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Anti‐PD1‐based first‐line treatment holds great promise in classical Hodgkin lymphoma. The management of immune‐related adverse events in the context of time‐limited combined checkpoint blockade and chemotherapy administered in curative intent is a challenge. Kuczmarski and Lynch provide a case‐based approach to key toxicities observed in this setting. Commentary on: Kuczmarski et al. Managing common toxicities associated with checkpoint inhibitor and chemotherapy combinations for untreated classic Hodgkin lymphoma. Br J Haematol 2024;205:100–108. [ABSTRACT FROM AUTHOR]

Multi-agent chemotherapy and RT for decades have remained mainstay of HL therapy and provided cure to the majority of patients. Nearly 80 years after the first reports of curative treatment with radiotherapy (RT) and cytostatic agents, the therapeutic landscape of classical Hodgkin lymphoma (HL) has evolved dramatically. [Extracted from the article]

Summary: First‐line treatments for classical Hodgkin lymphoma (HL) include ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) and BEACOPPescalated (escalated dose bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone). To further improve overall outcomes, positron emission tomography‐driven strategies and ABVD or BEACOPP variants incorporating the antibody‐drug conjugate brentuximab vedotin (BV) or anti‐PD1 antibodies are under investigation in advanced‐stage patients. The present study aimed to elicit preferences for attributes associated with ABVD, BEACOPPescalated and BV‐AVD (BV, adriamycin, vinblastine and dacarbazine) among patients and physicians. Cross‐sectional online discrete choice experiments were administered to HL patients (n = 381) and haematologists/oncologists (n = 357) in France, Germany and the United Kingdom. Included attributes were progression‐free survival (PFS), overall survival (OS), and the risk of neuropathy, lung damage, infertility and hospitalisation due to adverse events. Whereas 5‐year PFS and OS were the most important treatment attributes to patients, the relative importance of each attribute and preference weights for each level varied among physicians according to the description of the hypothetical patient for whom treatment was recommended. PFS and OS most strongly influenced physicians' recommendations when considering young female patients who did not want children or young male patients. Infertility was more important to physicians' treatment decision than PFS when considering young women with unknown fertility preferences, whereas hospitalisations due to adverse events played the largest role in treatment decisions for older patients. [ABSTRACT FROM AUTHOR]

With defined chemotherapy and radiotherapy (RT) and risk-adapted treatment, early-stage classical Hodgkin lymphoma (HL) has become curable in a majority of patients. Hence, a major current goal is to reduce treatment-related toxicity while maintaining long-term disease control. Patients with early-stage favorable disease (ie, limited stage without risk factors [RFs]) are frequently treated with 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (2xABVD) followed by 20-Gy involved-field or involved-site RT (IF/ISRT). In patients with early-stage unfavorable disease (ie, limited stage with RFs), 4 cycles of chemotherapy are usually consolidated with 30-Gy IF/ISRT. Compared with 4xABVD, 2 cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (2xBEACOPPescalated) followed by 2xABVD improved 5-year progression-free survival (PFS), with similar 5-year overall survival. Recently, treatment strategies based on [18F]fluorodeoxyglucose positron emission tomography (PET) response were evaluated. In early-stage unfavorable HL, a majority of patients achieved a negative interim PET after 2xABVD and an excellent outcome after 4xABVD, whereas in those with a positive interim PET, 2xBEACOPPescalated improved 5-year PFS. Furthermore, a PET-guided RT approach was evaluated to decrease long-term toxicity. Although both the RAPID and H10 trials reported poorer disease control without RT, PET-guided omission of RT can constitute a valid therapeutic option in patients with an increased risk of RT-associated toxicity (eg, because of sex, age, or disease localization). Implementation of drugs such as the anti-CD30 antibody-drug conjugate brentuximab vedotin or the anti--programmed death 1 antibodies nivolumab or pembrolizumab might allow further reduction of overall mortality and improve quality of life in affected patients. [ABSTRACT FROM AUTHOR]

Objective Brentuximab vedotin (BV) is an anti-CD30 antibody-drug conjugate licensed for the treatment of relapsed/refractory Hodgkin lymphoma (rrHL) following autologous stem cell transplant (ASCT) or at least two prior therapies when ASCT or multiagent chemotherapy is not an option. The objective of this study was to describe real-world outcomes with BV in patients with rrHL considered ASCT ineligible or who refuse ASCT. Methods This was a retrospective medical chart review study that enrolled patients ≥18 years old who were initially diagnosed with HL between January 1, 2008 and June 30, 2014, considered ASCT ineligible, and treated in routine care with BV for progressive disease after multidrug chemotherapy regimens. Clinical outcomes included best response to treatment, progression-free survival (PFS), overall survival (OS), and adverse events. Results A total of 136 patients were included, with a median age of 70 years at initial HL diagnosis. The most common reasons for ASCT ineligibility were comorbidities (74%) and age (57%). Overall response rate was 74%, and PFS and OS were 15.1 and 17.8 months, respectively. Peripheral neuropathy was observed in 9.6% of patients. Conclusion The results of this study provide real-world evidence on the feasibility and effectiveness of BV in elderly or frail ASCT-ineligible patients with rrHL in a real-world setting. [ABSTRACT FROM AUTHOR]

Physiological immune checkpoint pathways are important to regulate self-tolerance, limit immune reactions, and moderate autoimmunity. Various cancers are commonly exploiting these mechanisms to evade the host immune system by restraining a durable, efficient antitumor immune response. Immune checkpoints include, but are not limited to, the programmed death 1 (PD1) and the cytotoxic T-lymphocyte-associated protein-4 (CTLA4) axis, which are both druggable by monoclonal antibodies referred to as checkpoint inhibitors (CIs). To date, the anti-PD1 antibodies nivolumab and pembrolizumab are approved for relapsed or refractory classical Hodgkin lymphoma (cHL) due to high response rates with a favorable yet distinct safety profile, and other agents are under investigation. This review summarizes the available preclinical and clinical data including the toxicity and efficacy of different CIs in cHL. It also provides future perspectives based on ongoing clinical trials, potentially synergistic combinatory approaches, and their fit in the therapeutic landscape in cHL. [ABSTRACT FROM AUTHOR]

Hodgkin lymphoma (HL) has become a highly curable malignancy even in advanced stages when treated adequately. However, relapsed or refractory disease and treatment-related toxicity constitute a significant clinical challenge. Innovative approaches are thus needed to improve treatment of these mainly young patients. In HL lesions, very few malignant Hodgkin and Reed-Sternberg (HRS) cells are embedded in an immunosuppressive microenvironment of reactive cells. Novel approaches such as bispecific antibodies, antibody-drug conjugates, immune-checkpoint inhibitors or adoptive cellular therapies are currently being investigated with promising results in relapsed or refractory patients. Encouraging response rates and a favorable toxicity profile have recently been reported in early phase clinical trials with antibodies blocking the programed-death receptor 1 (PD1). This review will summarize the current clinical knowledge on mechanism, safety and efficacy of the different agents and discuss potential future strategies, which are partly already investigated within clinical trials. [ABSTRACT FROM AUTHOR]

Accurate clinical staging is crucial for adequate risk-adapted treatment in Hodgkin lymphoma ( HL) to prevent patients from under- or over-treatment. Within the latest German Hodgkin Study Group trial generation, diagnostic findings such as histopathology, computerized tomography imaging and clinical risk factors were re-evaluated by expert panels. Here, we retrospectively analysed 5965 patients and identified 399 in who major discordant findings changed their first-line treatment allocation. Histopathology review did not confirm the initial diagnosis of HL in 87 patients. Treatment allocation was revised in 312 of the remaining 5878 patients: 176 were assigned to a higher and 128 to a lower risk group, respectively; the correct treatment group remained unclear in 8 patients. Cases of revised treatment allocation accounted for 9·8%, 6·0%, 0·8%, and 14·8% of patients initially assigned to the HD13, HD14, HD15 trials and stage IA lymphocyte-predominant HL project, respectively. Most revisions were due to wrong application of clinical stage (20·5% of 312 patients with revised treatment group), histological subtype (9·0%) or the risk factors ≥3 involved areas (46·8%) or large mediastinal mass (9·3%). In conclusion, centralized review by experienced experts changed risk-adapted first-line treatment in a relevant proportion of HL patients. Quality control measures clearly improve the accuracy of treatment and should be implemented in clinical practice. [ABSTRACT FROM AUTHOR]

Accounting for 15% of all lymphomas, Hodgkin lymphoma (HL) is a relatively rare disease but the most common malignancies among young adults. Over the last decades prognosis markedly improved with the refinement of evidence based therapies. Current riskadapted therapies usually consist of polychemotherapies such as ABVD or BEACOPPesc and up to 90% of all patients may be considered cured after adequate first-line treatment. Due to this favorable development recent research focused on reduction of therapeutic intensity and more individualized approaches. Prognosis is worse in relapsed or refractory HL (rrHL), where high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) is associated with progression-free survival (PFS) of only 50%. Outcomes tend to be inferior in elderly patients or those ineligible for intensified therapies due to comorbidities. This review delineates the development of current standard approaches in first-line and rrHL treatment and summarizes key findings of recent large scale clinical trials. Innovative approaches including response-guided therapy or implementation of novel agents are covered in a separate article. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 39-year-old man admitted to emergency department with nausea, vomiting, malaise, headache, and slowly deteriorating alertness. He had diabetes mellitus of an unknown type and a history of cholelithiasis and cholecystitis and he had very high levels of triglycerides and cholesterol as well as elevated hemoglobin. He was treated with intravenous infusions of insulin, glucose, heparin, and piperacillin–tazobactam.

The DNA double-strand break (DSB) is the most cytotoxic lesion and compromises genome stability. In an attempt to efficiently repair DSBs, cells activate ATM kinase, which orchestrates the DNA damage response (DDR) by activating cell cycle checkpoints and initiating DSB repair pathways. In physiological B cell development, however, programmed DSBs are generated as intermediates for effective immune responses and the maintenance of genomic integrity. Disturbances of these pathways are at the heart of B cell lymphomagenesis. Here, we review the role of DNA repair and cell cycle control on B cell development and lymphomagenesis. In addition, we highlight the intricate relationship between the DDR and the tumor microenvironment (TME). Lastly, we provide a clinical perspective by highlighting treatment possibilities of defective DDR signaling and the TME in mantle cell lymphoma, which serves as a blueprint for B cell lymphomas. [ABSTRACT FROM AUTHOR]

Summary: High programmed cell death 1 ligand 1 (PD‐L1) protein expression and copy number alterations (CNAs) of the corresponding genomic locus 9p24.1 in Hodgkin‐ and Reed–Sternberg cells (HRSC) have been shown to be associated with favourable response to anti‐PD‐1 checkpoint inhibition in relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). In the present study, we investigated baseline 9p24.1 status as well as PD‐L1 and major histocompatibility complex (MHC) class I and II protein expression in 82 biopsies from patients with early stage unfavourable cHL treated with anti‐PD‐1‐based first‐line treatment in the German Hodgkin Study Group (GHSG) NIVAHL trial (ClinicalTrials.gov Identifier: NCT03004833). All evaluated specimens showed 9p24.1 CNA in HRSC to some extent, but with high intratumoral heterogeneity and an overall smaller range of alterations than reported in advanced‐stage or r/r cHL. All but two cases (97%) showed PD‐L1 expression by the tumour cells in variable amounts. While MHC‐I was rarely expressed in >50% of HRSC, MHC‐II expression in >50% of HRSC was found more frequently. No obvious impact of 9p24.1 CNA or PD‐L1 and MHC‐I/II expression on early response to the highly effective anti‐PD‐1‐based NIVAHL first‐line treatment was observed. Further studies evaluating an expanded panel of potential biomarkers are needed to optimally stratify anti‐PD‐1 first‐line cHL treatment. [ABSTRACT FROM AUTHOR]

The article provides information on a study which observed the link between different blood count parameters at baseline with response and progression-free survival (PFS) in relapsed or refractory (r/r) classical Hodgkin lymphoma (cHL) patients treated with the anti-PD1 antibody, nivolumab. Topics discussed include role of eosinophils as co-effectors of the immune response, and results of the study.

Summary: B‐cell content in the tumour microenvironment (TME) of classic Hodgkin lymphoma (HL) is known to be associated with prognosis. Here we demonstrate that whole slide image analysis using routinely available slides predicts outcomes in patients treated with ABVD in a prospective trial with a high B‐cell content being associated with a favourable prognosis. B cells in the TME did not correlate with B cells in peripheral blood. In the TME maturation, stages of B cells (naive and memory) were consistent. However, we detected down‐regulation of CD73 in HL with low B cells suggestive of an antibody‐independent function of B cells in the TME of HL. [ABSTRACT FROM AUTHOR]

Objectives: Patients with classical Hodgkin lymphoma (cHL) relapsing after second‐line therapy have a dismal prognosis and novel approaches are required for this patient group. Based on promising (pre‐)clinical data and the favourable toxicity profile, we performed a phase II clinical trial with the JAK inhibitor ruxolitinib in patients with relapsed or refractory cHL (r/r cHL). Methods: Patients ≥18 years with histologically confirmed r/r cHL who failed second‐line treatment were included. Ruxolitinib was given orally at a dose of 25 mg twice daily in continuous 28‐day cycles until progression or unacceptable toxicity. Primary endpoint was the PET/CT‐based overall response rate (ORR; complete response (CR) or partial response (PR)) after 2 cycles; secondary endpoints included progression‐free (PFS) and overall survival (OS) as well as feasibility. The Jericho Trial adopted a 2‐stage phase 2 design (Simon 1989). Results: Among the 12 included patients in stage 1, 2 had a PR, 3 had a stable disease (SD) and 6 had progressive disease (PD) after two treatment cycles (ORR: 2/12 evaluable patients, 16.7%). Median PFS was 3.6 months, the 1‐year OS estimate was 50.6% (median not reached). The toxicity profile was favourable with only one grade IV adverse event (7.1%) reported. Conclusion: Ruxolitinib exhibited a favourable side effect profile but modest activity in r/r cHL. Although the formal stopping criterion after stage 1 was not met, the trial did not continue to stage 2 due to the low response and PFS rates observed in stage 1. [ABSTRACT FROM AUTHOR]

Background: Burkitt lymphoma (BL) and diffuse large B‐cell lymphoma (DLBCL) are aggressive B‐cell non‐Hodgkin lymphomas (B‐NHL) with a generally favorable prognosis after immunochemotherapy. The outcome of BL is superior to DLBCL. In 2016, a distinct group of lymphomas displaying characteristics of both BL and DLBCL (high grade B‐cell lymphoma, HGBL) was introduced into the WHO classification. Histopathological discrimination of BL, DLBCL, and HGBL may be challenging. Data on the frequency of histopathological difficulties resulting in revision of the final diagnosis of BL/DLBCL/HGBL and its impact on the prognosis are limited. Methods: We assessed histopathological features and clinical outcomes of 66 patients with suspected diagnosis of BL at the reporting institution between 2010 and 2020. Results: The median age was 51 years (range 19‐82) and final histopathological diagnosis revealed BL (n = 40), DLBCL (n = 12), or HGBL (n = 14). Patients with DLBCL and HGBL were either treated with DLBCL‐directed (83.3% and 35.7%) or BL‐directed (16.7% and 64.3%) protocols. Patients in whom diagnosis was revised from DLBCL to BL after initiation of DLBCL‐directed treatment had a significantly inferior progression‐free survival (PFS) than patients initially diagnosed with BL (p = 0.045), thus resembling rather the prognosis of DLBCL/HGBL. There was no difference between patients with DLBCL and HGBL, respectively, regarding PFS and OS (p = 0.38 and p = 0.27). Conclusion: These results suggest that timely and precise histopathological diagnosis as well as reference histopathological review of the underlying lymphoma is critical to determine up‐front treatment strategies. Consequently, selection of more aggressive treatment protocols in case of difficulties with discrimination between DLBCL/HGBL/BL may be a reasonable approach. [ABSTRACT FROM AUTHOR]

Summary: Reinduction chemotherapy followed by high‐dose chemotherapy and autologous stem cell transplant (HDCT + ASCT) is second‐line standard of care for transplant‐eligible patients with relapsed/refractory classical Hodgkin lymphoma (r/r cHL) but has a high failure rate. Because response to reinduction is predictive of the outcome after HDCT + ASCT, we aimed to improve the standard dexamethasone, high‐dose cytarabine and cisplatinum (DHAP) reinduction regimen by addition of the oral mammalian target of rapamycin inhibitor everolimus (everDHAP). Transplant‐eligible patients aged 18–60 years with histologically confirmed r/r cHL were included in this experimental phase I/II trial. Everolimus (10 mg/day, determined in phase‐I‐part) was administered on day 0–13 of each DHAP cycle. From July 2014 to March 2018, 50 patients were recruited to the phase II everDHAP group; two were not evaluable, three discontinued due to toxicity. Randomization to a placebo group stopped in October 2015 due to poor recruitment after nine patients. The primary end‐point of computed tomography (CT)‐based complete remission (CR) after two cycles of everDHAP was expected to be ≥40%. With a CT‐based CR rate of 27% (n = 12/45) after two cycles of everDHAP the trial did not meet the primary end‐point. Adding everolimus to DHAP is thus feasible; however, the everDHAP regimen failed to show an improved efficacy. [ABSTRACT FROM AUTHOR]

Background: Primary central nervous system lymphoma (PCNSL) is a rare type of aggressive lymphoma of the central nervous system. Treatment strategies improved significantly over the past decades differ regionally but mainly consist of rituximab and high‐dosed methotrexate (MTX)‐based therapies. Methods: We assessed clinical outcomes of 100 patients with newly diagnosed PCNSL between 2010‐2020 at the University Hospital of Cologne, Germany. Results: Patients were 23‐88 years of age and either treated with MTX‐based regimens (PRIMAIN, MARTA, MATRix), individual regimens, or best supportive care, respectively. Overall response rates were generally high (66,7‐83,8%), but different organ toxicities required dose adjustments in most groups. Two‐year overall survival rates were 57,9% (PRIMAIN), 63,6% (MARTA), 65,4% (MATRix), and 37,5% (Other), respectively. Out of 9 patients suffering from relapse >12 months from primary diagnosis, 7 patients (77,8%) received methotrexate‐based salvage therapy with 2‐year overall survival of 4/6 patients (66,7%). Conclusion: Although a relevant proportion of patients are not eligible for clinical trials due to age, performance status, or comorbidities, these results prove feasibility of different MTX‐based treatment strategies in clinical routine. Even elderly patients displayed surprisingly favorable outcomes. However, with compromising organ toxicities, reduction of intensity should be part of strategies in future clinical trials. [ABSTRACT FROM AUTHOR]

This retrospective study compared effectiveness of (brentuximab vedotin) BV to other chemotherapies in patients with rrHL following an autologous stem cell transplant (ASCT). Data originated from a medical chart review of patients treated in real-world clinical settings at 50 sites in the United Kingdom and Germany. Inverse probability of treatment weights based on propensity scores were used to adjust for differences in baseline characteristics between treatment groups. Among 312 rrHL patients included, 196 received BV and 116 received physicians’ choice chemotherapy. Median PFS was significantly longer (27.0 months vs. 13.4 months; p = .0144) and 12-month OS survival greater (78.1% vs. 65.9%; p = .0129) with BV compared to chemotherapy. Documented adverse events included leukopenia (12.8%) and peripheral neuropathy (8.7%) for BV and leukopenia (12.1%), anemia (5.2%) and diarrhea (5.2%) for chemotherapy. In this real-world study, rrHL patients treated for relapse after ASCT with BV had longer median PFS and 12-month OS than patients receiving chemotherapy. [ABSTRACT FROM AUTHOR]

Doxorubicin, bleomycin, vinblastine sulfate, and dacarbazine (ABVD) is associated with severe toxicity in older patients, particularly from bleomycin-induced lung toxicity (BLT). Therefore, using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients, especially in early-stage HL. We therefore analyzed feasibility, toxicity, and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients. We included patients ≥60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2 x ABVD; n = 137) or AVD (23AVD; n= 82), each followed by involved-field radiotherapy (IF-RT), with patients randomized to 43ABVD1IFRT (n568). Patients' median age was 65 years (range, 60-75) with comparable patient and disease characteristics. Grade III-IV adverse event rates were similar in patients receiving 23AVD and 2 x ABVD (40% and 39%, respectively), but considerably higher in patients receiving 43ABVD (65%). Similarly, BLT was rare in patients receiving 2 x ABVD/AVD, but occurred in 7/69 (10%) of patients randomized to 43ABVD, with 3 lethal events. In conclusion, no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy. However, we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD. These trials are registered at www.clinicaltrials.gov and www.isrctn.com as #NCT00265018 (HD10) and #ISRCTN63474366 (HD13). [ABSTRACT FROM AUTHOR]