Allogeneic Stem Cell Transplantation in Multiple Myeloma: Risk Factors and Outcomes in the Era of New Therapeutic Options-A Single-Center Experience.

BACKGROUND: Despite major treatment advances, multiple myeloma remains incurable. The outcome of patients who are refractory to immunomodulatory agents, proteasome inhibitors, and anti-CD38 monoclonal antibodies is poor, and improved treatment strategies for this difficult-to-treat patient population are an unmet medical need. METHODS: This retrospective, unicentric analysis included 38 patients with relapsed/refractory multiple myeloma or plasma cell leukemia who underwent allogeneic stem cell transplantation (allo-HSCT) between 2013 and 2022. Survival outcomes, relapse incidence, and non-relapse mortality were calculated according to remission status, date of allo-HSCT, cytogenetic risk status, timing, and number of previous autologous HSCTs. RESULTS: The median PFS was 13.6 months (95% CI, 7.7-30.4) and the median OS was 51.4 months (95% CI, 23.5-NA) in the overall cohort. The cumulative incidence of relapse at 3 years was 57%, and non-relapse mortality was 16%. The median PFS and OS were significantly longer in patients with very good partial remission (VGPR) or better compared to patients with less than VGPR at the time of allo-HSCT (mPFS 29.7 months (95% CI, 13.7-NA) vs. 6.5 months (95% CI, 2.6-17.0); p = 0.009 and mOS not reached vs. 18.6 months (95% CI, 7.0-NA); p = 0.006). CONCLUSION: For selected patients, allo-HSCT may result in favorable overall survival, in part by providing an appropriate hemato-immunological basis for subsequent therapies.

Web-Based Cognitive-Behavioral Therapy to Reduce Severe Cancer-Related Fatigue Among Survivors of Hodgkin Lymphoma: A Feasibility Study.

We investigated the feasibility of a web-based cognitive-behavioral therapy to reduce cancer-related fatigue (CRF) among survivors of Hodgkin lymphoma. In this before-and-after trial, patients were primarily recruited via the German Hodgkin Study Group (GHSG). We assessed feasibility (response and drop-out rate) and preliminary efficacy including CRF, quality of life (QoL), and depressive symptomatology. T tests compared baseline levels with t1 (post treatment) and t2 (3 months of follow-up). Among 79 patients contacted via the GHSG, 33 provided interest (42%). Among the seventeen participants, four were treated face-to-face (pilot patients), 13 underwent the web-based version. Ten patients completed the treatment (41%). Among all participants, CRF, depressive symptomatology, and QoL improved at t1 (p ≤ .03). The effect in one of the CRF measures remained at t2 (p = .03). Except for QoL, post-treatment effects were replicated among the completers of the web-based version (p ≤ .04). The potential for this program has been demonstrated, but needs to be re-assessed after identified issues on feasibility have been resolved.Trial registration: The study was registered at ClinicalTrials.gov (Number: NCT03968250).

Comparing revised latent state-trait models including autoregressive effects.

Understanding the longitudinal dynamics of behavior, their stability and change over time, are of great interest in the social and behavioral sciences. Researchers investigate the degree to which an observed measure reflects stable components of the construct, situational fluctuations, method effects, or just random measurement error. An important question in such models is whether autoregressive effects occur between the residuals, as in the trait-state occasion model (TSO model), or between the state variables, as in the latent state-trait model with autoregression (LST-AR model). In this article, we compare the two approaches by applying revised latent state-trait theory (LST-R theory). Similarly to Eid et al. (2017) regarding the TSO model, we show how to formulate the LST-AR model using definitions from LST-R theory, and we discuss the practical implications. We demonstrate that the two models are equivalent when the trait loadings are allowed to vary over time. This is also true for bivariate model versions. The different but same approaches to modeling latent states and traits with autoregressive effects are illustrated with a longitudinal study of cancer-related fatigue in Hodgkin lymphoma patients. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Impact of the first COVID-19 lockdown in Germany on the rate of acute infections during intensive chemotherapy for Hodgkin lymphoma.

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

Histopathological growth patterns in patients with advanced nodular lymphocyte-predominant Hodgkin lymphoma treated within the randomized HD18 study: a report from the German Hodgkin Study Group.

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

Treatment patterns and disease course of previously untreated Primary Central Nervous System Lymphoma: Feasibility of MTX-based regimens in clinical routine.

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.

PET-guided eBEACOPP treatment of advanced-stage Hodgkin lymphoma (HD18): follow-up analysis of an international, open-label, randomised, phase 3 trial.

BACKGROUND: The German Hodgkin Study Group's HD18 trial established the safety and efficacy of PET-guided eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) for the treatment of advanced-stage Hodgkin lymphoma. However, because of a protocol amendment during the enrolment period (June 1, 2011) that changed standard treatment from eight to six cycles, the results of the HD18 trial have been partially immature. We report a prespecified 5-year follow-up analysis of the completed HD18 trial. METHODS: HD18 was an international, open-label, randomised, phase 3 trial done in 301 hospitals and private practices in five European countries. Patients aged 18-60 years with newly diagnosed, advanced-stage Hodgkin lymphoma and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited. After receiving an initial two cycles of eBEACOPP (1250 mg/m2 intravenous cyclophosphamide [day 1], 35 mg/m2 intravenous doxorubicin [day 1], 200 mg/m2 intravenous etoposide [day 1-3], 100 mg/m2 oral procarbazine [day 1-7], 40 mg/m2 oral prednisone [day 1-14], 1·4 mg/m2 intravenous vincristine [day 8], and 10 mg/m2 intravenous bleomycin [day 8]), patients underwent a contrast-enhanced CT and PET scan (PET-2). Patients with positive PET-2 were randomly assigned to receive standard therapy (an additional six cycles of eBEACOPP; ie, eight cycles in total) or experimental therapy (an additional six cycles of eBEACOPP plus 375 mg/m2 intravenous rituximab; ie, eight cycles in total) until June 1, 2011. After June 1, 2011, all patients with positive PET-2 were assigned to the updated standard therapy with an additional four cycles of eBEACOPP (ie, six cycles in total). Patients with negative PET-2 were randomly assigned (1:1) to receive standard therapy (an additional six cycles of eBEACOPP [ie, eight cycles in total] until June 1, 2011; an additional four cycles of eBEACOPP [ie, six cycles in total] after June 1, 2011) or experimental therapy (an additional two cycles of eBEACOPP; ie, four cycles in total). Randomisation was done centrally with the minimisation method, including a random component, stratified by centre, age, stage, international prognostic score, and sex. The primary endpoint was progression-free survival. HD18 aimed to improve 5-year progression-free survival by 15% in the PET-2-positive intention-to-treat cohort and to exclude inferiority of 6% or more in 5-year progression-free survival in the PET-2-negative per-protocol population. This study is registered with ClinicalTrials.gov, NCT00515554, and is completed. FINDINGS: Between May 14, 2008, and July 18, 2014, 2101 patients were enrolled and 1945 were assigned to a treatment group according to their PET-2 result. In the PET-2-positive cohort, with a median follow-up of 73 months (IQR 59 to 94), 5-year progression-free survival was 89·9% (95% CI 85·7 to 94·1) in 217 patients assigned to eight cycles of eBEACOPP before the protocol amendment and 87·7% (83·1 to 92·4) in 217 patients assigned to eight cycles of rituximab plus eBEACOPP (p=0·40). Among 506 patients who received six cycles of eBEACOPP after the protocol amendment, 5-year progression-free survival was 90·1% (95% CI 87·2 to 92·9), with a median follow-up of 58 months (IQR 39 to 66). In the PET-2-negative cohort, with a median follow-up of 66 months (IQR 54 to 85) in the combined pre-amendment and post-amendment groups, 5-year progression-free survival was 91·2% (95% CI 88·4 to 93·9) in 446 patients who received eight or six cycles of eBEACOPP and 93·0% (90·6 to 95·4) in 474 patients who received four cycles of eBEACOPP (difference 1·9% [95% CI -1·8 to 5·5]). In the subgroup of PET-2-negative patients randomly assigned after protocol amendment, 5-year progression-free survival was 90·9% (95% CI 86·8 to 95·1) in 202 patients assigned to receive six cycles of eBEACOPP and 91·0% (86·6 to 95·5) in 200 patients assigned to receive four cycles of eBEACOPP (difference 0·1% [-5·9 to 6·2]). INTERPRETATION: Long-term follow-up confirms the efficacy and safety of PET-2-guided eBEACOPP in patients with advanced-stage Hodgkin lymphoma. The reduction from eight to four cycles of eBEACOPP represents a benchmark in the treatment of early-responding patients, who can now be potentially cured with a short and safe treatment approach. FUNDING: Deutsche Krebshilfe, Swiss State Secretariat for Education, Research and Innovation SERI (Switzerland), and Roche Pharma. TRANSLATION: For the German translation of the abstract see Supplementary Materials section.

Non-Hodgkin lymphoma after treatment for classical Hodgkin lymphoma: a report from the German Hodgkin Study Group.

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

In-depth cell-free DNA sequencing reveals genomic landscape of Hodgkin's lymphoma and facilitates ultrasensitive residual disease detection.

BACKGROUND: Individualization of treatment in Hodgkin's lymphoma is necessary to improve cure rates and reduce treatment side effects. Currently, it is hindered by a lack of genomic characterization and sensitive molecular response assessment. Sequencing of cell-free DNA is a powerful strategy to understand the cancer genome and can be used for extremely sensitive disease monitoring. In Hodgkin's lymphoma, a high proportion of cell-free DNA is tumor-derived, whereas traditional tumor biopsies only contain a little tumor-derived DNA. METHODS: We comprehensively genotype and assess minimal residual disease in 121 patients with baseline plasma as well as 77 follow-up samples from a subset of patients with our targeted cell-free DNA sequencing platform. FINDINGS: We present an integrated landscape of mutations and copy number variations in Hodgkin's lymphoma. In addition, we perform a deep analysis of mutational processes driving Hodgkin's lymphoma, investigate the clonal structure of Hodgkin's lymphoma, and link several genotypes to Hodgkin's lymphoma phenotypes and outcome. Finally, we show that minimal residual disease assessment by repeat cell-free DNA sequencing, as early as a week after treatment initiation, predicts treatment response and progression-free survival, allowing highly improved treatment guidance and relapse prediction. CONCLUSIONS: Our targeted cell-free DNA sequencing platform reveals the genomic landscape of Hodgkin's lymphoma and facilitates ultrasensitive detection of minimal residual disease. FUNDING: Mildred Scheel School of Oncology Aachen-Bonn-Cologne-Düsseldorf MD Research Stipend, Next Generation Sequencing Competence Network grant 423957469, Deutsche Krebshilfe grant 70112502, Deutsche Forschungsgemeinschaft (DFG) grant EN 179/13-1, the HL MRD consortium, and the Frau-Weiskam und Christel Ruranski-Stiftung.

Facial nerve paralysis caused by a T-cell lymphoma.

Facial nerve paralysis due to the infiltration by a lymphoma is rare and the prognosis remains poor. If perineural spread and meningeosis are suspected, quick interdisciplinary diagnostic work-up is recommended. It should include magnetic resonance imaging, biopsy of the lesion, bone marrow biopsy, and lumbar puncture. Therapy should be initiated immediately.

The interplay between cancer-related fatigue and functional health in Hodgkin lymphoma survivors.

OBJECTIVE: Cancer-related fatigue (CRF) is among the most distressing symptoms reported by cancer survivors as compromising their quality of life. This study investigates the complex interplay between CRF and functional health (FH) in survivors of Hodgkin lymphoma by using longitudinal data to clarify the etiology of CRF. METHODS: Data from N = 3596 survivors (HD13-15) from the German Hodgkin Study Group was analyzed using bivariate latent curve models with structured residuals to model how the interplay between CRF and FH unfolds over time across and within individuals. CRF and FH were measured with the EORTC QLQ-C30. Assessed FH domains were physical, cognitive, emotional, social, and role functioning. Age at diagnosis, gender, country, baseline fatigue, and cancer stage were included as covariates. RESULTS: The latent curve models with structured residuals had an adequate model fit (χ² = 416.63-548.28, df = 114, p < .001, root mean square error of approximation = .03, comparative fit index = .98-.99, Tucker-Lewis index = .97-.98). On the between-person level, CRF and all FH domains were strongly negatively correlated (r = -.72 to r = -.84). On the within-person level, earlier CRF (ρF = -.05 to ρF = -.12) and FH deviations (ρFH = -.05 to ρFH = -.13) negatively predicted subsequent deviations of the respective other variable. Time-specific within-person improvements in physical, cognitive, and emotional functioning reduced CRF more than vice versa, whereas the effect of CRF was stronger for social functioning. Role functioning had a balanced relation with CRF. CONCLUSIONS: This analysis reveals a complex reciprocal relation between CRF and FH with distinct between- and within-person effects. The results contribute to a better understanding of CRF in survivors of Hodgkin lymphoma and could inform the development of much-needed targeted interventions. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Health-Related Quality of Life in Patients With Hodgkin Lymphoma: A Longitudinal Analysis of the German Hodgkin Study Group.

PURPOSE: Many important details of health-related quality of life (HRQoL) after diagnosis and treatment of Hodgkin lymphoma (HL) are still unknown because large longitudinal studies of HRQoL are rare. Therefore, we analyzed a systematically assessed, comprehensive range of HRQoL domains in patients with HL of all stages from diagnosis up to 5 years of survivorship. PATIENTS AND METHODS: We included patients with HL age 18-60 years at diagnosis from the German Hodgkin Study Group trials HD13, HD14, and HD15. We analyzed HRQoL using all functional and symptom scales of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 including deviations from reference values. We estimated the effect of different disease, patient, and treatment characteristics using multiple regression and repeated measures analysis and computed correlations of HRQoL scores. RESULTS: We analyzed 4,215 patients with any HRQoL assessment within 5 years after treatment. Higher tumor burden at diagnosis was associated with impaired baseline scores in many HRQoL domains. During survivorship, cognitive, emotional, role, and social functioning and fatigue, dyspnea, sleep, and financial problems were severely and persistently affected. From year 2 on, mean deviations from reference values ranged between 12 and 29 points, with 10 points being a commonly used margin of clinical relevance. In all 3 trials, HRQoL domains 2 and 5 years after therapy were significantly influenced by baseline scores and age but not by randomized treatments. Fatigue was most closely correlated with other symptoms and scales. CONCLUSION: Our results show a high and persistent amount of different HRQoL deficits in survivors of HL that are largely independent of the applied chemotherapies. Our analysis underscores the high, unmet medical need of these rather young survivors of HL regarding the psychosocial adverse effects of the cancer experience.

Pretreatment Vitamin D Deficiency Is Associated With Impaired Progression-Free and Overall Survival in Hodgkin Lymphoma.

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

Survivors' perspectives on risks and benefits of Hodgkin lymphoma treatment: results of a survey by the German Hodgkin Study Group.

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

Intensive treatment strategies in advanced-stage Hodgkin's lymphoma (HD9 and HD12): analysis of long-term survival in two randomised trials.

BACKGROUND: Although intensified chemotherapy regimens have improved tumour control and survival in advanced-stage Hodgkin's lymphoma, data on the long-term sequelae are scarce. We did preplanned follow-up analyses of the German Hodgkin Study Group (GHSG) trials HD9 and HD12 to assess whether the primary results of these trials-which had shown that intensive initial therapy in advanced-stage Hodgkin's lymphoma has a beneficial effect on treatment outcomes-would continue with longer follow-up. METHODS: In HD9 (Feb 1, 1993, to March 10, 1998), 1282 patients with newly diagnosed, histology-proven, advanced-stage Hodgkin's lymphoma received eight alternating cycles of COPP and ABVD (COPP/ABVD), eight cycles of bBEACOPP, or eight cycles of eBEACOPP. In HD12 (Jan 4, 1999, to Jan 13, 2003; registered with ClinicalTrials.gov [NCT00265031]), 1670 patients with newly diagnosed, histology-proven, advanced-stage Hodgkin's lymphoma received eight cycles of eBEACOPP or four cycles of eBEACOPP plus four cycles of bBEACOPP (4 + 4), plus consolidation radiotherapy to initial bulk and residual disease or no radiotherapy, to analyse two non-inferiority objectives. In both trials, randomisation was done centrally in the GHSG trial coordination centre using the minimisation method including a random component, stratified according to centre, age, stage, international prognostic score, the presence or absence of a large mediastinal mass, and bulky disease. Patients and investigators were not masked to treatment allocation. All analyses were done on the intention-to-treat principle. The primary endpoint of this follow-up analysis was progression-free survival (time from first diagnosis to progressive disease, relapse, or death from any cause or censoring at the date of last information on disease status). To assess whether long-term outcome might be impaired by long-term sequelae, we analysed overall survival and second primary malignant neoplasm incidence as key secondary endpoints. FINDINGS: Median observation time was 141 months (IQR 101-204) in HD9 and 97 months (69-143) in HD12. For HD9 trial patients, 15-year progression-free survival was 57·0% (95% CI 50·0-64·0) for COPP/ABVD, 66·8% (61·9-71·8) for bBEACOPP, and 74·0% (69·0-79·0) for eBEACOPP, 15-year overall survival was 72·3% (95% CI 66·5-78·1), 74·5% (70·1-78·9), and 80·9% (76·7-85·0), respectively. Progression-free survival and overall survival in the eBEACOPP group remained significantly better than in the COPP/ABVD group (hazard ratio [HR] 0·53, 95% CI 0·41-0·69, p<0·0001, and 0·68, 0·50-0·93, p=0·015, respectively). The 15-year cumulative incidence of second primary malignant neoplasms was 7·2% (95% CI 3·7-10·7) after COPP/ABVD, 13·0% (9·1-16·9) after bBEACOPP, and 11·4% (7·6-15·1) after eBEACOPP. For HD12 trial patients, non-inferiority of 4 + 4 was shown, with 10-year progression-free survival of 82·6% (95% CI 79·6-85·6) for eBEACOPP and 80·6% (77·4-83·7) for 4 + 4 (HR 1·13 [0·89-1·43], within non-inferiority margin of 1·50), and 10-year overall survival of 87·3% (95% CI 84·7-89·9) and 86·8% (84·2-89·4), respectively (HR 1·02 [95% CI 0·77-1·36]). Among 555 (37%) patients with residual disease after chemotherapy, omission of radiotherapy was associated with significantly worse 10-year progression-free survival (89·7% [95% CI 85·8-93·6] radiotherapy vs 83·4% [78·2-88·5] for no radiotherapy; p=0·027) and 10-year overall survival (94·4% [91·4-97·3] vs 88·4% [83·8-93·0]; p=0·025). 10-year cumulative second primary malignant neoplasms incidence was 6·4% (95% CI 3·3-9·5) for 4 + 4 and 8·8% (5·2-12·4) for eBEACOPP. INTERPRETATION: Long-term follow-up of HD9 and HD12 shows an ongoing benefit of intensive first-line treatment and consolidation radiotherapy to residual disease in terms of progression-free survival and overall survival. Our results support the use of eBEACOPP in advanced-stage Hodgkin's lymphoma. However, because late toxicities such as second primary malignant neoplasms contribute to mortality, less toxic but equally effective treatments need to be developed to further improve overall survival. FUNDING: Deutsche Krebshilfe e.V.

Incorporation of brentuximab vedotin into first-line treatment of advanced classical Hodgkin's lymphoma: final analysis of a phase 2 randomised trial by the German Hodgkin Study Group.

BACKGROUND: A high proportion of patients with relapsed classical Hodgkin's lymphoma achieve a response with the antibody-drug conjugate brentuximab vedotin, and the drug is well tolerated. We modified the escalated BEACOPP regimen (eBEACOPP; bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) and implemented brentuximab vedotin with the aim to reduce toxic effects while maintaining the protocol's efficacy. METHODS: We did an open-label, multicentre, randomised phase 2 study at 20 study sites in Germany. Adult patients (aged 18-60 years) with newly diagnosed, advanced, classical Hodgkin's lymphoma were randomly assigned (1:1) to treatment with six cycles of either BrECAPP (brentuximab vedotin 1·8 mg/kg on day 1, etoposide 200 mg/m2 on days 2-4, doxorubicin 35 mg/m2 on day 2, cyclophosphamide 1250 mg/m2 on day 2, procarbazine 100 mg/m2 on days 2-8, and prednisone 40 mg/m2 on days 2-15) or BrECADD (brentuximab vedotin 1·8 mg/kg on day 1, etoposide 150 mg/m2 on days 2-4, doxorubicin 40 mg/m2 on day 2, cyclophosphamide 1250 mg/m2 on day 2, dacarbazine 250 mg/m2 on days 3-4, and dexamethasone 40 mg on days 2-5). Randomisation was done centrally by stratified minimisation, with study site and sex as stratification factors. The co-primary endpoints were complete response to chemotherapy and complete remission at the end of treatment, which were assessed by intention to treat. Patients who were found not to meet inclusion criteria after randomisation or without restaging data after two cycles of study treatment were excluded from the primary endpoint analysis. All patients who started study treatment were assessable for safety. This report presents the final analysis at a median follow-up of 17 months (IQR 13·2-21·5). The preplanned 2-year follow-up analysis is yet to be reported. This trial is registered with ClinicalTrials.gov, number NCT01569204. FINDINGS: Between Oct 26, 2012, and May 15, 2014, 104 patients were enrolled to the study (52 were assigned to each study arm). Two patients dropped out before the start of study treatment because of acute infection (n=1) and withdrawal of consent (n=1) and one patient was excluded because of intermediate-stage disease (all were assigned BrECAPP). 42 (86%, 95% CI 73-94) of 49 patients assigned BrECAPP achieved a complete response after chemotherapy and 46 (94%, 95% CI 83-99) had complete remission as their final treatment outcome. In the BrECADD group, 46 (88%, 95% CI 77-96) of 52 patients achieved both a complete response after chemotherapy and complete remission as their final treatment outcome. 58 serious adverse events were reported, 32 events in 21 of 50 patients who received BrECAPP and 26 events in 18 of 52 patients who received BrECADD. The most common grade 3-4 toxic effects were haematological adverse events (91 [89%] of 102 patients). Grade 3-4 organ toxic effects were reported in seven (17%) of 42 patients assigned BrECAPP and two (4%) of 46 allocated BrECADD. 16 (32%) of 50 patients assigned BrECAPP and 18 (35%) of 52 allocated BrECADD had grade 1-2 peripheral neuropathy, and one (2%) patient assigned BrECAPP developed grade 3 peripheral neuropathy; all but one case (allocated BrECAPP) resolved. No deaths were reported during the follow-up period. INTERPRETATION: Both eBEACOPP variants met the co-primary efficacy endpoints. Particularly, the BrECADD regimen was associated with a more favourable toxicity profile and was, therefore, selected to challenge standard eBEACOPP for the treatment of advanced classical Hodgkin's lymphoma in the phase 3 HD21 study by the German Hodgkin Study Group (NCT02661503), which aims to further reduce treatment-related morbidity. FUNDING: Takeda Pharmaceuticals.

Long-Term Follow-Up of Contemporary Treatment in Early-Stage Hodgkin Lymphoma: Updated Analyses of the German Hodgkin Study Group HD7, HD8, HD10, and HD11 Trials.

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