proteins

2026-03-18 | Lipegfilgrastim for primary prophylaxis of febrile neutropenia in patients treated for advanced-stage classical hodgkin lymphoma: successful outcomes from a multicenter cohort study.

In patients with classical Hodgkin lymphoma (c-HL) undergoing ABVD chemotherapy for advanced disease, the optimal strategy to prevent febrile neutropenia (FN)—defined as fever ≥ 38 °C with absolute neutrophil count (ANC) < 1000/mm³—remains debated. Possible prophylaxis approaches include: i) secondary prophylaxis with on-demand granulocyte colony-stimulating factor (G-CSF, filgrastim), ii) primary prophylaxis with filgrastim, or iii) primary prophylaxis with long-acting G-CSF formulations such as pegylated or glyco-pegylated G-CSF (lipegfilgrastim). We conducted a multicenter retrospective cohort study from 2010 to 2024 involving 450 untreated c-HL patients (Ann Arbor stage IIB-IV) scheduled for six ABVD cycles, divided into three five-year periods, each with a different G-CSF prophylaxis strategy. From 2010 to 2014, 131 patients received on-demand filgrastim when ANC ≤ 1 × 10^9/L (on-demand- group); from 2015 to 2019, 152 patients systematically received filgrastim six times per cycle (filgrastim-group); from 2020 to 2024, 167 patients received lipegfilgrastim twice per cycle as primary prophylaxis (lipegfilgrastim-group). A total of 85 neutropenia episodes occurred: 52 in the on-demand-group, 30 in the filgrastim-group, and 3 in the lipegfilgrastim-group (P < 0.001); FN incidence was 24%, 14%, and 2%, respectively (P < 0.0001). Chemotherapy disruptions due to FN were 14%, 6%, and 1%, respectively (P < 0.001). Grade 3 bone pain occurred in 5% of patients and was managed with analgesics. Primary prophylaxis with lipegfilgrastim significantly reduced FN rates, hospitalizations, and chemotherapy interruptions in patients with advanced-stage c-HL treated with ABVD, demonstrating improved tolerability of chemotherapy.

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2025-10-22 | Abstract C064: Anemia, transfusions, and health-related quality of life in patients with advanced-stage classic Hodgkin lymphoma receiving multiagent therapy: Findings from the HD21 study

Abstract Introduction: The German Hodgkin Study Group (GHSG) HD21 trial of multiagent therapy in classic Hodgkin lymphoma (cHL) showed significantly reduced treatment-related morbidity (TRMB) with at least 1 TRMB reported in 42% and 59% of patients (pts) treated with BrECADD and eBEACOPP respectively. The HD21 study also showed a reduction in red blood cell (RBC) and platelet transfusions in BrECADD. Anemia is hypothesized to negatively impact pts’ health-related quality of life (HRQoL). This post-hoc analysis explored the association between anemia and HRQoL. Methods: The study randomized 1,500 pts (1:1) to BrECADD or eBEACOPP in 4 or 6, 21-day, treatment cycles. The patient-reported outcomes (PRO) measure European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire – Core 30 items (QLQ-C30) was administered at baseline, during the treatment and posttreatment follow-up (FU) periods up to 60 months. Physical functioning (PF), Social functioning (SF), and Fatigue (FA) were identified as key concepts that could be negatively associated with anemia. Anemia was assessed through RBC transfusions received (0 vs. 1 transfusion or more) and hemoglobin (Hgb) groups (≤8g/dL, &gt;8g/dL but ≤10g/dL, &gt;10g/dL but ≤12g/dL, and &gt;12g/dL). PRO scores were described according to transfusions received and Hgb groups and multivariable analyses were conducted over the treatment period to describe scores according to Hgb groups, adjusted for the transfusions received, age, sex, international prognostic score groups, and baseline PRO score. As this was an exploratory post-hoc analyses, no formal statistical testing was performed; results are interpreted descriptively. Results: The PRO analysis set (all pts with a baseline PRO and at least one postbaseline PRO from the intent-to-treat population) included 732 pts (54% male, mean age 34 years, and 68% with baseline ECOG of 0). At restaging after chemotherapy (RaC), mean PRO score in pts without transfusions vs. pts with transfusion was 76.1 vs. 69.1 for PF, 59.7 vs. 49.5 for SF, and 49.8 vs. 56.1 for FA, respectively. Mean scores in pts with Hgb &lt;8g/dL vs. Hgb ≥12g/dL ranged from 64.1 to 80.4 for PF, 47.4 to 62.8 for SF, and 58.1 to 45.2 for FA at RaC. These results suggest poorer physical and social functioning and more severe fatigue in pts with transfusion or with lower Hgb levels at RaC. Similar results were seen at Staging after 2 cycles. Multivariable analysis showed consistent results with mean estimates numerically lower (PF and SF) or higher (FA) in pts with Hgb &lt;8g/dL than in pts with Hgb ≥12g/dL. Conclusion: These findings indicate a negative association between anemia and pts’ HRQoL, notably at the end of the treatment period suggesting that treatments addressing anemia may not only offer clinical benefit but could also enhance pts’ experience during treatment for advanced stage cHL. Citation Format: Fjoralba Kristo, Flora Mazerolle, Thibaud Alin, Antoine Regnault, Justin Ferdinandus, Karolin Behringer, Janina Jablonski, Peter Borchmann, Ajibade Ashaye. Anemia, transfusions, and health-related quality of life in patients with advanced-stage classic Hodgkin lymphoma receiving multiagent therapy: Findings from the HD21 study [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C064.

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2022-01-06 | HGAL inhibits lymphoma dissemination by interacting with multiple cytoskeletal proteins.

Human germinal center-associated lymphoma (HGAL) is an adaptor protein specifically expressed in germinal center lymphocytes. High expression of HGAL is a predictor of prolonged survival of diffuse large B-cell lymphoma (DLBCL) and classic Hodgkin lymphoma. Furthermore, HGAL expression is associated with early-stage DLBCL, thus potentially limiting lymphoma dissemination. In our previous studies, we demonstrated that HGAL regulates B-cell receptor signaling and cell motility in vitro and deciphered some molecular mechanisms underlying these effects. By using novel animal models for in vivo DLBCL dispersion, we demonstrate here that HGAL decreases lymphoma dissemination and prolongs survival. Furthermore, by using an unbiased proteomic approach, we demonstrate that HGAL may interact with multiple cytoskeletal proteins thereby implicating a multiplicity of effects in regulating lymphoma motility and spread. Specifically, we show that HGAL interacts with tubulin, and this interaction may also contribute to HGAL effects on cell motility. These findings recapitulate previous observations in humans, establish the role of HGAL in dissemination of lymphoma in vivo, and explain improved survival of patients with HGAL-expressing lymphomas.

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2021-09-29 | The PTP1B mutant PTP1B∆2-4 is a positive regulator of the JAK/STAT signalling pathway in Hodgkin lymphoma.

The neoplastic Hodgkin/Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) depend on chronic activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling pathways to maintain survival and proliferation. Accumulating reports highlight the importance of the inactivation or reduced expression of negative JAK/STAT regulators such as the protein-tyrosine phosphatase 1B (PTP1B/PTPN1) in this process. Various PTPN1 mRNA variants as well as truncated PTP1B proteins were identified in cHL cell lines and primary cHL tumour samples. These PTPN1 mRNA variants lack either one or several exon sequences and therefore render these PTP1B variants catalytically inactive. Here, we show that one of these mutants, PTP1B∆2-4, is not only a catalytically inactive variant, but also augmented the IL-4-induced JAK/STAT activity similar to the recently reported PTP1B∆6 splice variant. Moreover, while PTP1B∆6 diminished the activity and protein levels of PTP1BWT, PTP1BWT remained unaffected by PTP1B∆2-4, arguing for different molecular mechanisms of JAK/STAT modulation by PTP1B∆6 and PTP1B∆2-4. Collectively, these data indicate that PTPN1 variants missing one or more exon sequences originated either from alternative splicing or from gene mutation, create PTP1B gain-of-function variants with oncogenic potential by augmenting JAK/STAT signalling in cHL.

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2021-04-27 | Primary prophylaxis with G-CSF may improve outcomes in patients with newly diagnosed stage III/IV Hodgkin lymphoma treated with brentuximab vedotin plus chemotherapy.

We investigate the impact of granulocyte-colony stimulating factor (G-CSF) primary prophylaxis (G-PP, N = 83) versus no G-PP (N = 579) on safety and efficacy of brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) in the ECHELON-1 study of previously untreated stage III/IV classical Hodgkin lymphoma. G-PP was associated with lower incidence of ≥ grade 3 neutropenia (29% versus 70%) and febrile neutropenia (11% versus 21%). Fewer dose delays (35% versus 49%), reductions (20% versus 26%), and hospitalizations (29% versus 38%) were observed. Seven neutropenia-associated deaths occurred in the A + AVD arm; none received G-PP. A + AVD with G-PP was associated with decreased risk of a modified progression-free survival event by 26% compared with A + AVD alone (95% CI: 0.40-1.37). G-PP reduced the rate and severity of adverse events, including febrile neutropenia, reduced treatment delays, dose reductions, and discontinuations, and may thus improve efficacy outcomes. These data support G-PP for all patients treated with A + AVD.

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antibodies

2026-09-28 | Immunophenotyping of CD8+ T Cells in Classical Hodgkin Lymphoma Reveals a Shift Toward Intermediate Exhaustion Following PD-1 Blockade.

The immune microenvironment of classical Hodgkin lymphoma (cHL) is characterized by rare Hodgkin-Reed-Sternberg (HRS) cells surrounded by dysfunctional lymphocytes. HRS cells exploit the PD-L1/PD-1 axis to suppress antitumor immunity. Although PD1 blockade is effective in some relapsed cHL patients, the mechanisms of resistance remain unclear. We investigated T-cell dynamics in cHL using whole-exome sequencing (WES) of plasma circulating tumor DNA and longitudinal single-cell RNA and T-cell receptor sequencing of peripheral blood lymphocytes from a relapsed patient before and after anti-PD1 therapy. Findings were validated by flow cytometry in 11 relapsed cHL patients (pre- and post anti-PD1) and 6 healthy age-matched controls, and by PhenoCycler imaging of 18 tissue biopsies (13 diagnostic, 5 post anti-PD1). WES identified two somatic mutations at relapse-MEX3B-Lys201* and TNFRSF10A-Tyr409His-potentially contributing to immune escape. Immune profiling revealed clonal expansion of CD8⁺ T cells at relapse and a shift from precursor-like (TCF1⁺) to intermediately exhausted (CX3CR1⁺) phenotypes. This pattern was confirmed in other relapsed cHL patients, in whom TCF1⁺ populations diminished, and CX3CR1⁺ T-bet⁺ populations became dominant among those progressing on anti-PD1 therapy. In post anti-PD1 treatment tissue biopsies, CD8⁺ T cells exhibited increased levels of exhaustion markers (TCF1⁻, CX3CR1⁺), a phenotype not observed in diagnostic cHL or healthy donors. These results suggest that durable anti-PD1 responses depend on the preservation of progenitor-exhausted T cells, whereas relapse post anti-PD1 is marked by the accumulation of intermediately exhausted clones. Strategies to prevent T-cell exhaustion or combine anti-PD1 with approaches targeting antigen burden may help overcome resistance.

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2026-09-25 | The influence of Epstein-Barr virus in the microenvironment of classic Hodgkin lymphoma: A focus on T-cells and macrophages.

The prominent immune landscape in classic Hodgkin lymphoma is an essential tool to understand the pathogenesis of the disease. The aim of this study was to evaluate the influence of the Epstein-Barr virus on the frequency and spatial distribution of lymphoid T-cells and macrophages in the immune microenvironment. Pre-treatment lymph node biopsies of 54 Epstein-Barr virus-positive and 91 virus-negative cases of classic Hodgkin lymphoma were studied. Different immune subsets, such as macrophages, T-helper, T-follicular helper, T-regulatory, and T-cytotoxic cells, were evaluated by digital image analysis according to their position in areas close to or distant from neoplastic cells. When compared to virus-negative cases, Epstein-Barr virus-positive classic Hodgkin lymphoma exhibited a higher prevalence of macrophages and CD8+ T-cells in both close and distant areas. Furthermore, CD4+ T-cells in distant areas and their subpopulations (T-regulatory and T-follicular helper) were diminished (p-values: CD68 close: p = 0.028, distant: p = 0.022; CD163 close p < 0.001, distant p = 0.003; CD8 close and distant p < 0.001; CD4 distant: p = 0.04). Clinically, Epstein-Barr virus-positive patients were older by a decade and had a higher stage of disease when compared to virus-negative cases. No associations of viral status with refractoriness to treatment, recurrence, or disease-related death were observed. Cases of Epstein-Barr virus-positive classic Hodgkin lymphoma are related to a cytotoxic predominance, a significant macrophage component, and a decrease in T-follicular helper and T-regulatory cell populations compared to virus-negative cases.

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2026-09-24 | Clinical outcomes and safety of the immune checkpoint inhibitor rechallenge in Hodgkin lymphoma: an off-trial analysis.

Immune checkpoint inhibitors (ICIs) are effective in classical Hodgkin lymphoma (cHL), but immune-related adverse events (irAEs) may lead to treatment interruption in some patients. We conducted a retrospective cohort study of 145 patients with cHL treated with ICIs between 2015 and 2024. Cohort 1 included 130 patients in which 15 received ICI rechallenge within the same treatment line following irAE-related interruption and 115 who did not undergo rechallenge. Another 15 patients who underwent ICI rechallenge in a subsequent line of therapy comprised cohort 2. In cohort 1, PFS and DOR did not differ between rechallenged and non-rechallenged patients (HR 1.7, 95% CI 0.31-9.3, p = 0.55; HR 2.7, 95% CI 0.24-31.2, p = 0.42, respectively). Recurrent irAEs occurred in 20%, with recurrence of the same irAE in 7% in cohort 1. In cohort 2, 53% had refractory disease, whereas 47% responded to initial ICI and were subsequently rechallenged at progression. The median PFS was 7.4 months (95% CI: 5.0-NE) and 13.5 months (95% CI 8.1-46.7), respectively. ICI rechallenge after irAE-related interruption was feasible in selected patients.

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2026-09-16 | Penpulimab: A next-generation Fc-engineered PD-1 inhibitor in cancer immunotherapy.

Penpulimab (AK105) is a novel Fc-engineered, humanised IgG₁ monoclonal antibody targeting programmed cell death protein-1 (PD-1). Unlike conventional PD-1 inhibitors, penpulimab has been designed to eliminate Fcγ receptor and complement C1q binding, thereby reducing Fc-mediated effector functions while maintaining antitumour immune activity. Preclinical studies have demonstrated enhanced structural stability, prolonged receptor occupancy, and high-affinity binding to PD-1. Clinical investigations across haematological and solid malignancies, including classical Hodgkin lymphoma, nasopharyngeal carcinoma, non-small-cell lung cancer, and hepatocellular carcinoma, have shown promising efficacy with durable responses and improved progression-free survival. Penpulimab has also demonstrated favourable outcomes when combined with chemotherapy and targeted therapies. The safety profile is generally manageable, with hypothyroidism, fatigue, rash, pyrexia, and gastrointestinal toxicities being the most commonly reported adverse events. Emerging evidence suggests that Fc engineering may contribute to reduced immune-related toxicity. Overall, penpulimab offers a promising next-generation PD-1 inhibitor with potential applications across multiple malignancies.

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2026-09-13 | Management Patterns and Outcomes for Relapsed or Refractory Hodgkin Lymphoma.

Relapsed and refractory classical Hodgkin lymphoma (r/r cHL) remains a therapeutic challenge, particularly in underserved populations with limited access to novel agents. Data on management patterns and outcomes in safety-net health systems are sparse. We conducted a retrospective review of patients with r/r cHL treated at a Los Angeles County safety-net hospital between 2014 and 2024. Treatment regimens, response rates, and toxicities were analyzed. Twenty-one patients with r/r cHL were included. Doxorubicin + bleomycin + vinblastine + dacarbazine was the predominant first-line regimen (85.7%). In the relapsed/refractory setting, outcomes differed by treatment class. Cytotoxic chemotherapy yielded an overall response rate (ORR) of 50% and complete response rate (CRR) of 25%. In comparison, immune checkpoint inhibitor (ICI) or brentuximab vedotin (BV) monotherapy demonstrated an ORR of 58% and CRR of 42%, while ICI/BV combination regimens achieved the highest observed response rates (ORR 100%, CRR 75%). One-year progression-free survival (PFS) was 38% with cytotoxic chemotherapy, 39% with ICI or BV monotherapy, and 63% with combination regimens. Median follow-up was 38 months, and overall survival (OS) for the entire cohort was 95% at 1 year and 85% at 5 years. In this real-world safety-net cohort, ICI- and BV-based regimens, particularly in combination, were associated with higher response rates compared with cytotoxic chemotherapy. These findings are consistent with prior studies and support the evolving role of targeted and immunotherapy-based approaches in r/r cHL, while highlighting the importance of access to novel therapies in underserved populations.

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small molecules

2026-09-23 | Ophelia-like Paraneoplastic Limbic Encephalitis with Haemorrhagic Temporal Lobe Involvement and Cauda Equina Dysfunction in Classical Hodgkin Lymphoma: A Case Report.

Ophelia syndrome is a rare paraneoplastic limbic encephalitis associated with classical Hodgkin lymphoma (cHL), most often with antibodies against metabotropic glutamate receptor 5 (mGluR5). We describe a 19-year-old man with newly diagnosed cHL who presented with generalised seizures, cognitive dysfunction, spastic paraparesis, cauda equina-related autonomic dysfunction, and a 35 × 31 mm haemorrhagic inflammatory lesion in the right temporal lobe. Brain biopsy showed dense intravascular and perivascular inflammatory infiltrates without neoplastic cells. Cerebrospinal fluid demonstrated pleocytosis and intrathecal IgG synthesis with type III oligoclonal bands. Serum and cerebrospinal fluid neuronal autoantibody panels were negative, but mGluR5 antibodies were not assessed. Cervical lymph node biopsy confirmed nodular sclerosis cHL, stage IIA. After exclusion of infectious encephalitis and central nervous system lymphoma, the presentation was considered most consistent with Ophelia-like paraneoplastic limbic encephalitis. ABVD chemotherapy was initiated, with rapid neurological improvement after the first cycle. Complete metabolic response was achieved after two cycles and sustained after six cycles. At 15-month follow-up, major neurological symptoms had not recurred, although bladder and bowel dysfunction persisted. This case highlights the importance of considering paraneoplastic limbic encephalitis in cHL despite negative standard neuronal antibody testing and of documenting whether mGluR5 antibodies were assessed.

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2026-09-06 | Ophelia Syndrome: Acute Stupor as a Primary Manifestation of Hodgkin Lymphoma Diagnosed by Fluorodeoxyglucose Positron Emission Tomography.

Ophelia syndrome is a rare form of paraneoplastic limbic encephalitis associated with Hodgkin lymphoma, mediated by autoantibodies targeting the metabotropic glutamate receptor type 5 (mGluR5). It is characterized by a spectrum of neurological and psychiatric manifestations. Impaired consciousness progressing to stupor as the presenting feature is uncommon and, combined with a non-diagnostic structural MRI, can substantially delay diagnosis and treatment. We report a 59-year-old male with recently diagnosed classical Hodgkin lymphoma who developed acute unexplained stupor after recovery from a hospital-acquired pneumonia, prior to any onco-specific treatment. A comprehensive workup, including brain MRI with 3-Tesla epilepsy protocol, cerebrospinal fluid analysis, viral multiplex PCR, flow cytometry, and extensive metabolic and autoimmune panels, was either normal or non-diagnostic. Only low-titer antinuclear antibodies (ANA, 1:80, speckled pattern) were detected. An empirical trial of levetiracetam for suspected non-convulsive status epilepticus produced no response. Given persistent stupor and exhaustive exclusion of alternative etiologies, a fluorodeoxyglucose brain positron emission tomography was performed. It revealed marked bilateral hippocampal hypermetabolism, diffuse cortical hypometabolism with relative metabolic preservation of the primary motor and visual cortices (the "tiara sign"), and hypermetabolism of the basal ganglia, a functional pattern highly consistent with paraneoplastic limbic encephalitis. Integrating these findings with subsequent histopathological confirmation of mixed-cellularity classical Hodgkin lymphoma yielded a Paraneoplastic Neurologic Syndrome (PNS)-Care Score of 7, classifying the case as definite paraneoplastic neurological syndrome. Rescue immunosuppression with methylprednisolone pulses (1 gram per day for three days) led to dramatic neurological recovery within 72 hours, and chemotherapy produced complete resolution of the neurological syndrome. This case highlights that a normal structural MRI does not exclude paraneoplastic limbic encephalitis. When unexplained stupor or coma occurs in an oncological patient with a non-diagnostic conventional workup, molecular functional imaging should be incorporated early into the diagnostic algorithm, as its functional metabolic signature enables timely classification under PNS-Care Score criteria and initiation of immunosuppressive therapy capable of reversing potentially life-threatening neurological deficits.

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2026-09-04 | Metachronous EBV-positive classical Hodgkin lymphoma following EBV-positive diffuse large B-cell lymphoma: a case report and literature review.

Epstein-Barr virus (EBV) is closely associated with the development of various malignancies, particularly in lymphomas. Diffuse large B-cell lymphoma (DLBCL), as the most common subtype of non-Hodgkin lymphoma, and classical Hodgkin lymphoma (CHL) both originate from B cells, yet they exhibit significant differences in pathological diagnosis and clinical management. While composite lymphoma (CL) with sequential or simultaneous DLBCL and CHL has been reported, cases where both components are EBV-positive remain rare. Here we report a rare case of composite lymphoma with EBV-positive DLBCL followed by EBV-positive CHL. The patient was a 35-year-old male diagnosed with EBV-positive DLBCL in 2019. After one cycle of CHOP regimen followed by seven cycles of DA-EPOCH-R regimen, he achieved clinical complete remission. Sixty-nine months later, the patient was readmitted due to multiple lymphadenopathy, and the pathological diagnosis was EBV-positive CHL (mixed cellularity type). After two cycles of ABVD chemotherapy, he achieved partial remission, but later showed disease progression and is still under treatment. We discuss this rare case in conjunction with literature review, aiming to provide reference for the diagnosis and treatment of similar cases.

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2026-08-27 | Radiation-Free Therapy for the Initial Treatment of Good Prognosis Early Non-Bulky Hodgkin Lymphoma, Defined by a Low Metabolic Tumor Volume and a Negative Interim PET After 2 Chemotherapy Cycles: The RAFTING Trial Protocol.

Radiation-free treatment for early-stage classic Hodgkin lymphoma (eHL) has been shown to be less effective than standard combined-modality treatment (CMT; chemotherapy plus involved-node radiotherapy (INRT)), which achieves long-term disease control of 94-95%. Approximately 70% of patients can be cured with chemotherapy alone, whereas about 5% fail CMT. Identifying patients who can safely receive chemotherapy alone and those requiring intensified CMT could enable a risk-adapted treatment strategy. The RAFTING trial (NCT04866654; EudraCT 2020-002382-33) is an international, prospective, phase 2, non-inferiority study enrolling patients 18-70 years, stage I-IIA eHL without bulky disease, B symptoms, or extranodal involvement. Low-risk (LR) patients are defined by total metabolic tumor volume (TMTV) <84 mL and negative PET-2. Those with at least one modified EORTC (mEORTC) risk factor, in which bulky disease is replaced by a large nodal mass (5-10 cm), receive four ABVD cycles, while those without risk factors receive two ABVD cycles alone. High-risk (HR) patients, defined by TMTV ≥84 mL and/or positive PET-2, receive "triple therapy": 4 ABVD cycles, INRT (20/30 Gy), and nivolumab (240 mg q2w, ≤doses). LR patients are monitored using cfDNA. Limited relapse is treated with INRT (36 Gy) and nivolumab. The RAFTING trial is the first prospective eHL study to personalize treatment using TMTV and PET-2. It aims to omit radiotherapy in LR patients, intensify treatment in HR patients, and spare relapsed LR patients high-dose chemotherapy and autologous transplantation. CfDNA is being evaluated as a relapse marker. Despite the protocol's complexity, this study exemplifies personalized medicine and could transform treatment practices.

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2026-08-22 | BrECADD in three days: Implementation of a condensed intensive first-line regimen in Hodgkin lymphoma.

Intensive multiagent treatment regimens have substantially improved outcomes in advanced-stage classic Hodgkin lymphoma (cHL). Brentuximab vedotin (BV), etoposide, cyclophosphamide, doxorubicin, dacarbazine and dexamethasone (BrECADD) demonstrated the highest efficacy in cHL reported to date in a randomised phase III trial. Cytotoxic agents are conventionally administered during the first 4 days of a 21-day cycle. A total of four cycles are applied to patients with a complete response after two cycles, otherwise six cycles. We developed a condensed BrECADD protocol, reducing intravenous administration days to only three (-25%). Between January 2024 and July 2026, 30 patients received 132 cycles of 3-day BrECADD at our institution. Primary objective was to describe feasibility and safety; secondary objectives included response, progression-free survival (PFS) and overall survival (OS). Grade ≥3 adverse events occurred in 23 patients (77%), predominantly haematological. Six patients (20%) had grade ≥3 infections (four viral, two bacterial) and six (20%) had pathogen-unspecified febrile neutropenia. Twenty-four patients (80%) required only four BrECADD cycles. There were no treatment discontinuations. After a median follow-up of 18 months (range 4-29), 1-year PFS and OS rates were both 100%. Based on these encouraging results, the condensed 3-day protocol is considered feasible and we recommend it for future BrECADD use.

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cell therapies

2026-07-31 | Haematopoietic cell transplantation for relapsed or refractory classical Hodgkin lymphoma: a retrospective, registry-based cohort study of 19 498 patients from the EBMT Lymphoma Working Group.

Autologous haematopoietic cell transplantation (auto-HCT) is the recommended treatment for chemosensitive relapsed Hodgkin lymphoma, while allogeneic haematopoietic cell transplantation (allo-HCT) is indicated for patients who had unsuccessful auto-HCT. The introduction of novel therapeutic agents, alongside advances in donor selection, conditioning regimens, and graft-versus-host disease prophylaxis, might improve post-transplantation outcomes, however supporting data remain limited. We aimed to evaluate changes in post-transplantation outcomes over the period 2010-22, and to identify predictors of these outcomes. We conducted a retrospective, registry-based cohort study of patients aged 18 years or older with relapsed or refractory classical Hodgkin lymphoma undergoing first auto-HCT or first allo-HCT between Jan 1, 2010, and Dec 31, 2022, registered with the European Society for Blood and Marrow Transplantation (EBMT), with data from more than 600 transplantation centres, across 53 countries, reporting all HCTs and yearly follow-ups. Patients who received allo-HCT for relapse after auto-HCT were included but tandem transplantations were excluded. For allo-HCT, we included patients who received grafts from matched related donors, mismatched related donors, and unrelated donors. The primary endpoints were overall survival and progression-free survival, which were assessed with the Kaplan-Meier method at 2 years and 5 years after HCT. Multivariate analyses were performed using the Cox proportional-hazards regression model to identify predictive factors. We identified 22 047 patients who received a first transplantation for relapsed or refractory Hodgkin lymphoma, after excluding 1324 patients with missing follow-up data and 1225 patients with nodular lymphocyte predominant Hodgkin lymphoma, 19 498 patients were retained: 15 648 received auto-HCT (6772 [43%] were female and 8839 [57%] were male, data were missing for 37 patients); median age at HCT was 35 years [IQR 27-47]; median follow-up was 2·4 years [IQR 2·3-2·5]), and 3850 received allo-HCT (1572 [41%] female and 2273 [59%] were male, data were missing for five patients; median age at HCT 32 years [IQR 26-42]; median follow-up was 3·9 years [IQR 3·8-4·1]). For auto-HCT, from years 2010-14 to years 2019-22, the 2-year progression-free survival increased from 63% (95% CI 62-65) to 73% (71-74) and overall survival increased from 85% (95% CI 84-86) to 93% (91-94). Partial response (hazard ratio [HR] 1·92 [95% CI 1·74-2·11]) or stable or progressive disease (2·45 [2·17-2·76]) at transplantation negatively affected progression-free survival. For allo-HCT, from years 2010-14 to years 2019-22, the 2-year progression-free survival, and overall survival, increased from 44% (95% CI 41-46) to 62% (58-66), and from 66% (63-68) to 72% (68-75), respectively. Partial response (HR 1·58 [95% CI 1·39-1·78]) or stable/progressive disease (2·28 [2·02-2·58]) at transplantation negatively affected progression-free survival. To our knowledge, this is the largest study on HCT for Hodgkin lymphoma in recent years, and our findings that outcomes after auto-HCT and allo-HCT improved over time provide relevant information that could set the basis for prospective trials or additional studies. None.

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2026-04-14 | Exploring EBNA3C Genetic Variability and Recombination in Epstein-Barr Virus-Associated Cancers.

Epstein-Barr virus is a globally disseminated oncovirus capable of causing various malignancies, including gastric cancer, Burkitt lymphoma, and Hodgkin's lymphoma. The influence of recombination on the EBV genome revealed limitations in the current traditional EBV classification, and the extent of these recombination events across the EBV genome is not fully understood. The nuclear antigen 3C (EBNA3C) is an indispensable gene in the oncogenesis of the virus. Despite its critical role, little is known about EBNA3C sequence variability. We examined 988 EBNA3C gene sequences extracted from EBV genomes in this context. Among the protein motifs, the interaction sites with Nm23-H1, RBP-Jk, and nuclear localization signal (NLS) 2 and 3 were the most divergent between EBV types, while NLS-1 and the leucine zipper-like showed high conservation. In our study of the impact of recombination vs. point mutations in the EBNA3C gene, we found that recombination contributed five times more to substitutions than mutation. Notably, Asian populations exhibited the highest variability and recombination rates. Importantly, our analysis revealed geographical rather than disease-specific markers. Furthermore, filtering for recombination regions did not affect the classical classification of EBV-1 and EBV-2. This finding suggests that recombination is pivotal in the architecture of EBV genetic diversity of the EBNA3C gene.

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2026-03-10 | Comprehensive Assessment of CD19 Immunohistochemical Staining in Classic Hodgkin Lymphoma.

Classic Hodgkin Lymphoma (CHL) remains difficult to treat in patients with relapsed and refractory disease. The utility of immunotherapies, many of which target B-cell markers, is still under investigation. Although the neoplastic Hodgkin and Reed-Sternberg (HRS) cells are thought to lose most B-cell markers, studies have shown retention of these markers, mainly CD20, in some cases. However, the CD19 staining profile of HRS cells has not been thoroughly assessed and warrants exploration in the era of CD19-directed immunotherapies. We assessed CD19 immunohistochemical staining in 41 cases of CHL and correlated with histologic subtype, other markers, and clinical parameters. 13/41 cases (31.7%) demonstrated CD19 staining in HRS cells, with variation in staining pattern and intensity. When compared with CD19-negative cases, CD19 positivity correlated significantly with mixed-cellularity subtype (53.8% vs. 7.1%, P =0.002), CD20 (46.2% vs. 14.3%, P =0.0485), CD79a (53.8% vs. 9.1%, P =0.006), Epstein-Barr Virus (EBV) positivity (53.8% vs. 7.1%, P =0.002), and older age (median age 52 vs. 28.5 y, P =0.0006). 7/9 (77.8%) EBV+ cases demonstrated CD19 expression on HRS cells. By Kaplan-Meier analysis, CD19+ cases demonstrated worse overall survival compared with CD19- cases ( P =0.011), with EBV-, CD19- cases demonstrating the best overall survival. On the basis of these findings, CD19 expression on HRS cells should not preclude the pathologic diagnosis of CHL, particularly in the context of mixed-cellularity or EBV+ disease. In addition, older patients with mixed-cellularity and/or EBV+ disease may represent a subgroup of patients with CHL who could benefit from CD19-directed therapies.

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2026-03-09 | Put the CAR-T before the HRS: Advances in Anti-CD30 Immunotherapy Targeting Hodgkin/Reed-Sternberg Cells in Classical Hodgkin Lymphoma.

Classical Hodgkin lymphoma (cHL) is characterized by rare Hodgkin/Reed-Sternberg (HRS) tumor cells that uniformly express cluster of differentiation (CD)30 molecules and orchestrate an immunosuppressive tumor microenvironment, making CD30 an attractive and selective therapeutic target. We summarize the biological rationale for CD30 as a therapeutic target and the preclinical and clinical evidence across major platforms: antibody-drug conjugates (brentuximab vedotin), monoclonal antibodies (including acimtamig and its combinations with Natural Killer cells), second- and third-generation chimeric antigen receptor (CAR)-T cells, and alternative modalities. Particular attention is given to standardized response assessment (IWG, Lugano, RECIL criteria), which enables appropriate cross-trial comparisons. Taken together, the data indicate that beyond the established role of brentuximab vedotin, CD30-directed CAR-T cells and bispecific antibodies demonstrate high activity in refractory cHL, especially when used with fludarabine-containing lymphodepletion, combined with programmed cell death 1 (PD-1) receptor blockade as a strategy to eradicate minimal residual disease. Key challenges include durable effector-cell persistence and optimization of sequencing and combinations; notably, loss of CD30 as an escape mechanism appears uncommon. Integrating mechanistic insights into HRS biology with clinical trial data highlights strategies to enhance the efficacy, safety, and accessibility of CD30-directed immunotherapy. This review aims to provide a concise overview of CD30-targeted approaches in cHL, emphasizing therapeutic outcomes and the evolution of CAR-T technologies.

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2026-03-08 | CD30 CAR-T cells in combination with anti-PD-1 camrelizumab in relapsed/refractory CD30+ lymphomas.

INTRODUCTION: Although CD30-directed chimeric antigen receptor (CAR)-T cell therapy has demonstrated antitumor activity in CD30+ lymphomas, its therapeutic efficacy remains suboptimal. We therefore conducted a prospective, phase II, single-arm, multicenter clinical trial (ChiCTR-2100046763) to evaluate the efficacy and safety of CD30 CAR-T cell therapy in combination with camrelizumab, an immune checkpoint inhibitor, in patients with relapsed/refractory (r/r) CD30+ lymphomas. METHODS: All participants received a lymphodepleting regimen followed by infusion of CD30 CAR-T cells at a dose of 1 × 107 cells/kg. Camrelizumab was subsequently administered on a scheduled basis starting 15 days after CAR-T infusion and continued until unacceptable toxicity or disease progression. RESULTS: A total of 18 patients were enrolled, of whom 12 (66.7%) completed the CD30 CAR-T infusion, including eight with classical Hodgkin lymphoma (cHL) and four with T-cell lymphomas. Among 11 efficacy-evaluable patients, the best objective response rate (ORR) was 63.6%, including four complete responses (CR, 36.3%). After a median follow-up of 30.8 months, the median overall survival (OS) was not reached, and the median progression-free survival (PFS) was 11.1 months (95% CI, 0–26.2). In the subset of seven cHL patients, the ORR and CR rates were 100.0% and 57.1%, with 2-year PFS and OS of 57.1% and 100.0%, respectively. Remarkably, five cHL patients who had previously failed PD-1 blockade still achieved an ORR of 100.0% and a CR rate of 40.0%; median OS was not reached, and median PFS was 15.0 months. In contrast, none of the four T-cell lymphoma patients achieved an objective response. Cytokine release syndrome occurred in eight patients (66.7%), all grade 1–2. The most frequent grade 3–4 toxicities were lymphopenia (58.3%) and neutropenia (41.7%). CONCLUSIONS: The combination of CD30 CAR T-cell therapy with camrelizumab demonstrated a favorable safety profile and elicited durable, clinically meaningful responses in patients with r/r cHL, including those who had failed prior PD-1 blockade. In contrast, although this regimen remained therapeutically well tolerated, its antitumor activity was limited in T-cell lymphomas, underscoring the need for alternative approaches or more effective combinatorial strategies in this disease context.

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2026-02-19 | Classic Hodgkin Lymphoma in the Older Adult: What's New?

Outcomes for older patients with classic Hodgkin lymphoma (cHL) are improving with the inclusion of novel agents into frontline therapy. The sequential brentuximab vedotin (BV) and doxorubicin, vinblastine, dacarbazine (AVD) regimen was standard of care for many older adults with cHL until the checkpoint inhibitor nivolumab (N) and AVD showed marked tolerability and efficacy compared with BV-AVD in the SWOG S1826 randomized, phase 3 clinical trial. Palliative regimens including BV-N are options for patients who are anthracycline-ineligible, and a forthcoming clinical trial will investigate the combination of gemcitabine and pembrolizumab in this population.

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2025-06-05 | Differentiated strategies for nanovaccines in lymphoma immunotherapy: advances and challenges.

Lymphomas constitute a molecularly and clinically heterogeneous group of hematological malignancies, classically classified into two distinct types: Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). These subtypes demonstrate fundamental divergences in their pathobiology and immune microenvironmental profiles. Nanovaccines-nanoparticle-based platforms encapsulating tumor-associated antigens (TAAs) or neoantigens-offer precision immunotherapy by enabling controlled antigen delivery and enhanced dendritic cell cross-presentation. Subtype-specific designs target EBV-associated HL (using LMP1/2 or EBNA1) or NHL (via CD19/CD20/CD22 or T-cell epitopes). However, challenges persist in the development of nanovaccines, particularly concerning antigen selection, carrier materials, and the optimization of vaccine formulations. These vaccines must overcome the immunosuppressive tumor microenvironment, ensure efficient delivery to tumor sites, and avoid toxicity. Despite these hurdles, evolving research in the immunotherapy field of lymphoma leads to the continued exploration of nanovaccines as promising additions to existing therapeutic regimens. This review serves to highlight the critical nature of further research to achieve a better understanding of the complicated interdependent interactions between nanovaccines, immune responses and tumor biology, culminating in more effective and personalised therapies for victims of lymphomas. This advanced strategy is expected to overcome the shortcomings of classic therapies including chemo and radiotherapy, in terms of improved specificity, fewer systemic side-effects and the potential for prolonged remission in patients with refractory or relapsed lymphomas. In conclusion, the integration of nanotechnology into lymphoma immunotherapy marks a vast advancement in the field of cancer therapy, with nanovaccines poised to play a crucial role in future therapeutic strategies.

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2025-04-25 | Immune Deficiency/Dysregulation-Associated EBV-Positive Classic Hodgkin Lymphoma

Classic Hodgkin lymphoma (cHL) in patients with immune deficiency/dysregulation represents a critical unmet need in hematology, demanding the appropriate revision of classification and therapeutic paradigms. Epstein–Barr virus (EBV) is a pivotal driver of lymphomagenesis in this high-risk subset, where viral oncoproteins (e.g., LMP1/2A) exploit immune vulnerabilities to activate NF-κB, rewire tumor microenvironments (TME), and evade immune surveillance. EBV-positive cHL, prevalent in immunosuppressed populations, exhibits distinct molecular hallmarks, including reduced somatic mutations, unique HLA associations, and profound PD-L1-mediated immune suppression, that diverge from EBV-negative cases reliant on genetic aberrations. Despite advances in combined antiretroviral therapy, HIV co-infection exacerbates pathogenesis, M2 macrophage dominance, and T-cell exhaustion, while links to other viruses remain ambiguous. Current therapies fail to adequately target these viral and immune complexities, leaving patients with poorer outcomes. This review synthesizes insights into EBV’s etiological role, immune contexture disparities, and the genetic–environmental interplay shaping cHL heterogeneity. The WHO classification highlights the need to reclassify EBV-associated cHL as a distinct subset, integrating viral status and immune biomarkers into diagnostic frameworks. Urgent priorities include global epidemiological studies to clarify causal mechanisms, development of virus-targeted therapies (e.g., EBV-specific T-cell strategies, PD-1/CTLA-4 blockade), and personalized regimens for immune-dysregulated cohorts.

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2021-12-03 | Potential Molecular Mechanisms of Rare Anti-Tumor Immune Response by SARS-CoV-2 in Isolated Cases of Lymphomas.

Recently, two cases of complete remission of classical Hodgkin lymphoma (cHL) and follicular lymphoma (FL) after SARS-CoV-2 infection were reported. However, the precise molecular mechanism of this rare event is yet to be understood. Here, we hypothesize a potential anti-tumor immune response of SARS-CoV-2 and based on a computational approach show that: (i) SARS-CoV-2 Spike-RBD may bind to the extracellular domains of CD15, CD27, CD45, and CD152 receptors of cHL or FL and may directly inhibit cell proliferation. (ii) Alternately, upon internalization after binding to these CD molecules, the SARS-CoV-2 membrane (M) protein and ORF3a may bind to gamma-tubulin complex component 3 (GCP3) at its tubulin gamma-1 chain (TUBG1) binding site. (iii) The M protein may also interact with TUBG1, blocking its binding to GCP3. (iv) Both the M and ORF3a proteins may render the GCP2-GCP3 lateral binding where the M protein possibly interacts with GCP2 at its GCP3 binding site and the ORF3a protein to GCP3 at its GCP2 interacting residues. (v) Interactions of the M and ORF3a proteins with these gamma-tubulin ring complex components potentially block the initial process of microtubule nucleation, leading to cell-cycle arrest and apoptosis. (vi) The Spike-RBD may also interact with and block PD-1 signaling similar to pembrolizumab and nivolumab- like monoclonal antibodies and may induce B-cell apoptosis and remission. (vii) Finally, the TRADD interacting "PVQLSY" motif of Epstein-Barr virus LMP-1, that is responsible for NF-kB mediated oncogenesis, potentially interacts with SARS-CoV-2 Mpro, NSP7, NSP10, and spike (S) proteins, and may inhibit the LMP-1 mediated cell proliferation. Taken together, our results suggest a possible therapeutic potential of SARS-CoV-2 in lymphoproliferative disorders.

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2021-10-25 | Relapsed and refractory classical Hodgkin lymphoma: could virotherapy help solve the equation?

Classical Hodgkin lymphoma is a neoplastic hematological disease. Standard first-line therapy, including chemotherapy and radiotherapy, is curative in >85% of early-stage patients, with a 5-year survival rate of >95%. However, approximately 15% of patients have hard-to-treat lymphoma with poor outcomes, and new treatment strategies are needed for these young adults. There are several well-documented cases in the medical literature on hematologic cancer remission following natural human viral infections. Therefore, hoping to reproduce these spontaneous tumor regressions, researchers have been investigating various viruses with oncolytic properties. There is a high rationale for using virotherapy in the treatment of Hodgkin lymphoma, in which tumor cells are often infected with the Epstein-Barr virus. Modern viral technologies and current knowledge about the relationship between viruses and cancer could accelerate the discovery of effective viral oncolytic therapies. This article reviews the use of oncolytic viruses as innovative therapies for treating Hodgkin lymphoma.

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