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Summary The Hodgkin lymphoma International Study for Individual Care (HoLISTIC) Consortium's A‐HIPI model, developed in 2022 for advanced‐stage classical Hodgkin lymphoma (cHL), predicts survival within 5 years amongst newly diagnosed patients. This study validates its performance in the Brazilian Hodgkin lymphoma registry. By 2022, the Brazilian HL registry included 1357 cHL patients, with a median 5‐year follow‐up. Probabilities for 5‐year progression‐free survival (PFS) and overall survival (OS) were calculated using A‐HIPI‐model equations. Discrimination (Harrell C‐statistic/Uno C‐statistic) and calibration measures assessed external validation and calibration. Lab values beyond the allowed range were excluded, mirroring the initial A‐HIPI analysis. A total of 694 advanced‐stage cHL patients met the original inclusion criteria (age 18–65 years, Stage IIB‐IV). Median age was 31 years; 46.3% were females. Stage distribution was IIB (33.1%), III (27.4%), IV (39.5%). Bulky disease in 32.6%. Five‐year PFS and OS were 68.4% and 86.0%, respectively. Harrell C‐statistics were 0.60 for PFS and 0.69 for OS, and Uno C‐statistics were 0.63 for PFS and 0.72 for OS. Calibration plots demonstrated well‐calibrated predictions with calibration slopes of 0.91 and 1.03 for 5‐year OS and PFS, respectively. Despite differing patient, clinical characteristics, and socioeconomic factors, the baseline prediction tool performed well in the Brazilian cohort, demonstrating adequate discrimination and calibration. This supports its reliability in diverse settings. [ABSTRACT FROM AUTHOR]

Background: Some cases of classic Hodgkin lymphoma (CHL) display similarities to nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) in terms of architecture, leading to potential challenges in diagnosis. However, these difficulties can be overcome by conducting a thorough set of immunohistochemical examinations. Objective: To examine cases of T-cell-rich CHL that closely resemble the diagnosis of NLPHL, specifically pattern D, which can pose challenges in accurately determining the diagnosis even after conducting a thorough immunophenotypic assessment. Materials and methods: Histopathology slides of three cases of T-cell-rich CHL were retrieved and thoroughly examined to assess their clinical, immunomorphologic, and molecular features. Results: We present three cases containing cells that resembled lymphocyte predominant and Hodgkin Reed–Sternberg cells, expressing some B-cell antigens and CHL markers but all were lacking Epstein–Barr virus-encoded small RNA. All three cases were found in a background rich in T-cells with focal remaining follicular dendritic cell meshwork in one case. Only one case had few eosinophils while the other two had no background of eosinophils and plasma cells. Two patients presented with stage IIA and B-symptoms presented in one of them. Two patients were treated with four and six cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), respectively. One patient planned to be treated with four cycles of ABVD plus Rituximab therapy. Conclusions: Some cases of Reed–Sternberg cells can show expression of both B-cell and CHL markers. This overlapping characteristic, which has not been extensively discussed in the existing literature, presents a unique challenge for treatment. Further research into these neoplasms may reveal valuable diagnostic and therapeutic implications. [ABSTRACT FROM AUTHOR]

Classical Hodgkin lymphoma (CHL) is characterized by a proliferation of malignant cells of the lymphoreticular system and often involves lymph nodes, spleen, liver, and bone marrow; it is rare in the head and neck region. A 58-year-old man had an enlargement with ulceration in the left palatine tonsil that was causing dysphagia. Microscopic examination revealed an infiltrate of large, atypical lymphoid cells positive for cluster of differentiation 30, cluster of differentiation 15, PAX5, and Epstein-Barr virus. Complementary tests initially ruled out other sites of the disease. The results led to diagnosis of a rare development of CHL in the palatine tonsil, which was staged as IIEB. Before therapy was initiated, nodal lesions developed in the neck and the CHL was restaged as IIB. The patient was treated successfully with a regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine. After a review of the literature, the authors found only 3 cases with the clinical, imaging, and microscopic features of primary CHL of the palatine tonsil. Despite being a rare event, CHL may first develop in extranodal sites, such as the palatine tonsil. In this context, the role of the dentist is pivotal for early diagnosis of the disease. Investigations into the development of primary tonsillar CHL in the oropharynx are needed because the disease has a different clinical course than nodal lesions. [ABSTRACT FROM AUTHOR]

Classical Hodgkin Lymphoma (CHL) is a rare malignant neoplasm of the lymphatic system. While CHL typically responds well to conventional treatments, some cases may experience relapse to other subtypes, with the development of secondary peripheral T-cell lymphoma (PTCL) being relatively uncommon. Herein, we report a rare case of nodal T follicular helper cell lymphomas,nos (nTFHL-NOS) secondary to CHL, accompanied by aberrant CD20 expression and clonal rearrangements of T-cell receptor (TCR) and immunoglobulin (IG). A 74-year-old male, was diagnosed with CHL, leaning toward the mixed cell type, 6 years ago. He received six cycles of the Adriamycin, Bleomycin, Vinblastine, Dacarbazine (ABVD) regimen, achieving complete clinical remission. The patient was admitted to our hospital due to the appearance of multiple skin nodules 66 months later. Histopathological analysis revealed nTFHL-NOS, with aberrant CD20 expression and clonal rearrangements of TCR and IG. The patient underwent two cycles of chemotherapy with brentuximab vedotin and the Gemcitabine-Oxaliplatin (G-mox) regimen, resulting in a reduction of the skin lesions to 2 cm × 1 cm. We discuss this rare case and review related literature. [ABSTRACT FROM AUTHOR]

Classical Hodgkin lymphoma (cHL) is a common B-cell cancer and a significant health concern, especially in Western and Asian countries. Despite the effectiveness of chemotherapy, many relapse cases are being reported, highlighting the need for improved treatments. This study aimed to address this issue by discovering biomarkers through the analysis of gene expression data specific to cHL. Additionally, potential anticancer inhibitors were explored to target the discovered biomarkers. This study proceeded by retrieving microarray gene expression data from cHL patients, which was then analyzed to identify significant differentially expressed genes (DEGs). Functional and network annotation of the upregulated genes revealed the active involvement of matrix metallopeptidase 12 (MMP12) and C-C motif metallopeptidase ligand 22 (CCL22) genes in the progression of cHL. Additionally, the mentioned genes were found to be actively involved in cancer-related pathways, i.e., oxidative phosphorylation, complement pathway, myc_targets_v1 pathway, TNFA signaling via NFKB, etc., and showed strong associations with other genes known to promote cancer progression. MMP12, topping the list with a logFC value of +6.6378, was selected for inhibition using docking and simulation strategies. The known anticancer compounds were docked into the active site of the MMP12 molecular structure, revealing significant binding scores of −7.7 kcal/mol and −7.6 kcal/mol for BDC_24037121 and BDC_27854277, respectively. Simulation studies of the docked complexes further supported the effective binding of the ligands, yielding MMGBSA and MMPBSA scores of −78.08 kcal/mol and −82.05 kcal/mol for MMP12-BDC_24037121 and −48.79 kcal/mol and −49.67 kcal/mol for MMP12-BDC_27854277, respectively. Our findings highlight the active role of MMP12 in the progression of cHL, with known compounds effectively inhibiting its function and potentially halting the advancement of cHL. Further exploration of downregulated genes is warranted, as associated genes may play a role in cHL. Additionally, CCL22 should be considered for further investigation due to its significant role in the progression of cHL. [ABSTRACT FROM AUTHOR]

The Hodgkin and Reed – Sternberg (HRS) cells in classical Hodgkin Lymphoma (cHL) actively modify the immune tumor microenvironment (TME) attracting immunosuppressive cells and expressing inhibitory molecules. A high frequency of myeloid cells in the TME is correlated with an unfavorable prognosis, but more specific and rare cell populations lack precise markers. Myeloid-derived suppressor cells (MDSCs) have been identified in the peripheral blood of cHL patients, where they appear to be correlated with disease aggressiveness. TNFRSF9 (CD137) is a T cell co-stimulator expressed by monocytic and dendritic cells. Its expression has also been described in HRS cells, where it is thought to play a role in reducing antitumor responses. Here, we perform qualitative and quantitative analyses of lymphocytic and MDSC subtypes and determine the CD137 cell distribution in cHL primary tumors using multiplex immunofluorescence and automated multispectral imaging. The results were correlated with patients’ clinical features. Cells were stained with specific panels of immune checkpoint markers (PD-1, PD-L1, CD137), tumor-infiltrating T lymphocytes (CD3, PD-1), and monocytic cells/MDSCs (CD68, CD14, CD33, Arg-1, CD11b). This approach allowed us to identify distinct phenotypes and to analyze spatial interactions between immune subpopulations and tumor cells. The results confirm CD137 expression by T, monocytic and HRS cells. In addition, the expression of CD137, T exhausted cells, and monocytic MDSCs (m-MDSCs) in the vicinity of malignant HRS cells were associated with a worse prognosis. Our findings reveal new elements of the TME that mediate immune escape, and confirm CD137 as a candidate target for immunotherapy in cHL.

Simple Summary: We explored how small non-coding RNAs, known as miRNAs, are involved in the pathogenesis of cHL, a lymphoma originating from B cells. While miRNAs have shown broad effects in normal cellular processes and cancers, their contribution to cHL has been less explored. We organized the published human miRNA profiling studies of cHL and selected genes that are crucial for cHL pathogenesis such as those leading to the loss of B-cell phenotypes, immune evasion, and promotion of tumor growth. By providing a detailed analysis of the interactions between these miRNAs and their target genes, our review not only enhances the understanding of cHL molecular mechanisms but also paves the way for further research into how specific miRNAs could be involved in cHL progression. Classical Hodgkin lymphoma (cHL) is a hematological malignancy of B-cell origin. The tumor cells in cHL are referred to as Hodgkin and Reed–Sternberg (HRS) cells. This review provides an overview of the currently known miRNA–target gene interactions. In addition, we pinpointed other potential regulatory roles of microRNAs (miRNAs) by focusing on genes related to processes relevant for cHL pathogenesis, i.e., loss of B-cell phenotypes, immune evasion, and growth support. A cHL-specific miRNA signature was generated based on the available profiling studies. The interactions relevant for cHL were extracted by comprehensively reviewing the existing studies on validated miRNA–target gene interactions. The miRNAs with potential critical roles included miR-155-5p, miR-148a-3p, miR-181a-5p, miR-200, miR-23a-3p, miR-125a/b, miR-130a-3p, miR-138, and miR-143-3p, which target, amongst others, PU.1, ETS1, HLA-I, PD-L1, and NF-κB component genes. Overall, we provide a comprehensive perspective on the relevant miRNA–target gene interactions which can also serve as a foundation for future functional studies into the specific roles of the selected miRNAs in cHL pathogenesis. [ABSTRACT FROM AUTHOR]

Patients with relapsed/refractory classical Hodgkin lymphoma (cHL) achieve complete response (CR) after decitabine‐plus‐camrelizumab therapy, while long‐term outcome especially after treatment discontinuation remains unclear. We present a retrospective analysis of 87 relapsed/refractory cHL patients who acquired CR after decitabine‐plus‐camrelizumab. Patients were divided into two groups and received consolidation treatment every 3–4 or 6–12 weeks, and 1‐year of continuous CR was guaranteed for treatment cessation. At a median follow‐up of 5.3 years, the median relapse‐free survival (RFS) after achieving CR with decitabine‐plus‐camrelizumab therapy was 4.5 years, and patients underwent consolidation per 3–4 weeks might have longer RFS. The baseline percentage of peripheral central memory T cells was not associated with RFS, while patients with higher pretreatment serum levels of interleukin‐6 (IL‐6) and lactate dehydrogenase (LDH) had significantly shorter RFS and increased risk for disease recurrence. Fifty‐seven patients completed and discontinued decitabine‐plus‐camrelizumab, and their median RFS had not been reached. The 2‐year RFS rate after treatment cessation was 78% (95% CI, 67–90%). Patients in the high‐risk subgroup with higher pretreatment IL‐6 and LDH levels showed poor treatment‐free remission. Moreover, decitabine‐plus‐camrelizumab therapy was safe and cost‐effective. In conclusion, patients who obtained CR with decitabine‐plus‐camrelizumab and received consolidation per 3–4 weeks can achieve long‐term remission after treatment discontinuation. [ABSTRACT FROM AUTHOR]

IntroductionIn classical Hodgkin lymphoma (cHL), the survival of neoplastic cells is mediated by the activation of NF-κB, JAK/STAT and PI3K/Akt signaling pathways. CK2 is a highly conserved serine/threonine kinase, consisting of two catalytic (α) and two regulatory (β) subunits, which is involved in several cellular processes and both subunits were found overexpressed in solid tumors and hematologic malignancies.Methods and resultsBiochemical analyses and in vitro assays showed an impaired expression of CK2 subunits in cHL, with CK2α being overexpressed and a decreased expression of CK2β compared to normal B lymphocytes. Mechanistically, CK2β was found to be ubiquitinated in all HL cell lines and consequently degraded by the proteasome pathway. Furthermore, at basal condition STAT3, NF-kB and AKT are phosphorylated in CK2-related targets, resulting in constitutive pathways activation. The inhibition of CK2 with CX-4945/silmitasertib triggered the de-phosphorylation of NF-κB-S529, STAT3-S727, AKT-S129 and -S473, leading to cHL cell lines apoptosis. Moreover, CX-4945/silmitasertib was able to decrease the expression of the immuno-checkpoint CD274/PD-L1 but not of CD30, and to synergize with monomethyl auristatin E (MMAE), the microtubule inhibitor of brentuximab vedotin.ConclusionsOur data point out a pivotal role of CK2 in the survival and the activation of key signaling pathways in cHL. The skewed expression between CK2α and CK2β has never been reported in other lymphomas and might be specific for cHL. The effects of CK2 inhibition on PD-L1 expression and the synergistic combination of CX-4945/silmitasertib with MMAE pinpoints CK2 as a high-impact target for the development of new therapies for cHL

Abstract Optimal management of patients who present with Hodgkin lymphoma continues to evolve. Most patients are cured with current treatment strategies, some but both short and long‐term morbidity and mortality from treatment have particular relevance given the youth of the patient population. Combininations of targeted agents together with conventional chemotherapy have recently been investigated in phase 3 cliniial trials for advanced‐stage Hodkgkin lymphoma, and have demonstrated improved efficacy compared with chemotherapy alone. These include both antibody‐drug conjugates and PD‐1 blockade. Treatment approaches have historically differed between pediatric and adult groups, but recent collaborations between adullt and pediatric groups via the NCTN mechanism have resulted in the successful completion of enrollment in an advanced‐stage Hodgkin lymphoma and the opening of an early‐stage trial that will enroll patients accross a broad age spectrum. Novel approachs incorporating targeted and immunomodulatory agents in the relapse setting are being actively investagated in the relapse setting as well.

Classical Hodgkin lymphoma (cHL) is a common B-cell cancer and a significant health concern, especially in Western and Asian countries. Despite the effectiveness of chemotherapy, many relapse cases are being reported, highlighting the need for improved treatments. This study aimed to address this issue by discovering biomarkers through the analysis of gene expression data specific to cHL. Additionally, potential anticancer inhibitors were explored to target the discovered biomarkers. This study proceeded by retrieving microarray gene expression data from cHL patients, which was then analyzed to identify significant differentially expressed genes (DEGs). Functional and network annotation of the upregulated genes revealed the active involvement of matrix metallopeptidase 12 (MMP12) and C-C motif metallopeptidase ligand 22 (CCL22) genes in the progression of cHL. Additionally, the mentioned genes were found to be actively involved in cancer-related pathways, i.e., oxidative phosphorylation, complement pathway, myc_targets_v1 pathway, TNFA signaling via NFKB, etc., and showed strong associations with other genes known to promote cancer progression. MMP12, topping the list with a logFC value of +6.6378, was selected for inhibition using docking and simulation strategies. The known anticancer compounds were docked into the active site of the MMP12 molecular structure, revealing significant binding scores of −7.7 kcal/mol and −7.6 kcal/mol for BDC_24037121 and BDC_27854277, respectively. Simulation studies of the docked complexes further supported the effective binding of the ligands, yielding MMGBSA and MMPBSA scores of −78.08 kcal/mol and −82.05 kcal/mol for MMP12-BDC_24037121 and −48.79 kcal/mol and −49.67 kcal/mol for MMP12-BDC_27854277, respectively. Our findings highlight the active role of MMP12 in the progression of cHL, with known compounds effectively inhibiting its function and potentially halting the advancement of cHL. Further exploration of downregulated genes is warranted, as associated genes may play a role in cHL. Additionally, CCL22 should be considered for further investigation due to its significant role in the progression of cHL.

The use of new chemotherapy regimens for Hodgkin lymphoma, containing immunotherapeutic drugs, such as brentuximab vedotin, is an urgent direction in the development of modern oncohematology. The inclusion of these drugs in programs of financial support for hematological oncology patients by the state requires an assessment of the rationality of their use under the conditions of the current health care resource provision. The aim of the research is to carry out a pharmacoeconomic evaluation of the rationality of the use of brentuximab vedotin drugs in the treatment of classic Hodgkin lymphoma. Materials – the results of clinical studies of the effectiveness of two chemotherapy regimens for Hodgkin lymphoma (BrECAPP and BrECADD), which were published by German scientists in 2017 (Cochrane Central Register of Controlled Trials, CN-01443068), data from the domestic market of anticancer drugs and state procurement of medicines. General theoretical and applied (organizational and economic, marketing and pharmacoeconomic analysis, mathematical and statistical, etc.) research methods were applied. According to the results of the pharmacoeconomic evaluation of the rationality of the use of the BrECAPP and BrECADD schemes in the treatment of Hodgkin lymphoma, it was established that according to the indices of complete response after chemotherapy (%) the BrECADD scheme has clinical and economic advantages of application, and according to the index of complete remission as the final result of treatment (%), the situation is quite the opposite, that is, the BrECAPP scheme has advantages. The evaluation of the safety profile of the application makes it possible to assert the advantages of the application of the BrECADD scheme. Thus, taking into account the three indices under study (organ toxicity (%), manifestations of peripheral neuropathies (%) and the development of hematological side effects (%)), the indicated scheme had a clinical and economic advantage over the alternative scheme in two indices. This is organ toxicity (%), CEA2 = UAH 3,323.87/unit. ef. (%) against CEA1 = UAH 3,854.52/unit. ef. (%) according to the BrECAPP scheme and the development of hematological side effects (%) – CEA2 = UAH 29,008.32/unit. ef. (%) against CEA1 = UAH 29,084.14/unit. ef. (%) according to the BrECAPP scheme. In general, it can be stated that the BrECADD scheme is more rational and has economic advantages in the treatment of classical Hodgkin lymphoma compared to the BrECAPP regimen in terms of clinical efficacy and safety profile.

Abstract Patients with relapsed/refractory classical Hodgkin lymphoma (cHL) achieve complete response (CR) after decitabine‐plus‐camrelizumab therapy, while long‐term outcome especially after treatment discontinuation remains unclear. We present a retrospective analysis of 87 relapsed/refractory cHL patients who acquired CR after decitabine‐plus‐camrelizumab. Patients were divided into two groups and received consolidation treatment every 3–4 or 6–12 weeks, and 1‐year of continuous CR was guaranteed for treatment cessation. At a median follow‐up of 5.3 years, the median relapse‐free survival (RFS) after achieving CR with decitabine‐plus‐camrelizumab therapy was 4.5 years, and patients underwent consolidation per 3–4 weeks might have longer RFS. The baseline percentage of peripheral central memory T cells was not associated with RFS, while patients with higher pretreatment serum levels of interleukin‐6 (IL‐6) and lactate dehydrogenase (LDH) had significantly shorter RFS and increased risk for disease recurrence. Fifty‐seven patients completed and discontinued decitabine‐plus‐camrelizumab, and their median RFS had not been reached. The 2‐year RFS rate after treatment cessation was 78% (95% CI, 67–90%). Patients in the high‐risk subgroup with higher pretreatment IL‐6 and LDH levels showed poor treatment‐free remission. Moreover, decitabine‐plus‐camrelizumab therapy was safe and cost‐effective. In conclusion, patients who obtained CR with decitabine‐plus‐camrelizumab and received consolidation per 3–4 weeks can achieve long‐term remission after treatment discontinuation.

Simple Summary: Approximately one in seven patients with classical Hodgkin lymphoma have refractory disease or relapse after standard front line chemotherapy. Prognostic biomarkers could help determine candidates for more effective treatment. The latest advances in research techniques have contributed to new insights in understanding the tumour microenvironment of Hodgkin lymphoma and the crucial role it plays in the disease course and response to treatment. Many new potential biomarkers are being explored in this setting and the results of these studies, as well as diagnostic methodologies, are presented in this review. 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. [ABSTRACT FROM AUTHOR]

Background Classical Hodgkin lymphoma (cHL) is a clonal lymphoid neoplasm derived from B cells. Cyclooxygenase 2 (COX2) and vascular endothelial growth factor-A (VEGF-A) play major roles in angiogenesis and impact cHL prognosis. Aim To measure COX2 and VEGF-A expression in cHL patients and assess their potential association with other laboratory and clinical parameters. Patients and methods Seventy-six cHL bone marrow (BM) biopsy specimens were histopathologically examined and immunohistochemically stained for COX2 and VEGF-A expression. Correlations between COX2 and VEGF-A expression and clinicopathologic factors were evaluated. Results COX2 and VEGF-A were expressed in 67/76 (88.2%) and 48/76 (63.2%) of BM specimens, respectively. VEGF-A was associated with advanced cHL stage (P=0.044) and BM infiltration confirmed by CD30 positivity (P=0.023). A significant association was found between VEGF-A positivity and mediastinal lymphadenopathy (P=0.049), inguinal lymphadenopathy (P=0.046), and pulmonary nodules (P=0.048). COX2 positivity was significantly associated with cervical lymphadenopathy (P=0.011). A positive association was found between expression of both markers (COX2 and VEGF-A) (P=0.001). Coexpression of COX2 and VEGF-A was associated with disease staging (P=0.016), mediastinal lymphadenopathy (P=0.019), and inguinal lymphadenopathy (P=0.044). Conclusion COX2 and VEGF-A, as major players in angiogenesis, are associated with tumor progression in cHL. These findings support targeting both markers as the potential therapeutic approach in cHL. [ABSTRACT FROM AUTHOR]

Classical Hodgkin Lymphoma (cHL) is a B-cell derived lymphoma with excellent cure rates, however poor functional status or co-morbid conditions limit treatment options. Brentuximab vedotin (BV), a CD30 antibody drug conjugate, has an expanding role in cHL treatment. A 53-year-old man with multiple co-morbidities including end stage renal disease (ESRD) presenting with pancytopenia was found to have cHL. Not a candidate for intensive chemotherapy, he was safely maintained on intermittent BV for three years. Literature on prolonged BV use in hemodialysis is extremely limited. This case suggests BV as a safe treatment option for CD30 positive cHL in patients with ESRD on hemodialysis.

Background: Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) has been regarded as the standard treatment regimen for classical Hodgkin lymphoma. In recent years, ABVD-like regimens, which emerged due to shortages and the lung toxicity of bleomycin or the emergence of immune checkpoint inhibitors and antibody–drug conjugates, may be favorable, but have not yet been tested. Methods: We compared the outcomes of ABVD with ABVD-like regimens, which include bleomycin was completely or partially omitted; meanwhile, etoposide or PD-1 inhibitors were added. Results: 5-Year progression-free survival (PFS) was higher for ABVD than ABVD-like regimens in young patients (82.1% vs. 67.0%, p = 0.029), patients with serum beta-2 microglobulin (β2-MG) ≥ 1.85 mg/L (75.8% vs. 57.6%, p = 0.046), and advanced-stage patients with IPS score 4–7(63.1%, 18.3%, p = 0.038). For elderly (60.5% vs.76.1%, p = 0.089), patients with β2-MG < 1.85 mg/L (83.1% vs 76.1%, p = 0.282), and advanced-stage patients with IPS score 0–3(84.6% vs. 81.3%, p = 0.476), 5-year PFS for ABVD did not differ from ABVD-like regimens. Elderly patients treated with bleomycin-free regimens showed a better survival trend compared with ABVD (99.3% vs. 61.3%, p = 0.270). Conclusion: ABVD is superior to ABVD-like regimens in achieving PFS in young patients or patients with poor prognosis including high IPS score and β2-MG level. ABVD-like regimens are as effective as ABVD in elderly or low-risk patients including low IPS score and β2-MG level; elderly patients treated with bleomycin-free regimens exhibit a better survival trend compared with ABVD. [ABSTRACT FROM AUTHOR]

Abstract Background The combination of anti-programmed death-1 antibodies and chemotherapy is effective; however, there are no reliable outcome prediction factors. We investigated the prognostic factors based on 18Fluorine-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) quantitative and hematological parameters to predict progression-free survival (PFS) in relapsed/refractory classical Hodgkin lymphoma (R/R cHL) patients treated with immune checkpoint inhibitors (ICIs) and chemotherapy. Methods This retrospective study included 31 patients who underwent 18F-FDG PET/CT before and during treatment. Pretreatment metabolic and hematological parameters were evaluated using Cox regression analysis to identify predictors of PFS. Based on the cut-off values calculated using the receiver operating characteristic (ROC) curve, patients were classified into low-, intermediate-, and high-risk groups. Kaplan–Meier curves and the log-rank test were used to compare survival differences between the groups. Results Cox multivariable analysis indicted that the treatment response based on Lactate dehydrogenase (LDH), Lugano classification and SUVmax were independent predictors of PFS (P = 0.004, 0.007 and 0.039, respectively). The optimal cut-off values for SUVmax and LDH were 11.62 and 258.5 U/L, respectively (P

Comprehensive clinical characteristics of Australian patients with classical Hodgkin Lymphoma (cHL) have not previously been systematically collected and described. We report real‐world data of 498 eligible patients from the first 5 years of the Lymphoma and Related Diseases Registry (LaRDR), including baseline characteristics, histologic subtype, and treatment patterns in first‐line therapy. Patient demographics and distribution of histopathological subtypes of cHL are similar to reported international cohorts. Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) was the most common therapy for both early and advanced‐stage disease, and 48% of patients with the early‐stage disease received radiotherapy. Treatment patterns are consistent with international guidelines. In comorbid patients ≥60 years of age with advanced‐stage disease, there is greater variation in treatment. In patients with a recorded response, the objective response rate (ORR) was 96% in early‐stage disease, and 88% in advanced‐stage disease. Early progression‐free survival data suggest Australian patients with cHL have good outcomes, similar to other international studies. [ABSTRACT FROM AUTHOR]

Simay Çokgezer,1 Tu&gbreve;rul Elverdi,2 Ay&scedil;e Saliho&gbreve;lu,2 Muhlis Cem Ar,2 &Scedil;eniz Öngören,2 Zafer Ba&scedil;lar,2 Ahmet Emre E&scedil;kazan2 1Department of Internal Medicine, Istanbul University-Cerrahpa&scedil;a, Cerrahpa&scedil;a Faculty of Medicine, Istanbul, Turkey; 2Division of Hematology, Department of Internal Medicine, Istanbul University-Cerrahpa&scedil;a, Cerrahpa&scedil;a Faculty of Medicine, Istanbul, TurkeyCorrespondence: Ahmet Emre E&scedil;kazan, Istanbul University-Cerrahpa&scedil;a, Cerrahpa&scedil;a Faculty of Medicine, Department of Internal Medicine, Division of Hematology, Fatih, Istanbul, Turkey, Tel +90 533 722 73 76, Fax +90 212 589 79 34, Email emre.eskazan@iuc.edu.trIntroduction: The aim of this study was to evaluate treatment responses, toxicity, and survival among cHL patients aged ≥ 50 years.Methods: We retrospectively identified all newly diagnosed cHL patients and only included cases who were ≥ 50 years old at the time of diagnosis and with data available between 1999 and 2020.Results: There were 101 patients, of which 52 were between 50 and 59 years of age, and 49 patients were ≥ 60 years old. Sixty-two patients were male, and the most common histopathological subtype was mixed cellularity cHL (58.4%). ECOG PS, CCI, CIRS, and ACE-27 scores were significantly higher in patients aged ≥ 60 years than those of 50– 59 age group. While all patients aged 50– 59 years received ABVD as first-line therapy, 79% (n=39) of cases aged ≥ 60 years had ABVD. In patients receiving ABVD, 95% and 92.7% of the cases aged 50– 59 and ≥ 60 years had CR, respectively (p=0.999). Age groups were comparable in terms of hematological and non-hematological toxicities (p=0.369, p=0.127, respectively). Although not statistically significant, median survival was longer in patients receiving a transplant than in those without transplantation (108 months vs 52 months, p=0.069). In multivariate analysis, the risk of progression was higher in patients with lymphocyte ≤ 600/mm3 and in those who were unresponsive to first-line therapy (p=0.002 and p< 0.001, respectively). Patients with B symptoms, age ≥ 60 years, and CIRS > 3 had higher risk of mortality (p=0.001, p=0.012, p=0.038, respectively). By using these 3 parameters, we defined a new risk score, which divided our patient cohort into two as low- and high-risk groups. Low-risk patients had significantly higher survival rates than the high-risk group (83.9% vs 40.5%, p< 0.001).Discussion: This new prognostic score should be further tested and validated in other patient populations. Although our study has some limitations including the limited number of patients and its retrospective nature, there are not so many studies in elderly cHL patients and elderly and/or frail patients are generally excluded in most of the clinical trials. Thus, this real-life single-center experience would contribute to the literature.Keywords: classical Hodgkin lymphoma, cHL, elderly patients, survival, toxicity

Composite mantle cell lymphoma and classical Hodgkin lymphoma is very rare and the actual origin of it is still unclear. Here we reported a new case of composite mantle cell lymphoma and classical Hodgkin lymphoma and analyzed its molecular changes. Eight mutations were identified in its Hodgkin component through next-generation sequencing. In addition, we reviewed the published cases of composite mantle cell lymphoma and classical Hodgkin lymphoma and summarized the molecular changes of reported cases as well as the current case to explore the possible pathway of histogenesis.

Classical Hodgkin lymphoma (cHL) is a unique neoplastic ecosystemcharacterized by a heterogeneous immune infiltrate surrounding the rare malignant Hodgkin Reed-Sternberg cells. Though less abundant than T-cells, tumor-infiltrating macrophages play a pivotal role in supporting HRS survival through cell-to-cell and paracrine interactions. Traditional immunohistochemistry based upon the M1-M2 dichotomy yielded controversial results about the composition, functional role and prognostic impact of macrophages in cHL. More recent studies exploiting single-cell technologies and image analyses have highlighted the heterogeneity and the peculiar spatial arrangement of the macrophagic infiltrate, with the most immunosuppressive subpopulations lying in close proximity of HRS cells and the most tumor-hostile subsets kept far away from the neoplastic niches. Highthroughput analysis of peripheral blood mononuclear cells in cHL patients have also identified a novel, potentially cytotoxic, subpopulation predicting better response to PD-1 blockade. This review examines the phenotypic profile, spatial localization and clinical impact of tumor-infiltrating macrophages and circulating monocytes in cHL, providing an up-do-date portrait of these innate immune cells with possible translational applications. [ABSTRACT FROM AUTHOR]

Background: The combination of anti-programmed death-1 antibodies and chemotherapy is effective; however, there are no reliable outcome prediction factors. We investigated the prognostic factors based on 18Fluorine-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) quantitative and hematological parameters to predict progression-free survival (PFS) in relapsed/refractory classical Hodgkin lymphoma (R/R cHL) patients treated with immune checkpoint inhibitors (ICIs) and chemotherapy. Methods: This retrospective study included 31 patients who underwent 18F-FDG PET/CT before and during treatment. Pretreatment metabolic and hematological parameters were evaluated using Cox regression analysis to identify predictors of PFS. Based on the cut-off values calculated using the receiver operating characteristic (ROC) curve, patients were classified into low-, intermediate-, and high-risk groups. Kaplan–Meier curves and the log-rank test were used to compare survival differences between the groups. Results: Cox multivariable analysis indicted that the treatment response based on Lactate dehydrogenase (LDH), Lugano classification and SUVmax were independent predictors of PFS (P = 0.004, 0.007 and 0.039, respectively). The optimal cut-off values for SUVmax and LDH were 11.62 and 258.5 U/L, respectively (P < 0.01). Survival curves showed that LDH ≥ 258.5U/L and SUVmax ≥ 11.62 were correlated to shorter PFS (P < 0.001, P = 0.003, respectively). The differences in PFS between the low-, intermediate-, and high-risk groups were statistically significant (P = 0.0043). Conclusion: In R/R cHL patients treated with ICIs and chemotherapy, Lugano classification, SUVmax, and LDH were significantly correlated with PFS. The combination of metabolic and hematological parameters predicts PFS and may help to improve patient selection. [ABSTRACT FROM AUTHOR]

Classical Hodgkin lymphoma (CHL) is characterized by extensive inflammatory immune cells, which predict the disease prognosis. Therefore, this study aimed to explore the significance of different tumor-infiltrated immune cells and subpopulation ratios observed in the tumor microenvironment of CHL, particularly relating to the disease's prognosis-focusing on overall survival (OS) and event-free survival (EFS). Utilizing immunohistochemistry, the quantification and exploration of selected immune cells' subsets, including CD3+, CD4+, CD8+, FOXP3+, CD20+, and CD68+ were conducted on 102 histological samples with primary CHL. Eosinophils were pathologically assessed. Besides, we determined the ratios between different tumor-infiltrated immune cells for each patient. Kaplan-Meier method and Cox regression modeling were used for survival analysis. We demonstrated that among all ratios and immune cells individually, only a higher FOXP3+/CD68+ ratio (≥1.36 cutoff) displayed a tendency towards a favorable OS (p = 0.057, HR = 0.43 [0.18–1.02]) and EFS (p = 0.067, HR = 0.44 [0.18–1.06]) using Cox regression modeling. Moreover, the Kaplan-Meier method showed an association of a higher FOXP3+/CD68+ ratio with a longer 5-years OS (p = 0.037) and a tendency to a better EFS (p = 0.051); however, neither the combined FOXP3+ and CD68+ nor FOXP3+ or CD68+ separately was correlated to the CHL survival. Together, these results demonstrated that the FOXP3+/CD68+ ratio could predict the outcomes of CHL, providing more informative significance than FOXP3+ and CD68+ combined or FOXP3+ and CD68+ individually and might be a potential indicator of risk stratification, which has an important value for guiding the clinical treatment. [ABSTRACT FROM AUTHOR]

Improved biomarkers are needed to guide patient selection for autologous stem cell transplantation (ASCT) and post-ASCT maintenance therapies in relapsed/refractory classical Hodgkin lymphoma (cHL). To assess the prognostic value of minimal residual disease (MRD) using immunoglobulin-based high-throughput sequencing (Ig-HTS), we analyzed pre- and post-ASCT peripheral blood and pre-ASCT apheresis stem cell (ASC) samples in 36 cHL patients. A tumor clonotype was detected in only 12 patients (33%). Among these patients, MRD within plasma samples was closely associated with impending relapse. All patients (n = 3) with detectable MRD in any post-ASCT plasma sample relapsed (100% specificity), and MRD was not detected in any patients in remission. MRD testing from cellular specimens (peripheral blood mononuclear cell or ASC samples) was not associated with relapse. In this small cohort, plasma-based MRD testing appeared to be a promising biomarker in cHL, but given low clonotype detection rates with Ig-HTS, alternative MRD approaches should be investigated. [ABSTRACT FROM AUTHOR]

The present case report investigated the clinicopathological features and potential mechanisms underlying the transformation to peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), following treatment for classical Hodgkin lymphoma (CHL) in a 73-year-old man. The patient was admitted to hospital in 2012 and underwent a left cervical lymph node biopsy, which confirmed CHL of the nodular sclerosing type, with evident bone marrow involvement. The patient received four cycles of doxorubicin, bleomycin, vinblastine and dacarbazine chemotherapy, after which they achieved complete remission. However, after 3 years, the patient presented with enlarged left inguinal lymph nodes and a biopsy revealed PTCL-NOS. Molecular studies indicated a T-cell receptor-γ gene rearrangement. A literature review, together with the current case, identified 11 patients with CHL that transformed into PTCL-NOS. Among these, nine patients (81.82%) were middle-aged or elderly (>45 years old), and eight (72.73%) experienced transformation within 3 years post-treatment of CHL. Among these eight patients, seven (87.50%) predominantly exhibited the nodular sclerosis subtype, with a median recurrence time of 26 months. Five (45.45%) patients died of the disease. The rare transformation of CHL to PTCL-NOS, primarily among men, underscores its clinical significance. Notably, nodular sclerosing-type CHL appears to be particularly prone to transformation into PTCL-NOS. The poor prognosis in such cases may be attributed to the complex tumor microenvironment of CHL. [ABSTRACT FROM AUTHOR]

Classical Hodgkin lymphoma (cHL) is a unique neoplastic ecosystem characterized by a heterogeneous immune infiltrate surrounding the rare malignant Hodgkin Reed-Sternberg cells. Though less abundant than T-cells, tumor-infiltrating macrophages play a pivotal role in supporting HRS survival through cell-to-cell and paracrine interactions. Traditional immunohistochemistry based upon the M1-M2 dichotomy yielded controversial results about the composition, functional role and prognostic impact of macrophages in cHL. More recent studies exploiting single-cell technologies and image analyses have highlighted the heterogeneity and the peculiar spatial arrangement of the macrophagic infiltrate, with the most immunosuppressive subpopulations lying in close proximity of HRS cells and the most tumor-hostile subsets kept far away from the neoplastic niches. High-throughput analysis of peripheral blood mononuclear cells in cHL patients have also identified a novel, potentially cytotoxic, subpopulation predicting better response to PD-1 blockade. This review examines the phenotypic profile, spatial localization and clinical impact of tumor-infiltrating macrophages and circulating monocytes in cHL, providing an up-do-date portrait of these innate immune cells with possible translational applications.

Simple Summary: Composite/synchronous lymphoma is a rare entity, for which the histopathological diagnosis is difficult due to the co-occurrence of at least two lymphomas, sometimes mixed in the same anatomical site. In the present review, we gathered available data on composite lymphomas associating a classical Hodgkin lymphoma (cHL) with another lymphoma. We report the clinical, histopathological, immunohistochemical, and molecular data for each composite lymphoma. These data reinforce the hypothesis of a common clonal origin and a transdifferentiation phenomenon during lymphomagenesis. One of the greatest challenges for the pathologist is to differentiate real Hodgkin cells of cHL from Hodgkin-like cells associated with a non-Hodgkin lymphoma, in order to individualize both contingents for the diagnosis. In contrast, the clinician's challenge is to optimally treat these rare composite pathologies as a single clinical entity. This review could thus be a useful diagnostic support for pathologists and could help clinicians improve management of these uncommon lymphomas. The co-occurrence of several lymphomas in a patient defines composite/synchronous lymphoma. A common cellular origin has been reported for both contingents of such entities. In the present review, we aimed to gather the available data on composite lymphomas associating a classical Hodgkin lymphoma (cHL) with another lymphoma, to better understand the plasticity of mature B and T-cells. This review highlights that >70% of patients with a composite lymphoma are ≥55 years old, with a male predominance. The most reported associations are cHL with follicular lymphoma or diffuse large B-cell lymphoma, with over 130 cases reported. The cHL contingent is often of mixed cellularity type, with a more frequent focal/weak CD20 expression (30% to 55.6%) compared to de novo cHL, suggesting a particular pathophysiology. Moreover, Hodgkin cells may express specific markers of the associated lymphoma (e.g., BCL2/BCL6 for follicular lymphoma and Cyclin D1 for mantle cell lymphoma), sometimes combined with common BCL2/BCL6 or CCND1 rearrangements, respectively. In addition, both contingents may share similar IgH/IgK rearrangements and identical pathogenic variants, reinforcing the hypothesis of a common clonal origin. Finally, cHL appears to be endowed with a greater plasticity than previously thought, supporting a common clonal origin and a transdifferentiation process during lymphomagenesis of composite lymphomas. [ABSTRACT FROM AUTHOR]

(1) This study aimed to investigate whether baseline clinical and Positron Emission Tomography/Computed Tomography (bPET)-derived parameters could help predicting early response to the first two cycles of chemotherapy (Deauville Score at interim PET, DS at iPET) in patients with classical Hodgkin lymphoma (cHL) to identify poor responders (DS ≥ 4) who could benefit from first-line treatment intensification at an earlier time point. (2) cHL patients with a bPET and an iPET imaging study in our Centre's records (2013–2019), no synchronous/metachronous tumors, no major surgical resection of disease prior to bPET, and treated with two cycles of ABVD chemotherapy before iPET were retrospectively included. Baseline International Prognostic Score for HL (IPS) parameters were collected. Each patient's bPET total metabolic tumor volume (TMTV) and highest tumoral SUVmax were collected. ROC curves and Youden's index were used to derive the optimal thresholds of TMTV and SUVmax with regard to the DS (≥4). Chi-square or Fisher's exact test were used for the univariate analysis. A multivariate analysis was then performed using logistic regression. The type I error rate in the hypothesis testing was set to 5%. (3) A total of 146 patients were included. The optimal threshold to predict a DS ≥ 4 was >177 mL for TMTV and >14.7 for SUVmax (AUC of 0.65 and 0.58, respectively). The univariate analysis showed that only TMTV, SUVmax, advanced disease stage, and age were significantly associated with a DS ≥ 4. A multivariate model was finally derived from TMTV, SUVmax, and age, with an AUC of 0.77. (4) A multivariate model with bPET parameters and age at diagnosis was satisfactorily predictive of poor response at iPET after ABVD induction chemotherapy in cHL patients. More studies are needed to validate these results and further implement DS-predictive factors at baseline in order to prevent poor response and intensify therapeutic strategies a-priori when needed. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to develop a new risk stratification tool to predict freedom from progression (FFP) for newly diagnosed advanced classical Hodgkin lymphoma (cHL). Methods: We collected data from 386 patients with advanced cHL diagnosed between December 8, 2000 and October 29, 2018, and treated with curative intent with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or an ABVD‐equivalent regimen. Cases were randomly divided into training and validation cohorts at a ratio of 7:3. The new model was constructed based on the results of Cox proportional hazards model in the training cohort. Comparisons of discrimination between the new model and other models in the training and validation cohorts for FFP prediction were measured by time‐dependent area under curve (tAUC) and Harrell's C‐index. Calibration plots were constructed to compare the consistency between the predicted and observed estimates of survival probability for the new model in the training and validation cohorts. Results: The new model (IPSPLR) composed of International Prognostic Score (IPS)‐3 and platelet/lymphocyte ratio (PLR) provided four distinct risk groups. The IPSPLR showed better discriminative ability when compared with IPS‐3 and IPS‐7. The AUC of IPSPLR was consistently higher than that of IPS‐3 and IPS‐7 between 12 and 120 months. The C‐index of the IPSPLR was higher than that of IPS‐7 and IPS‐3. The calibration plots showed an excellent agreement between the IPSPLR‐predicted and observed estimates of 5‐year FFP. Conclusion: The IPSPLR is an easily used tool for FFP prediction for newly diagnosed advanced cHL. Validation of this tool in other large datasets is needed. [ABSTRACT FROM AUTHOR]

Purpose of Review: This review aims to discuss recent advances in elucidating the tumor microenvironment (TME) in B lymphomas and resultant novel therapeutic development. Recent Findings: While tumor morphology, immunophenotype, and molecular profile are established factors that predict outcome and guide therapy, the prognostic impact of infiltrating, non-tumor cells is now emerging. This is simultaneously facilitating the development of new therapies that target non-tumor cells. Summary: The tumor microenvironment (TME) is a complex ecosystem composed of infiltrating cells and byproducts, extracellular matrix, and other non-cellular tissues. In lymphomas, our current understanding of the role of the TME is principally informed by studies in B-cell lineage diseases. As we improve our understanding of lymphoma biology, the importance of the impact of the non-tumor cell microenvironment is becoming more apparent. This lays the foundation for the investigation and development of novel therapies and combination strategies that target non-tumor cells and tumor cell/non-tumor cell interactions. [ABSTRACT FROM AUTHOR]

Objective: Classical Hodgkin lymphoma (CHL) is a common lymphoid neoplasm with a wide range of differential diagnosis. Although it has a specific immunophenotype, aberrant expression of antigens can cause problems at its diagnosis. In this study we evaluated the usefulness of GATA3 in differential diagnosis of classical Hodgkin lymphoma., Material and Method: One hundred CHL cases and a control group of 106 lymphoma cases, which include anaplastic large cell lymphoma (ALK (+) and (-)), EBV (+) large B cell lymphoma, T-cell/ histiocyte rich B cell lymphoma, primary mediastinal large B cell lymphoma, nodular lymphocyte predominant Hodgkin lymphoma and mediastinal grey zone lymphoma, were included in the study. GATA3 immunohistochemistry were applied to all cases and its nuclear expression was accepted as positive. Expression status of GATA3 was compared in between the CHL and the control group, as well as among each lymphoma subtype. In addition, whether the biopsy type effects its diagnostic performance is assessed. In CHLs relationship with EBV status and GATA3 expression is evaluated., Results: GATA3 expression was significantly higher in CHL cases compared to the control group (p<0,001). When compared with the individual subgroups GATA3 is still found to be useful in differential diagnosis except for ALK (-) ALCL (p=0,678) and mediastinal gray zone lymphomas (p=0,327). GATA3 expression is significantly higher in EBV (-) CHLs (p=0,02). In core needle biopsies its diagnostic performance is limited (p=0,178)., Conclusions: GATA3 is a useful marker for differentiating CHL from B-cell non-Hodgkin lymphomas but its efficiency is limited in ALK (-) ALCL and mediastinal grey zone lymphomas. Due to the heterogeneous reaction diagnostic value is limited in core needle biopsies.

Discordant lymphomas are defined as two or more distinct pathological lymphomas occurring in the same patient. Due to the rarity of discordant lymphomas, which is due in large part to the difficulty in establishing the diagnosis, the literature is limited to small case series and case reports. Consequently, guidelines on therapeutic strategies are lacking. This article presented a case of primary refractory discordant large B-cell lymphoma and classic Hodgkin lymphoma in a young man based on cervical node and mediastinal mass biopsy, respectively. This case illustrates the difficulty in establishing the diagnosis, which ultimately warranted a high index of clinical suspicion and pursuit of multiple sequential biopsies, as well as a novel treatment strategy using an immune checkpoint inhibitor., Competing Interests: The authors declare that they have no conflict of interest to declare., (Copyright 2024, Bai et al.)

A 65-year-old man with generalized lymphadenopathy was diagnosed with classical Hodgkin lymphoma-Mixed cellularity via left cervical lymph node biopsy. Initial treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine led to complete metabolic remission (CMR); however, recurrence developed after 6 months. Brentuximab vedotin induced partial remission followed by systemic relapse after 10 months. Nivolumab led to a second CMR, but disease progression persisted over nearly 4 years, despite treatment adjustments and local radiotherapy. Eventually, the patient was diagnosed with diffuse large B-cell lymphoma during routine esophagogastroduodenoscopy. Four courses of rituximab-CHOP therapy led to a CMR. This case highlights the importance of performing re-biopsies to detect the recurrence or progression of lymphoma.

Classical Hodgkin lymphoma (cHL) is a common lymphoma that affects young patients. Fortunately, the disease is highly curable as it is susceptible to the currently available treatment modalities. Disease monitoring with Positron Emission Tomography and Computed Tomography (PET/ CT) is an integral part of managing these patients. PET guided protocols are currently used to adjust treatment according to the response. The pivotal idea behind the use of response-adapted approaches is to preserve efficacy while decreasing the toxicity. It also helps to intensify therapy in patients in need because of suboptimal response. However, imaging techniques are limited by their sensitivity and specificity. Minimal Residual Disease (MRD) assessment is a newly emerging concept in many hematologic malignancies. It utilizes various molecular techniques such as polymerase chain reaction (PCR), and next-generation sequencing (NGS) as well as flow cytometry, to detect disease traces. This review looks into MRD detection techniques, its current applications, and the evidence in the literature for its use in cHL., Competing Interests: Declaration of Competing Interest None of the authors declares any relevant conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The ECHELON-1 trial demonstrated the effectiveness of brentuximab vedotin (BV) in combination with doxorubicin, vinblastine, and dacarbazine as a frontline treatment regimen in classical Hodgkin lymphoma. However, peripheral neuropathy (PN) is common with this regimen, occurring in up to two-thirds of patients. While standard prescribing information recommends BV dose modification at the onset of grade 2 PN, management strategies for PN are not well-defined. Most commonly, clinicians dose reduce or discontinue BV, vinblastine, or both. We review evidence-based and practical approaches for managing peripheral neuropathy, emphasizing early detection and dose modification., Competing Interests: Declaration of Competing Interest Jeremy Abramson declares support for the present manuscript (no payments made)– Seagen; grants or contracts from any entity – Seagen, Merck, Mustang Bio, Cellectis, Bristol Myers Squibb, Genentech/Roche; consulting fees – Bristol Myers Squibb, AstraZeneca, AbbVie, Genentech/Roche, Kite Pharma/Gilead, Seagen, Interius, BeiGene, Cellectar, Lilly, Incyte, Caribou Biosciences, Takeda, Janssen, Epizyme, Century Therapeutics, MorphoSys, Mustang Bio, Ono Pharma, Kymera; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events – Genmab, Bristol Myers Squibb, AstraZeneca, Regeneron, AbbVie. Robert Stuver declares no conflicts related to this manuscript. Alex Herrera declares grants or contracts from any entity – Bristol Myers Squibb, Genentech, Merck, Seagen, AstraZeneca, Karyopharm, Kite Pharma, Gilead Sciences, AstraZeneca, ADC Therapeutics; consulting fees – Bristol Myers Squibb, Genentech, Merck, Seagen, AstraZeneca, Karyopharm, ADC Therapeutics, Takeda, Tubulis, Regeneron, Genmab, Pfizer, Caribou Biosciences, Adicet Bio, AbbVie, Allogene. Emily Patterson declares no conflicts related to this manuscript. Yi-Ping Wen declares no conflicts related to this manuscript. Alison Moskowitz declares grants or contracts from any entity – Leukemia Lymphoma Society – Career Development Program, Incyte, Merck, Secura Bio, Bristol Myers Squibb, Syndax, Seagen, Genentech, Kite Pharma, Gilead Sciences, AstraZeneca, ADC Therapeutics; consulting fees – Bristol Myers Squibb, Genentech, Merck, Seagen, AstraZeneca, ADC Therapeutics, Takeda, Genmab, Pfizer, Caribou Biosciences, Adicet Bio, AbbVie, Allogene Therapeutics; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events – Affimed, Bio Ascend, Canadian Heme Conference, Janpix, Physician Education Resource, Academic Medical Education, BP, Great Debates & Updates, Harborside Press, Imbrium Therapeutics, International Symposium on Hodgkin Lymphoma, Kyowa Hakko Pharma, Medscape, Merck Sharp & Bohue, Ahompr, Seagen, Takeda, Tessa, Triangle Insights Group, UpToDate, WebMD; participation on a data safety monitoring board or advisory board – Affimed, Janpix, Seagen, Kyowa Hakko Pharma., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Primary CNS involvement is very rare in Hodgkin lymphoma. Here we present two cases of spinal cord dissemination. Two women of 40 and 65 years of age presented symptoms of spinal cord injury; imaging showed an intramedullary mass in T10 and T2, respectively, without vertebral involvement and upper diaphragmatic lymph nodes. Lymph-node biopsy confirmed the diagnosis of classical Hodgkin lymphoma in both patients. The first patient received four cycles of chemotherapy (escalated BEACOPP and ABVD) with intrathecal therapy, and the second four cycles of doxorubicin, vinblastine, dacarbazine (AVD) and local irradiation after surgery decompression. Complete metabolic response was obtained at the end of treatment. After 5 and 7 years of follow-up respectively, neurological deficits persisted in both.

Simple Summary: Relapsed/refractory classical Hodgkin's lymphoma (cHL) accounts for 10–30% of patients. Historically, such patients were treated with salvage chemotherapy regimens followed by autologous stem cell transplantation. Introduction of novel agents such as brentuximab vedotin and immunotherapy to the treatment algorithm for cHL may change the choice of salvage therapy regimens. The purpose of this article is to review the various salvage regimens used to treat first relapse or primary refractory disease that incorporate novel agents, discuss the recent literature and propose an algorithm to determine the treatment approach for this patient population. The treatment landscape for relapsed/refractory classical Hodgkin's lymphoma (cHL) has evolved with the introduction of several novel agents. Historically, the standard of care for relapsed cHL was salvage chemotherapy followed by autologous stem cell transplant (ASCT). However, many patients are ineligible for ASCT or will have poor responses to salvage chemotherapy and ASCT. Brentuximab vedotin (BV) and checkpoint inhibitors (nivolumab/pembrolizumab) were initially approved in the post-ASCT setting. However, as a result of excellent responses and durable outcomes in this setting, they are now being studied and explored in earlier lines of therapy. Additionally, these agents are also being studied for post-transplant consolidation and maintenance with promising results in improving progression-free survival. We will review current salvage therapy options involving these novel agents and provide comparisons between regimens to aid the clinician in selecting the appropriate salvage regimen for patients who progress after first-line therapy. [ABSTRACT FROM AUTHOR]

Background: Nearly all anti-PD-1 antibodies are of the IgG4 isotype, and thus possess residual FcR effector functions. Such anti-PD-1 antibodies are also associated with immune tolerance and escape due to instability of the CH3 domain and Fc-Fc interaction. In this trial, we examined the efficacy and safety of penpulimab, a novel IgG1 anti-PD-1 antibody that does not bind to the Fc receptor, in patients with refractory or relapsed classical Hodgkin lymphoma (R/R cHL). Methods: Adult patients (≥18 years of age) with R/R cHL received 200 mg penpulimab once biweekly until disease progression or unacceptable toxicities for a maximum of 24 months. The primary endpoint was objective response rate (ORR) based on the Independent Radiology Review Committee per Lugano 2014 criteria. Secondary endpoints included progression-free survival (PFS), overall survival (OS), treatment-related adverse events (TRAEs) and immune-related adverse events (irAEs). Results: A total of 94 patients were enrolled. The median follow-up was 15.8 months. The ORR was 89.4% (95% CI 80.8%, 95.0%) in the full analysis set (85 patients). Forty (47.1%) patients achieved complete remission, 36 (42.4%) patients achieved partial remission. The 12-month PFS rate was 72.1% (95% CI 60.5%, 80.8%) and the 18-month OS rate was 100%. Totally 97.9% (92/94) of patients experienced at least one TRAE. The rate of grade 3 and above TRAEs was 26.6% (25/94). In addition, 51 (54.3%) patients experienced an irAE, and 4 (4.3%) patients developed grade 3 or above irAEs. No irAE-related death occurred. Conclusions: Penpulimab was effective and safe in patients with R/R cHL. [ABSTRACT FROM AUTHOR]

Simple Summary: The unique tumor composition of classical Hodgkin lymphoma (cHL), with only a small fraction of malignant Hodgkin and Reed–Sternberg cells within the tumor tissue, has created many challenges to characterize the genetic alterations that drive this lymphoid malignancy. Major advances in sequencing technologies and detailed analysis of circulating tumor DNA in blood samples of patients have provided important contributions to enhance our understanding of the pathogenesis of cHL. In this review, we provide an overview of the recent advances in genotyping the clonal and mutational landscape of cHL. In addition, we discuss different next-generation sequencing applications to characterize tumor tissue and cell-free DNA, which are now available to improve the diagnosis of cHL, and to monitor therapeutic response or disease progression during treatment and follow up of cHL patients. Classical Hodgkin lymphoma (cHL) represents a B-cell lymphoproliferative disease characterized by clonal immunoglobulin gene rearrangements and recurrent genomic aberrations in the Hodgkin Reed–Sternberg cells in a reactive inflammatory background. Several methods are available for the molecular analysis of cHL on both tissue and cell-free DNA isolated from blood, which can provide detailed information regarding the clonal composition and genetic alterations that drive lymphoma pathogenesis. Clonality testing involving the detection of immunoglobulin and T cell receptor gene rearrangements, together with mutation analysis, represent valuable tools for cHL diagnostics, especially for patients with an atypical histological or clinical presentation reminiscent of a reactive lesion or another lymphoma subtype. In addition, clonality assessment may establish the clonal relationship of composite or subsequent lymphoma presentations within one patient. During the last few decades, more insight has been obtained on the molecular mechanisms that drive cHL development, including recurrently affected signaling pathways (e.g., NF-κB and JAK/STAT) and immune evasion. We provide an overview of the different approaches to characterize the molecular composition of cHL, and the implementation of these next-generation sequencing-based techniques in research and diagnostic settings. [ABSTRACT FROM AUTHOR]

Background: To investigate the prognostic role of red blood cell distribution width (RDW) and platelet/lymphocyte ratio (PLR) in early-stage classical Hodgkin lymphoma (cHL). Materials & methods: Data from 402 patients with newly diagnosed early-stage cHL were retrospectively collected. The impact of factors on complete response (CR) rate and freedom from progression (FFP) was analyzed. Results: High PLR was associated with lower CR, but high RDW was not. The univariate analysis showed that RDW and PLR were predictive of FFP. On multivariate analysis, high PLR was an independent risk factor for inferior FFP. Subgroup analysis and a prognostic model for FFP based on PLR validated the prognostic role of PLR. Conclusion: PLR was a robust prognostic factor for newly diagnosed early-stage cHL. [ABSTRACT FROM AUTHOR]

Abstract Treatment for patients > 60 years with classical Hodgkin lymphoma (cHL) is problematic; there is no gold standard, and outcome is poor. Using the Swedish Lymphoma Registry, we analysed all Swedish patients diagnosed with cHL between 2000 and 2014 (N = 2345; median age 42 years; 691 patients were >60 years). The median follow‐up time was 6.7 years. Treatment for elderly patients consisted mainly of ABVD or CHOP, and the younger patients were treated with ABVD or BEACOPP (with no survival difference). In multivariable analysis of patients > 60 years, ABVD correlated with better survival than CHOP (p = 0.027), and ABVD became more common over time among patients aged 61–70 years (p = 0.0206). Coinciding with the implementation of FDG‐PET/CT, the fraction of advanced‐stage disease increased in later calendar periods, also in the older patient group. Survival has improved in cHL patients > 60 years (p = 0.027), for whom ABVD seems superior to CHOP.

Introduction: Hodgkin lymphomas are B-cell lymphoid neoplasms histologically characterized by a mixed inflammatory cellular component and few Hodgkin/Reed-Sternberg neoplastic cells. Classical Hodgkin Lymphoma (CHL) represents 10% of all lymphoma cases and 85% of all Hodgkin Lymphomas. According to the current World Health Organization classification, CHL is divided into 4 types: Nodular Sclerosing (NS), Mixed Cellularity (MC), Lymphocyte-Rich (LR), and Lymphocyte-Depleted (LD). Objetive: We reviewed all cases of Classical Hodgkin Lymphoma in the Pathological Anatomy Department at Edgardo Rebagliati Martins National Hospital during 2015 to 2019, in order to determine the most frequent type, the incidence according to age and gender, phenotypical characteristics and relation to Epstein Barr Virus (EBV). Materials and Methods: We performed a retrospective descriptive case study of Classical Hodgkin Lymphoma and its 4 clinical-pathological types in the Pathological Anatomy Department at Edgardo Rebagliati Martins National Hospital during 2015 to 2019. 72 patients were identified with Classical Hodgkin Lymphoma diagnosis, of which only 64 were selected for the study. The exclusion criteria were the absence of confirmatory immunohistochemical tests and relapse cases. Results: The most frequent type observed was Nodular Sclerosing with 34 cases (53.12%) and the least frequent type was Lymphocyte-Rich with 2 cases (3.12%). Likewise, a predominance in the male gender was observed, with 42 cases, 20 of which were Nodular Sclerosing and 14 not classified, as the most frequent types, and a greater incidence among those 41 to 50 years of age, without detection of the bimodal peak referenced in international literature. The most frequent immunohistochemical profile of Hodgkin/ Reed- Sternberg was CD15 and CD30 positive, with CD45 negative. EBV was present in 36% of cases and is more frequent in the Mixed Cellularity and Lymphocyte-Depleted types. Conclusions: Classical Hodgkin Lymphoma is a group of lymphoid neoplasms with clinical, histological, and phenotypically defined characteristics. It is more frequent in men between 41 and 50 years of age. A complete clinical information and a good biopsy, preferably excisional, is required for an adequate diagnosis. The Nodular Sclerosing type is the most frequent and the Lymphocyte-Rich is the least frequent type. Hodgkin/ Reed- Sternberg cells are usually CD-15 and CD-30 positive and CD-45 negative. The Pax-5 mild positivity allows it to be differentiated from B-cell Non-Hodgkin Lymphomas. EBV is most frequent in Mixed Cellularity and Lymphocyte-Depleted types.

OBJECTIVES: The 2015 Workshop of the Society for Hematopathology/European Association for Haematopathology submitted small and large B-cell lymphomas (BCLs), including classical Hodgkin lymphoma (CHL), in the context of immunodeficiency. METHODS: Clinicopathologic and molecular features were studied to explore unifying concepts in malignant B-cell proliferations across immunodeficiency settings. RESULTS: Cases submitted to the workshop spanned small BCLs presenting as nodal or extranodal marginal zone lymphoma and lymphoplasmacytic lymphoma, Epstein-Barr virus (EBV) positive in 75% of cases. Submitted large BCLs formed a spectrum from diffuse large B-cell lymphoma (DLBCL) to CHL across immunodeficiency settings. Additional studies demonstrated overexpression of PD-L1 and molecular 9p24 alterations in the large BCL spectrum and across different immunodeficiency settings. CONCLUSIONS: Small BCLs occur in all immunodeficiency settings, and EBV positivity is essential for their recognition as immunodeficiency related. Large BCLs include a spectrum from DLBCL to CHL across all immunodeficiency settings; immunohistochemical and molecular features are suggestive of shared pathogenetic mechanisms involving PD-L1 immune checkpoints.