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Background: This study aimed to evaluate the correlation between progression-free (PFS) and overall survival (OS) after first-line treatment of classical Hodgkin lymphoma (HL) and to assess the potential of PFS as a surrogate parameter for OS., Patients and Methods: We analyzed individual patient data collected during and after treatment with polychemotherapy in nine randomized phase III trials [German Hodgkin Study Group (GHSG) HD7-HD15] between January 1993 and August 2018. The effects of 16 experimental treatments on PFS and OS at the trial level were evaluated using Cox proportional hazards (PH) regression and linear weighted least squares regression. At the patient level, marginal Cox PH models for multiple endpoints were applied using the Wei-Lin-Weissfeld method., Results: At least one PFS and OS event was recorded in 1682 and 1064 of 10 605 patients, respectively. At the trial level, there was a strong correlation between treatment effects on PFS and OS (weighted Pearson r = 0.72, R 2  = 0.54, P < 0.001). At the patient level, a moderate to strong correlation between treatment effects on PFS and OS was observed, with Pearson r values ranging between 0.61 and 0.85 (each P < 0.001) and an overall r = 0.74. A regression model that accounted for different types of experimental treatments and historical progress across trial generations achieved a very strong correlation (R 2  = 0.93). When applied to data from the contemporary first-line ECHELON-1 trial, this model successfully predicted OS from PFS {prognosticated ln[HR(OS)] = -0.68 as compared with observed ln[HR(0.59)] = -0.53}., Conclusion: In first-line trials of HL, PFS and OS, as well as treatment effects and prognostic effects on these endpoints, are strongly correlated. PFS serves as a strong predictor of treatment effects on OS, providing valuable insights many years before OS can be reliably assessed., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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. UN reports consulting fees for the institution from Janssen-Cilag, Celgene (BMS), Takeda, AstraZeneca, Roche, Novartis, Incyte, BeiGene, Kyowa Kiin, Gileag, and Pierre Fabre; payment or honoraria for lectures, presentations, speakers bureaus, manuscript, writing or educational events for the institution from Celgene (BMS), Novartis, Takeda, and Gilead; support to the institution for attending meetings or travel from Janssen, Roche, Gilead, and Takeda; and participating on a data safety monitoring board or advisory board for Janssen-Cilag, Celgene (BMS), Takeda, AstraZeneca, Roche, Novartis, Incyte, BeiGene, Kyowa Kiin, Gileag, and Pierre Fabre. JM reports consulting fees from MSD. AZi reports payment for presentations from Novartis, Oncopeptides, Takeda, Incyte, and Roche and travel support from Oncopeptides, Roche, and Novartis. AF reports consulting fees and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda. AV reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche, BMS, and AbbVie; support for attending meetings or travel from Janssen, Kite/Gilead, BMS, and AbbVie; and participation on a data safety monitoring board or advisory board from Roche, BMS, AbbVie, and Kite/Gilead. SS reports travelling support from AbbVie and Jazz and reports support for attending meetings or travel from and having a leadership or fiduciary role in another board, society, committee or advocacy group (paid or unpaid) with Pfizer, Amgen, and Novartis. VV reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda and participation on an advisory board for Takeda and MSD. AK reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche, Celgene, AbbVie, Sobi, BMS, and Takeda and support for attending meetings or travel from AbbVie, BeiGene, Sobi, Takeda, EUSA Pharma, Novartis, and Alexion. KT-G reports consulting fees and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda. PK reports travel support from Roche Pharmaceuticals and Takeda. 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.)

Background: Persisting cancer-related fatigue impairs health-related quality of life (HRQoL) and social reintegration in patients with Hodgkin's lymphoma (HL). The GHSG HD18 trial established treatment de-escalation for advanced-stage HL guided by positron emission tomography after two cycles (PET-2) as new standard. Here, we investigate the impact of treatment de-escalation on long-term HRQoL, time to recovery from fatigue (TTR-F), and time to return to work (TTR-W)., Patients and Methods: Patients received European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and life situation questionnaires at baseline, interim, end of treatment, and yearly follow-up. TTR-F was defined as time from the end of chemotherapy until the first fatigue score <30. TTR-W was analyzed in previously working or studying patients and measured from the end of treatment until the first documented work or education. We compared duration of treatment on TTR-F and TTR-W using Cox proportional hazards regression adjusted for confounding variables., Results: HRQoL questionnaires at baseline were available in 1632 (83.9%) of all randomized patients. Overall, higher baseline fatigue and age were significantly associated with longer TTR-F and TTR-W and male sex with shorter TTR-W. Treatment reduction from eight to four chemotherapy cycles led to a significantly shorter TTR-F [hazard ratio (HR) 1.41, P = 0.008] and descriptively shorter TTR-W (HR 1.24, P = 0.084) in PET-2-negative patients. Reduction from six to four cycles led to non-significant but plausible intermediate accelerations. The addition of rituximab caused significantly slower TTR-F (HR 0.70, P = 0.0163) and TTR-W (HR 0.64, P = 0.0017) in PET-2-positive patients. HRQoL at baseline and age were the main determinants of 2-year HRQoL., Conclusions: Individualized first-line treatment in patients with advanced-stage HL considerably shortens TTR-F and TTR-W in PET-2-negative patients. Our results support the use of response-adapted shortened treatment duration for patients with HL., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Abstract: State-of-the-art response assessment of central nervous system lymphoma (CNSL) by magnetic resonance imaging is challenging and an insufficient predictor of treatment outcomes. Accordingly, the development of novel risk stratification strategies in CNSL is a high unmet medical need. We applied ultrasensitive circulating tumor DNA (ctDNA) sequencing to 146 plasma and cerebrospinal fluid (CSF) samples from 67 patients, aiming to develop an entirely noninvasive dynamic risk model considering clinical and molecular features of CNSL. Our ultrasensitive method allowed for the detection of CNSL-derived mutations in plasma ctDNA with high concordance to CSF and tumor tissue. Undetectable plasma ctDNA at baseline was associated with favorable outcomes. We tracked tumor-specific mutations in plasma-derived ctDNA over time and developed a novel CNSL biomarker based on this information: peripheral residual disease (PRD). Persistence of PRD after treatment was highly predictive of relapse. Integrating established baseline clinical risk factors with assessment of radiographic response and PRD during treatment resulted in the development and independent validation of a novel tool for risk stratification: molecular prognostic index for CNSL (MOP-C). MOP-C proved to be highly predictive of outcomes in patients with CNSL (failure-free survival hazard ratio per risk group of 6.60; 95% confidence interval, 3.12-13.97; P < .0001) and is publicly available at www.mop-c.com. Our results highlight the role of ctDNA sequencing in CNSL. MOP-C has the potential to improve the current standard of clinical risk stratification and radiographic response assessment in patients with CNSL, ultimately paving the way toward individualized treatment., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

The optimal first-line treatment for nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) diagnosed in early stages is largely undefined. We, therefore, analyzed 100 NLPHL patients treated in the randomized HD16 (early-stage favorable; n = 85) and HD17 (early-stage unfavorable; n = 15) studies. These studies investigated the omission of consolidation radiotherapy (RT) in patients with a negative interim positron emission tomography (iPET) (ie, Deauville score <3) after chemotherapy (HD16: 2× doxorubicin, bleomycin, vinblastine, and dacarbazine [ABVD]; HD17: 2× escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone [BEACOPP] plus 2× ABVD). Patients with NLPHL treated in the HD16 and HD17 studies had 5-year progression-free survival (PFS) rates of 90.3% and 92.9%, respectively. Thus, the 5-year PFS did not differ significantly from that of patients with classical Hodgkin lymphoma treated within the same studies (HD16: P = .88; HD17: P = .50). Patients with early-stage favorable NLPHL who had a negative iPET after 2× ABVD and did not undergo consolidation RT tended to have a worse 5-year PFS than patients with a negative iPET who received consolidation RT (83% vs 100%; P = .05). There were 10 cases of NLPHL recurrence. However, no NLPHL patient died during follow-up. Hence, the 5-year overall survival rate was 100%. Taken together, contemporary Hodgkin lymphoma-directed treatment approaches result in excellent outcomes for patients with newly diagnosed early-stage NLPHL and, thus, represent valid treatment options. In early-stage favorable NLPHL, consolidation RT appears necessary after 2× ABVD to achieve the optimal disease control irrespective of the iPET result., (© 2023 by The American Society of Hematology.)

CD19-directed chimeric antigen receptor (CAR) T cells have evolved as a new standard-of-care (SOC) treatment in patients with relapsed/refractory (r/r) large B-cell lymphoma (LBCL). Here, we report the first German real-world data on SOC CAR T-cell therapies with the aim to explore risk factors associated with outcomes. Patients who received SOC axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) for LBCL and were registered with the German Registry for Stem Cell Transplantation (DRST) were eligible. The main outcomes analyzed were toxicities, response, overall survival (OS), and progression-free survival (PFS). We report 356 patients who received axi-cel (n = 173) or tisa-cel (n = 183) between November 2018 and April 2021 at 21 German centers. Whereas the axi-cel and tisa-cel cohorts were comparable for age, sex, lactate dehydrogenase (LDH), international prognostic index (IPI), and pretreatment, the tisa-cel group comprised significantly more patients with poor performance status, ineligibility for ZUMA-1, and the need for bridging, respectively. With a median follow-up of 11 months, Kaplan-Meier estimates of OS, PFS, and nonrelapse mortality (NRM) 12 months after dosing were 52%, 30%, and 6%, respectively. While NRM was largely driven by infections subsequent to prolonged neutropenia and/or severe neurotoxicity and significantly higher with axi-cel, significant risk factors for PFS on the multivariate analysis included bridging failure, elevated LDH, age, and tisa-cel use. In conclusion, this study suggests that important outcome determinants of CD19-directed CAR T-cell treatment of LBCL in the real-world setting are bridging success, CAR-T product selection, LDH, and the absence of prolonged neutropenia and/or severe neurotoxicity. These findings may have implications for designing risk-adapted CAR T-cell therapy strategies., (© 2022 by The American Society of Hematology.)

Background: Patients suffering from refractory aggressive B-cell lymphoma not responding to salvage chemotherapy have a dismal prognosis. CAR T-cells or allogeneic stem cell transplantation (SCT) are potentially curative approaches. However, obtaining a remission, and lowering tumor burden before consolidation seems crucial for long-term efficacy of both treatment modalities., Materials and Methods: In this retrospective analysis, we reviewed patients with chemoresistant aggressive B-cell lymphoma, defined as being refractory or progressive to at least second line salvage chemotherapy including the regimen immediately preceding autologous stem cell transplantation (ASCT), treated at 2 tertiary centers, who were eligible for intensive treatment using single agent high-dose (HD) melphalan to obtain a remission before consolidating therapy., Results: We identified 36 patients that received single agent HD melphalan and ASCT as remission induction followed by CAR T-cells or allogeneic stem cell transplantation (SCT). Thirteen of the evaluable patients (39.4%) achieved a partial remission and 9 patients (27.73%) a complete remission, resulting in an overall response rate (ORR) of 66.7%. High remission rates were seen across all subgroups including patients with primary refractory lymphoma (ORR 58.3%), uncontrolled disease and high tumor burden as indicated by increased LDH levels (ORR 66.7% for patients with elevated LDH above 2 times upper limit of norm). 22 patients proceeded to allogeneic SCT and 5 to CAR T-cell therapy. Treatment related mortality of ASCT was 5.5% (2 patients, both due to infections). Two-year overall survival of all patients was 15.8%, primarily due to a high non-relapse mortality (45.5%) of allogeneic SCT patients treated with myeloablative conditioning chemotherapy., Conclusion: Single agent HD melphalan produces high remission rates in patients with chemoresistant, uncontrolled aggressive B-cell lymphoma and provides a window of opportunity for consolidation therapy., Microabstract: Patient with refractory/relapsed aggressive B-cell lymphoma after salvage therapy are an unmet medical need because of their very poor prognosis. In our retrospective analysis of 36 patients we showed that single agent high-dose melphalan can achieve high response rates (ORR 66.7%) even in uncontrolled disease enabling consolidation therapy e.g. with allogeneic stem cell transplantation or CAR T-cell therapy., (Copyright © 2022. Published by Elsevier Inc.)

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.)

In newly diagnosed systemic diffuse large B-cell lymphoma, next-generation sequencing of plasma-derived cell-free DNA (cfDNA) detects somatic mutations as accurate as genotyping of the tumor biopsy. A distinct diffuse large B-cell lymphoma entity confined to the central nervous system is primary central nervous system lymphoma (PCNSL), which requires intracerebral biopsy and neuropathologic analysis to establish the diagnosis. So far, a biomarker for diagnosis and follow-up of PCNSL that can be investigated in blood has not been identified. This article addresses the question whether somatic mutations of the CD79B and MYD88 driver genes of PCNSL can be detected in cfDNA at disease diagnosis. Stereotactic biopsies and cfDNA of 27 PCNSL patients were analyzed for CD79B and MYD88 mutations. As control, cfDNA derived from six healthy volunteers was used. CD79B and MYD88 hot spot mutations were identified in 16 of 27 (59%) and 23 of 27 (85%) PCNSL biopsies, respectively, but only in 0 of 27 (0%) and 1 of 27 (4%) corresponding cfDNA samples, respectively. In cfDNA of one of four patients with Waldenstrom disease, as a further control, the MYD88 L265P mutation was readily detected, despite complete clinical remission. These data suggest that in PCNSL even if they carry such mutations, alterations of CD79B and MYD88 cannot be reliably detected in blood-derived cfDNA obtained before intracerebral biopsy., (Copyright © 2020 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Six cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) are the standard treatment for aggressive B-cell non-Hodgkin lymphoma. In the FLYER trial, we assessed whether four cycles of CHOP plus six applications of rituximab are non-inferior to six cycles of R-CHOP in a population of patients with B-cell non-Hodgkin lymphoma with favourable prognosis., Methods: This two-arm, open-label, international, multicentre, prospective, randomised phase 3 non-inferiority trial was done at 138 clinical sites in Denmark, Israel, Italy, Norway, and Germany. We enrolled patients aged 18-60 years, with stage I-II disease, normal serum lactate dehydrogenase concentration, ECOG performance status 0-1, and without bulky disease (maximal tumour diameter <7·5 cm). Randomisation was computer-based and done centrally in a 1:1 ratio using the Pocock minimisation algorithm after stratification for centres, stage (I vs II), and extralymphatic sites (no vs yes). Patients were assigned to receive either six cycles of R-CHOP or four cycles of R-CHOP plus two doses of rituximab. CHOP comprised cyclophosphamide (750 mg/m 2 ), doxorubicin (50 mg/m 2 ), and vincristine (1·4 mg/m 2 , with a maximum total dose of 2 mg), all administered intravenously on day 1, plus oral prednisone or prednisolone at the discretion of the investigator (100 mg) administered on days 1-5. Rituximab was given at a dose of 375 mg/m 2 of body surface area. Cycles were repeated every 21 days. No radiotherapy was planned except for testicular lymphoma treatment. The primary endpoint was progression-free survival after 3 years. The primary analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. A non-inferiority margin of -5·5% was chosen. The trial, which is completed, was prospectively registered at ClinicalTrials.gov, NCT00278421., Findings: Between Dec 2, 2005, and Oct 7, 2016, 592 patients were enrolled, of whom 295 patients were randomly assigned to receive six cycles of R-CHOP and 297 were assigned to receive four cycles of R-CHOP plus two doses of rituximab. Four patients in the four-cycles group withdrew informed consent before the start of treatment, so 588 patients were included in the intention-to-treat analysis. After a median follow-up of 66 months (IQR 42-100), 3-year progression-free survival of patients who had four cycles of R-CHOP plus two doses of rituximab was 96% (95% CI 94-99), which was 3% better (lower limit of the one-sided 95% CI for the difference was 0%) than six cycles of R-CHOP, demonstrating the non-inferiority of the four-cycles regimen. 294 haematological and 1036 non-haematological adverse events were documented in the four-cycles group compared with 426 haematological and 1280 non-haematological adverse events in the six-cycles group. Two patients, both in the six-cycles group, died during study therapy., Interpretation: In young patients with aggressive B-cell non-Hodgkin lymphoma and favourable prognosis, four cycles of R-CHOP is non-inferior to six cycles of R-CHOP, with relevant reduction of toxic effects. Thus, chemotherapy can be reduced without compromising outcomes in this population., Funding: Deutsche Krebshilfe., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The prognosis of Hodgkin lymphoma (HL) is excellent rendering research into treatment complications highly important. An important complication of cancer and its treatment is thrombosis. Thrombotic events are regularly observed in HL patients but precise information on incidence and risk factors is lacking and the value of prophylactic anticoagulation unclear., Patients and Methods: Thus, we comprehensively studied thrombotic events in 5773 patients from the German Hodgkin Study Group (GHSG) HD13-15 trials in early-favorable, intermediate and advanced HL. We estimated the incidence of and identified risk factors for thrombotic events. Additionally, we provide detailed data on the time course and characteristics of thrombotic events., Results: A total of 193 thrombotic events occurred for an incidence of 3.3%. Out of these, 175 (90.7%) were venous thromboses, 3 (1.5%) newly emerging post-thrombotic syndromes and 15 (7.8%) arterial thromboses. There were 11 (0.7%) events in early-favorable, 27 (1.3%) in early-unfavorable and 155 (7.3%) in advanced patients, the latter incidence being significantly higher (P < 0.001). The most common locations were deep vein thrombosis of the arm (46.3%) and leg (24.6%). Most venous thrombotic events occurred during chemotherapy (78.9%). We observed 59 (30.6%) catheter-associated events and a descriptively increased risk of venous thrombotic events in patients with oral contraception use during treatment (6.8% versus 3.9%). In advanced HL, the incidence of venous thrombotic events was increased upon treatment with BEACOPP-14 (9.4%, P = 0.0079) compared with 5.1% with 6×BEACOPPesc and 5.7% with 8×BEACOPPesc. Among commonly applied risk factors, including the Khorana score, only age and smoking were prognostic., Conclusions: The incidence of thrombotic events in advanced stage HL is comparable to other high-risk cancer patients, especially if treated with dose-dense regimens. Additional risk factors are higher age and smoking. Selected HL patients could benefit from prophylactic anticoagulation, however, further interventional studies are needed before general recommendations can be made., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The HD18 study for patients with newly diagnosed advanced-stage Hodgkin lymphoma (HL) used positron emission tomography (PET) after 2 cycles (PET-2) of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses (eBEACOPP) to guide further treatment. Here, we analyzed the impact of PET-2 results in the context of eBEACOPP according to the Deauville score (DS) in patients treated within the HD18 trial. Residual tissue was visually compared with reference regions according to DS. We analyzed the association between PET-2 uptake and baseline characteristics, progression-free survival (PFS), and overall survival (OS). One thousand five patients (52%) had DS1 or DS2, 471 (24%) had DS3, and 469 (24%) DS4. PET-2 uptake was associated with baseline risk factors large mediastinal mass, extranodal disease, and high International Prognostic Score ( P < .0001 each). Among 722 patients receiving standard therapy with 6 cycles of eBEACOPP, 3-year PFS rates were 92.2%, 95.9%, and 87.6% with DS1-2, DS3, and DS4, respectively. Univariate hazard ratio (HR) for PFS in patients with DS4 vs DS1-3 was 2.3 (1.3-3.8; P = .002). DS4 was the only factor remaining significant for PFS in a multivariate analysis including the associated baseline risk factors. Three-year OS rates were 97.6% for DS1-2, 99.0% for DS3, and 96.8% for DS4, with a univariate HR for DS4 vs DS1-3 of 2.6 (1.0-6.6; P = .04). Residual uptake above that in the liver at PET-2 (ie, DS4) is an important risk factor regarding survival outcomes for patients treated with eBEACOPP upfront. We thus recommend DS4 as the cutoff value for PET-2 positivity. This trial was registered at www.clinicaltrials.gov as #NCT00515554., (© 2018 by The American Society of Hematology.)

The optimal treatment of patients with relapsed or refractory nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is ill defined. To shed more light on treatment options and outcome, we performed an analysis using the database of the German Hodgkin Study Group (GHSG). Ninety-nine patients who had received first-line treatment within 12 prospective GHSG studies conducted between 1993 and 2009, and subsequently developed disease recurrence (n = 91) or had primary disease progression (n = 8), were included. At initial NLPHL diagnosis, the median age was 40 years and 76% of patients were male. First-line treatment consisted of radiotherapy (RT) alone (20%), chemotherapy with or without RT (74%), and the anti-CD20 antibody (Ab) rituximab (6%), respectively. The median follow-up from initial diagnosis was 11.2 years. The median time to disease recurrence was 3.7 years. The applied salvage approaches included single-agent anti-CD20 Ab treatment or RT alone (37%), conventional chemotherapy (CT) with or without anti-CD20 Ab treatment with or without RT (27%) and high-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) (31%). No salvage treatment was given in 4% of patients. The 5-year progression-free survival and overall survival estimates after NLPHL recurrence were 75.6% and 89.5% (74.1% and 97.2% after single-agent anti-CD20 Ab treatment or RT alone; 68.0% and 77.8% after CT with or without anti-CD20 Ab treatment with or without RT; 84.6% and 89.8% after HDCT and ASCT). Hence, patients with relapsed or refractory NLPHL had a good overall prognosis. Factors such as time to disease recurrence and previous treatment may guide the choice of the optimal salvage approach for the individual patient., (© 2018 by The American Society of Hematology.)

Background: Bone marrow (BM) involvement defines advanced-stage Hodgkin lymphoma and thus has impact on the assignment to treatment. Our aim was to evaluate whether the established BM biopsy may be omitted in patients if 18F-fluorodeoxyglucose positron emission tomography (PET) scanning is carried out during staging., Patients and Methods: Our analysis set consisted of 832 Hodgkin lymphoma patients from the German Hodgkin Study Group trials HD16, HD17, and HD18 who underwent both PET scanning and BM biopsy before treatment. All PET studies were centrally reviewed and BM was categorized as showing focal involvement or not., Results: Taking BM biopsy as reference standard, baseline PET showed a negative predictive value of 99.9% [95% confidence interval (CI) 99.2% to 100%] with true-negative results in 702 of 703 cases. The sensitivity of PET for detecting BM involvement was 95.0% (95% CI 75.1% to 99.9%) as it could identify 19 out of 20 patients with positive BM biopsy. Moreover, PET found 110 additional subjects with focal BM lesions who would have been considered negative by biopsy., Conclusions: When compared with BM biopsy, PET was able to detect focal BM lesions in a large number of additional patients. This indicates that conventional BM biopsy may substantially underestimate the actual incidence of BM involvement. Given the high negative predictive value, baseline PET scanning can safely be used to exclude BM involvement in Hodgkin lymphoma. BM biopsy should be considered only in such patients in whom PET-detected lesions lead to a change of treatment protocol., Registered Trials: The trials included in this analysis were registered at ClinicalTrials.gov: HD16-NCT00736320, HD17-NCT01356680, and HD18-NCT00515554.

Background: The intensive polychemotherapy regimen eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) is very active in patients with advanced-stage Hodgkin's lymphoma, albeit at the expense of severe toxicities. Individual patients might be cured with less burdensome therapy. We investigated whether metabolic response determined by PET after two cycles of standard regimen eBEACOPP (PET-2) would allow adaption of treatment intensity, increasing it for PET-2-positive patients and reducing it for PET-2-negative patients., Methods: In this open-label, randomised, parallel-group phase 3 trial, we recruited patients aged 18-60 years with newly diagnosed, advanced-stage Hodgkin's lymphoma in 301 hospitals and private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. After central review of PET-2, patients were assigned (1:1) to one of two parallel treatment groups on the basis of their PET-2 result. Patients with positive PET-2 were randomised to receive six additional cycles of either standard eBEACOPP (8 × eBEACOPP in total) or eBEACOPP with rituximab (8 × R-eBEACOPP). Those with negative PET-2 were randomised between standard treatment with six additional cycles of eBEACOPP (8 × eBEACOPP) or experimental treatment with two additional cycles (4 × eBEACOPP). A protocol amendment in June, 2011, introduced a reduction of standard therapy to 6 × eBEACOPP; after this point, patients with positive PET-2 were no longer randomised and were all assigned to receive 6 × eBEACOPP and patients with negative PET-2 were randomly assigned to 6 × eBEACOPP (standard) or 4 × eBEACOPP (experimental). Randomisation was done centrally using the minimisation method including a random component, stratified according to centre, age (<45 vs ≥45 years), stage (IIB, IIIA vs IIIB, IV), international prognostic score (0-2 vs 3-7), and sex. eBEACOPP was given as previously described; rituximab was given intravenously at a dose of 375 mg/m 2 (maximum total dose 700 mg). The primary objectives were to show superiority of the experimental treatment in the PET-2-positive cohort, and to show non-inferiority of the experimental treatment in the PET-2-negative cohort in terms of the primary endpoint, progression-free survival. We defined non-inferiority as an absolute difference of 6% in the 5-year progression-free survival estimates. Primary analyses in the PET-2-negative cohort were per protocol; all other analyses were by intention to treat. This trial was registered with ClinicalTrials.gov, number NCT00515554., Findings: Between May 14, 2008, and July 18, 2014, we recruited 2101 patients, of whom 137 were found ineligible before randomisation and a further 19 were found ineligible after randomisation. Among 434 randomised patients (217 per arm) with positive PET-2, 5-year progression-free survival was 89·7% (95% CI 85·4-94·0) with eBEACOPP and 88·1% (83·5-92·7) with R-eBEACOPP (log-rank p=0·46). Patients with negative PET-2 randomly assigned to either 8 × eBEACOPP or 6 × eBEACOPP (n=504) or 4 × eBEACOPP (n=501) had 5-year progression-free survival of 90·8% (95% CI 87·9-93·7) and 92·2% (89·4-95·0), respectively (difference 1·4%, 95% CI -2·7 to 5·4). 4 × eBEACOPP was associated with fewer severe infections (40 [8%] of 498 vs 75 [15%] of 502) and organ toxicities (38 [8%] of 498 vs 91 [18%] of 502) than were 8 × eBEACOPP or 6 × eBEACOPP in PET-2-negative patients. Ten treatment-related deaths occurred: four in the PET-2-positive cohort (one [<1%] in the 8 × eBEACOPP group, three [1%] in the 8 × R-eBEACOPP group) and six in the PET-2-negative group (six [1%] in the 8 × eBEACOPP or 6 × eBEACOPP group)., Interpretation: The favourable outcome of patients treated with eBEACOPP could not be improved by adding rituximab after positive PET-2. PET-2 negativity allows reduction to only four cycles of eBEACOPP without loss of tumour control. PET-2-guided eBEACOPP provides outstanding efficacy for all patients and increases overall survival by reducing treatment-related risks for patients with negative PET-2. We recommend this PET-2-guided treatment strategy for patients with advanced-stage Hodgkin's lymphoma., Funding: Deutsche Krebshilfe, Swiss State Secretariat for Education and Research, and Roche Pharma AG., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Novel agents are changing the treatment of relapsed or refractory Hodgkin lymphoma (HL). Nevertheless, high-dose chemotherapy and autologous stem-cell transplantation (ASCT) are considered standard of care in eligible patients. To identify patients who could benefit most from novel therapeutic approaches, we investigated a comprehensive set of risk factors (RFs) for survival after ASCT., Methods: In this multinational prognostic multivariable modeling study, 23 potential RFs were retrospectively evaluated in HL patients from nine prospective trials with multivariable Cox proportional hazards regression analyses (part I). The resulting prognostic score was then validated in an independent clinical sample (part II)., Results: In part I, we identified 656 patients treated for relapsed/refractory HL between 1993 and 2013 with a median follow-up of 60 months after ASCT. The majority of potential RFs had significant impact on progression-free survival (PFS) with hazard ratios (HR) ranging from 1.39 to 2.22. The multivariable analysis identified stage IV disease, time to relapse ≤3 months, ECOG performance status ≥1, bulk ≥5 cm and inadequate response to salvage chemotherapy [

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.)

AFM13 is a bispecific, tetravalent chimeric antibody construct (TandAb) designed for the treatment of CD30-expressing malignancies. AFM13 recruits natural killer (NK) cells via binding to CD16A as immune effector cells. In this phase 1 dose-escalation study, 28 patients with heavily pretreated relapsed or refractory Hodgkin lymphoma received AFM13 at doses of 0.01 to 7 mg/kg body weight. Primary objectives were safety and tolerability. Secondary objectives included pharmacokinetics, antitumor activity, and pharmacodynamics. Adverse events were generally mild to moderate. The maximum tolerated dose was not reached. Pharmacokinetics assessment revealed a half-life of up to 19 hours. Three of 26 evaluable patients achieved partial remission (11.5%) and 13 patients achieved stable disease (50%), with an overall disease control rate of 61.5%. AFM13 was also active in brentuximab vedotin-refractory patients. In 13 patients who received doses of ≥1.5 mg/kg AFM13, the overall response rate was 23% and the disease control rate was 77%. AFM13 treatment resulted in a significant NK-cell activation and a decrease of soluble CD30 in peripheral blood. In conclusion, AFM13 represents a well-tolerated, safe, and active targeted immunotherapy of Hodgkin lymphoma. A phase 2 study is currently planned to optimize the dosing schedule in order to further improve the therapeutic efficacy. This phase 1 study was registered at www.clinicaltrials.gov as #NCT01221571., (© 2015 by The American Society of Hematology.)

Background: The role of bleomycin and dacarbazine in the ABVD regimen (ie, doxorubicin, bleomycin, vinblastine, and dacarbazine) has been questioned, especially for treatment of early-stage favourable Hodgkin's lymphoma, because of the drugs' toxicity. We aimed to investigate whether omission of either bleomycin or dacarbazine, or both, from ABVD reduced the efficacy of this regimen in treatment of Hodgkin's lymphoma., Methods: In this open-label, randomised, multicentre trial (HD13) we compared two cycles of ABVD with two cycles of the reduced-intensity regimen variants ABV (doxorubicin, bleomycin, and vinblastine), AVD (doxorubicin, vinblastine, and dacarbazine), and AV (doxorubicin and vinblastine), in patients with newly diagnosed, histologically proven, classic or nodular, lymphocyte predominant Hodgkin's lymphoma. In each treatment group, 30 Gy involved-field radiotherapy (IFRT) was given after both cycles of chemotherapy were completed. From Jan 28, 2003, patients were centrally randomly assigned (1:1:1:1) with a minimisation method to the four groups. Because of high event rates, assignment to the AV and ABV groups stopped early, on Sept 30, 2005, and Feb 10, 2006; assignment to ABVD and AVD continued (1:1) until Sept 30, 2009. Our primary objective was to show non-inferiority of the experimental variants compared with ABVD in terms of freedom from treatment failure (FFTF), by excluding a difference of 6% after 5 years corresponding to a hazard ratio (HR) of 1.72, via a 95% CI. Analyses reported here include qualified patients only, and between-group comparisons include only patients recruited during the same period. The trial was registered, number ISRCTN63474366., Findings: Of 1502 qualified patients, 566, 198, 571, and 167 were randomly assigned to receive ABVD, ABV, AVD, or AV, respectively. 5 year FFTF was 93.1%, 81.4%, 89.2%, and 77.1% with ABVD, ABV, AVD, and AV, respectively. Compared with ABVD, inferiority of the dacarbazine-deleted variants was detected with 5 year differences of -11.5% (95% CI -18.3 to -4.7; HR 2.06 [1.21 to 3.52]) for ABV and -15.2% (-23.0 to -7.4; HR 2.57 [1.51 to 4.40]) for AV. Non-inferiority of AVD compared with ABVD could also not be detected (5 year difference -3.9%, -7.7 to -0·1; HR 1.50, 1.00 to 2.26). 178 (33%) of 544 patients given ABVD had WHO grade III or IV toxicity, compared with 53 (28%) of 187 given ABV, 142 (26%) of 539 given AVD, and 40 (26%) of 151 given AV. Leucopenia was the most common event, and highest in the groups given bleomycin., Interpretation: Dacarbazine cannot be omitted from ABVD without a substantial loss of efficacy. With respect to our predefined non-inferiority margin, bleomycin cannot be safely omitted either, and the standard of care for patients with early-stage favourable Hodgkin's lymphoma should remain ABVD followed by IFRT., Funding: Deutsche Krebshilfe and Swiss State Secretariat for Education and Research., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Therapy-related acute myeloid leukemia and myelodysplastic syndromes (t-AML/MDS) represent severe late effects in patients treated for Hodgkin lymphoma (HL). Because more recent data are scarce, we retrospectively analyzed incidence, outcome, and risk factors for the development of t-AML/MDS after HL. A total of 11,952 patients treated for newly diagnosed HL within German Hodgkin Study Group trials between 1993 and 2009 were considered. At a median follow-up of 72 months, t-AML/MDS was diagnosed in 106/11,952 patients (0.9%). Median time from HL treatment to t-AML/MDS was 31 months. The median age of patients with t-AML/MDS was higher than in the whole patient group (43 vs 34 years, P < .0001). Patients who received 4 or more cycles of BEACOPP(escalated) had an increased risk to develop t-AML/MDS when compared with patients treated with less than 4 cycles of BEACOPP(escalated) or no BEACOPP chemotherapy (1.7% vs 0.7% vs 0.3%, P < .0001). The median overall survival (OS) for all t-AML/MDS patients was 7.2 months. However, t-AML/MDS patients proceeding to allogeneic stem cell transplantation had a significantly better outcome with a median OS not reached after a median follow-up of 41 months (P < .001).

Background: In early-stage Hodgkin's lymphoma (HL), treatment according to the early favorable or unfavorable subgroup is guided by staging definitions, which differ between various study groups worldwide. We analyzed risk factors used in different international staging systems and their impact on the outcome of early-stage HL patients., Patients and Methods: In 1173 early-stage HL patients treated homogenously within the German Hodgkin Study Group (GHSG) trials HD10 and HD11, the impact of three staging systems developed and used by the GHSG, the European Organization for Research and Treatment of Cancer (EORTC), and the National Comprehensive Cancer Network (NCCN) in discriminating risk groups for progression-free survival (PFS) and overall survival (OS) was assessed and the relevance of their single risk factors was investigated., Results: All the three staging systems defined an unfavorable risk group out of early-stage patients of comparable size (56%, 55%, and 57%), having a significantly poorer PFS and OS as compared with the corresponding favorable group; 5-year differences between early favorable and early unfavorable in terms of PFS were 9.4% (HR 2.61, 95% CI 1.74-3.91), 6.7% (HR 2.10, 95% CI 1.41-3.13), and 8.6% (HR 2.14, 95% CI 1.45-3.16) with the GHSG, EORTC, and NCCN definition, respectively. Sensitivity was high for all systems (84%, 79%, and 83%); however, there was a low specificity with high rates of false-positive results (1-specificity 54%, 53%, and 55%, respectively). Models of high sensitivity included risk factors associated with large tumor burden and high tumor activity. Most risk factors for tumor-specific end points were also predictive of OS., Conclusions: Differentiating between a favorable and an unfavorable risk group has significant impact on PFS and OS in early-stage HL patients in the modern treatment era. Risk-adapted treatment strategies using new risk factors with higher specificity are needed.

Background: Treatment options for patients with nonbulky stage IA-IIA Hodgkin lymphoma include combined modality therapy (CMT) using doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) plus involved-field radiation therapy (IFRT), and chemotherapy with ABVD alone. There are no mature randomized data comparing ABVD with CMT using modern radiation techniques., Patients and Methods: Using German Hodgkin Study Group HD10/HD11 and NCIC Clinical Trials Group HD.6 databases, we identified 588 patients who met mutually inclusive eligibility criteria from the preferred arms of HD10 or 11 (n = 406) and HD.6 (n = 182). We evaluated time to progression (TTP), progression-free (PFS) and overall survival, including in three predefined exploratory subset analyses., Results: With median follow-up of 91 (HD10/11) and 134 (HD.6) months, respective 8-year outcomes were for TTP, 93% versus 87% [hazard ratio (HR) 0.44, 95% confidence interval (CI) 0.24-0.78]; for PFS, 89% versus 86% (HR 0.71, 95% CI 0.42-1.18) and for overall survival, 95% versus 95% (HR 1.09, 95% CI 0.49-2.40). In the exploratory subset analysis including HD10 eligible patients who achieved complete response (CR) or unconfirmed complete response (CRu) after two cycles of ABVD, 8-year PFS was 87% (HD10) versus 95% (HD.6) (HR 2.8; 95% CI 0.64-12.5) and overall survival 96% versus 100%. In contrast, among those without CR/CRu after two cycles of ABVD, 8-year PFS was 88% versus 74% (HR 0.35; 95% CI 0.16-0.79) and overall survival 95% versus 91%, respectively (HR 0.42; 95% CI 0.12-1.44)., Conclusions: In patients with nonbulky stage IA-IIA Hodgkin lymphoma, CMT provides better disease control than ABVD alone, especially among those not achieving complete response after two cycles of ABVD. Within the follow-up duration evaluated, overall survivals were similar. Longer follow-up is required to understand the implications of radiation and chemotherapy-related late effects., Clinical Trials: The trials included in this analysis were registered at ClinicalTrials.gov: HD10 - NCT00265018, HD11 - NCT00264953, HD.6 - NCT00002561.

Background: To evaluate long-term toxicity and efficacy of a combined modality strategy including extended-field radiotherapy (EF-RT) or involved-field radiotherapy (IF-RT), the German Hodgkin Study Group carried out a follow-up analysis in patients with early unfavorable Hodgkin's lymphoma (HL)., Patients and Methods: One thousand two hundred and four patients were randomized to four cycles of chemotherapy followed by either 30 Gy EF- or 30 Gy IF-RT (HD8 trial); 532 patients in each treatment arm were eligible., Results: At 10 years, no arm differences were revealed with respect to freedom from treatment failure (FFTF) (79.8% versus 79.7%), progression-free survival (79.8% versus 80.0%), and overall survival (86.4% versus 87.3%). Non-inferiority of IF-RT was demonstrated for the primary end point FFTF (95% confidence interval for hazard ratio 0.72-1.25). Elderly patients had a poorer outcome when treated with EF-RT. So far, 15.0% of patients in arm A and 12.2% in arm B died, mostly due to secondary malignancies (5.3% versus 3.4%) or HL (3.2% versus 3.4%). After EF-RT, there were more secondary malignancies overall (58 versus 45), especially acute myeloid leukemias (11 versus 4)., Conclusion: Radiotherapy intensity reduction to IF-RT does not result in poorer long-term outcome but is associated with less acute toxicity and might be associated with less secondary malignancies.

The CD30-targeting Ab-drug conjugate brentuximab vedotin (SGN-35) was recently approved for the treatment of relapsed Hodgkin lymphoma and anaplastic large-cell lymphoma by the Food and Drug Administration. In the present study, we report the experience of the German Hodgkin Study Group with brentuximab vedotin as single agent in 45 patients with refractory or relapsed CD30(+) Hodgkin lymphoma who were treated either in a named patient program (n = 34) or in the context of a safety study associated with the registration program of this drug. In these very heavily pretreated patients, an objective response rate of 60%, including 22% complete remissions, could be documented. The median duration of response was 8 months. This retrospective analysis supports the previously reported excellent therapeutic efficacy of brentuximab vedotin in heavily pretreated CD30(+) malignancies.

Background: In the HD14 trial, 2×BEACOPPescalated+2×ABVD (2+2) has improved the primary outcome. Compared with 4×ABVD, this benefit might be compromised by more infertility in women. Therefore, we analyzed gonadal function and fertility., Patients and Methods: Women≤45 years in ongoing remission at least 1 year after therapy were included. Hormone parameters, menopausal symptoms, measures to preserve fertility, menstrual cycle, pregnancies, and offspring were evaluated., Results: Three hundred and thirty one of 579 women addressed participated (57.2%) and 263 per-protocol treated patients qualified (A=ABVD: 137, B=2+2: 126, mean time after therapy 42 and 43 months, respectively). Regular menstrual cycle after treatment (A: 87%, B: 83%) and time to recovery (≤12 months) were not different. Follicle-stimulating hormone and anti-Muellerian hormone were significantly better in arm A. However, pregnancies after therapy favored arm B (A: 15%, B: 26%, P=0.043) and motherhood rates were equivalent to the German normal population. Multivariate analysis revealed prophylactic use of gonadotropin-releasing hormone (GnRH) analogues as highly significant prognostic factor for preservation of fertility (odds ratio=12.87, P=0.001). Severe menopausal symptoms were frequent in women≥30 years (A: 21%, B: 25%)., Conclusions: Hormonal levels after 2+2 indicate a reduced ovarian reserve. However, 2+2 in combination with GnRH analogues does not compromise fertility within the evaluated observation time.

Background: The intensity of chemotherapy and need for additional radiotherapy in patients with advanced stage Hodgkin's lymphoma has been unclear. We did a prospective randomised clinical trial comparing two reduced-intensity chemotherapy variants with our previous standard regimen. Chemotherapy was followed by PET-guided radiotherapy., Methods: In this parallel group, open-label, multicentre, non-inferiority trial (HD15), 2182 patients with newly diagnosed advanced stage Hodgkin's lymphoma aged 18-60 years were randomly assigned to receive either eight cycles of BEACOPP(escalated) (8×B(esc) group), six cycles of BEACOPP(escalated) (6×B(esc) group), or eight cycles of BEACOPP(14) (8×B(14) group). Randomisation (1:1:1) was done centrally by stratified minimisation. Non-inferiority of the primary endpoint, freedom from treatment failure, was assessed using repeated CIs for the hazard ratio (HR) according to the intention-to-treat principle. Patients with a persistent mass after chemotherapy measuring 2·5 cm or larger and positive on PET scan received additional radiotherapy with 30 Gy; the negative predictive value for tumour recurrence of PET at 12 months was an independent endpoint. This trial is registered with Current Controlled Trials, number ISRCTN32443041., Findings: Of the 2182 patients enrolled in the study, 2126 patients were included in the intention-to-treat analysis set, 705 in the 8×B(esc) group, 711 in the 6×B(esc) group, and 710 in the 8×B(14) group. Freedom from treatment failure was sequentially non-inferior for the 6×B(esc) and 8×B(14) groups as compared with 8×B(esc). 5-year freedom from treatment failure rates were 84·4% (97·5% CI 81·0-87·7) for the 8×B(esc) group, 89·3% (86·5-92·1) for 6×B(esc) group, and 85·4% (82·1-88·7) for the 8×B(14) group (97·5% CI for difference between 6×B(esc) and 8×B(esc) was 0·5-9·3). Overall survival in the three groups was 91·9%, 95·3%, and 94·5% respectively, and was significantly better with 6×B(esc) than with 8×B(esc) (97·5% CI 0·2-6·5). The 8×B(esc) group showed a higher mortality (7·5%) than the 6×B(esc) (4·6%) and 8×B(14) (5·2%) groups, mainly due to differences in treatment-related events (2·1%, 0·8%, and 0·8%, respectively) and secondary malignancies (1·8%, 0·7%, and 1·1%, respectively). The negative predictive value for PET at 12 months was 94·1% (95% CI 92·1-96·1); and 225 (11%) of 2126 patients received additional radiotherapy., Interpretation: Treatment with six cycles of BEACOPP(escalated) followed by PET-guided radiotherapy was more effective in terms of freedom from treatment failure and less toxic than eight cycles of the same chemotherapy regimen. Thus, six cycles of BEACOPP(escalated) should be the treatment of choice for advanced stage Hodgkin's lymphoma. PET done after chemotherapy can guide the need for additional radiotherapy in this setting., Funding: Deutsche Krebshilfe and the Swiss Federal Government., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Approximately 20% of all Hodgkin lymphoma (HL) patients are older than 60 years and have a poor prognosis, mainly because of increased treatment-related toxicity resulting in reduced overall dose intensity and more treatment-related mortality. To possibly improve the treatment of elderly HL patients, the German Hodgkin Study Group developed a new regimen, PVAG (prednisone, vinblastine, doxorubicin, and gemcitabine). In this multicenter phase 2 study, elderly HL patients in early unfavorable and advanced stages received 6 to 8 cycles of PVAG and additional radiotherapy if they were not in complete remission (CR) after chemotherapy. Endpoints included feasibility, acute toxicity, and response rate. Fifty-nine patients 60 to 75 years of age (median, 68 years) were eligible for analysis; 93% had advanced stage disease. WHO grade 3/4 toxicities were documented in 43 patients; 46 patients responded with CR/CR uncertain (78%). Within 37 months median observation time, 15 progressions or relapses and 17 deaths were observed, of which 8 were related to HL and 1 was the result of treatment-related toxicity. The 3-year estimates for overall survival and progression-free survival were 66% (95% CI, 50%-78%) and 58% (95% CI, 43%-71%), respectively. We conclude that PVAG is safe and feasible in elderly HL patients. This trial was registered at www.clinicaltrials.gov as #NCT00147875.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) accounts for ∼ 5% of Hodgkin lymphoma cases. The disease is characterized by a strong CD20 expression on the malignant cells and a more indolent clinical course compared with classic HL. Anti-CD20 antibody treatment has shown clinical activity in relapsed NLPHL. In this phase 2 trial, we investigated rituximab in newly diagnosed stage IA NLPHL patients. Four weekly applications at 375 mg/m(2) were given. Among the 28 evaluable patients, overall response rate was 100%, 24 patients (85.7%) achieved complete remission, and 4 (14.3%) achieved partial remission. At a median follow-up of 43 months, overall survival was 100%; progression-free survival at 12, 24, and 36 months was 96.4%, 85.3%, and 81.4%, respectively. No grade 3 or 4 toxicity was observed. Although treatment results with rituximab appear inferior compared with radiotherapy and combined-modality approaches in early-stage patients, investigation of anti-CD20 antibody-based combinations in NLPHL is warranted. This study was registered at www.clinicaltrials.gov as #NCT00346684.

Background: The reduction of treatment-related toxic effects is the main goal in the current trials of the German Hodgkin Study Group (GHSG). In this regard, the protection of the ovarian reserve in young women is very important. Therefore, the GHSG investigated the use of gonadotropin-releasing hormone-analogues (GnRH-a) and oral contraceptives (OC) in young women with advanced-stage Hodgkin lymphoma (HL)., Patients and Methods: Women (18-40 years) were randomly assigned either to receive daily OC or monthly GnRH-a during escalated combination therapy with bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc). Hormonal levels were determined at baseline, during therapy, and at follow-up., Results: The study was closed prematurely after an interim analysis of 12 patients in arm A (OC) and 11 in arm B (GnRH-a), 9 and 10 are assessable for the primary end point. Women's median age was 25 years in both arms. The anti-Mullerian hormone level after at least 12 months was reduced in all patients. For the entire study cohort, the respective ovarian follicle preservation rate was 0% (95% confidence interval 0% to 12%)., Conclusion: We observed no protection of the ovarian reserve with hormonal co-treatment during BEACOPPesc. This result supports efforts of ongoing trials to reduce chemotherapy intensity and toxicity. Alternative strategies for the protection of fertility must be offered to young female HL patients before the start of BEACOPPesc therapy.

For older patients with early unfavorable or advanced stage Hodgkin lymphoma (HL) the prognosis is much worse than for younger HL patients. We thus developed a new regimen, BACOPP (bleomycin, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone), to improve both tolerability and efficacy of treatment for older HL patients. Between 2004 and 2005, 65 patients with early unfavorable or advanced stage HL aged between 60 and 75 years were enrolled in this phase 2 trial. Treatment consisted of 6 to 8 cycles of BACOPP. Residual tumor masses were irradiated. Primary endpoints were feasibility as determined by adherence to protocol and overall response rate. Secondary endpoints included toxicity, freedom from treatment failure, and progression free and overall survival. For the final analysis 60 patients (92%) were eligible; 75% of treatment courses were administered according to protocol. World Health Organization grade 3/4 toxicities occurred in 52 patients. Fifty-one patients (85%) achieved complete remission, 2 (3%) partial remission, and 4 (7%) developed progressive disease. With a median observation time of 33 months, 18 patients died (30%), including 7 treatment-associated deaths. Three patients died before response assessment. Thus, the BACOPP regimen is active in older HL patients but is compromised by a high rate of toxic deaths. This trial was registered at www.clinicaltrials.gov as #NCT00284271.

In the HD15 trial of the German Hodgkin Study Group, the negative predictive value (NPV) of positron emission tomography (PET) using [(18)F]-fluorodeoxyglucose in advanced-stage Hodgkin lymphoma (HL) was evaluated. A total of 817 patients were enrolled and randomly assigned to receive BEACOPP-based chemotherapy. After completion of chemotherapy, residual disease measuring more than or equal to 2.5 cm in diameter was assessed by PET in 311 patients. The NPV of PET was defined as the proportion of PET(-) patients without progression, relapse, or irradiation within 12 months after PET review panel. The progression-free survival was 96% for PET(-) patients (95% confidence interval [CI], 94%-99%) and 86% for PET(+) patients (95% CI, 78%-95%, P = .011). The NPV for PET in this analysis was 94% (95% CI, 91%-97%). Thus, consolidation radiotherapy can be omitted in PET(-) patients with residual disease without increasing the risk for progression or early relapse compared with patients in complete remission. The impact of this finding on the overall survival at 5 years must be awaited. Until then, response adapted therapy guided by PET for HL patients seems to be a promising approach that should be further evaluated in clinical trials. This trial is registered at http://isrctn.org study as #ISRCTN32443041.

Because nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) express CD20, rituximab may be used as a nonmutagenic treatment option to avoid late toxicities in this rather indolent entity. Between 1999 and 2004, the German Hodgkin Study Group (GHSG) investigated the activity of rituximab (375 mg/m(2) in 4 doses) in a phase 2 trial in 21 relapsed or refractory NLPHL patients. The initial diagnosis of NLPHL was confirmed in 15 of the 21 enrolled patients by reference pathology. The remaining cases were reclassified as Hodgkin lymphoma transformed to T-cell rich B-cell lymphoma (TCRBCL; n = 2) or CD20(+) classical Hodgkin lymphoma (cHL; n = 4). In NLPHL patients the overall response rate was 94%, including 8 complete remission (CR) and 6 partial remission (PR). With a median follow-up of 63 months (range, 3-84), the median time to progression was 33 months, with the median overall survival (OS) not reached. Thus, rituximab is highly effective in relapsed and refractory NLPHL. This study is registered at http://www.klinisches-studienzentrum.de/trial/285.

The inability of the immune system to recognize and kill malignant plasma cells in patients with multiple myeloma (MM) has been attributed in part to the ineffective activation of natural killer (NK) cells. In order to activate and target NK cells to the malignant cells in MM we designed a novel recombinant bispecific protein (ULBP2-BB4). While ULBP2 binds the activating NK receptor NKG2D, the BB4 moiety binds to CD138, which is overexpressed on a variety of malignancies, including MM. ULBP2-BB4 strongly activated primary NK cells as demonstrated by a significant increase in interferon-gamma (IFN-gamma) secretion. In vitro, ULBP2-BB4 enhanced the NK-mediated lysis of 2 CD138+ human MM cell lines, U-266 and RPMI-8226, and of primary malignant plasma cells in the allogenic and autologous setting. Moreover, in a nude mouse model with subcutaneously growing RPMI-8226 cells, the cotherapy with ULBP-BB4 and human peripheral blood lymphocytes abrogated the tumor growth. These data suggest potential clinical use of this novel construct in patients with MM. The use of recombinant NK receptor ligands that target NK cells to tumor cells might offer new approaches for other malignancies provided a tumor antigen-specific antibody is available.

5F11, a fully human monoclonal antibody directed against CD30, effectively induces killing of CD30-expressing lymphoma cell lines in vitro and in animal models. A recently conducted phase 1/2 study shows that 5F11 is well tolerated in heavily pretreated patients with relapsed and refractory CD30(+) lymphoma and has some clinical activity. In the present study, we demonstrate that 5F11 activates nuclear factor kappaB (NF-kappaB) and the anti-apoptotic protein cellular FLICE (Fas-associating protein with death domain-like interleukin-1beta-converting enzyme) inhibitory protein (c-flip) in Hodgkin lymphoma (HD)-derived cell lines, which might cause apoptosis resistance, thus limiting the clinical use of 5F11. To overcome this resistance, we combined 5F11 with the proteasome inhibitor bortezomib, which has been shown to suppress NF-kappaB activity. This combination revealed a synergistic cytotoxic effect in vitro and in a human HD xenograft model provided that 5F11 precedes bortezomib treatment. We conclude that initial 5F11-mediated NF-kappaB signaling sensitizes the tumor cells to bortezomib-induced cell death. These data suggest a therapeutic value of this combination for HD patients.

CD30 is a promising target for antibody-based immunotherapy of Hodgkin lymphoma (HL) and anaplastic large cell lymphoma. To overcome the limitations from currently available murine anti-CD30 monoclonal antibodies (mAbs), a new fully human anti-CD30 antibody was generated. Binding properties were evaluated by recombinant CD30 capture enzyme-linked immunosorbent assay (ELISA) and fluorescence-activated cell-sorter (FACS) flow cytometry. Activity of this new mAb was assessed in vitro using growth inhibition and antibody-dependent cellular cytotoxicity (ADCC) assays on several cell lines. In vivo activity was determined in a solid as well as in a disseminated xenografted model of HL in severe combined immunodeficiency (SCID) mice. The mAb 5F11 showed specific binding to CD30 (cluster A). The ADCC assays indicated dose-dependent lysis of L540 cells when 5F11 was combined with human effector cells. Upon cross-linking in vitro, 5F11 inhibited the growth of CD30-expressing cell lines. In vivo, treatment with 5F11 induced a marked growth delay or even a complete regression of established xenografted HL in SCID mice. In the disseminated HL model, a high proportion of 5F11-treated mice experienced long-term survival. The new human anti-CD30 monoclonal antibody 5F11 shows promise as a means of CD30-targeted immunotherapy of malignant lymphomas. Based on these results, a clinical phase 1 study in patients with refractory CD30+ lymphoma has been initiated.

Background: Immunotoxins (ITs) consist of cell binding ligands coupled to toxins or their subunits. Hodgkin's lymphoma (HL) is an excellent target for ITs since lymphocyte activation markers such as CD25 and CD30 are expressed in large numbers. The ITs RFT5.dgA (anti CD25) and Ki-4.dgA (anti CD30) were constructed by linking the monoclonal antibodies RFT5 and Ki-4 to deglycosylated ricin A-chain (dgA). Both ITs showed potent specific activity against HL cells in vitro and in vivo in animal models, and were subsequently evaluated in phase I/II clinical trials in humans., Patients and Methods: In two separate trials, the ITs were administered i.v. four times every other day over 4 h. The objectives of the phase I trials included the determination of the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, antitumor activity and immune response against the IT., Results: Twenty-seven patients with refractory HL were included in the phase I/II study of RFT5.dgA and 17 patients were included in the phase I study of Ki-4.dgA. The MTD of RFT5.dgA was 15 mg/m(2), whereas that of Ki-4.dgA was 5 mg/m(2). DLTs were related to vascular leak syndrome, consisting of edema, tachycardia, dyspnea, weakness and myalgia. Measurement of serum levels of RFT5.dgA demonstrated a C(max) of 0.2-9.7 micro g/ml with a half-life (t()) varying from 4 to 10.5 h. Peak serum concentration of Ki-4.dgA ranged from 0.23 to 1.7 micro g/ml. In both trials approximately 60% of patients developed human anti-mouse and/or anti-dgA antibodies. Seventeen of 18 patients treated at the MTD of RFT5.dgA were evaluable for clinical response. Responses included two partial remissions (PR), one minor response (MR) and five stable diseases (SD). Fifteen of 17 patients treated with Ki-4.dgA were evaluable for clinical response. Responses included one PR, one MR and two SD., Conclusions: RFT5.dgA and Ki-4.dgA showed moderate efficacy in heavily pretreated refractory patients with HL. Ki-4.dgA was less well tolerated than RFT5.dgA. This might be due, at least in part, to the formation of Ki-4.dgA/sCD30 complexes.

CD30 is an excellent target for immunotherapy of Hodgkin lymphoma (HL) because it is overexpressed on Hodgkin and Reed-Sternberg cells. We developed a novel bispecific molecule (BSM) consisting of F(ab') fragments derived from the murine anti-CD30 monoclonal antibody (MoAb) Ki-4 and the humanized CD64-specific MoAb H22. In vitro experiments of H22xKi-4 demonstrated specific phagocytosis of HL-derived cell lines. Patients (pts) with refractory CD30(+) HL were treated with escalating doses of H22xKi-4 at doses of 1, 2.5, 5, 10, and 20 mg/m(2)/d, respectively (administered intravenously on days 1, 3, 5, and 7). The main study objectives were to determine the maximum tolerated dose and the dose-limiting toxicities of H22xKi-4, to define its pharmacokinetic profile, and to document clinical response. Ten pts were enrolled and are evaluable for toxicity and response. Side effects were transient and mild with hypotension (4 of 10), tachycardia (6 of 10), fatigue (10 of 10), and fever (2 of 10 grade I, 3 of 10 grade II). Pharmacokinetic (PK) data revealed an elimination half-life of 11.1 hours, resulting in a significant accumulation of H22xKi-4. The BSM was shown to bind to both monocytes and malignant cells. Response to H22xKi-4 included 1 complete remission (CR), 3 partial remissions (PR), and 4 pts with stable disease. The new BSM H22xKi-4 can be given safely to pts with refractory CD30(+) HL in doses up to 80 mg/m(2) per cycle. Although this dose is not the maximum tolerated dose (MTD) as defined by toxicity criteria, surrogate parameters suggest a biologic effective regimen. H22xKi-4 shows activity in heavily pretreated HL patients warranting further clinical evaluation.

Many new approaches involving antibody-based agents have given promising results in experimental Hodgkin's disease (HD) models. Clinical trials with monoclonal antibodies, immunotoxins, bispecific constructs and radioimmunoconjugates have demonstrated some clinical efficacy in patients with advanced refractory HD. Although it seems unlikely that resistant patients with larger tumor masses will be cured by either of these approaches, it might be feasible to treat bulky disease by conventional therapy and then administer biological agents to kill residual Hodgkin and Reed-Sternberg cells. Future phase III trials will have to prove a possible superior effect of this combined immunochemotherapy. Currently, the evaluation of the most promising approaches continues.

Background: BBR 2778 is a novel aza-anthracenedione showing no cardiotoxicity and superior activity compared to doxorubicin and mitoxantrone in animal models. Objectives of this phase I study included the determination of the maximum tolerated dose (MTD), the dose limiting toxicity (DLT), clinical pharmacokinetics (PK), and antitumor activity. Patients with relapsed or refractory, advanced non-Hodgkin's lymphoma were included., Patients and Methods: Patients were treated with a q1w x 3 schedule on the basis of a modified Fibonacci dose escalation method. Seven groups with a total of twenty-six patients were treated at dosages of 5, 10, 16.5, 25, 34, 56 or 84 mg/m2/w, respectively., Results: DLT was observed on the seventh dose level with neutropenia WHO grade 4 in three of six patients. Pharmacokinetic analysis showed a large volume of distribution (13.5-17.5 l/kg), a high plasma clearance (0.65-1.74 l/h/kg) and a long elimination half-life (14.7-31.9 h). Tumor response included three complete remissions and two partial remissions., Conclusions: Neutropenia is the DLT of the new aza-anthracenedione BBR 2778. The recommend dose is 84 mg/m2 in a q1w x 3 schedule. PK data are consistent with a linear kinetic of BBR 2778 comparable to mitoxantrone. This new drug shows promising activity in intensively pretreated patients with relapsed or refractory NHL. Based on this results, phase II studies with this new compound are underway.

In the treatment of Hodgkin's disease (HD) remission rates of 80% have been achieved with combination regimens such as COPP/ABVD; 30%-50% of these patients relapse, however, and less than 25% of those in first relapse can be cured. Although 90% of adults with advanced Hodgkin's disease (HD) achieve a complete remission with new polychemotherapy regimens such as BEACOPP, it is too early to assess how many patients ultimately can be cured. In addition, these regimens are associated with severe side effects including infertility, cardiomyopathy or second malignancies. Thus, alternative strategies for improving the outcome of patients with HD have been developed. These approaches include new cytostatic drugs and biological agents. Here, we review the most recent developments including the new vinca alkaloid vinorelbine, the anthracycline idarubicin, the nitrogen mustard bendamustine, the recently developed nucleoside analogue gemcitabine, and immunotoxins against Hodgkin/Reed-Sternberg cells. We conclude that current polychemotherapy regimens could possibly be improved by introducing new agents with a different mechanism of action such as gemcitabine. In addition, some of these new drugs including gemcitabine or vinorelbine could contribute to the reduction of toxic side effects, thus resulting in an improved quality of life for patients with HD.