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Background: Intensified systemic chemotherapy has the highest primary cure rate for advanced-stage, classical Hodgkin lymphoma but this comes with a cost of severe and potentially life long, persisting toxicities. With the new regimen of brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD), we aimed to improve the risk-to-benefit ratio of treatment of advanced-stage, classical Hodgkin lymphoma guided by PET after two cycles., Methods: This randomised, multicentre, parallel, open-label, phase 3 trial was done in 233 trial sites across nine countries. Eligible patients were adults (aged ≤60 years) with newly diagnosed, advanced-stage, classical Hodgkin lymphoma (ie, Ann Arbor stage III/IV, stage II with B symptoms, and either one or both risk factors of large mediastinal mass and extranodal lesions). Patients were randomly assigned (1:1) to four or six cycles (21-day intervals) of escalated doses of etoposide (200 mg/m 2 intravenously on days 1-3), doxorubicin (35 mg/m 2 intravenously on day 1), and cyclophosphamide (1250 mg/m 2 intravenously on day 1), and standard doses of bleomycin (10 mg/m 2 intravenously on day 8), vincristine (1·4 mg/m 2 intravenously on day 8), procarbazine (100 mg/m 2 orally on days 1-7), and prednisone (40 mg/m 2 orally on days 1-14; eBEACOPP) or BrECADD, guided by PET after two cycles. Patients and investigators were not masked to treatment assignment. Hierarchical coprimary objectives were to show (1) improved tolerability defined by treatment-related morbidity and (2) non-inferior efficacy defined by progression-free survival with an absolute non-inferiority margin of 6 percentage points of BrECADD compared with eBEACOPP. An additional test of superiority of progression-free survival was to be done if non-inferiority had been established. Analyses were done by intention to treat; the treatment-related morbidity assessment required documentation of at least one chemotherapy cycle. This trial was registered at ClinicalTrials.gov (NCT02661503)., Findings: Between July 22, 2016, and Aug 27, 2020, 1500 patients were enrolled, of whom 749 were randomly assigned to BrECADD and 751 to eBEACOPP. 1482 patients were included in the intention-to-treat analysis. The median age of patients was 31 years (IQR 24-42). 838 (56%) of 1482 patients were male and 644 (44%) were female. Most patients were White (1352 [91%] of 1482). Treatment-related morbidity was significantly lower with BrECADD (312 [42%] of 738 patients) than with eBEACOPP (430 [59%] of 732 patients; relative risk 0·72 [95% CI 0·65-0·80]; p<0·0001). At a median follow-up of 48 months, BrECADD improved progression-free survival with a hazard ratio of 0·66 (0·45-0·97; p=0·035); 4-year progression-free survival estimates were 94·3% (95% CI 92·6-96·1) for BrECADD and 90·9% (88·7-93·1) for eBEACOPP. 4-year overall survival rates were 98·6% (97·7-99·5) and 98·2% (97·2-99·3), respectively., Interpretation: BrECADD guided by PET after two cycles is better tolerated and more effective than eBEACOPP in first-line treatment of adult patients with advanced-stage, classical Hodgkin lymphoma., Funding: Takeda Oncology., Competing Interests: Declaration of interests PB reports consulting fees from Takeda, BMS, Roche, Amgen, Novartis, Celgene, Miltenyi Biotech, and Gilead; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda, Novartis, BMS, Roche, MSD, Celgene, Miltenyi Biotech, Gilead, and AbbVie; and funding for scientific research from Takeda Oncology, MSD, and Novartis. JF reports funding and consulting fees from Takeda Oncology and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda Oncology and Roche Pharma. RG reports consulting fees from Celgene, Novartis, Roche, Takeda, AbbVie, Astra Zeneca, MSD, Merck, Gilead, Daiichi Sanko, and Sanofi; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, AbbVie, Gilead, Daiichi Sankyo, and Sanofi; support for attending meetings or travel from Roche, Amgen, Janssen, Astra Zeneca, Novartis, BMS, AbbVie, and Daiichi Sankyo; participating on a data safety monitoring board or advisory board for Celgene, Novartis, Roche, BMS, Takeda, AbbVie, Astra Zeneca, Janssen, MSD, Merck, Gilead, Daiichi Sankyo, and Sanofi; and stock or stock options from Novo Nordisk and Lilly. MHe reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda. AH reports payment for speakers bureau, funding, and travel support from, and participation on an advisory board for Takeda. FK reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events, and support for attending meetings or travel from Takeda. MHä reports consulting fees from Pfizer, Incyte, Roche, Amgen, Sanofi/Aventis, Sobi, Kite/Gilead, Janssen, and BMS and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Sobi, Novartis, Kite/Gilead, Falk Foundation, and BMS. 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BvT reports institutional grants or contracts from Esteve, Merck Sharp & Dohme, Novartis, and Takeda; consulting fees from Allogene, Amgen, BMS/Celgene, Cerus, Gilead Kite, Incyte, IQVIA, Janssen-Cilag, Lilly, Merck Sharp & Dohme, Miltenyi, Novartis, Noscendo, Pentixapharm, Pfizer, Pierre Fabre, Qualworld, Roche, Sobi, and Takeda; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, AstraZeneca, BMS/Celgene, Gilead Kite, Incyte, Lilly, Merck Sharp & Dohme, Novartis, Roche, and Takeda; support for attending meetings or travel from AbbVie, AstraZeneca, Gilead, Kite, Lilly, Merck Sharp & Dohme, Pierre Fabre, Roche, Takeda, and Novartis; payment from Takeda and Regeneron (INSIGHTFUL study); payment to institution from the Olympia 3 study; and participation on a data safety monitoring board or advisory board for Takeda and Regeneron. SB reports consulting fees from Galapagos; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events and consultation from Takeda; support for attending meetings or travel from Takeda; having a leadership role in another board, society, committee, or advocacy group (paid or unpaid), and holding stock or stock options for Liqomics. KB reports funding and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda Oncology. MF reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Celgene, BMS, Takeda, and Janssen. AZo reports Takeda stocks and being an employee of Takeda Oncology. SK reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events, payment for expert testimony, and support for attending meetings or travel from, and participating on a data safety monitoring board or advisory board for Takeda. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Hodgkin lymphoma is a B-cell lymphoma often affecting young adults. Outcomes following intensive chemo- and radiotherapy are generally favourable but leave patients at high risk for early and late toxicities frequently reducing quality of life. Relapsed/refractory disease is regularly difficult to treat and ultimately results in death in a relevant subset of patients. Current strategies for risk stratification and response evaluation rely on clinical features and imaging only, and lack discriminatory power to detect patients at risk for disease progression. Here, we explore how circulating tumor DNA sequencing might help to overcome these shortcomings. We provide an overview over recent technical and methodological developments and suggest potential use cases for different clinical situations. Circulating tumor DNA sequencing offers the potential to significantly augment current risk stratification strategies with the ultimate goal of further individualizing treatment strategies for patients with HL., Competing Interests: Declaration of Competing Interest JMH is an advisor/consultant for Miltenyi; reports research funding from Incyte and Novartis; and reports travel support from Kite-Gilead and Novartis. Sven Borchmann is a shareholder and has a leadership role in Liqomics and is a consultant for Galapagos. The other authors declare no potential conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma that has traditionally been considered a subgroup of Hodgkin lymphoma. However, morphology, surface marker expression, genetics, and clinical course are different from classic Hodgkin lymphoma. While most patients experience indolent disease with slow progression, some patients can also have more aggressive disease. Nevertheless, outcomes are excellent, and excess mortality due to NLPHL is at most very low. The treatment of newly diagnosed NLPHL has historically mirrored that of classic Hodgkin lymphoma. However, evidence for deviations from that approach has emerged over time and is discussed herein. Less evidence is available for the optimal management of relapsed patients. So-called variant histology has recently emerged as a biological risk factor, providing at least a partial explanation for the observed heterogeneity of NLPHL. Considering variant histology together with other risk factors and careful observation of the clinical course of the disease in each patient can help to assess individual disease aggressiveness. Also important in this mostly indolent disease are the preferences of the patient and host factors, such as individual susceptibility to specific treatment side effects. Considering all this together can guide individualized treatment recommendations, which are paramount in this rare disease., (Copyright © 2022 by The American Society of Hematology.)

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., (© 2022 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

While classical Hodgkin lymphoma (HL) is highly susceptible to anti-programmed death protein 1 (PD1) antibodies, the exact modes of action remain controversial. To elucidate the circulating lymphocyte phenotype and systemic effects during anti-PD1 1st-line HL treatment we applied multicolor flow cytometry, FluoroSpot and NanoString to sequential samples of 81 HL patients from the NIVAHL trial (NCT03004833) compared to healthy controls. HL patients showed a decreased CD4 T-cell fraction, a higher percentage of effector-memory T cells and higher expression of activation markers at baseline. Strikingly, and in contrast to solid cancers, expression for 10 out of 16 analyzed co-inhibitory molecules on T cells (e.g., PD1, LAG3, Tim3) was higher in HL. Overall, we observed a sustained decrease of the exhausted T-cell phenotype during anti-PD1 treatment. FluoroSpot of 42.3% of patients revealed T-cell responses against ≥1 of five analyzed tumor-associated antigens. Importantly, these responses were more frequently observed in samples from patients with early excellent response to anti-PD1 therapy. In summary, an initially exhausted lymphocyte phenotype rapidly reverted during anti-PD1 1st-line treatment. The frequently observed IFN-y responses against shared tumor-associated antigens indicate T-cell-mediated cytotoxicity and could represent an important resource for immune monitoring and cellular therapy of HL., (© 2021. The Author(s).)

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., (© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

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., (© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Individualization of treatment in Hodgkin's lymphoma is necessary to improve cure rates and reduce treatment side effects. Currently, it is hindered by a lack of genomic characterization and sensitive molecular response assessment. Sequencing of cell-free DNA is a powerful strategy to understand the cancer genome and can be used for extremely sensitive disease monitoring. In Hodgkin's lymphoma, a high proportion of cell-free DNA is tumor-derived, whereas traditional tumor biopsies only contain a little tumor-derived DNA., Methods: We comprehensively genotype and assess minimal residual disease in 121 patients with baseline plasma as well as 77 follow-up samples from a subset of patients with our targeted cell-free DNA sequencing platform., Findings: We present an integrated landscape of mutations and copy number variations in Hodgkin's lymphoma. In addition, we perform a deep analysis of mutational processes driving Hodgkin's lymphoma, investigate the clonal structure of Hodgkin's lymphoma, and link several genotypes to Hodgkin's lymphoma phenotypes and outcome. Finally, we show that minimal residual disease assessment by repeat cell-free DNA sequencing, as early as a week after treatment initiation, predicts treatment response and progression-free survival, allowing highly improved treatment guidance and relapse prediction., Conclusions: Our targeted cell-free DNA sequencing platform reveals the genomic landscape of Hodgkin's lymphoma and facilitates ultrasensitive detection of minimal residual disease., Funding: Mildred Scheel School of Oncology Aachen-Bonn-Cologne-Düsseldorf MD Research Stipend, Next Generation Sequencing Competence Network grant 423957469, Deutsche Krebshilfe grant 70112502, Deutsche Forschungsgemeinschaft (DFG) grant EN 179/13-1, the HL MRD consortium, and the Frau-Weiskam und Christel Ruranski-Stiftung., Competing Interests: Declaration of Interests P.J.B. reports research grants from BeiGene, Bristol Myers Squibb, Merck Sharpe & Dohme, and Takeda and personal fees and non-financial support from Bristol-Myers Squibb, Celgene, and Takeda, all outside the submitted work. S.S. received travel grants from GSK. D.M.P. reports being founder and CSO of Exbiome and an occasional advisor for Takeda. B.v.T. reports personal fees and nonfinancial support from Bristol-Myers Squibb; personal fees from Amgen, Pfizer, Gilead Sciences, Pentixapharm, and Roche; grants, personal fees, and nonfinancial support from MSD and Takeda; and grants, personal fees, and nonfinancial support from Novartis. S.B. reports being founder, CEO, and shareholder of Liqomics and personal fees and non-financial support from Bristol-Myers Squibb and Takeda outside the submitted work., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Classic Hodgkin lymphoma (cHL) is the cancer type most susceptible to antibodies targeting programmed cell death protein 1 (PD1) and is characterized by scarce Hodgkin and Reed-Sternberg cells (HRSCs), perpetuating a unique tumor microenvironment (TME). Although anti-PD1 effects appear to be largely mediated by cytotoxic CD8+ T cells in solid tumors, HRSCs frequently lack major histocompatibility complex expression, and the mechanism of anti-PD1 efficacy in cHL is unclear. Rapid clinical responses and high interim complete response rates to anti-PD1 based first-line treatment were recently reported for patients with early-stage unfavorable cHL treated in the German Hodgkin Study Group phase 2 NIVAHL trial. To investigate the mechanisms underlying this very early response to anti-PD1 treatment, we analyzed paired biopsies and blood samples obtained from NIVAHL patients before and during the first days of nivolumab first-line cHL therapy. Mirroring the rapid clinical response, HRSCs had disappeared from the tissue within days after the first nivolumab application. The TME already shows a reduction in type 1 regulatory T cells and PD-L1+ tumor-associated macrophages at this early time point of treatment. Interestingly, a cytotoxic immune response and a clonal T-cell expansion were not observed in the tumors or peripheral blood. These early changes in the TME were distinct from alterations found in a separate set of cHL biopsies at relapse during anti-PD1 therapy. We identify a unique very early histologic response pattern to anti-PD1 therapy in cHL that is suggestive of withdrawal of prosurvival factors, rather than induction of an adaptive antitumor immune response, as the main mechanism of action., (© 2020 by The American Society of Hematology.)

Introduction : Hodgkin Lymphoma (HL) carries an overall excellent prognosis for young patients treated with multimodal therapy. Predicting an individual patient's prognosis is currently heavily dependent on imaging modalities such as Positron Emission Tomography (PET). Areas covered : Potential biomarkers from serum, tissue, circulating nucleic acids and non-tumor derived cells have all been reported to be of prognostic relevance in HL. We review a range of these biomarkers and discuss the integration of new biomarkers into individualized patient care. Expert opinion : Better prognostic markers are needed to predict an individuals response to HL therapy. Interim PET-scan improves the ability to predict long-term treatment responders. However, it is our opinion that supplementation of PET results with additional biomarkers (including circulating tumor DNA, protein biomarkers, tissue genotyping and metabolic tumor volume) are likely to improve risk stratification for future patients with HL.

Purpose: Vitamin D deficiency is described as a modifiable risk factor for the incidence of and mortality in many common cancers; however, data in Hodgkin lymphoma (HL) are lacking., Patients and Methods: We thus performed a study measuring pretreatment vitamin D levels in prospectively treated patients with HL and correlated this with clinical outcomes. A total of 351 patients from the German Hodgkin Study Group clinical trials (HD7, HD8, and HD9) were included., Results: Fifty percent of patients were vitamin D deficient (< 30 nmol/L) before planned chemotherapy. Pretreatment vitamin D deficiency was more common in relapsed/refractory patients than matched relapse-free controls (median baseline vitamin D, 21.4 nmol/L v 35.5 nmol/L; proportion with vitamin D deficiency, 68% v 41%; P < .001). Vitamin D-deficient patients had impaired progression-free survival (10-year difference, 17.6%; 95% CI, 6.9% to 28.4%; hazard ratio, 2.13; 95% CI, 1.84 to 2.48; P < .001) and overall survival (10-year difference, 11.1%; 95% CI, 2.1% to 20.2%; hazard ratio, 1.82; 95% CI, 1.53 to 2.15; P < .001), consistent across trials and treatment groups. We demonstrated that vitamin D status is an independent predictor of outcome and hypothesized that vitamin D status might be important for the chemosensitivity of HL. We subsequently performed experiments supplementing physiologic doses of vitamin D (calcitriol) to cultured HL cell lines and demonstrated increased antiproliferative effects in combination with chemotherapy. In an HL-xenograft animal model, we showed that supplemental vitamin D (dietary supplement, cholecalciferol) improves the chemosensitivity of tumors by reducing the rate of tumor growth compared with vitamin D or chemotherapy alone., Conclusion: On the basis of our clinical and preclinical findings, we encourage that vitamin D screening and replacement be incorporated into future randomized clinical trials to properly clarify the role of vitamin D replacement therapy in HL.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare subtype of lymphoma that, like other Hodgkin lymphomas, has historically been treated aggressively. However, in most cases, NLPHL has an indolent course, which raises the question of to what extent these patients require aggressive upfront treatment. We describe the management and outcomes of consecutive NLPHL patients diagnosed at Memorial Sloan Kettering Cancer Center (MSK), with a focus on evaluating active surveillance. All patients aged 16 years or older diagnosed and followed at MSK between 1974 and 2016 were included. Treatment outcomes were compared between management with active surveillance and other strategies. We identified 163 consecutive patients who were treated with radiotherapy alone (46%), active surveillance (23%), chemotherapy (16%), combined modality (12%), or rituximab monotherapy (4%). Median follow-up was 69 months. Five-year progression-free survival (PFS), second PFS (PFS2), and overall survival (OS) estimates were 85% (95% confidence interval [CI], 78-90), 97% (95% CI, 92-99), and 99% (95% CI, 95-100), respectively. Only 1 of 7 deaths was lymphoma related. Patients managed with active surveillance had slightly shorter PFS than those receiving any active treatment, with 5-year PFS of 77% (95% CI, 56-89) vs 87% (95% CI, 79-92; P = .017). This difference did not translate into better PFS2 or OS. Only 10 patients managed with active surveillance (27%) eventually required treatment, after a median of 61 months, and none died. NLPHL has an excellent prognosis. Within the limitations of a retrospective analysis, active surveillance is a viable initial management strategy for selected NLPHL patients., (© 2019 by The American Society of Hematology.)

The majority of patients with Hodgkin Lymphoma (HL) can be cured with stage and risk adapted treatment today. Therefore, current research focuses on reducing long-term sequelae of treatment. Osteonecrosis (ON) is a severe long-term complication of HL treatment which has so far not been systematically evaluated. Hence, we investigated incidence, risk factors and timing of symptomatic ON in HL patients. Further endpoints included localization, intervention and outcome of ON. We included all qualified HL patients of the randomized German Hodgkin Study Group trials HD10-15 and HD18, recruited between 05/1998 and 07/2014 and aged from 16 to 60 years. Among 11 330 patients, 66 developed symptomatic ON after first-line treatment, 83.3% within three years. The incidence of symptomatic ON was 0.2% in early-stage HL and 1.0% in advanced-stage HL. Logistic regression revealed the total cumulative corticosteroid dose to be a strong risk factor interacting with younger age. Male sex additionally increased the risk of symptomatic ON. The prognostic value of the corresponding logistic regression model was rather high (AUC = 0.78). Other tested potential risk factors including obesity, IPS and radiotherapy did not further increase the risk of ON. Further development of current treatment protocols should aim to reduce the cumulative corticosteroid dose.

Hodgkin Lymphoma (HL) is an unusual B-cell lymphoma because the malignant cells exist as a minority population in a densely cellular microenvironment. The microenvironment is comprised predominately of inflammatory and immune cells with fibrosis in some cases. There are multiple dysregulated signalling pathways that sustain HL within this microenvironment, such as the Nuclear factor-κB and Janus kinase/signal transducers and activators of transcription pathways. Advances in genomic medicine have enabled a better characterisation of the rare tumour cells and improved our understanding of the signalling mechanisms that exist between the malignant cell and its microenvironment. Current therapy for HL produces excellent clinical outcomes in most younger patients. However, problems with current treatment approaches include poorer outcomes in the elderly, toxicity of highly-effective combination chemotherapy regimens and relapse in high-risk patients. Better understanding of disease biology aids in upfront prognostication of patients, defines new methods for treatment monitoring and assists in the recognition of novel targets for therapy. Biology-driven therapies, including anti-CD30 antibody conjugates, cellular immunotherapies and immune modulation, particularly with checkpoint inhibitors, have changed treatment algorithms for relapsed/refractory patients. Future challenges exist in incorporating immune-based therapies earlier in treatment algorithms to reduce toxicity and prevent relapse for patients with HL., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)

Purpose of Review: We aim to summarize the current knowledge on the treatment of elderly Hodgkin lymphoma patients with a focus on evidence from clinical trials and novel drugs., Recent Findings: For elderly Hodgkin lymphoma patients above 60 years without precluding comorbidities a curative treatment approach is warranted. Early favorable stage patients should receive two cycles of multiagent chemotherapy followed by 20 Gy localized radiotherapy. Early unfavorable stage patients should receive four cycles of multiagent chemotherapy followed by 30 Gy localized radiotherapy. For advanced stage patients six cycles of multiagent chemotherapy can be recommended and should be followed by localized radiotherapy on residual disease manifestations. Relapsed or refractory patients should be treated in an individually tailored approach that considers both the patient's objectives and comorbidities. The antibody-drug conjugate brentuximab vedotin is a very effective option for elderly patients with a high response rate albeit limited durability. Anti-programed cell death protein 1 antibodies might also be effective in elderly Hodgkin lymphoma patients with a mechanism of action distinct from chemotherapy., Summary: In conclusion, the goal of treatment in newly diagnosed elderly Hodgkin lymphoma patients is curative whenever possible and prospective and retrospective evidence has shown that this is feasible for all disease stages with a variety of multiagent chemotherapy regimen. Relapsed and refractory elderly Hodgkin lymphoma patients can mostly only be treated with the goal of palliation. However, it remains to be seen if novel substances and new combination regimen are able to change that.

Seasonal variations in incidence and mortality after a Hodgkin lymphoma (HL) diagnosis have been previously described with partly conflicting results. The goal of this analysis is to provide a comprehensive analysis of these seasonal variations. In total, 41,405 HL cases diagnosed between 1973 and 2012 in the 18 Surveillance, Epidemiology, and End Results registries were included. Cosinor analysis and Cox proportional-hazards models were employed to analyze seasonality of incidence and mortality, respectively. HL shows a sinusoid seasonal incidence pattern (p < 0.001). Estimated incidence in March is 15.4% [95%-CI: 10.8-20.0] higher than in September. This sinusoid pattern is more pronounced at higher latitudes (p = 0.023). The risk of dying within the first three years after a HL diagnosis in winter is significantly increased compared to a HL diagnosis in summer at higher latitudes (HR = 1.082 [95%-CI: 1.009-1.161], p = 0.027). Furthermore, increasing northern latitude increases the additional mortality risk conferred by a diagnosis in winter (p interaction 0.033). The seasonality patterns presented here provide epidemiological evidence that Vitamin D might play a protective role in HL. Further evidence on the direct association between Vitamin D levels and the clinical course of HL needs to be collected to advance the understanding of the role of Vitamin D in HL.

Classical Hodgkin lymphoma (cHL) is the most common hematological malignancy in young adults and can be cured in most cases. However, relapsed and refractory Hodgkin lymphoma, certain patient groups, such as elderly patients, and toxicity of first-line treatment still pose significant challenges. Consequently, new treatment options are needed. Recently, many new treatment concepts have been evaluated in clinical trials. Targeted drug-antibody conjugates and immune checkpoint inhibitors have decisively changed treatment approaches. This review aims to give a comprehensive overview of novel agents in Hodgkin lymphoma that have been recently or are currently being evaluated in clinical trials. In addition to dedicated sections on brentuximab vedotin (BV) and immune checkpoint inhibitors, other emerging substances and concepts are discussed. In doing so, this review compares trial results regarding safety and efficacy. A special focus lies on the effect novel agents will have on the different treatment settings faced by clinicians involved in the treatment of Hodgkin lymphoma.

Purpose of Review: The goal of this review is to give an overview of the genetics of classical Hodgkin lymphoma. Copy number changes, somatic mutations, genome-wide association studies, changes in gene expression, familial classical Hodgkin lymphoma and epigenetic changes will be reviewed. In doing so, special focus is placed on the way recent discoveries have influenced clinical research, diagnostics, treatment and remission monitoring. Furthermore, emphasis is put on how these advances can help to advance the treatment of elderly patients who have a markedly worse prognosis than younger patients., Recent Findings: Frequent amplifications of the 9p24.1 locus in classical Hodgkin lymphoma could be the basis for the success of immune checkpoint inhibitors targeting PD-1 or PD-L1 in this disease. The same amplification also affects the JAK/STAT pathway, which has also been targeted in recent clinical trials. Hodgkin lymphoma-specific copy number alterations and mutations have recently been found to be detectable in cell-free DNA. This could provide the basis for advances in the detection of residual disease during treatment and while monitoring patients in remission., Summary: The advent of new technologies such as massive parallel sequencing has improved our understanding of the genetics of classical Hodgkin lymphoma. Some of these discoveries are now being translated into clinical research in the form of new diagnostics and treatments.

Purpose Combined-modality treatment is widely considered the standard of care in early-stage Hodgkin lymphoma (HL), and treatment intensity has been reduced over the last years. Long-term follow-up is important to judge both efficacy and safety of the different therapies used. Patients and Methods We analyzed updated follow-up data on 4,276 patients treated within the German Hodgkin Study Group trials HD7 and HD10 for early-stage favorable HL and HD8 and HD11 for early-stage unfavorable HL between 1993 and 2003. Results In HD7 (N = 627; median follow-up, 120 months), combined-modality treatment was superior to extended-field radiotherapy (RT), with 15-year progression-free survival (PFS) of 73% versus 52% (hazard ratio [HR], 0.5; 95% CI, 0.3 to 0.6; P < .001), without differences in overall survival (OS). In HD10 (N = 1,190; median follow-up, 98 months), noninferiority of two cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) plus 20 Gy involved-field (IF)-RT to more intensive four cycles of ABVD plus 30 Gy IF-RT was confirmed with 10-year PFS of 87% each (HR, 1.0; 95%, 0.6 to 1.5) and OS of 94% each (HR, 0.9; 95% CI, 0.5 to 1.6), respectively. In both trials, no differences in second neoplasias were observed. In HD8 (N = 1,064; median follow-up, 153 months), noninferiority of involved-field RT to extended-field RT regarding PFS was confirmed (HR, 1.0; 95% CI, 0.8 to 1.2). In HD11 (N = 1,395; median follow-up, 106 months), superiority of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone at baseline over ABVD was not observed. After BEACOPP baseline , 20 Gy IF-RT was noninferior to 30 Gy (10-year PFS, 84% v 84%; HR, 1.0; 95% CI, 0.7 to 1.5). In contrast, PFS was inferior in ABVD-treated patients receiving 20 Gy instead of 30 Gy IF-RT (10-year PFS, 76% v 84%; HR, 1.5; 95% CI, 1.0 to 2.1). No differences in OS or second neoplasias were observed in in both trials. Conclusion Long-term follow-up data of the four randomized trials largely support the current risk-adapted therapeutic strategies in early-stage HL. Nevertheless, continued follow-up is necessary to assess the long-term safety of currently applied therapeutic strategies.

Purpose of Review: After presenting the current treatment recommendations for early-stage Hodgkin lymphoma, we give an overview on recently published clinical trials in this setting. Furthermore, the potential influence of current trials on the treatment of early-stage Hodgkin lymphoma and integration of newly emerging drugs into treatment protocols will be discussed., Recent Findings: Trials attempting treatment de-escalation and omission of radiotherapy on the basis of early interim PET-scans have been disappointing so far, but results of some large trials employing this strategy are still awaited. In contrast, a more defensive strategy of starting treatment with less aggressive doxorubicine, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy and intensifying treatment in early interim PET-positive patients has shown encouraging results. New drugs such as brentuximab vedotin and immune checkpoint inhibitors have shown promising results in relapsed and refractory Hodgkin lymphoma. Clinical trials of brentuximab vedotin in early-stage Hodgkin lymphoma have been initiated. Additionally, biomarker-based treatment de-escalation might be a possible route for future improvements., Summary: The challenge for future clinical research in early-stage Hodgkin lymphoma is to continue to cure the majority of patients with first-line treatment while reducing long-term toxicity. New strategies to achieve that goal are currently being developed and will further refine treatment of early-stage Hodgkin lymphoma.

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×ABVD; n = 137) or AVD (2×AVD; n = 82), each followed by involved-field radiotherapy (IF-RT), with patients randomized to 4×ABVD+IF-RT (n = 68). 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 2×AVD and 2×ABVD (40% and 39%, respectively), but considerably higher in patients receiving 4×ABVD (65%). Similarly, BLT was rare in patients receiving 2×ABVD/AVD, but occurred in 7/69 (10%) of patients randomized to 4×ABVD, 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)., (© 2016 by The American Society of Hematology.)