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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]

Summary: Different studies have characterized the microenvironment and its prognostic impact in classic Hodgkin lymphoma whereas such analyses are pending for nodular lymphocyte‐predominant Hodgkin lymphoma (NLPHL). We thus investigated characteristics of tumour cells and microenvironment in NLPHL and evaluated possible correlations with the clinical presentation. Lymph node samples from 152 NLPHL patients who had first‐line treatment within the randomized German Hodgkin Study Group HD16–HD18 trials were available and analysed with regard to IgD status and nuclear size of the tumour cells as well as presence of PD1‐positive follicular T helper cells and CD163‐positive macrophages in the microenvironment. While large tumour cell nuclei and high numbers of PD1‐positive follicular T helper cells in the microenvironment were more common in patients presenting with early/intermediate stages than in patients with advanced‐stage disease (p < 0.0001, unpaired t‐test; p = 0.0022, Mann–Whitney test), no differences between risk groups were observed in terms of the IgD status of the tumour cells and the content of CD163‐positive macrophages in the microenvironment. PD1‐positive follicular T helper cells were present in both cases with typical and variant growth patterns and rosetting around the tumour cells was observed in 96% of patients, indicating an important role of PD1‐positive follicular T helper cells in NLPHL. [ABSTRACT FROM AUTHOR]

In patients with relapse of classical Hodgkin lymphoma (cHL) after autologous stem cell transplant, brentuximab vedotin and anti-PD1 treatment, the outcome is poor. To assess the efficacy of the bispecific anti-CD30/CD16A, NK-cell engaging antibody AFM13 and to select the optimal treatment schedule (arm A–C), we initiated a randomized two-stage phase II trial (NCT02321592). Due to slow recruitment, the trial was terminated after treatment of 25 patients. Treatment with AFM13 was well tolerated: only two treatment-associated serious adverse events (SAEs) were reported; all SAEs resolved completely. With an objective response rate (ORR) of 16.7% (1/5 in arm A, 1/11 in arm B, and 2/8 in arm C) and a 12-month progression-free survival (PFS) of 12.6% (95% CI 3.2–28.9), treatment efficacy of AFM13 monotherapy in all evaluable patients was modest. The continuous application schedule (arm C) might be more effective, but the visit schedule should be better aligned with patients' daily life. [ABSTRACT FROM AUTHOR]

Purpose: Evidence on the effect of self-protection via social distancing and wearing face-masks on infections during chemotherapy is currently not available. We asked if the occurrence of acute infections during chemotherapy for advanced-stage Hodgkin lymphoma (HL) decreased when COVID-19 protection measures were in effect. Methods: We analyzed the occurrence of infections during all documented eBEACOPP cycles starting between 01 March and 30 June of 2017 to 2020 in patients treated within the GHSG HD21 study in Germany and compared the infection rates and characteristics by logistic regression models and means of descriptive statistics. Results: We analyzed 911 cycles of 313 adult patients treated with 4 to 6 cycles of eBEACOPP. We found a significant decrease in the occurrence of infections during chemotherapy for HL during COVID-19 lockdown from 131 (19.6%) of 670 cycles in 2017–2019 to 30 (12.6%) of 239 cycles during COVID-19 lockdown [OR 0.574 (95% CI 0.354–0.930), P = 0.024]. The strongest effect was evident for unspecified infections with 39 cycles (5.8%) during 2017–2019 in comparison to 5 cycles (2.1%) during COVID-19 lockdown. 20 (24.1%) of 83 patients had an infection during the COVID-19 lockdown versus 99 (43.2%) of 229 patients in the years 2017–2019 (P = 0.0023). Conclusion: The significant decrease of infections during chemotherapy for HL during COVID-19 lockdown reveals the protective measures' potential to shield patients from transmissible pathogens. We conclude that these measures could be recommended for HL patients at risk for infections during chemotherapy. [ABSTRACT FROM AUTHOR]

Background: 18F -fluorodeoxyglucose (FDG) positron emission tomography (PET) plays an important role in the staging and response assessment of lymphoma patients. Our aim was to explore the predictive relevance of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) in patients with early stage Hodgkin lymphoma treated within the German Hodgkin Study Group HD16 trial.Methods: 18F-FDG PET/CT images were available for MTV and TLG analysis in 107 cases from the HD16 trial. We calculated MTV and TLG using three different threshold methods (SUV4.0, SUV41% and SUV140%L), and then performed receiver-operating-characteristic analysis to assess the predictive impact of these parameters in predicting an adequate therapy response with PET negativity after 2 cycles of chemotherapy.Results: All three threshold methods analyzed for MTV and TLG calculation showed a positive correlation with the PET response after 2 cycles chemotherapy. The largest area under the curve (AUC) was observed using the fixed threshold of SUV4.0 for MTV- calculation (AUC 0.69 [95% CI 0.55-0.83]) and for TLG-calculation (AUC 0.69 [0.55-0.82]). The calculations for MTV and TLG with a relative threshold showed a lower AUC: using SUV140%L AUCs of 0.66 [0.53-0.80] for MTV and 0.67 for TLG [0.54-0.81]) were observed, while with SUV41% an AUC of 0.61 [0.45-0.76] for MTV, and an AUC 0.64 [0.49-0.80]) for TLG were seen.Conclusions: MTV and TLG do have a predictive value after two cycles ABVD in early stage Hodgkin lymphoma, particularly when using the fixed threshold of SUV4.0 for MTV and TLG calculation.Trial Registration: ClinicalTrials.gov NCT00736320 . [ABSTRACT FROM AUTHOR]

Value of bone marrow biopsy in Hodgkin lymphoma patients staged by FDG PET: results from the German Hodgkin Study Group trials HD16, HD17, and HD18. Keywords: bone marrow involvement; Hodgkin lymphoma; intensive chemotherapy; positron emission tomography; prognosis EN bone marrow involvement Hodgkin lymphoma intensive chemotherapy positron emission tomography prognosis e5 e8 4 03/30/22 20220401 NES 220401 Newly diagnosed advanced-stage Hodgkin lymphoma (HL) has become a curable malignancy in the vast majority of patients.1,2 With response-adapted treatment comprising four or six cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) in escalated dose (eBEACOPP), outstanding cure rates are achieved through a comparatively short and safe treatment approach.3,4 Around 5 to 15% of HL patients present with bone marrow (BM) involvement, as assessed by conventional biopsy.5-7 According to the Ann Arbor classification, BM involvement reflects a high tumour burden and therefore defines stage IV disease.8 Positron emission tomography (PET) using SP 18 sp F-fluoro-2-deoxy-d-glucose (FDG) has demonstrated superior sensitivity compared to BM biopsy.9-11 In paediatric advanced HL, only individuals showing three or more BM lesions were assumed to be at higher risk for progression or relapse.12 Yet, there are insufficient data available to establish whether this also holds true for adult patients receiving intensive first-line treatment. PET imaging was shown to identify BM lesions at a higher sensitivity than biopsy of the iliac bone and has become part of diagnostic work-up in most countries.15 Current study protocols no longer recommend BM biopsy in PET-negative individuals. [Extracted from the article]

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]

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]

Summary: We retrospectively investigated histopathological growth patterns in individuals with advanced nodular lymphocyte‐predominant Hodgkin lymphoma (NLPHL) treated within the randomized HD18 study. In all, 35/60 patients (58%) presented with atypical growth patterns. Patients with atypical growth patterns more often had stage IV disease (P = 0·0354) and splenic involvement (P = 0·0048) than patients with typical growth patterns; a positive positron emission tomography after two cycles of chemotherapy (PET‐2) tended to be more common (P = 0·1078). Five‐year progression‐free survival [hazard ratio (HR) = 0·86; 95% confidence interval (CI) = 0·49–1·47] and overall survival (HR = 0·85; 95% CI = 0·49–1·51) did not differ between the groups after study treatment with PET‐2‐guided escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). Thus, advanced NLPHL is often associated with atypical growth patterns but their prognostic impact is compensated by PET‐2‐guided escalated BEACOPP. [ABSTRACT FROM AUTHOR]

Introduction: Consolidation radiotherapy in intermediate stage Hodgkin´s lymphoma (HL) has been the standard of care for many years as involved field radiotherapy (IFRT) after chemotherapy. It included initially involved region(s). Based on randomized studies, radiation volumes could be reduced and involved site radiation therapy (ISRT) became the new standard. ISRT includes the initially affected lymph nodes. In young adults suffering from HL, infertility and hypogonadism are major concerns. With regard to these questions, we analyzed the influence of modern radiotherapy concepts such as consolidating ISRT in infradiaphragmatic involvement of HL after polychemotherapy. Patients and Methods: Five hundred twelve patients treated within German Hodgkin Study Group (GHSG) HD14 and HD17 trials were evaluated. We analyzed log-adjusted follicle-stimulating-hormone (FSH)- and luteinizing-hormone (LH)-levels of HD14-patients with infradiaphragmatic radiotherapy (IDRT) in comparison with HD14-patients, who had a supradiaphragmatic radiotherapy (SDRT). In a second step, we compared IFRT with ISRT of female HD17 patients regarding the effects on ovarian function and premature menopause. Results: We analyzed FSH- and LH-levels of 258 female and 241 male patients, all treated with IFRT. Of these 499 patients, 478 patients had SDRT and 21 patients had IDRT. In a multiple regression model, we could show that log-adjusted FSH (p=0.0006) and LH values (p=0.0127) were significantly higher after IDRT than after SDRT. The effect of IDRT on gonadal function was comparable to two cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc). We compared the effect of IFRT with ISRT in thirteen female HD17 patients with infradiaphragmatic (ID) involvement. The mean ovarian dose after ISRT was significantly lower than after IFRT. The calculated proportion of surviving non-growing follicles (NGFs) increased significantly from 11.87% to 24.48% in ISRT compared to IFRT, resulting in a significantly longer calculated time to menopause. The younger the age at therapy, the greater the absolute time gain until menopause. Conclusion: Infradiaphragmatic IFRT impairs gonadal function to a similar extent as two cycles of BEACOPPesc. In comparison, the use of ISRT target volume definition significantly reduced radiation dose to the ovaries and significantly extends the time interval from treatment to premature menopause. [ABSTRACT FROM AUTHOR]

Summary: Data on non‐Hodgkin lymphoma (NHL) after classical Hodgkin lymphoma (cHL) are scarce. We therefore performed a retrospective analysis comprising 11·841 cHL patients who had first‐line treatment within the randomized German Hodgkin Study Group (GHSG) HD7–HD15 studies. After a median follow‐up of 106 months, 175 patients (1·5%) had developed NHL. The median time to NHL was 44 months, the median age at NHL diagnosis was 54 years. The five‐year event‐free survival and overall survival estimates from the diagnosis of NHL were 36·9% and 44·2%, respectively. Thus, NHL after cHL is a rare event primarily affecting older individuals and often resulting in the patient´s death. [ABSTRACT FROM AUTHOR]

The amended EU Shareholder Rights Directive introduces a comprehensive regime of ex ante review for potentially conflicted transactions between listed companies and 'related parties' (major shareholders, managers, and others). If considered material, these transactions will have to be evaluated in advance by the board of directors, the shareholders' meeting, or the stock market. The most important choice to be made by member states in implementing the directive concerns the definition of 'materiality'. We use hand-collected data based on IAS 24 reporting of related party transactions to estimate the number of German companies affected by quantitative materiality thresholds based on accounting assets, sales, market capitalisation, and other financials. One important recommendation derived from the analysis is to use more than one single quantitative test to define material related party transactions. [ABSTRACT FROM AUTHOR]

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma of B-cell origin with frequent expression of functional B-cell receptors (BCRs). Here we report that expression cloning followed by antigen screening identifies DNA-directed RNA polymerase beta’ (RpoC) from Moraxella catarrhalis as frequent antigen of BCRs of IgD+ LP cells. Patients show predominance of HLA-DRB1*04/07 and the IgVH genes encode extraordinarily long CDR3s. High-titer, light-chain-restricted anti-RpoC IgG1/κ-type serum-antibodies are additionally found in these patients. RpoC and MID/hag, a superantigen co-expressed by Moraxella catarrhalis that is known to activate IgD+ B cells by binding to the Fc domain of IgD, have additive activation effects on the BCR, the NF-κB pathway and the proliferation of IgD+ DEV cells expressing RpoC-specific BCRs. This suggests an additive antigenic and super-antigenic stimulation of B cells with RpoC-specific IgD+ BCRs under conditions of a permissive MHC-II haplotype as a model of NLPHL lymphomagenesis, implying future treatment strategies. [ABSTRACT FROM AUTHOR]

What is it that we actually see when looking at PET (positron emission tomography)-positive signals in Hodgkin lymphoma (HL)? Thus, the question of how to manage PET-positive lesions at the end of frontline therapy in HL is indeed crucial, because undertreating a disease that can be cured with firstline treatment in 80-90% of cases must definitely be avoided. As a result the authors concluded that it may not always be decisive to perform a biopsy for PET-positive residual mediastinal tissue after frontline therapy and that it was safe and appropriate to first closely observe asymptomatic patients instead of directly intensifying treatment. In the GHSG HD15 trial Engert et al. assessed whether administering RT only to patients with persistent PET-positive residues after chemotherapy was justifiable compared to earlier trials where irradiation was given to all initial bulky findings and all residual disease. [Extracted from the article]

The large mediastinal mass (LMM) at initial staging represents a risk factor in Hodgkin lymphoma (HL) and is measured by X-ray. Depending on location of the LMM, different results can occur regardless of the initial lymphoma volume. To assess this risk factor more accurately, we evaluated the method of volumetry in 77 patients of HD13/14 study of the German Hodgkin Study Group. Furthermore, volume calculations based on three or only one diameter, were performed to simplify volume assessment. Inter-rater reliability was good for all methods. The 3-diameter measurement produced larger volumes than volumetric assessment with an intraclass correlation coefficient (ICC) of 0.93, which could be improved to 0.95 by multiplying volumes with a correction factor of 0.86. The 1-dimensional measurement strongly overestimated the volume with an ICC of 0.7. In conclusion, the simplified volume estimation based on 3 largest diameters provides a reliable concept for the staging of HL patients. [ABSTRACT FROM AUTHOR]

We performed a survey in Hodgkin lymphoma survivors to learn more about their perspectives on treatment risks and benefits. We sent questions to 1149 survivors from the GHSG's HD13-15 trials with (N = 249) or without (N =900) documented progression or relapse. The participation rate was 52% (N =581). After median follow-up of 106 months, 40% of relapse-free and over 60% of relapsed survivors were still worried about late effects and the possibility of relapse. Chemotherapy, largely independent of its intensity, had been a strain on 74% of relapse-free and 90% of relapsed survivors. Most physical, psychological, and socio-economic sequelae were more frequent among relapsed survivors (p <.05) and described as very burdensome. 74% of relapse-free and 61% of relapsed survivors considered primary cure from Hodgkin lymphoma as the most important aspect in the choice of treatment. Accordingly, primary optimal lymphoma control is of utmost importance from the patients' perspective. [ABSTRACT FROM AUTHOR]

Summary: About 30% of all Hodgkin lymphoma (HL) patients are ≥60 years old. As lenalidomide has promising single agent activity in multiple relapsed HL, we replaced bleomycin in ABVD with lenalidomide in this phase‐I trial. Patients aged ≥60 years with early‐unfavourable‐ or advanced‐stage HL (Eastern Cooperative Oncology Group performance status ≤2, Cumulative Illness Rating Scale for Geriatrics score 0–7) received 4–8 cycles of AVD (doxorubicin, vinblastine, dacarbazine) and lenalidomide in escalation with overdose control. Dose‐limiting toxicities (DLTs) included thromboembolism ≥grade 2, severe haematological toxicity, neutropenic fever and prolonged therapy delay. Twenty‐five patients with a median age of 68 years were included, 68% had advanced‐stage HL. A pre‐defined stopping criterion for dose escalation after DLT evaluation of 20/24 patients suggested a recommended phase II dose (RPTD) of 20 mg. DLTs occurred in 10/24 evaluable patients, all treated with ≥20 mg, however, median relative dose intensity was 97% (interquartile range 49–104%). Grade 3 or higher toxicities occurred in all 22 patients at ≥20 mg lenalidomide but no treatment‐related deaths occurred. Overall response rate was 80% for all patients (20/25) and 86% (19/22) at ≥20 mg lenalidomide. Three‐year estimates for progression‐free survival and OS were 69·7% (95% CI: 50·3–89·1%) and 83·8% (95%‐CI: 69·3–98·4%), respectively. In conclusion, AVD with lenalidomide 20 mg is feasible and highly effective in older HL patients. [ABSTRACT FROM AUTHOR]

Summary: About 30% of all Hodgkin lymphoma (HL) patients are ≥60 years old. As lenalidomide has promising single agent activity in multiple relapsed HL, we replaced bleomycin in ABVD with lenalidomide in this phase‐I trial. Patients aged ≥60 years with early‐unfavourable‐ or advanced‐stage HL (Eastern Cooperative Oncology Group performance status ≤2, Cumulative Illness Rating Scale for Geriatrics score 0–7) received 4–8 cycles of AVD (doxorubicin, vinblastine, dacarbazine) and lenalidomide in escalation with overdose control. Dose‐limiting toxicities (DLTs) included thromboembolism ≥grade 2, severe haematological toxicity, neutropenic fever and prolonged therapy delay. Twenty‐five patients with a median age of 68 years were included, 68% had advanced‐stage HL. A pre‐defined stopping criterion for dose escalation after DLT evaluation of 20/24 patients suggested a recommended phase II dose (RPTD) of 20 mg. DLTs occurred in 10/24 evaluable patients, all treated with ≥20 mg, however, median relative dose intensity was 97% (interquartile range 49–104%). Grade 3 or higher toxicities occurred in all 22 patients at ≥20 mg lenalidomide but no treatment‐related deaths occurred. Overall response rate was 80% for all patients (20/25) and 86% (19/22) at ≥20 mg lenalidomide. Three‐year estimates for progression‐free survival and OS were 69·7% (95% CI: 50·3–89·1%) and 83·8% (95%‐CI: 69·3–98·4%), respectively. In conclusion, AVD with lenalidomide 20 mg is feasible and highly effective in older HL patients. [ABSTRACT FROM AUTHOR]

Objectives: Domatinostat (4SC‐202) is a selective class I histone deacetylase inhibitor (HDACi). This phase I study investigated safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and antitumor activity in patients with advanced hematological malignancies. Methods: Domatinostat was administered orally once (QD) or twice daily (BID) on days 1‐14 with 7 days off or continuously days 1‐21 in a 3 + 3 design at 7 dose levels from 25 to 400 mg total daily dose (TDD). Twenty‐four patients were treated with domatinostat. Results: No formal maximum tolerated dose (MTD) was determined. One dose‐limiting toxicity (DLT, grade 4 hypercalcemia) occurred during 200 mg BID continuous treatment. Six patients were reported with ≥ grade 3 treatment‐related adverse events (TRAE; grade 3 hematological in three patients, grade 3 and grade 4 liver enzyme increase in 2 patients, grade 4 pulmonary embolism, and grade 4 hypercalcemia in one patient each). Higher grade hepatic TRAE occurred in the 200 mg BID continuous treatment cohort. Out of 24 patients, 1 achieved a complete response, 1 achieved a partial response, and 18 had stable disease as best response. Conclusion: Administration of domatinostat was safe, well tolerated with signs of antitumor activity. Four hundred milligram TDD in a 200 mg BID schedule (14 + 7) is the recommended phase II dose for monotherapy. [ABSTRACT FROM AUTHOR]

Summary: Some patients with relapsed/refractory Hodgkin lymphoma (HL) are not considered suitable for stem cell transplant (SCT) and have a poor prognosis. This phase IV study (NCT01990534) evaluated brentuximab vedotin (1·8 mg/kg intravenously once every 3 weeks) in 60 patients (aged ≥18 years) with CD30‐positive relapsed/refractory HL, a history of ≥1 prior systemic chemotherapy regimen, who were considered unsuitable for SCT/multi‐agent chemotherapy. Primary endpoint was overall response rate (ORR) per independent review facility (IRF). Secondary endpoints included duration of response (DOR), progression‐free survival (PFS) per IRF, overall survival (OS), proportion proceeding to SCT and safety. The ORR was 50%, with 12% CR; 47% proceeded to SCT. Median DOR was 4·6 months and median duration of CR was 6·1 months. After a median follow‐up of 6·9 and 16·6 months, median PFS and OS were 4·8 months (95% confidence interval, 3·0–5·3) and not reached, respectively; estimated OS rate was 86% at 12 months. Most common adverse events (≥10%) were peripheral neuropathy (35%), pyrexia (18%), diarrhoea and neutropenia (each 10%). Brentuximab vedotin showed notable activity with a safety profile consistent with known toxicities, and may act as a bridge to SCT, enabling high‐risk patients who achieve suboptimal response to frontline/salvage chemotherapy/radiotherapy to receive potentially curative SCT. [ABSTRACT FROM AUTHOR]

Background: Hodgkin lymphoma is the most common neoplasm in young adults, with an incidence of 2 to 3 cases per 100 000 persons per year. Risk-adapted chemotherapy and radiotherapy usually lead to cure. Finding ways to lessen the treatment-associated morbidity and mortality is a major goal of current research. Methods: For the creation of an updated guideline (DKH grant number 111778), a systematic literature search was carried out in medical databases (MEDLINE, CENTRAL) and guideline databases (GIN) (search dates: January 2012 to June 2017). Results: Results from 10 meta-analyses, 89 randomized and controlled trials, and 81 prospective or retrospective trials were evaluated. The use of positron emission tomography (PET) is strongly recommended in the initial diagnostic evaluation, as well as for the guidance of treatment in advanced stages. In early stages, two cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and involved-site radiotherapy (IS-RT) at a dose of 20 Gy are recommended. For the treatment of intermediate stages, two cycles of escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) + two cycles of ABVD and 30 Gy IS-RT are recommended. In advanced stages, two cycles of escalated BEACOPP are administered, and then PET is performed for the guidance of further treatment: two further cycles of escalated BEACOPP are recommended if the PET is negative and four further cycles if it is positive, followed by radiotherapy of PET-positive residual tumor tissue. The five-year survival of patients with Hodgkin lymphoma i s 95%. In case of disease recurrence, high-dose chemotherapy followed by autologous stem-cell transplantation is performed, and targeted drugs including brentuxi-mab vedotin, nivolumab, and pembrolizuab are used. Conclusion: The highly favorable long-term prognosis of HL necessitates careful consideration of the intensity of treatment as well as thorough follow-up to enable the detection of late sequelae, such as second tumors or organ damage. [ABSTRACT FROM AUTHOR]

Secretion of extracellular vesicles (EVs) is a ubiquitous mechanism of intercellular communication based on the exchange of effector molecules, such as growth factors, cytokines, and nucleic acids. Recent studies identified tumor-derived EVs as central players in tumor progression and the establishment of the tumor microenvironment (TME). However, studies on EVs from classical Hodgkin lymphoma (cHL) are limited. The growth of malignant Hodgkin and Reed–Sternberg (HRS) cells depends on the TME, which is actively shaped by a complex interaction of HRS cells and stromal cells, such as fibroblasts and immune cells. HRS cells secrete cytokines and angiogenic factors thus recruiting and inducing the proliferation of surrounding cells to finally deploy an immunosuppressive TME. In this study, we aimed to investigate the role of tumor cell-derived EVs within this complex scenario. We observed that EVs collected from Hodgkin lymphoma (HL) cells were internalized by fibroblasts and triggered their migration capacity. EV-treated fibroblasts were characterized by an inflammatory phenotype and an upregulation of alpha-smooth muscle actin (α-SMA), a marker of cancer-associated fibroblasts. Analysis of the secretome of EV-treated fibroblast revealed an enhanced release of pro-inflammatory cytokines (e.g., IL-1α, IL-6, and TNF-α), growth factors (G-CSF and GM-CSF), and pro-angiogenic factors such as VEGF. These soluble factors are known to promote HL progression. In line, ingenuity pathway analysis identified inflammatory pathways, including TNF-α/NF-κB-signaling, as key factors directing the EV-dependent phenotype changes in fibroblasts. Confirming the in vitro data, we demonstrated that EVs promote α-SMA expression in fibroblasts and the expression of proangiogenic factors using a xenograft HL model. Collectively, we demonstrate that HL EVs alter the phenotype of fibroblasts to support tumor growth, and thus shed light on the role of EVs for the establishment of the tumor-promoting TME in HL. [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.

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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]

Should managers be liable for ill-conceived business decisions? One answer is given by U.S. courts, which almost never hold managers liable for their mistakes. In this paper, we address the question in a theoretical model of delegated decision making. We find that courts should indeed be lenient as long as contracts are restricted to be linear. With more general compensation schemes, the answer depends on the precision of the court's signal. If courts make many mistakes in evaluating decisions, they should not impose liability for poor business judgment. [ABSTRACT FROM AUTHOR]

The article discusses a study on the use of the oral deacetylase inhibitor panobinostat to treat patients with Hodgkin lymphoma. The study examined 27 patients who received panobinostat and 14 patients who were given placebos. The results revealed relapse in patients after they received high dose chemotherapy and underwent autologous stem cell transplants.

Background: Independent central review of clinical imaging remains the standard for oncology clinical trials with registration potential. A limited independent central review strategy has been proposed for solid tumor trials based on concordance between central and local evaluation of response. Concordance between independent central review and local evaluation of response in hematological malignancies is not known. Methods: We retrospectively evaluated concordance between prospectively performed central and local assessments of response using the Revised Response Criteria for Malignant Lymphoma across two international, open-label, single-arm, registration studies of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma (N = 102) or systemic anaplastic large-cell lymphoma (N = 58). Results: Overall objective response rates were similar between assessors for both the trial in Hodgkin lymphoma (75% independent central review, 72% local evaluation) and the trial in anaplastic large-cell lymphoma (86% independent central review, 83% local evaluation). Patient-specific objective response concordance was also substantial (Hodgkin lymphoma: kappa = 0.68; anaplastic large-cell lymphoma: kappa = 0.74). Median progression-free survival was similar between assessors for patients with anaplastic large-cell lymphoma (14.3 months by independent central review (95% confidence interval: 6.9, -); 14.5 months by local evaluation (95% confidence interval: 9.4, -)), but longer by local evaluation in patients with Hodgkin lymphoma (5.8 months by independent central review (95% confidence interval: 5.0, 9.0); 9.0 months by local evaluation (95% confidence interval: 7.1, 12.0)). Median duration of response was longer by local evaluation in both malignancies, which was primarily attributable to earlier computed tomography and positron emission tomography–based scoring of progression by independent central review. Conclusion: A limited independent review audit strategy for clinical trials of some lymphomas appears feasible and practical based on substantial concordance in assessments of overall objective response by central and local evaluation in two international, prospective, registration trials in lymphoma. Some variability between assessors in the time-to-event endpoints was observed, which appeared attributable to earlier assignments of progression by independent central review compared with local evaluation. [ABSTRACT FROM AUTHOR]