodgkin Lymphoma.

Arina Martynchyk, Rakin Chowdhury, Eliza A Hawkes, Colm Keane.

  Classical Hodgkin lymphoma (cHL) accounts for 0.4% of all new cancer cases globally. Despite high cure rates with standard treatment, approximately 15% of patients still experience relapsed or refractory (RR) disease, and many of these eventually die from lymphoma-related causes. Exciting new targeted agents such as anti-PD-1 agents and brentuximab vedotin have changed the therapeutic paradigm beyond chemotherapy and radiotherapy alone. Advances in understanding of the molecular biology are providing insights in the context of novel therapies. The signature histology of cHL requires the presence of scant malignant Hodgkin Reed-Sternberg cells (HRSCs) surrounded by a complex immune-rich tumour microenvironment (TME). The TME cellular composition strongly influences outcomes, yet knowledge of the precise characteristics of TME cells and their interactions with HRSCs is evolving. Novel high-throughput technologies and single-cell sequencing allow deeper analyses of the TME and mechanisms elicited by HRSCs to propagate growth and avoid immune response. In this review, we explore the evolution of knowledge on the prognostic role of immune cells within the TME and provide an up-to-date overview of emerging prognostic data on cHL from new technologies that are starting to unwind the complexity of the cHL TME and provide translational insights into how to improve therapy in the clinic.

Keywords:  Classical Hodgkin lymphoma; PD-L1; T-cells; immune checkpoint inhibitors; prognostic markers; tumour microenvironment; tumour-associated macrophages

DOI:  https://doi.org/10.3390/cancers15215217
J Clin Pathol. 2023 Nov 17. pii: jcp-2023-209097. [Epub ahead of print]

Whole slide imaging of tumour microenvironment in classical Hodgkin's lymphoma: development of a clinical prediction model based on programmed death-ligand 1 and tumorous Reed-Sternberg cells.

Antonio Santisteban Espejo, Irene Bernal-Florindo, Pedro Montero-Pavon, Jose Perez-Requena, Lidia Atienza-Cuevas, Ana Villalba-Fernandez, Marcial Garcia-Rojo.

   AIMS: The prognostic impact of programmed death-ligand 1 (PD-L1) cells in classic Hodgkin lymphoma (cHL) tumour microenvironment remains undefined.
METHODS: Model development via Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis guidelines were followed. PD-L1+ and CD30+ tumoral Reed-Sternberg cells were quantified through whole slide imaging and digital image analysis in 155 digital histopathological slides of cHL. Univariate and multivariate survival analyses were performed. The analyses were reproduced for patients with advanced stages (IIB, III and IV) using the Advanced-stage cHL International Prognostic Index.
RESULTS: The PD-L1/CD30 ratio was statistically significantly associated with survival outcomes. Patients with a PD-L1/CD30 ratio above 47.1 presented a shorter overall survival (mean OS: 53.7 months; 95% CI: 28.7 to 78.7) in comparison with patients below this threshold (mean OS: 105.4 months; 95% CI: 89.6 to 121.3) (p=0.04). When adjusted for covariates, the PD-L1/CD30 ratio retained prognostic impact, both for the OS (HR: 1.005; 95% CI: 1.002 to 1.008; p=0.000) and the progression-free survival (HR: 3.442; 95% CI: 1.045 to 11.340; p=0.04) in a clinical and histopathological multivariate model including the male sex (HR: 3.551; 95% CI: 0.986 to 12.786; p=0.05), a percentage of tumoral cells ≥10.1% (HR: 1.044; 95% CI: 1.003 to 1.087; p=0.03) and high risk International Prognostic Score (≥3 points) (HR: 6.453; 95% CI: 1.970 to 21.134; p=0.002).
CONCLUSIONS: The PD-L1/CD30 ratio identifies a group of cHL patients with an increased risk of treatment failure. Its clinical application can be performed as it constitutes an easy to implement pathological information in the diagnostic work-up of patients with cHL.

Keywords:  hematologic diseases; image processing, computer-assisted; lymphoma; pathology, molecular

DOI:  https://doi.org/10.1136/jcp-2023-209097
SAGE Open Med Case Rep. 2023 ;11 2050313X231208968

A rare presentation of vanishing bile duct syndrome in Hodgkin lymphoma: Case report.

Bharat Patodiya, Vinod K Ramani, Padaki Nagaraja Rao, Mithun Sharma, Shalini Patodiya, D Nageshwar Reddy.

  In this report, we present the case of vanishing bile duct syndrome in the setting of classical Hodgkin lymphoma. Vanishing bile duct syndrome was diagnosed retrospectively in this patient with Hodgkin lymphoma, who initially presented with a hepatic abnormality presumed to be drug induced. Vanishing bile duct syndrome is characterized by the disappearance of bile ducts, with the progressive damage resulting in cholestasis. Thus, nivolumab therapy was initiated for Hodgkin lymphoma, in place of the standard ABVD (Doxorubicin, bleomycin, vinblastine, dacarbazine) regimen, which resulted in autoimmune hemolytic anemia. Alternatively, GDP (gemcitabine, dexamethasone, and carboplatin) chemotherapy with protocol modification resulted in better tolerance and remission of Hodgkin lymphoma. Granulocyte colony-stimulating factor support and romiplostim supplement were provided to prevent chemotherapy-induced neutropenia and thrombocytopenia, respectively. Due to the deranged liver function in our case, we initially suspected the etiology as drug-induced cholestatic injury. While hepatic failure is the leading cause of mortality among patients with Hodgkin lymphoma-related vanishing bile duct syndrome, our case report suggests a complete remission of vanishing bile duct syndrome following an adequate treatment of Hodgkin lymphoma and an improvement in the hepatic function. To conclude, our report describes the rare case of vanishing bile duct syndrome which heralded the diagnosis of Hodgkin lymphoma, and the effective management of Hodgkin lymphoma which precedes the improvement of hepatic abnormality.

Keywords:  Bile ducts; Hodgkin disease; bilirubin; cholestasis

DOI:  https://doi.org/10.1177/2050313X231208968
J Chemother. 2023 Nov 16. 1-8

Does discontinuing bleomycin due to toxicity increase the risk of lymphoma progression? Real-life data from a homogeneous population of advanced stage Hodgkin lymphoma.

Umut Yılmaz, Güldane Zulfaliyeva, Adnan Nuri Güzelli, Deniz Özmen, Tuğrul Elverdi, Ayşe Salihoğlu, Ahmet Emre Eskazan, Şeniz Öngören, Zafer Başlar, Muhlis Cem Ar.

  Hodgkin Lymphoma (HL) is often curable with ABVD therapy and improving outcomes is a main goal of ongoing research. Bleomycin-associated pneumonitis (BAPT) is a potentially life-threatening complication that necessitates bleomycin discontinuation. We conducted this study on a homogenous cohort of advanced stage HL treated only with ABVD for frontline therapy to assess if bleomycin discontinuation increases the risk of lymphoma progression. After the exclusion of patients who received radiotherapy or other drugs, 106 and 28 patients in the six-cycle ABVD and BAPT groups respectively had similar survival curves for progression and death with a 49-month median follow-up. PFS rates were also very similar at two and four years from diagnosis with 2-year PFS rates of 83.9% and 82.1% (RR = 1.1 95%CI = 0.45-2.2). Outcome comparisons were also similar between the two groups when stratified according to early response assessment with PET/CT. Patients who discontinued bleomycin due to toxicity did not experience an increased risk of progression compared to patients who completed six ABVD cycles.

Keywords:  Hodgkin lymphoma; adverse events; bleomycin toxicity; pneumonitis; risk of progression; supportive care

DOI:  https://doi.org/10.1080/1120009X.2023.2281089
Ann Hematol. 2023 Nov 13.

Tislelizumab monotherapy in patients with previously untreated early-stage classical Hodgkin lymphoma: a real-world study.

Peng Sun, Hang Yang, Yu Wang, Baitian Zhao, Man Nie, Kangming Huang, Zhiming Li.

  The anti-PD-1 antibodies have been reported to show a striking effect in relapsed and refractory(R/R) classical Hodgkin lymphoma (cHL), however, there is still limited real-world data assessing the role of anti-PD-1 antibody monotherapy in early-stage cHL. In this retrospective analysis, we reported the effectiveness and safety of tislelizumab monotherapy in the first-line therapy of early-stage cHL. Twenty-three consecutive patients (10 males and 13 females) with previously untreated stage I A-II B cHL were included. At interim evaluation after 2 doses of tislelizumab monotherapy, 11 of 23 patients (47.8%) achieved complete response (CR). At the end of tislelizumab monotherapy (EOTM), objective response was observed in 22 of 23 patients (95.7%), with CR in 16 patients (69.6%). Among six patients with PR-EOTM, two patients underwent 4 cycles of ABVD chemotherapy and one patient underwent 4 cycles of tislelizumab plus AVD. One patient who developed progressive disease (PD) after 4 doses of tislelizumab subsequently underwent 4 cycles of ABVD chemotherapy. Except for four patients with CR-EOTM, consolidative radiotherapy was given to 19 patients. All patients obtained CR at the end of all treatments. With a median follow-up time of 21.3 months (range, 6.9-32.7 months), the estimated 2-year PFS rate and 2-year OS rate were 95.65% and 100%, respectively. Except for grade 3 lymphocyte count decreased, no other grade 3/4 TRAE was observed. In addition, no serious AE was reported. Our preliminary data observed that tislelizumab monotherapy was safe and highly effective in previously untreated early-stage cHL.

Keywords:  Early-stage; Hodgkin Lymphoma; Monotherapy; Tislelizumab

DOI:  https://doi.org/10.1007/s00277-023-05541-7
Clin Nucl Med. 2023 Nov 17.

"Wandering Spleen" With Lymphomatous Involvement.

Feyza Cagliyan, Zeynep Ceren Balaban Genc, Fuat Dede, Tanju Yusuf Erdil.

ABSTRACT: Wandering spleen is a rare condition caused by either lack or the laxity of ligaments, which results malposition in the lower abdomen or pelvis. FDG PET/CT is the cornerstone of the staging procedures in the management of lymphomas leading to upstaging and picking up occult lesions in the spleen and extranodal sites. Herein, we reported initial staging 18F-FDG PET/CT findings of a woman with Hodgkin lymphoma whose spleen was absent in normal position and multiple intense heterogenous hypermetabolism in a pelvic mass raised a suspicion of wandering splenic involvement. The confirmation was made with selective spleen SPECT/CT images thereafter.

DOI: https://doi.org/10.1097/RLU.0000000000004949
Ann Hematol. 2023 Nov 15.

A different perspective on PET/CT before treatment in patients with Hodgkin lymphoma: importance of volumetric and dissemination parameters.

Ayşegül Aksu, Kadir Alper Küçüker, Şerife Solmaz, Bülent Turgut.

  The aim of this study is to investigate the role of the combination of volumetric and dissemination parameters obtained from pretreatment 18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in predicting the interim response and progression status in patients with Hodgkin lymphoma (HL). Pretreatment PET/CT images of HL patients were analyzed with LIFEx software, and volumes of interest (VOIs) were drawn with a fixed SUV 4.0 threshold. MTV, SUVmax, and TLG values were obtained from each VOI. Total MTV (tMTV) was calculated by summing the MTV values in all VOIs, and similarly, total TLG (tTLG) was obtained by summing the TLG values. The distance between the centers of the lesions was noted as Dmax, and the distance between the outermost voxels of the lesions as DmaxVox. tMTV/DmaxVox was calculated by dividing the tMTV value by the DmaxVox value, and tTLG/DmaxVox was calculated by dividing the tTLG value by the DmaxVox value. The correlation of pretreatment PET parameters with response groups (complete/poor) and relapse/progression status (stable/progressive) was statistically evaluated. A total of 52 patients were included in the study. Bulky disease, tMTV, tTLG, and tMTV/DmaxVox values were found to be significantly higher in the poor response group. tMTV > 190.60 ml was found to be the only prognostic factor predicting interim PET response. The tMTV/DmaxVox and tTLG/DmaxVox showed statistically significant differences between the groups with and without progression. tMTV/DmaxVox > 7.70 was found to be the only prognostic factor in predicting relapse/progression. The evaluation of tumor burden and dissemination together in 18F-FDG PET/CT before treatment in patients with HL can help us to predict the results of the patients.

Keywords:  Dmax; Hodgkin lymphoma; PET/CT; Volumetric

DOI:  https://doi.org/10.1007/s00277-023-05547-1
Front Oncol. 2023 ;13 1221414

Analysis of redox status and HDL subclasses in patients with lymphoma and the associations with FDG-PET/CT findings.

Bosa Mirjanic-Azaric, Sinisa Stankovic, Lana Nezic, Zana Radic Savic, Dragana Malcic-Zanic, Ranko Skrbic, Jelena Kotur-Stevuljevic, Natasa Bogavac-Stanojevic.

  Newer research points to alterations in the plasma redox status and the HDL subclass distributions in cancer. We aimed to assess the redox status and the HDL subclass distributions, lipids, and inflammatory markers in lymphoma patients in order to determine whether they were correlated with changes in FDG-PET/CT scans. At the beginning of this study, redox status, HDL subclasses, lipids, and inflammation biomarkers were determined in 58 patients with lymphoma (Hodgkin lymphoma, n=11 and non-Hodgkin lymphoma, n=47), and these same measurements were reassessed during their ensuing treatment (in 25 patients). Initially, the total oxidation status (TOS), the prooxidant-antioxidant balance (PAB), the OS index (OSI), the total protein sulfhydryl groups (SH-groups), and the advanced oxidation protein products (AOPP) were significantly higher in lymphoma patients as compared to healthy subjects, but the total antioxidant status (TAS) was significantly reduced. The PAB had a strong correlation with the CRP and interleukin-6 (rho=0.726, p<0.001; rho=0.386, p=0.003). The correlations between these parameters and the maximum standardized uptake values (SUVmax) were: PAB, rho=0.335 and p=0.010; SH-groups, rho=0.265 and p=0.044; CRP, rho=0.391 and p=0.002; HDL3b, rho=0.283 and p=0.031; HDL2b, rho= -0.294 and p=0.025; and HDL size, rho= -0.295 and p=0.024. The reductions in SUVmax between two follow-up points were associated with increases in the OSI, TOS, and SH-groups, as well as a reduction in the PAB and TAS. In conclusion, the redox parameters in patients with lymphoma were consistent with FDG-PET/CT findings. Targeting the redox status parameters and the HDL subclasses could be potential strategies in the molecular fight against lymphoma.

Keywords:  HDL subclasses; Hodgkin lymphoma; SUVmax; non-Hodgkin lymphoma; redox status

DOI:  https://doi.org/10.3389/fonc.2023.1221414
Blood. 2023 Nov 18. pii: blood.2023021564. [Epub ahead of print]

Phase 2 LYSA study of prednisone, vinblastine, doxorubicin, bendamustine for untreated older Hodgkin lymphoma patients.

Herve Ghesquieres, Daphné Krzisch, Emmanuelle Nicolas Virelizier, Salim Kanoun, Anne Claire Gac, Stéphanie Guidez, Mohamed Touati, Kamel Laribi, Franck Morschhauser, Christophe Bonnet, Agathe Waultier Rascalou, Frederique Orsini Piocelle, Marc Andre, Marguerite Fournier, Fabienne Morand, Alina Berriolo-Riedinger, Barbara Burroni, Diane Damotte, Alexandra Traverse-Glehen, Philippe Quittet, Olivier Casasnovas.

Older classical Hodgkin lymphoma (cHL) patients require more effective and less toxic therapies. In this multicenter, prospective, phase 2 study, we investigated a new first-line therapy regimen comprising 6 cycles of prednisone (40 mg/m2 Day 1-5), vinblastine (6 mg/m2, Day 1), doxorubicin (40 mg/m2, Day 1), bendamustine (120 mg/m2, Day 1) (PVAB regimen) every 21 days for newly diagnosed classical HL patients aged 61 years or older with an advanced Ann Arbor stage. A Mini Nutritional Assessment (MNA) score ≥ 17 was the cutoff value for including patients ≥70 years old. The primary endpoint was the complete metabolic response (CMR) rate after 6 cycles. The median age of the 89 included patients was 68 years (range, 61-88), with 35 patients aged ≥70 years old (39%). Seventy-eight patients (88%) completed the 6 cycles. The toxicity rate was acceptable, with a 20% rate of related serious adverse events. CMR was achieved by 69 patients (77.5%; 95% CI, 67-86). After a median follow-up of 42 months, 31 patients progressed or relapsed (35%), and 24 died (27%) from HL (n=11), toxicity during treatment (n=4), secondary cancers (n=6), or other causes (n=3). The 4-year progression-free survival (PFS) and overall survival rates were 50% and 69%, respectively. Multivariate analysis showed that liver involvement (P =0.001), lymphopenia (P =0.001), CRP (P =0.0005), comedications (P =0.003) were independently associated with PFS. The PVAB regimen yielded a high CMR rate with acceptable toxicity. Over long-term follow-up, survival endpoints were influenced by unrelated lymphoma events. Registration at www.clinicaltrials.gov was NCT02414568.

DOI: https://doi.org/10.1182/blood.2023021564