German Hodgkin Study Group Trials Research Articles

Circulating Tumor DNA Sequencing for Biologic Classification and Individualized Risk Stratification in Patients With Hodgkin Lymphoma.

Current clinical challenges in Hodgkin lymphoma (HL) include difficult-to-treat relapsed/refractory disease and considerable long-term toxicities of treatment. Since clinical risk factors lack discriminatory power, intensity of therapy is mainly based on tumor burden. Exploring HL genetics and tumor microenvironment (TME) might provide valuable insights for improved risk stratification. In this study, we applied circulating tumor DNA sequencing to 243 patients obtained from pivotal German Hodgkin Study Group trials to identify subtypes of HL. Independent validation of the subtypes was performed in 96 patients treated in the EuroNet-PHL-C2 study. Outcome differences of subtypes were assessed in an event-enriched clinical validation cohort comprising 72 patients from the HD21 trial, using a refined, validated, and clinically feasible assay. We propose a biologic classification of HL consisting of three distinct subtypes: inflammatory immune escape HL is characterized by frequent copy-number variations including immune escape variants such as high-level amplifications of the PD-L1 locus and an inflammatory TME. Virally-driven HL is associated with Epstein-Barr virus and/or human herpesvirus 6 and an inflammatory TME with neutrophils and macrophages, while the tumor mutational burden (TMB) is low. Oncogene-driven HL is defined by a high TMB, recurrent mutations in oncogenic drivers such as TNFAIP3, ITPKB, and SOCS1, and a cold TME. A refined and validated assay version aiming at clinically feasible risk stratification showed significant progression-free survival differences between subtypes. In addition, assessment of minimal residual disease (MRD) allowed for the detection of patients at very high risk of relapse within the subtypes. We propose a clinically feasible, noninvasive method for individualized risk stratification and MRD monitoring in patients with HL on the basis of circulating tumor DNA sequencing.

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

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. 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. 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. 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.

Long-Term Follow-Up of Patients With Nodular Lymphocyte-Predominant Hodgkin Lymphoma Treated in the HD7 to HD15 Trials: A Report From the German Hodgkin Study Group.

The optimal treatment of newly diagnosed nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is ill defined. We therefore conducted a retrospective analysis using the database of the German Hodgkin Study Group (GHSG). The long-term course of 471 patients with NLPHL (early stages, n = 251; intermediate stages, n = 76; advanced stages, n = 144) who had received stage-adapted first-line treatment in the randomized GHSG HD7 to HD15 studies was investigated. Treatment consisted of radiotherapy alone, chemotherapy alone, or combined-modality approaches. The median age at NLPHL diagnosis was 39 years (range, 16 to 75 years). Patients were mostly male (75.8%). The median observation time was 9.2 years. At 10 years, progression-free survival and overall survival estimates were 75.5% and 92.1% (early stages, 79.7% and 93.3%; intermediate stages, 72.1% and 96.2%; advanced stages, 69.8% and 87.4%), respectively. A total of 48 patients (10.2%) developed a second malignancy during follow-up (non-Hodgkin lymphoma, n = 13; leukemia, n = 6; solid tumor, n = 25; unspecified malignancy, n = 4). Death occurred in 43 patients (9.1%). However, only a minority of deaths were NLPHL related (n = 10), whereas second malignancies (n = 20) and nonmalignant conditions possibly associated with radiotherapy or chemotherapy (n = 13) caused the death in the majority of patients. The overall outcome of patients with NLPHL who had received Hodgkin lymphoma-directed first-line treatment in randomized GHSG trial protocols was good. Nonetheless, treatment optimization is still necessary to reduce toxicity in standard-risk patients and to improve the prognosis in high-risk patients.

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

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. 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. 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. 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. Deutsche Krebshilfe e.V.

Value of bone marrow biopsy in Hodgkin lymphoma patients staged by FDG PET: results from the German Hodgkin Study Group trials HD16, HD17, and HD18

BackgroundBone 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 methodsOur 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. ResultsTaking 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. ConclusionsWhen 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 trialsThe trials included in this analysis were registered at ClinicalTrials.gov: HD16—NCT00736320, HD17—NCT01356680, and HD18—NCT00515554.

Symptomatic osteonecrosis as a treatment complication in Hodgkin lymphoma: an analysis of the German Hodgkin Study Group (GHSG).

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

Outcome of Patients With Early-Stage Infradiaphragmatic Hodgkin Lymphoma: A Comprehensive Analysis From the German Hodgkin Study Group.

Purpose The prognostic effect of isolated infradiaphragmatic involvement in Hodgkin lymphoma (HL) is controversial, and there are little data about patients treated with current therapies. Therefore, we performed a risk factor analysis to focus on isolated nodal infradiaphragmatic disease in patients treated within the German Hodgkin Study Group trials HD13 (clinical trial information: ISRCTN63474366) and HD14 (clinical trial information: ISRCTN04761296) for early-stage HL. Patients and Methods Characteristics and outcomes of patients who had infradiaphragmatic HL were compared with patients who had supradiaphragmatic disease. Progression-free survival (PFS) and overall survival (OS) were estimated according to Kaplan-Meier methods and were compared between groups using the log-rank test and Cox proportional hazards regression, which was also applied for multivariable analyses that adjusted for relevant baseline characteristics. Results Of 2,903 qualified patients, 223 (7.7%) were diagnosed with isolated nodal infradiaphragmatic disease. In general, these patients were older, had a poorer performance status, were more often male, and had the nodular sclerosis subtype less often than those with supradiaphragmatic disease. After a median follow-up time of 51 months, PFS and OS were significantly worse in patients with infradiaphragmatic disease (5-year PFS and OS, 80.1% and 91.5% v 91.2% and 97.6% in patients with supradiaphragmatic disease; each P < .001). In multivariable analyses, infradiaphragmatic HL remained a significant risk factor in terms of PFS (hazard ratio [HR], 1.5; 95% CI, 1.04 to 2.2; P = .03) and OS (HR, 2.0; 95% CI, 1.2 to 3.5; P = .01). However, inferior PFS and OS could not be observed among those patients treated with the more intensive chemotherapy (two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine [ABVD] in HD13, and two cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone [BEACOPPescalated] plus two cycles of ABVD in HD14; all patients received 30 Gy of involved-field radiotherapy). Conclusion Early-stage HL that presents with infradiaphragmatic disease only represents a distinct patient group with an inferior outcome. However, this adverse outcome can be outweighed by appropriate combined modality treatment.

Metabolic Tumour Volume for Response Prediction in Advanced-Stage Hodgkin Lymphoma.

Rationale: (18F)fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) for staging Hodgkin lymphoma may allow for accurate and reliable assessment of the metabolic tumour volume (MTV) as baseline risk factor. Our aim was to analyse the prognostic impact of MTV measurements, obtained by different means in advanced-stage Hodgkin lymphoma patients treated within the German Hodgkin Study Group HD18 trial. Methods: Within the German Hodgkin Study Group trial HD18, 310 patients underwent 18F-FDG PET/CT scanning for staging which was available to the central review panel for quantitative analysis. We calculated the MTV by four different thresholding methods and performed receiver operating characteristic (ROC) analysis to evaluate the potential for prediction of early response determined by PET after two cycles (PET-2) dose-escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP). Logistic regression was used to evaluate its prognostic value concerning progression-free survival (PFS) and overall survival (OS). Results: All different MTV calculations used predicted PET-2 response to a moderate and comparable degree (area under the curve = 0.62-0.63, P = 0.01-0.06). With none of the measuring methods did the ROC curves point to any unique cut-off values, but indicated a wide range of possible cut-offs. However, none of the MTV measurements was prognostic for PFS (Hazard ratio 1.2-1.5, P = 0.15-0.52) or OS (Hazard ratio 1.0-1.5, P = 0.95 - 0.27). Conclusion: Baseline MTV as determined by different means, is a predictive factor for early response to eBEACOPP after two cycles. However, value as a prognostic factor after highly effective PET-2 adapted treatment strategy could not be observed.

Reduced-Intensity Chemotherapy in Patients With Advanced-Stage Hodgkin Lymphoma: Updated Results of the Open-Label, International, Randomised Phase 3 HD15 Trial by the German Hodgkin Study Group.

The international, randomized phase 3 HD15 trial established 6xeBEACOPP as standard therapy for patients with newly diagnosed advanced-stage Hodgkin lymphoma (HL) within the German Hodgkin Study Group (GHSG). We performed a follow-up analysis to assess long-term efficacy and safety of this approach. Between 2003 and 2008, 2182 patients aged 18 to 60 years were recruited and randomized in a 1:1:1 ratio between 8 or 6 cycles of eBEACOPP or 8 cycles of the dose-dense BEACOPP-14 regimen, each followed by 30 Gy radiotherapy in case of positron emission tomography (PET)-positive residual lesions ≥2.5 cm. The study aimed at demonstrating non-inferiority regarding efficacy of the 2 experimental arms on a significance level of 2.5% each. The intention-to-treat analysis comprised 2126 patients with a median follow-up of 102 months. Ten-year progression-free survival was 81% (97.5% CI 77–85) with 8xeBEACOPP, 84% (80–87) with 6xeBEACOPP, and 84% (80–87) with 8xBEACOPP-14; the non-inferiority margin of 1.51 for the hazard ratio (HR) could be excluded for both comparisons (6xeBEACOPP, HR = 0.7, 97.5% CI 0.5–1.0; 8xBEACOPP-14, HR = 0.9, 97.5% CI 0.7–1.2). Overall survival at 10 years was 88% (85–91), 90% (88–93), and 92% (89–94), respectively. A total of 142 second malignancies corresponding to 10-year cumulative incidences of 10%, 7%, and 7% and standardized incidence ratios of 4.3, 2.5, and 2.8 were reported for 8xeBEACOPP, 6xeBEACOPP, and 8xBEACOPP-14, respectively. This updated analysis of the HD15 trial thus confirms the efficacy and reports on the long-term safety of a shortened first-line chemotherapy consisting of 6xeBEACOPP followed by PET-guided radiotherapy in advanced-stage HL.

Late Relapse of Classical Hodgkin Lymphoma: An Analysis of the German Hodgkin Study Group HD7 to HD12 Trials.

Purpose Clinical characteristics, therapeutic approaches, and prognosis of late relapse (LR) in patients with classic Hodgkin lymphoma (cHL) are poorly understood. We performed a comprehensive analysis of LR of Hodgkin lymphoma (LR-HL). Methods To estimate the incidence of LR-HL, we retrospectively analyzed 6,840 patients with cHL included in the German Hodgkin Study Group trials HD7 to HD12. Patients who experienced a relapse > 5 years into remission were compared with patients in continued remission for > 5 years and with those who experienced a relapse ≤ 5 years after first diagnosis. Results With a median observation time of 10.3 years, 141 incidences of LR-HL were observed. Cumulative incidences at 10, 15, and 20 years rose linearly and were 2.5%, 4.3%, and 6.9%, respectively. The standardized incidence ratio for HL with respect to age- and sex-matched German reference data was 84.5 (95% CI, 71.2 to 99.7). LR-HL was more frequently observed in patients with early-stage favorable than unfavorable or advanced stage at first diagnosis (15-year cumulative incidence, 5.3% v 3.9% and 3.9%, respectively; P = .01). Overall survival from first diagnosis was worse after LR compared with nonrelapse survivors (10-year estimate, 95.8% v 86.1%; hazard ratio, 2.5; 95% CI, 1.7 to 3.5; P < .001). In patients with LR-HL, survival was better compared with 466 patients with earlier relapse (hazard ratio, 0.6; 95% CI, 0.4 to 0.9, P = .01). Forty-four percent and 49% of patients with LR-HL and earlier relapse, respectively, received stem cell transplantations. Conclusion Apart from treatment-associated adverse effects, survivors after initially successful therapy for cHL are at an 85-fold risk for recurrence of disease compared with the general German population. After risk-adapted treatment strategies, especially in early-stage favorable HL, regular clinical follow-up is recommended for timely detection of LR-HL. With adequate treatment, prognosis of LR-HL is better compared with early relapses.

Impact of centralized diagnostic review on quality of initial staging in Hodgkin lymphoma: experience of the German Hodgkin Study Group.

Accurate clinical staging is crucial for adequate risk-adapted treatment in Hodgkin lymphoma (HL) to prevent patients from under- or over-treatment. Within the latest German Hodgkin Study Group trial generation, diagnostic findings such as histopathology, computerized tomography imaging and clinical risk factors were re-evaluated by expert panels. Here, we retrospectively analysed 5965 patients and identified 399 in who major discordant findings changed their first-line treatment allocation. Histopathology review did not confirm the initial diagnosis of HL in 87 patients. Treatment allocation was revised in 312 of the remaining 5878 patients: 176 were assigned to a higher and 128 to a lower risk group, respectively; the correct treatment group remained unclear in 8 patients. Cases of revised treatment allocation accounted for 9·8%, 6·0%, 0·8%, and 14·8% of patients initially assigned to the HD13, HD14, HD15 trials and stage IA lymphocyte-predominant HL project, respectively. Most revisions were due to wrong application of clinical stage (20·5% of 312 patients with revised treatment group), histological subtype (9·0%) or the risk factors ≥3 involved areas (46·8%) or large mediastinal mass (9·3%). In conclusion, centralized review by experienced experts changed risk-adapted first-line treatment in a relevant proportion of HL patients. Quality control measures clearly improve the accuracy of treatment and should be implemented in clinical practice.

Impact Of Dose Reduction Of Bleomycin and Vincristine In Patients With Advanced Hodgkin Lymphoma Treated With Beacopp: A Comprehensive Analysis Of The German Hodgkin Study Group (GHSG) HD12 and HD15 Trials

▪ IntroductionBEACOPPescalated is the standard treatment for advanced Hodgkin Lymphoma (HL) within the German Hodgkin Study Group (GHSG) and other cooperative groups. Bleomycin and vincristine cause significant acute and long-term toxicity and are frequently discontinued during the course of therapy. However, the impact of dose reduction of these drugs on outcome and tolerability of BEACOPP has not been systematically assessed. Thus, we performed a retrospective analysis of patients treated within the GHSG trials HD12 (8xBEACOPPescalated versus 4xBEACOPPescalated plus 4xBEACOPPbaseline) and HD15 (8xBEACOPPescalated versus 6xBEACOPPescalated versus 8xBEACOPP14) trials for advanced stages. MethodsBased on the intention-to-treat analysis, characteristics and outcome of patients receiving the full number of cycles of HD12 and HD15 were analyzed with respect to bleomycin and/or vincristine discontinuation. Progression-free survival (PFS) and overall survival (OS) were estimated from end of chemotherapy according to the Kaplan-Meier method and compared between groups using the log-rank test. To compare differences in patient characteristics, Fisher's exact test was used for rates and Wilcoxon's rank-sum test was used for continuous parameters. Receiver operating characteristic (ROC) analyses were performed in patients who had an event or were followed for at least 2 years after therapy. Results3309 (89.4%) of patients received the full number of planned cycles and had complete chemotherapy documentation available. Bleomycin was discontinued in 10.5% and vincristine in 21.7% of cases. All other drugs had discontinuation rates less than 1.5%. 157 (4.7%) of patients received ≤4 cycles of bleomycin and 218 (6.6%) of patients received ≤3 cycles of vincristine; these were compared to patients with >4 cycles of bleomycin (3152 patients [95.3%]) and >3 cycles of vincristine (3091 patients [93.4%]). Discontinuation of bleomycin or vincristine was more frequent in patients aged 50 or older (4.4% and 7.4% with ≤4 cycles of bleomycin in patients <50 and ≥ 50 years, respectively, p=0.001; 6.2% and 9.5% with ≤3 cycles of vincristine in patients <50 and ≥ 50 years, respectively, p=0.015). More female patients had vincristine discontinued (8.4% and 5.5% female and male patients, respectively, with ≤3 cycles, p=0.001) whereas there was no significant difference between female and male patients regarding bleomycin discontinuation (p=0.6). After a median follow-up of 59 and 67 months for PFS and OS, respectively, there was no significant PFS or OS difference in patients with ≤4 or >4 cycles of bleomycin (6-year PFS-difference 0.3% [95%CI -5.7 to 6.2%]; 6-year OS-difference 0.4% [95%CI -3.7 to 4.5%]; Figure 1A). Similarly, there was no significant PFS or OS difference in patients with ≤3 or >3 cycles of vincristine (6-year PFS-difference -1.6% [95%CI -6.4 to 3.2%]; 6-year OS-difference 1.9% [95%CI -2.5% to 6.3%]; Figure 1B). To assess if the number of bleomycin and vincristine cycles received had an impact on 2-year PFS and OS, ROC analyses were performed. However, failure could not be predicted irrespective of the number of cycles chosen as cutpoint. Detailed analyses and comparisons of patient characteristics, dose delivery of chemotherapy and toxicity will be presented. [Display omitted] ConclusionBleomycin and vincristine discontinuation due to drug-specific side effects seemed to be safe in this setting. Given the limitations of this retrospective analysis, our data suggest that bleomycin and vincristine may have a limited role in the BEACOPP regimen. Disclosures:von Tresckow:Novartis: honoraria for acting as a consultant: Consultancy; Takeda Pharma GmbH: reimbursement of congress, travel, and accommodation costs and honoraria for preparation of scientific educational events: Honoraria. Böll:Celgene: Travel Grant Other. Borchmann:Millenium The Takeda Oncology Company: Research Funding; Takeda Pharma GmbH: Travel Grants, Travel Grants Other. Engert:Seattle Genetics, Inc.: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Takeda: Honoraria.

Treatment-Related Mortality in Patients With Advanced-Stage Hodgkin Lymphoma: An Analysis of the German Hodgkin Study Group

The introduction of BEACOPP(escalated) (escalated-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) has significantly improved tumor control and overall survival in patients with advanced-stage Hodgkin lymphoma. However, this regimen has also been associated with higher treatment-related mortality (TRM). Thus, we analyzed clinical course and risk factors associated with TRM during treatment with BEACOPP(escalated). In this retrospective analysis, we investigated incidence, clinical features, and risk factors for BEACOPP(escalated)-associated TRM in the German Hodgkin Study Group trials HD9, HD12, and HD15. Among a total of 3,402 patients, TRM of 1.9% (64 of 3,402) was mainly related to neutropenic infections (n = 56; 87.5%). Twenty of 64 events occurred during the first course of BEACOPP(escalated) (31.3%). Higher risk of TRM was seen in patients age ≥ 40 years with poor performance status (PS) and in patients age ≥ 50 years. PS and age were then used to construct a new risk score; those with a score ≥ 2 had TRM of 7.1%, whereas patients who scored 0 or 1 had TRM of 0.9%. The individual risk of TRM associated with BEACOPP(escalated) can be predicted by a simple algorithm based on age and PS. High-risk patients should receive special clinical attention.

Lymphocyte-Depleted Classical Hodgkin's Lymphoma: A Comprehensive Analysis From the German Hodgkin Study Group

To investigate the clinical characteristics and treatment outcome of patients with lymphocyte-depleted classical Hodgkin's lymphoma (LDCHL) compared with other histologic subtypes of Hodgkin's lymphoma (HL). From a total of 12,155 evaluable patients with biopsy-proven HL treated within the German Hodgkin Study Group trials HD4 to HD15, 10,019 patients underwent central expert pathology review. Eighty-four patients with LDCHL (< 1%) were identified and confirmed. The median follow-up time was 67 months. Patients with LDCHL, compared with patients with other histologic subtypes, presented more often with advanced disease (74% v 42%, respectively; P < .001) and "B" symptoms (76% v 41%, respectively; P < .001). Other risk factors were also more frequent in patients with LDCHL. Complete remission or unconfirmed complete remission was achieved in 82% of patients with LDCHL compared with 93% of patients with other HL subtypes (P < .001), and more patients with LDCHL had progressive disease. At 5 years, progression-free survival (PFS) and overall survival (OS) were significantly lower in patients with LDCHL compared with patients with other HL subtypes (PFS, 71% v 85%, respectively; P < .001; OS, 83% v 92%, respectively; P = .0018). However, when analyzing the subgroup of patients who underwent treatment with intensified or dose-dense bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, patients with LDCHL (n = 39) had similar outcomes when compared with patients with other subtypes of HL (n = 3,564; P = .61). LDCHL has a different pattern from other HL subtypes with more clinical risk factors at initial diagnosis and significantly poorer prognosis. Patients with LDCHL should be treated with modern dose-intense treatment strategies.

Evolution of Radiation Therapy Within the German Hodgkin Study Group Trials

Since its beginning, more than 16,000 patients have been enrolled in the multicentric randomized trials of the German Hodgkin Study Group (GHSG) for adult patients. Within 6 study generations, the treatment of Hodgkin lymphoma has been developed stepwise by using the results of the completed protocols. Now the sixth generation is active. According to the role of radiotherapy, the study group successfully evaluated different dose-effect relationships and could also prove the efficacy of involved-field radiotherapy in early stages in combination with effective chemotherapy. Currently, a radiation dose of 20 Gy to the involved field after a mildly aggressive chemotherapy (2 cycles of adriamycin, bleomycin, vinblastine, and dacarbazine [ABVD]) should be the standard for early-favorable stages according to the GHSG classification. In early-unfavorable or intermediate-risk stages, involved-field radiation therapy with 30 Gy is sufficient; the optimal chemotherapy has to be fixed. For the advanced stages, the question of radiotherapy is still unclear. Preliminary results of the GHSG and others show that additive radiotherapy after intensive chemotherapy might be useful for elective subgroups of patients. The extensive radiotherapy quality assurance program, performed by the GHSG and its radiotherapy reference center, has proven to be successful and necessary to ensure that, with reduced radiation doses and reduced radiation volumes, precise radiotherapy, as defined by the protocol, will be performed by the participating radiotherapy departments.

Secondary MDS/AML In Hodgkin Lymphoma Patients Treated within German Hodgkin Study Group (GHSG) Clinical Trials After Introduction of the BEACOPP Protocol

AbstractAbstract 2682 Background:With modern multi-agent chemotherapy regimens optionally combined with radiotherapy, even patients with advanced Hodgkin lymphoma (HL) are cured in over 80% of cases. Since there is only little room for further therapeutic improvements, one major focus of current clinical research in HL consists in reducing treatment-related late effects such as secondary malignancies. Secondary MDS/AML represents a relevant problem since it was reported to be associated with a very poor prognosis. To shed some more light on incidence, course and outcome of patients with secondary MDS/AML after HL treatment, we performed an analysis addressing this issue. Patients treated within German Hodgkin Study Group (GHSG) clinical trials after introduction of the BEACOPP protocol were included. Methods and patients:11891 HL patients of all stages aged 16 to 75 and treated within the third (HD7-HD9, 1993–1998), fourth (HD10-HD12, 1998–2003) and fifth (HD13-HD15, 2003–2009) GHSG trial generation, the BEACOPP14 pilot study (1997-2000) and a phase II trial evaluating the role of GnRH analogues and oral contraceptives in female patients receiving BEACOPPescalated were retrospectively analyzed. Treatment consisted of radiotherapy alone, chemotherapy alone or combined-modality approaches. Results:With a median follow-up of 70 months, overall secondary MDS/AML rate was 0.8% (99 patients). However, 13 patients had a concurrent event (i.e. progress/relapse of HL or another secondary malignancy requiring salvage treatment) prior to MDS/AML diagnosis so that 86 patients were included in the present analyses. Median time from HL treatment to MDS/AML diagnosis was 28.3 months. The median age of patients developing secondary MDS/AML was significantly higher than the median age in the whole patient group (41 vs 34 years, p=.0002). To determine the impact of treatment intensity on the risk to develop secondary MDS/AML, patients were assigned into three groups. Groups consisted of patients who had received no BEACOPP-containing treatment, less than four cycles of BEACOPPescalated and four or more cycles of BEACOPPesclated, respectively. As a result, patients receiving four or more cycles of BEACOPPescalated had a significantly increased risk to develop secondary MDS/AML when compared to the other groups (5-year cumulative incidence 1.5% vs 0.5% and 0.3%, respectively, log-rank p<.0001). In 36 patients included in this analysis, allogeneic stem cell transplantation (aSCT) was applied to treat secondary MDS/AML. Patients who received aSCT had a significantly lower median age than those treated with conventional chemotherapy or supportive care only (35 vs 50 years, p=.0016) and showed an improved outcome. However, median overall survival (OS) after MDS/AML diagnosis was only 7.2 months. Conclusions:Secondary MDS/AML is a relevant problem after HL therapy particularly in patients diagnosed with advanced stages treated with intensive first-line protocols. However, the clinical benefit achieved by the use of these more intensive protocols clearly outweighs the risk of developing secondary MDS/AML. To reduce the risk of developing secondary MDS/AML, novel treatment strategies should include risk-adapted early treatment stratification based on modern tools such as positron emission tomography (PET) to prevent overtreatment whenever possible. Disclosures:No relevant conflicts of interest to declare.

Quality of Life in a 2-Year Follow-up: Signs of PNP Predicting Cognitive Functioning in Survivors Treated in the HD10–12 Trials of the German Hodgkin Study Group (GHSG).

Purpose: Hodgkin Lymphoma (HL) is one of the best curable cancers in adults. Thus, current research is focusing on the increasing proportion of HL survivors with respect to the long-term consequences of therapy. Especially health related quality of life (QoL) needs thorough investigation since this is relevant for HL patients, complex and so far there is limited knowledge. QoL incorporates different aspects such as general QoL, fatigue, emotional, physical, role, social, sexual and cognitive functions. This analysis is focusing on QoL in the HD10–12 trials of the GHSG with special emphasis on cognitive functions (CF) and possible predictors in a 2 year follow-up.Methods: Patients of the GHSG trials HD10–12 completed the QLQ-C30, the MFI20 and some additional items at the time of diagnosis, after chemotherapy, after radiotherapy and at follow-up examinations. We describe the courses of the QLQ-C30 scales with means and 95%-confidence intervals for each measurement point and in relation to the respective norm values. In accordance with well established criteria, we used a cut off point of 10 points below the expected value to define self reported cognitive deficits (CD). In multiple regressions we analysed the role of the following predictors for cognitive functions 2 years after treatment: age, sex, disease stage, treatment modality, baseline score of cognitive functioning and symptoms of peripheral neuropathy (PNP) before and after chemotherapy application.Results: In the sample of 3608 patients all scales showed abnormal values from the beginning, further deterioration to the end of chemotherapy and continuous recovery from the end of radiotherapy on. Most scales improved clearly beyond their pre-treatment values but only physical functioning finally approached normal values. The CF scale showed a remarkable flat long term course and, opposed to the other scales, reached no improvement beyond the pre-treatment level. In 1044 patients with baseline and 2 year results, 439 met the criteria of relevant CD at baseline. Of these, 60.4% still felt handicapped after 2 years and 39.6% were in the range of normal values. 605 patients reported no CD at baseline and 69.6 % of them remained unaffected after 2 years (30.4% had developed CD). After adjustment for age, sex, disease stage, treatment modality and CF baseline scores, the regression analyses showed significant impact of symptoms of PNP before (p<.001) and after (p=.002) chemotherapy on CF after 2 years.Conclusion: In this large prospective study most QoL domains are remarkably improved after recovery from HL. In contrast CD occur frequently and show virtually no improvement. Symptoms of PNP as well as baseline values of CF are specifically predictive of future cognitive complaints. Further studies are necessary to investigate whether these results could be used for treatment modification or the development of intervention strategies.

Lymphocyte-Predominant and Classical Hodgkin's Lymphoma: A Comprehensive Analysis From the German Hodgkin Study Group

Lymphocyte-predominant Hodgkin's lymphoma (LPHL) is rare and differs in histologic and clinical presentation from classical Hodgkin's lymphoma (cHL). To shed more light on the prognosis and outcome of LPHL, we reviewed all LPHL patients registered in the German Hodgkin Study Group (GHSG) database, comparing patient characteristics and treatment outcome with cHL patients. We analyzed retrospectively 8,298 HL patients treated within the GHSG trials HD4 to HD12, of whom 394 had LPHL and 7,904 had cHL. Complete remission and unconfirmed complete remission after first-line treatment was achieved in 91.6% v 85.9% of patients in early favorable stages, 85.7% v 83.3% of patients in early unfavorable stages, and 76.8% v 77.8% of patients in advanced stages of LPHL compared with cHL, respectively. Tumor control (freedom from treatment failure [FFTF]) for LPHL and cHL patients at a median observation of 50 months was 88% and 82% (P = .0093) and overall survival (OS) was 96% and 92%, respectively (P = .0166). In LPHL patients, negative prognostic factors were advanced stage (P = .0092), Hb less than 10.5 g/dL (P = .0171), and lymphopenia (P = .010) for FFTF. Age >or= 45 years (P = .0125), advanced stage (P = .0153), and Hb less than 10.5 g/dL (P = .0014) were negative prognostic factors for OS. The better prognosis of LPHL as compared with cHL might allow different treatment strategies, particularly for early-stage LPHL patients.

Differences in Survival Rates for Patients with Hodgkin Lymphoma, Who Were Treated Inside vs. Outside Therapy Optimisation Protocols in Germany.

Introduction: Despite the improvements and knowledge brought by clinical trials to cancer treatment, it remained unclear how beneficial participation in a clinical trial with Therapy Optimisation Protocol (TOP) is for patients (pts) with Hodgkin Lymphoma (HL) in relation to pts treated outside of trials. In the TOPiCS project, trial participants (TOP) were compared with non-trial pts (non-TOP).Methods: In the population-based survey NLL, which aimed to register all incident HL-cases 356 pts were recorded in six counties of northern Germany with a first diagnosis of HL in 1988–1998. Data on staging, therapy, adverse events and survival were collected. The dataset was additionally screened for patients fulfilling inclusion and exclusion criteria for clinical trials of the German Hodgkin Study Group (GHSG). A total of 328 pts were documented of whom 198 pts (60%) met the inclusion criteria of the GHSG. Of these, 125 pts (63%) have not been recruited into GHSG trials (non-TOP pts). They were compared retrospectively with 4963 TOP pts randomised nation-wide between 1988–1998 in the GHSG trials HD4-HD9. Endpoints were Overall Survival (OS) and Progression Free Survival (PFS) which considered progression, relapse and death of any cause as events. Survival analysis was performed using Kaplan-Meier method and log-rank tests. Cox regression analysis was used for multivariable modelling of risk of death or progression and included 118 non-TOP pts and 4958 TOP pts.Results: The demographic parameters were not well balanced between the two groups: TOP pts were younger, had more often advanced stage and diagnosis in the later study generation than the non-TOP pts. The median observation time for OS was 7 yrs for the TOP group and 10 yrs for the non-TOP group. The 5-yrs OS for TOP pts is 89% (95%–CI [88–90]) and for non-TOP 89% (95%-CI [82–94])(p=0.63). The 5-year PFS for TOP pts is 79% (95%–CI [78–80]) and for non-TOP pts 68% (95%–CI [59–76])(p<0.001). According to Cox-regression analysis, 5 parameters were significantly (p<0.01) associated with poor OS and PFS: male sex, older age, advanced stage (according to DHSG classification considering Ann Arbor stage, B-symptoms and risk factors) and earlier study generation. Participation in a TOP-trial did not contribute independently for OS (Hazard Ratio (HR)=1.12, 95%–CI [0.71–1.79]) but contributed independently and positively for PFS (HR=0.66, 95%–CI [0.49–0.89]). The difference is mainly due to a higher number of relapses.Conclusion: For German patients fulfilling inclusion and exclusion criteria for TOP, a participation in therapy optimisation protocols results in a higher PFS, allowing for the influence of other factors, than for patients who were treated outside of TOP-trials. However, no difference was observed in OS.

FDG-PET for Assessment of Residual Tissue after Completion of Chemotherapy in Hodgkin Lymphoma - Report on the 2nd Interim Analysis of the PET Investigation in the Trial HD15 of the GHSG.

Introduction The prospectively randomized HD15 multicenter trial of the German Hodgkin Study Group (GHSG) included advanced-stage Hodgkin lymphoma patients comparing 8 cycles of BEACOPPescalated with 6 cycles or 8 cycles time-condensed BEACOPPbaseline. One other main study endpoint was the prognostic value of 18F-fluorodesoxyglucose (FDG) positron emission tomography (PET) following chemotherapy. The aim was to specify the negative predictive value of PET (NPV) in patients with residual tumour mass after chemotherapy.Methods Entry criteria for the PET question were partial remission (PR) after the end of chemotherapy with at least one involved nodal site measuring more than 2.5 cm in diameter by computed tomography (CT). Exclusion criteria included diabetes, elevated blood sugar levels and skeletal involvement with risk of instability. Calculations were restricted to those cases with either progressive disease (PD) or relapse within 12 months after PET or at least 12 months of follow-up. A total of 275 patients were eligible for this analysis. The assessment was based on those patients confirmed by an expert panel as being PET-negative. CT verification was performed to identify false positive PET findings. The NPV was defined as the proportion of patients without progression or relapse within 12 months.Results 9/216 patients with PET-negative residues and 9/59 patients with PET-positive residues had PD or relapse within one year of follow-up. The NPV was 0.958% (95% CI 0.931 – 0.985%). In 244/245 cases with PET-negative residual masses, no irradiation was given. In the 62/66 cases with PET-positive residues, additional radiotherapy was performed. Progression/relapse rates were significantly different between those patients with residual mass being PET-negative or PET-positive (p=0.0053). PET-negative patients, who were assessed as partial response by CT, had a prognosis similar to those in complete remission. There was no significant difference in the progression free survival in this trial and the prior GHSG trials HD12 (arms pooled) and HD9 (arm C) for advanced-stage HL (p=0.266). Importantly, the proportion of patients receiving radiotherapy decreased from 70% (HD9-C) to 39% (HD12) and 12% (HD15).Discussion The high NPV of PET suggests that radiotherapy following 6 or 8 cycles of BEACOPP might be restricted to those patients who are PET-positive after chemotherapy.