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To evaluate patterns of rrHL after contemporary first-line treatment we studied 409 patients with first rrHL (HD13: n = 87, HD14: n = 118, HD15: n = 188, HDR3i: n = 51) at a median age of 37.4 years (18.4-76.8) from the GHSG database. Time to first relapse was ≤12 months in 49% and stage III/IV rrHL present in 52% of patients. In total, 291 patients received high-dose chemotherapy and autologous stem-cell transplantation (ASCT) and intended ASCT failed in 38 patients. ASCT was primarily not intended in 80 patients largely due to low risk disease or age/comorbidities. Overall, 10-year progression-free (PFS) and overall survival (OS) rates after first relapse were 48.2% (95% CI 41.9-54.2%) and 59.4% (95% CI 53.0-65.2%), respectively, with significant differences between subgroups. Inferior survival was observed with no ASCT due to advanced age/comorbidities (five-year PFS 36.2%, 95% CI 17.7-55.0%) or failure of salvage therapy (five-year PFS 36.3%, 95% CI 19.7-53.2%). Similarly, presence of primary refractory disease or stage IV at rrHL conferred inferior survival. In patients with low-risk disease, however, survival appeared favorable even without ASCT (10 y PFS 72.6%, 95% CI 53.7-84.8%). We herein confirm the curative potential of current rrHL treatments providing a robust benchmark to evaluate novel therapeutic strategies in rrHL. Approximately 50% of rrHL patients experienced a consecutive relapse., (© 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: Primary central nervous system lymphoma (PCNSL) is a rare type of aggressive lymphoma of the central nervous system. Treatment strategies improved significantly over the past decades differ regionally but mainly consist of rituximab and high-dosed methotrexate (MTX)-based therapies., Methods: We assessed clinical outcomes of 100 patients with newly diagnosed PCNSL between 2010-2020 at the University Hospital of Cologne, Germany., Results: Patients were 23-88 years of age and either treated with MTX-based regimens (PRIMAIN, MARTA, MATRix), individual regimens, or best supportive care, respectively. Overall response rates were generally high (66,7-83,8%), but different organ toxicities required dose adjustments in most groups. Two-year overall survival rates were 57,9% (PRIMAIN), 63,6% (MARTA), 65,4% (MATRix), and 37,5% (Other), respectively. Out of 9 patients suffering from relapse >12 months from primary diagnosis, 7 patients (77,8%) received methotrexate-based salvage therapy with 2-year overall survival of 4/6 patients (66,7%)., Conclusion: Although a relevant proportion of patients are not eligible for clinical trials due to age, performance status, or comorbidities, these results prove feasibility of different MTX-based treatment strategies in clinical routine. Even elderly patients displayed surprisingly favorable outcomes. However, with compromising organ toxicities, reduction of intensity should be part of strategies in future clinical trials., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: To improve the long-term tumour control in early, unfavourable Hodgkin Lymphoma, the German Hodgkin Study Group (GHSG) HD14 trial compared four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with an intensified chemotherapy regimen consisting of two cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (escalated BEACOPP) plus two cycles of ABVD. The final analysis of the trial showed a significant advantage in terms of freedom from treatment failure (difference 7·2% [95% CI 3·8-10·5] at 5 years) for patients who received two cycles of escalated BEACOPP and two cycles of ABVD. However, there was no difference in overall survival between the two groups. To evaluate long-term efficacy and toxicity of this strategy, we did a follow-up analysis., Methods: Patients aged 18-60 years with performance status of 2 or less and primary diagnosis of early, unfavourable Hodgkin lymphoma (all histologies) were included in an international, randomised, open-label, phase 3 trial. Patients were randomly assigned to receive four cycles of ABVD (ABVD group) or two cycles of escalated BEACOPP and two cycles of ABVD (2 + 2 group), both groups also received 30 Gy involved field radiotherapy. The ABVD dosing regimen was doxorubicin 25 mg/m 2 (days 1 and 15), bleomycin 10 mg/m 2 (days 1 and 15), vinblastine 6 mg/m 2 (days 1 and 15), and dacarbazine 375 mg/m 2 (days 1 and 15), repeated on day 29. The escalated BEACOPP dosing regimen was cyclophosphamide 1250 mg/m 2 (day 1), doxorubicin 35 mg/m 2 (day 1), etoposide 200 mg/m 2 (days 1-3), procarbazine 100 mg/m 2 (days 1-7), prednisone 40 mg/m 2 (days 1-14), vincristine 1·4 mg/m 2 (day 8; maximum 2 mg), and bleomycin 10 mg/m 2 (day 8), repeated on day 22. After closure of the ABVD group according to prespecified rules, patients were assigned to receive two cycles of escalated BEACOPP and two cycles of ABVD (non-randomised 2 + 2 group), which continued until the end of the predefined 5-year recruitment period. In this prespecified long-term follow-up analysis, we aimed to evaluate the secondary endpoints progression-free survival, overall survival, and long-term toxicity. To this end, we did a descriptive intention-to-treat analysis of all qualified HD14 patients and on the predefined subsets of randomised qualified HD14 patients and patients in the non-randomised 2 + 2 group. The trial was registered on the International Standard Randomised Controlled Trial database, 04761296., Findings: Between Jan 28, 2003, and Dec 29, 2009, 1686 patients were randomly assigned to the ABVD group (847 [50·2%] patients) and the 2 + 2 group (839 [49·8%] patients). 370 additional patients were recruited to the non-randomised 2 + 2 group. 1550 (92%) randomly assigned patients (median observation time 112 months [IQR 80-132]) and 339 (92%) patients in the non-randomised 2 + 2 group (median observation time 74 months [58-100]) were included in the qualified analysis set. 10-year overall survival in the randomly assigned patients was 94·1% (95% CI 92·0-95·7) for the ABVD group and 94·1% (91·8-95·7) for the 2 + 2 group (HR 1·0 [95% CI 0·6-1·5]; p=0·88). 8-year overall survival in the non-randomised 2 + 2 group was 95·1% (95% CI 91·6-97·2). 10-year progression-free survival in the randomly assigned patients was 85·6% (95% CI 82·6-88·1) for the ABVD group and 91·2% (88·4-93·3) for the 2 + 2 group (HR 0·5% [95% CI 0·4-0·7]; p=0·0001), accounting for a significant difference of 5·6% (95% CI 1·9-9·2) favouring the 2 + 2 group (p=0·0001). In the non-randomised 2 + 2 group, 8-year progression-free survival was 94·5% (95% CI 91·1-96·6). Standardised incidence ratios of second primary malignancies were similar between the ABVD group (2·3 [95% CI 1·6-3·1]) and the 2 + 2 group (2·5 [1·8-3·4]; Gray's p=0·80). Standardised incidence ratio of second primary malignancies was 3·1 (95% CI 1·7-5·0) in the non-randomised 2 + 2 group., Interpretation: This long-term analysis confirms superior tumour control in the 2 + 2 group compared with the ABVD group without translating into an overall survival difference. At longer follow-up, there is no difference regarding second primary malignancies between groups. In conclusion, the 2 + 2 regimen spares a significant number of patients from the burden of relapse and additional treatment without increased long-term toxicity., Funding: Deutsche Krebshilfe eV and Swiss Federal Government., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Importance: In early-stage unfavorable classic Hodgkin lymphoma (cHL), conventional therapy induces high cure rates but also relevant acute and long-term toxic effects. Nivolumab is well tolerated and highly effective in relapsed/refractory cHL but has not been adequately studied in first-line treatment of early-stage cHL. The NIVAHL trial evaluated nivolumab in this setting with the aim to develop a highly effective yet tolerable systemic therapy to ultimately mitigate morbidity in patients who survive cHL., Objective: To evaluate efficacy of 2 experimental nivolumab-based first-line treatment strategies in patients with early-stage unfavorable cHL., Design, Setting, and Participants: This was an open-label, multicenter, phase 2 randomized clinical trial, open between April 2017 and October 2018. The trial took place at 35 trial centers across Germany, ranging from academic centers to private offices. Eligibility was defined by age 18 to 60 years, cHL confirmed by expert pathology review, early-stage unfavorable disease by German Hodgkin Study Group criteria (stage I to II with risk factor[s]), and absence of serious concomitant disease or organ dysfunction. Among 110 enrolled patients, 109 were eligible., Interventions: Systemic therapy, per random assignment (1:1) to either concomitant treatment with 4 cycles of nivolumab and doxorubicin, vinblastine, and dacarbazine (N-AVD) or sequential treatment with 4 doses of nivolumab, 2 cycles of N-AVD, and 2 cycles of AVD at standard doses, followed by 30-Gy involved-site radiotherapy., Main Outcomes and Measures: Complete remission (CR) rate after study treatment, aiming at excluding a CR rate of 80% or lower via a 2-sided 95% CI for each treatment group., Results: Of 109 patients included in this study, 65 (59.6%) were women, and the median (range) age was 27 (18-60) years. At interim staging after 2 cycles of N-AVD or 4 doses of nivolumab monotherapy, 54 of 54 (100%) and 49 of 51 (96%) response-eligible patients, respectively, achieved an objective response, with CR in 47 (87%) and 26 (51%) patients, respectively. Among 101 patients eligible for primary end point analysis, 46 of 51 (90%; 95% CI, 79%-97%) patients receiving concomitant therapy and 47 of 50 (94%; 95% CI, 84%-99%) patients receiving sequential therapy achieved CR after study treatment. With a median follow-up of 13 months, 12-month progression-free survival was 100% for patients receiving concomitant treatment and 98% (95% CI, 95%-100%) for patients receiving sequential therapy., Conclusions and Relevance: Both strategies combining nivolumab and AVD are feasible and resulted in high remission rates. Despite narrowly missing the efficacy benchmark in the concomitant group, the excellent 12-month progression-free survival and the unexpectedly high CR rate after 4 doses of nivolumab monotherapy warrant further evaluation of this approach in the first-line treatment of patients with early-stage cHL., Trial Registration: ClinicalTrials.gov Identifier: NCT03004833.

First-line treatments for classical Hodgkin lymphoma (HL) include ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) and BEACOPP escalated (escalated dose bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone). To further improve overall outcomes, positron emission tomography-driven strategies and ABVD or BEACOPP variants incorporating the antibody-drug conjugate brentuximab vedotin (BV) or anti-PD1 antibodies are under investigation in advanced-stage patients. The present study aimed to elicit preferences for attributes associated with ABVD, BEACOPP escalated and BV-AVD (BV, adriamycin, vinblastine and dacarbazine) among patients and physicians. Cross-sectional online discrete choice experiments were administered to HL patients (n = 381) and haematologists/oncologists (n = 357) in France, Germany and the United Kingdom. Included attributes were progression-free survival (PFS), overall survival (OS), and the risk of neuropathy, lung damage, infertility and hospitalisation due to adverse events. Whereas 5-year PFS and OS were the most important treatment attributes to patients, the relative importance of each attribute and preference weights for each level varied among physicians according to the description of the hypothetical patient for whom treatment was recommended. PFS and OS most strongly influenced physicians' recommendations when considering young female patients who did not want children or young male patients. Infertility was more important to physicians' treatment decision than PFS when considering young women with unknown fertility preferences, whereas hospitalisations due to adverse events played the largest role in treatment decisions for older patients., (© 2018 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

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

Objective: Brentuximab vedotin (BV) is an anti-CD30 antibody-drug conjugate licensed for the treatment of relapsed/refractory Hodgkin lymphoma (rrHL) following autologous stem cell transplant (ASCT) or at least two prior therapies when ASCT or multiagent chemotherapy is not an option. The objective of this study was to describe real-world outcomes with BV in patients with rrHL considered ASCT ineligible or who refuse ASCT., Methods: This was a retrospective medical chart review study that enrolled patients ≥18 years old who were initially diagnosed with HL between January 1, 2008 and June 30, 2014, considered ASCT ineligible, and treated in routine care with BV for progressive disease after multidrug chemotherapy regimens. Clinical outcomes included best response to treatment, progression-free survival (PFS), overall survival (OS), and adverse events., Results: A total of 136 patients were included, with a median age of 70 years at initial HL diagnosis. The most common reasons for ASCT ineligibility were comorbidities (74%) and age (57%). Overall response rate was 74%, and PFS and OS were 15.1 and 17.8 months, respectively. Peripheral neuropathy was observed in 9.6% of patients., Conclusion: The results of this study provide real-world evidence on the feasibility and effectiveness of BV in elderly or frail ASCT-ineligible patients with rrHL in a real-world setting., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)