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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.

Zusammenfassung Hintergrund Zu den zahlreichen Therapiemöglichkeiten in der Behandlung des Glaukoms gehören seit mehreren Jahren auch die Glaukomdrainageimplantate (GDI). Ziel dieser Studie ist der Vergleich verschiedener Operationstechniken bez. des früh postoperativen Outcomes. Material und Methoden 269 Augen von 250 Patienten, die zwischen Februar 2010 und September 2016 im Zentrum für Augenheilkunde der Uniklinik Köln ein GDI erhalten hatten, wurden in die Studie eingeschlossen. Folgende Parameter wurden erfasst: Basisdaten der Patienten (Alter, Geschlecht, Augeninnendruck, Visus, augendrucksenkende Medikation, Diagnose, operiertes Auge (rechts oder links), Anzahl der Voroperationen (inkl. Lasereingriffe), Dauer des stationären Aufenthaltes sowie alle Komplikationen und glaukom- bzw. komplikationsbezogenen Folgeoperationen. Ergebnisse Die mittlere individuelle Drucksenkung betrug 39, 42 bzw. 46% nach jeweils 6, 12 bzw. 24 Monaten bei einer gleichzeitigen Verringerung des Medikationsscores um 38, 42 bzw. 50%. Die Erfolgsraten nach 1 bis 5 Jahren lagen bei 75, 60, 57, 50 bzw. 37%, wobei das mediane Implantatüberleben 48 Monate betrug. Frühkomplikationen traten bei 86 (32%), Spätkomplikationen bei 156 Augen (56%) auf. 52% der Augen (n = 139) mussten reoperiert werden. Die Technik der Tunnelpräparation hatte statistisch signifikanten Einfluss auf die früh postoperative Hypotonie (p Schlussfolgerung Die Verwendung einer 22-G-Kanüle zur Tunnelpräparation reduziert im Gegensatz zum Fibrinkleber das Hypotonierisiko. Dieses wird durch Venting Slits nicht erhöht. Bei Einsatz eines Zweitimplantats sollte an das erhöhte Risiko für Bindehautarrosionen gedacht werden.

Classical Hodgkin Lymphoma (cHL) is a B cell-derived lymphoid malignancy, affecting 2.5–3/100,000 people per year. To date, in patients diagnosed with advanced cHL no reliable tool is able to—a priori—distinguish the subset of patients at high risk for relapse or refractory disease. Clinical risk indices for cHL, such as the International Prognostic Score (IPS), have not been successfully applied as a treatment decision tool in advanced stage cHL [1]. In this study we show, that a previously published gene expression-based predictor in advanced stage cHL patients treated with ABVD [2] does not prove prognostic in 401 BEACOPP-treated advanced stage cHL patients. Using transcriptome profiling, we identified however that three individual genes, PDGFRA, TNFRSF8 (encoding CD30) and CCL17 (encoding TARC), were significantly associated with progression-free survival (PFS) after multiple test correction in the BEACOPP-treated cohort, highlighting the potential of a modified gene expression profiling approach for pre-treatment risk assessment., Letter

EClinicalMedicine 39, 101082 (2021). doi:10.1016/j.eclinm.2021.101082, Published by Elsevier, Amsterdam

Summary Background Advanced stage Hodgkin's lymphoma represents a heterogeneous group of patients with different risk profiles. Data suggests that interim PET assessment during chemotherapy is superior to baseline international prognostic scoring in terms of predicting long-term treatment outcome in patients with Hodgkin's lymphoma. We therefore hypothesised that early interim PET-imaging after two courses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) might be suitable for guiding treatment in patients with advanced stage Hodgkin's lymphoma. We aimed to assess whether intensifying standard chemotherapy (BEACOPP escalated ) by adding rituximab would improve progression-free survival in patients with positive PET after two courses of chemotherapy. Methods In this open-label, international, randomised, phase 3 study, we recruited patients aged 18–60 years with newly diagnosed, advanced stage Hodgkin's lymphoma from 160 hospitals and 77 private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. Interim PET-imaging was done after two cycles of BEACOPP escalated and centrally assessed by an expert panel. Patients with a positive PET after 2 cycles of BEACOPP escalated chemotherapy (PET-2) were randomly assigned (1:1) to receive six additional courses of either BEACOPP escalated (BEACOPP escalated group) or BEACOPP escalated plus rituximab (R-BEACOPP escalated group). PET-2 was assessed using a 5-point scale with 18 FDG uptake higher than the mediastinal blood pool (corresponding to Deauville scale 3) defined as positive. BEACOPP escalated was given as previously described; rituximab was given intravenously at a dose of 375 mg/m 2 (maximum total dose 700 mg), the first administration starting 24 h before starting the fourth cycle of BEACOPP escalated (day 0 and day 3 in cycle 4, day 1 in cycles 5–8). Randomisation was done centrally and used the minimisation method including a random component, stratified according to centre, age, stage, international prognostic score, and sex. The primary efficacy endpoint was 5 year progression-free survival, analysed in the intention-to-treat population. We are reporting this second planned interim analysis as the final report of the trial. The trial is registered with ClinicalTrials.gov, number NCT00515554. Findings Between May 14, 2008, and May 31, 2011, we enrolled 1100 patients. 440 patients had a positive PET-2 and were randomly assigned to either the BEACOPP escalated group (n=220) or the R-BEACOPP escalated group (n=220). With a median follow-up of 33 months (IQR 25–42) for progression-free survival, estimated 3 year progression-free survival was 91·4% (95% CI 87·0–95·7) for patients in the BEACOPP escalated group and 93·0% (89·4–96·6) for those in the R-BEACOPP escalated group (difference 1·6%, 95% CI −4·0 to 7·3; log rank p=0·99). Common grade 3–4 adverse events were leucopenia (207 [95%] of 218 patients in the BEACOPP escalated group vs 211 [96%] of 220 patients in the R-BEACOPP escalated group), and severe infections (51 [23%] vs 43 [20%] patients). Based on a futility analysis, the independent data monitoring committee recommended publication of this second planned interim analysis as the final result. Six (3%) of 219 patients in the BEACOPP escalated group and ten (5%) of 220 in the R-BEACOPP escalated group died; fatal treatment-related toxic effects occurred in one ( escalated group and three (1%) in the R-BEACOPP escalated group, all of them due to infection. Interpretation The addition of rituximab to BEACOPP escalated did not improve the progression-free survival of PET-2 positive patients with advanced stage Hodgkin's lymphoma. However, progression-free survival for PET-2 positive patients was much better than expected, exceeding even the outcome of PET-2-unselected patients in the previous HD15 trial. Thus, PET-2 cannot identify patients at high-risk for treatment failure in the context of the very effective German Hodgkin Study Group standard treatment for advanced stage Hodgkin's lymphoma. Funding Deutsche Krebshilfe; Swiss State Secretariat for Education, Research and Innovation (SERI); and Roche Pharma.

In glaucoma therapy, there are many treatment options, such as glaucoma drainage devices (GDI). The aim of this study is to compare postoperative outcomes after using different surgical techniques.269 eyes of 250 patients who received a GDI at the ophthalmological center at the university hospital in Cologne between February 2010 and September 2016 were included in this study. The patients' baseline parameters were collected: age, sex, intraocular pressure, visual acuity, glaucoma medication, diagnosis, operated eye (right or left), number of previous eye surgeries (including laser therapy), duration-of-stay at the hospital as well as all glaucoma complications and complication-related reoperations.The mean individual pressure reduction was 39, 42 and 46% after 6, 12 and 24 months respectively, while the use of medication was reduced by 38, 42 and 50%. The success rates after 1 to 5 years was 75, 60, 57, 50 and 37% with a median survival of 48 months. 86 eyes (32%) experienced early complications and 156 eyes (56%) experienced late complications. 52% of the eyes (n = 139) had to be re-operated. The technique of creating a track to enter the anterior chamber had statistically significant influence on the early postoperative hypotony (p 0,001). Fibrin glue had no influence on early hypotony. In the univariate analysis of early postoperative hypertension requiring paracentesis, the implant type (p = 0,009), tracking-technique with a paracentesis knife or a 22-gauge needle (p = 0,004), the occlusion method (p = 0,001) and the application of viscoelastics (p = 0,001) were statistically significant parameters. If GDI were implanted as a second implant, significantly more conjunctival erosion was recorded (p = 0.040).The use of a 22-gauge needle entering the anterior chamber reduces the hypotony risk when compared to fibrin glue. That risk is not increased by adding venting slits. When implanting GDI as a second implant, the higher risk of conjunctival erosion should be considered.Zu den zahlreichen Therapiemöglichkeiten in der Behandlung des Glaukoms gehören seit mehreren Jahren auch die Glaukomdrainageimplantate (GDI). Ziel dieser Studie ist der Vergleich verschiedener Operationstechniken bez. des früh postoperativen Outcomes.269 Augen von 250 Patienten, die zwischen Februar 2010 und September 2016 im Zentrum für Augenheilkunde der Uniklinik Köln ein GDI erhalten hatten, wurden in die Studie eingeschlossen. Folgende Parameter wurden erfasst: Basisdaten der Patienten (Alter, Geschlecht, Augeninnendruck, Visus, augendrucksenkende Medikation, Diagnose, operiertes Auge (rechts oder links), Anzahl der Voroperationen (inkl. Lasereingriffe), Dauer des stationären Aufenthaltes sowie alle Komplikationen und glaukom- bzw. komplikationsbezogenen Folgeoperationen.Die mittlere individuelle Drucksenkung betrug 39, 42 bzw. 46% nach jeweils 6, 12 bzw. 24 Monaten bei einer gleichzeitigen Verringerung des Medikationsscores um 38, 42 bzw. 50%. Die Erfolgsraten nach 1 bis 5 Jahren lagen bei 75, 60, 57, 50 bzw. 37%, wobei das mediane Implantatüberleben 48 Monate betrug. Frühkomplikationen traten bei 86 (32%), Spätkomplikationen bei 156 Augen (56%) auf. 52% der Augen (n = 139) mussten reoperiert werden. Die Technik der Tunnelpräparation hatte statistisch signifikanten Einfluss auf die früh postoperative Hypotonie (p 0,001). Fibrinkleber hatte keinen Einfluss auf Hypotonien. Bei der punktionspflichtigen früh postoperativen Hypertension waren in der univariaten Analyse der Implantattyp (p = 0,009), die Technik der Tunnelpräparation mit Lanze oder 22-G-Kanüle (p = 0,004), die Okklusionsmethode (p = 0,001) und die Verwendung von Viskoelastika (p = 0,001) statistisch signifikante Einflussfaktoren. Wurden GDI als Zweitimplantat eingesetzt, traten signifikant häufiger Bindehautarrosionen auf (p = 0,040).Die Verwendung einer 22-G-Kanüle zur Tunnelpräparation reduziert im Gegensatz zum Fibrinkleber das Hypotonierisiko. Dieses wird durch Venting Slits nicht erhöht. Bei Einsatz eines Zweitimplantats sollte an das erhöhte Risiko für Bindehautarrosionen gedacht werden.

579 Background: The phase II trial WSG-ADAPT TN randomized triple-negative breast cancer (TNBC) patients to receive 12 weeks of neoadjuvant nab-paclitaxel (nab-pac) combined with carboplatin (carbo) vs gemcitabine (gem) and showed a substantial improvement of pathological complete response (pCR: ypT0/is, ypN0) with carbo (45.9% vs 28.7%). pCR had a strong favorable impact on iDFS after 3-year follow-up. Distribution of tumor mutations in BC-associated genes and impact of BRCA mutation status on pCR and outcome are analyzed here. Methods: NGS-based mutational analysis of BRCA1/2 and 18 further (potentially) BC-associated genes was performed on DNA derived from pretreatment FFPE samples (gem: n = 158, carbo: n = 108) using a customized gene panel. Variants with a variant fraction of ≥5% were included and classified according to IARC and ENIGMA guidelines. Results: In 42 of the 266 analyzed samples, at least one deleterious BRCA1/2-variant was found (15.8%; BRCA1 n = 37, BRCA2 n = 3, BRCA1+ BRCA2 n = 2) one of which displayed an additional STK11-mutation. In the BRCA1/2-negative cohort, a mutation in one of 14 further analyzed (potential) BC-risk genes was found in 19 samples (7.1%; BARD1 n = 3, CHEK2 n = 2, CDH1 n = 2, FANCM n = 3, PALB2 n = 5, RAD50 n = 1, RAD51C n = 1, RAD51D n = 1, XRCC2 n = 1; no deleterious mutations were found in ATM, BRIP1, MRE11A, NBN). At least one deleterious variant in TP53, PIK3CA, PTEN or MAP3K1 was seen in 89.1% (n = 237; TP53 n = 233, PIK3CA n = 22 PTEN n = 15, MAP3K1 n = 1). In 22 samples (8.3%) no deleterious mutation was identified in the analyzed genes. Overall, patients with tumor BRCA mutation (carbo n = 14, gem n = 28) had 45.2% vs 34.4% pCR (OR = 1.58, 95%-CI: 0.81-3.07, p =.18) without a mutation. pCR in the small group with mutation receiving carbo (n = 14) was 64.3% vs. 34.5% in all others (OR = 3.41, 95%-CI: 1.11-10.50; p =.03); direct comparison to BRCA-positive patients receiving gem (n = 28, 35.7%, OR = 3.2, 95%-CI: 0.85-12.36, p = 0.079) did not reach statistical significance. The results suggest that the strong favorable impact of pCR on iDFS is preserved even among BRCA-positive patients (n = 42, p =.07), as well as in the BRCA-negative subgroup (p

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.

Purpose To determine, in the setting of advanced-stage of Hodgkin lymphoma (HL), whether relapses occur in the irradiated planning target volume and whether the definition of local radiation therapy (RT) used by the German Hodgkin Study Group (GHSG) is adequate, because there is no harmonization of field and volume definitions among the large cooperative groups in the treatment of advanced-stage HL. Methods and Materials All patients with residual disease of ≥2.5 cm after multiagent chemotherapy (CTX) were evaluated using additional positron emission tomography (PET), and those with a PET-positive result were irradiated with 30 Gy to the site of residual disease. We re-evaluated all sites of disease before and after CTX, as well as the PET-positive residual tumor that was treated in all relapsed patients. Documentation of radiation therapy (RT), treatment planning procedures, and portal images were carefully analyzed and compared with the centrally recommended RT prescription. The irradiated sites were compared with sites of relapse using follow-up computed tomography scans. Results A total of 2126 patients were enrolled, and 225 patients (11%) received RT. Radiation therapy documents of 152 irradiated patients (68%) were analyzed, with 28 irradiated patients (11%) relapsing subsequently. Eleven patients (39%) had an in-field relapse, 7 patients (25%) relapsed outside the irradiated volume, and an additional 10 patients (36%) showed mixed in- and out-field relapses. Of 123 patients, 20 (16%) with adequately performed RT relapsed, compared with 7 of 29 patients (24%) with inadequate RT. Conclusions The frequency and pattern of relapses suggest that local RT to PET-positive residual disease is sufficient for patients in advanced-stage HL. Insufficient safety margins of local RT may contribute to in-field relapses.

Aim Intraosseous (IO)-access plays an alternative route during resuscitation. Our study was performed to investigate the successful rate of IO-access in preterm and term stillborns using different devices and techniques. Methods The cadavers used were legal donations. 16 stillborns, median: 29.2 weeks (IQR 27.2–38.4) were investigated. Two different needles (a: Butterfly needle, 21G, Venofix® Fa.Braun; b: Arrow®EZ-IO®15G, Teleflex, Dublin, Ireland) were used. Needles were inserted i: manually, using a Butterfly needle; ii: manually, using EZ-IO® needle or iii: using a battery-powered semi-automatic drill (Arrow®EZ-IO®). Spectral-CT's were performed. The diameter of the corticalis was determined from the CT-images. Successful hit rates with 95% confidence intervals (CI) and odds ratios between the three methods were estimated using a generalised linear mixed model (GLMM). Results Estimated success rate was 61.1% (95%CI:39.7%–78.9%) for the Butterfly needle, 43.0% (95%CI:23.4%–65.0%) for hand-twisted EZ-IO® screwing and 39.7% (95%CI:24.1–57.7%) for the semi-automatic drill (Arrow®EZ-IO®), all referring to an average diameter of the corticalis of 1.2 mm. The odds of a correct position were 2.4 times higher (95%CI:0.8–7.6) when using the Butterfly needle than with the drill. In contrast, the odds of correct positioning when inserting the needle by hand were not significantly different from using the drill (odds ratio 1.1, 95%CI: 0.4–3.3). Neither of these effects nor the diameter of the corticalis with an odds ratio near one were significant in the model. Median diameter of the bone marrow cavity was 4.0 mm [IQR 3.3–4.7]. Conclusion Intraosseous access for premature and neonatal infants could be best achieved by using a manually twisted Butterfly needle.

Introduction: Induction chemotherapy followed by BEAM high dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplant (PBSC transplant) is standard of care for transplant-eligible patients with relapsed or refractory classical Hodgkin lymphoma (rrHL). However, approx. 50% of patients relapse and therefore, this strategy must be improved. As response to induction therapy is predictive of the outcome after HDCT, this trial aimed at improving the response to induction therapy by adding oral everolimus to time-intensified standard DHAP (Ever-DHAP). Methods: We included patients with histologically confirmed rrHL aged 18-60 years in this phase I/II trial. Dosage of everolimus was pre-determined in the phase I part with 10 mg/day given parallel to DHAP for 14 days within each of two cycles. The phase II part started as a randomized controlled trial comparing 50 patients in the everolimus group to 50 patients in a placebo group. The primary endpoint of the phase II part was the CT-based complete remission (CR-) rate after two cycles of Ever-DHAP. This CR-rate would be expected to be ≥ 40% if adding everolimus was effective. Secondary efficacy endpoints of the trial were PET-based CR-rate after two cycles of induction, progression-free and overall survival. Secondary feasibility endpoints were time to recovery, CTC-based adverse events, duration of induction therapy, discontinuation rates and the rates of successful PBSC collection. The trial was registered at ClinicalTrials.gov with ID NCT01453504. Results: From 7/2014 to 3/2018 we recruited a total of 59 patients in the phase II part. Because of poor recruitment the placebo group was closed in 9/2015 after 9 patients were randomized. These patients are analyzed in a descriptive way only. Of 50 patients in the everolimus group two were not evaluable because of retracting consent and not starting therapy; three additional patients discontinued Ever-DHAP because of toxicity. PBSC collection was successful in 37/39 documented patients receiving Ever-DHAP (95%). After two cycles of therapy we observed a CT-based CR in 12/45 patients of the everolimus group (27%) and in 2/9 patients of the placebo group (22%). A PET-based CR was achieved by 19/38 patients of the everolimus group (50%) and by 4/5 patients of the placebo group. In the everolimus group two patients had refractory disease (4%) and two died (4%), 3 and 4 months after starting but not related to Ever-DHAP. Final results and additional analyses will be presented. Conclusions: Adding everolimus to time-intensified DHAP is feasible, however, the Ever-DHAP regimen failed to show an improved efficacy. Disclosures von Tresckow: Novartis: Honoraria, Other: Travel support, Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding; MSD: Honoraria, Other: Travel support, Research Funding. Hüttmann:Celgene: Other: Travel expenses; Roche: Other: Travel expenses. Viardot:Amgen: Consultancy; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Gilead Kite: Consultancy, Honoraria. Topp:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Regeneron Pharmaceuticals, Inc.: Honoraria, Research Funding. Borchmann:Novartis: Consultancy, Honoraria.

SummaryThe aim was to analyze the degree of agreement between the central review panel and the local PET interpretation within the HD15 trial and its impact on subsequent treatment and progression free survival. Patients, methods: The analysis set consisted of 739 patients with residues ≥ 2.5 cm after 6 or 8 cycles of BEACOPPesc from the HD15 trial performed by the German Hodgkin Study Group. The recommendation for or against further radiotherapy was based on the central [18F]FDG-PET interpretation. Central PET interpretation was compared to the local PET interpretation and concordance was measured using Cohen's Kappa coefficient. Prognostic impact of the analysis of concordance between local and central PET interpretations was evaluated using progression free survival (PFS); groups were compared with the log rank test. Results: The central panel rated 548 of 739 patients (74%) as PET negative. Of these, 513 were also rated as PET negative in the local PET interpretation. PET positivity was seen by central reviewers in the remaining 191 patients (26%), in concordance with local reviewers in 155 cases. Even though substantial agreement was found (Cohen's Kappa 0.81), the interpretation of the central PET review panel led to a different therapeutic recommendation in 71/739 (10%) patients. PFS was equally high in groups in which the therapeutic regime had been changed on the basis of the central panel decision. Conclusion: High concordance is found between local and central reviewers with regard to PET interpretation in residual tissue after intense chemotherapy. The existence of the central PET review panel allows the identification of additional patients as PET negative so that radiotherapy can be safely omitted (35 of 548 patients = 4.7%).

Advanced stage Hodgkin's lymphoma represents a heterogeneous group of patients with different risk profiles. Data suggests that interim PET assessment during chemotherapy is superior to baseline international prognostic scoring in terms of predicting long-term treatment outcome in patients with Hodgkin's lymphoma. We therefore hypothesised that early interim PET-imaging after two courses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) might be suitable for guiding treatment in patients with advanced stage Hodgkin's lymphoma. We aimed to assess whether intensifying standard chemotherapy (BEACOPPIn this open-label, international, randomised, phase 3 study, we recruited patients aged 18-60 years with newly diagnosed, advanced stage Hodgkin's lymphoma from 160 hospitals and 77 private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. Interim PET-imaging was done after two cycles of BEACOPPBetween May 14, 2008, and May 31, 2011, we enrolled 1100 patients. 440 patients had a positive PET-2 and were randomly assigned to either the BEACOPPThe addition of rituximab to BEACOPPDeutsche Krebshilfe; Swiss State Secretariat for Education, Research and Innovation (SERI); and Roche Pharma.

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

Purpose Eight cycles of BEACOPPescalated (escalated dose of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) followed by radiotherapy (RT) to initial bulk or residual tumor mass is the German Hodgkin Study Group standard of care for advanced-stage Hodgkin's lymphoma (HL). However, treatment-related toxicity is a concern, and the role of RT in this setting is unclear. The HD12 study thus aimed to reduce toxicity while maintaining efficacy. Patients and Methods In this prospectively randomized multicenter trial, eight cycles of BEACOPPescalated was compared with four cycles of BEACOPPescalated followed by four cycles of the baseline dose of BEACOPP (BEACOPPbaseline; 4 + 4), and RT with no RT in the case of initial bulk or residual disease. The study was designed to exclude a difference in 5-year freedom from treatment failure (FFTF) rate of 6%. Results Between January 1999 and January 2003, 1,670 patients age 16 to 65 years were enrolled onto the HD12 study. At 5 years, FFTF was 86.4% in the BEACOPPescalated arm and 84.8% in the 4 + 4 arm (difference, −1.6%; 95% CI, −5.2% to 1.9%), and overall survival was 92% versus 90.3% (difference, −1.7%; 95% CI, −4.6% to 1.1%). Deaths related to acute toxicity of chemotherapy were observed in 2.9% of patients (BEACOPPescalated, n = 19; 4 + 4, n = 27). FFTF was inferior without RT (90.4% v 87%; difference, −3.4%; 95% CI, −6.6% to −0.1%), particularly in patients who had residual disease after chemotherapy (difference, −5.8%; 95% CI, −10.7% to −1.0%), but not in patients with bulk in complete response after chemotherapy (difference, −1.1%; 95% CI, −6.2% to 4%). Conclusion The reduction of BEACOPP to the 4 + 4 regimen did not substantially reduce severe toxicity but might decrease efficacy. Our results do not support the omission of consolidation RT for patients with residual disease. Alternative strategies for improving the risk-to-benefit ratio for patients with advanced HL are needed.

Purpose To determine whether epoetin alfa reduces anemia-related fatigue, improves other aspects of health-related patient-recorded outcomes (PROs), reduces the number of RBC transfusions, and has an impact on freedom from treatment failure (FFTF) and overall survival (OS) in patients with advanced-stage Hodgkin's lymphoma (HL). Patients and Methods The prospectively randomized HD15EPO study performed by the German Hodgkin Study Group investigated epoetin alfa administered at doses of 40,000 U weekly during and after chemotherapy (six to eight cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone [BEACOPP]) in a double-blind, placebo-controlled setting. The study accrued 1,379 patients, of whom 1,328 were assessable for safety, 1,303 were assessable for clinical outcome, and 930 were assessable for PROs. Results PROs were not different in patients receiving placebo or epoetin alfa, both after the end of chemotherapy and 6 months thereafter. There was no difference between patients treated with epoetin alfa or placebo with respect to FFTF and OS. There were also no differences in the numbers of deaths, progressions, relapses, and thromboembolic events. The median number of RBC transfusions was reduced from four per patient in the placebo group to two per patient in the epoetin alfa group (P < .001), with 27.4% of patients needing no RBC transfusion in the placebo group compared with 36.7% of patients in the epoetin alfa group (P < .001). Conclusion Epoetin alfa administered at 40,000 U weekly parallel to BEACOPP chemotherapy was safe in patients with advanced-stage HL and reduced the number of RBC transfusions but had no impact on fatigue and other PRO domains.

Background: The optimal treatment of elderly patients with Hodgkin’s lymphoma (HL) is still a matter of debate. Since many of these patients receive combined modality treatment, we evaluated the impact of different radiation field sizes, that is extended-field (EF) or involved-field (IF) technique when given after four cycles of chemotherapy. Patients and methods: In the multicenter HD8 study of the German Hodgkin Study Group, 1204 patients with early-stage unfavorable HL were randomized to receive four cycles of chemotherapy followed by either radiotherapy (RT) of 30 Gy EF + 10 Gy to bulky disease (arm A) or 30 Gy IF + 10 Gy to bulky disease (arm B). A total of 1064 patients were assessable for the analysis. Of these, 89 patients (8.4%) were 60 years or older. Results: Elderly patients had a poorer risk profile. Acute toxicity from RT was more pronounced in elderly patients receiving EF-RT compared with IF-RT [World Health Organization (WHO) grade 3/4: 26.5% versus 8.6%)]. Freedom from treatment failure (FFTF, 64% versus 87%) and overall survival (OS, 70% versus 94%) after 5 years was lower in elderly patients compared with younger patients. Importantly, elderly patients had poorer outcome when treated with EF-RT compared with IF-RT in terms of FFTF (58% versus 70%; P = 0.034) and OS (59% versus 81%; P = 0.008). Conclusion: Elderly patients with early-stage unfavorable HL generally have a poorer risk profile and outcome when compared with younger patients. Treatment with EF-RT instead of IF-RT after chemotherapy has a negative impact on survival of elderly patients and should be avoided.

The increasing number of patients surviving severe traumatic brain injury (sTBI) but with significant sensorimotor and neuropsychological deficits is a challenge to rehabilitation medicine. So far, most research initiatives have focused on mortality rates, physiological or economic parameters to estimate therapeutic effects of rehabilitation strategies. Investigations on health-related quality of life (HRQoL) after TBI with and without concomitant polytrauma are rare compared to other disorders.A prospective study was conducted to investigate HRQoL using the SF-36 questionnaire in 49 patients with sTBI (Glasgow Coma Scale9 for more than 24 hours) with and without concomitant polytrauma 6 and 12 months after injury.The SF-36 score profiles 6 and 12 months after trauma were similar. Scores 12 months after trauma, however, were higher in 7/8 dimensions indicating an improvement over time. Similar observations were made for physical and mental sum scores. There was no difference in the SF-36 scoring pattern between the patients with isolated TBI and the patients with concomitant polytrauma, except for physical functioning after 12 months.While there is significant overall improvement of HRQoL over time, sTBI appears to bear major influence on post-traumatic HRQoL and outcome.

Purpose The role of bleomycin and vincristine in the treatment of patients with advanced Hodgkin lymphoma (HL) is unclear, and the impact of dose reductions of these drugs on outcome and tolerability has not been systematically assessed. Because both drugs can cause significant toxicity and are frequently discontinued, we performed an analysis of patients with HL treated with BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) in the German Hodgkin Study Group HD12 and HD15 trials. Patients and Methods Characteristics and outcome of patients were analyzed with respect to discontinuation of bleomycin and/or vincristine. Results With 3,309 patients with HL analyzed, bleomycin was discontinued in 17.6% and vincristine in 32.6%. A total of 157 patients (4.7%) received ≤ four cycles of bleomycin, and 218 (6.6%) received ≤ three cycles of vincristine; these were compared with patients receiving > four cycles of bleomycin or > three cycles of vincristine, respectively. After a median follow-up of 59 and 67 months for progression-free survival (PFS) and overall survival (OS), respectively, there was no significant difference in PFS or OS in patients receiving ≤ or > four cycles of bleomycin (5-year PFS difference, 1.7%; 95% CI, −4.2% to 7.6%; 5-year OS difference, 1.5%; 95% CI, −2.6% to 5.5%). Similarly, there was no significant difference in patients receiving ≤ or > three cycles of vincristine (5-year PFS difference, −1.3%; 95% CI, −5.6% to 3.1%; 5-year OS difference, −0.1%; 95% CI, −3.1% to 2.9%). Conclusion Bleomycin and vincristine discontinuation because of drug-specific adverse effects does not affect the efficacy of treatment in this setting.

Summary 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.

Background/Aims: The prevalence of anti-erythropoietin antibodies in renal patients without clinical evidence of pure red cell aplasia (PRCA) who respond poorly to epoetin is unknown. This study tested for anti-erythropoietin antibodies in hemodialysis patients who were either hypo- or normoresponsive to epoetin treatment. Methods: Epoetin hyporesponsiveness (hemoglobin ≤10.5 g/dl and epoetin ≧9,000 IU/week) and normoresponsiveness (hemoglobin >10.5 g/dl and epoetin Results: Anti-erythropoietin antibodies were detected in 3 hyporesponsive and 3 normoresponsive patients using ELISA. One patient per group was verified as borderline by RIP testing; the other 4 were negative. The bioassay was negative for 1 patient; the other died unrelated to PRCA before testing. Follow-up with RIP testing after 15 months under continuous epoetin treatment was negative (4 patients, 2 deceased). Conclusion: This survey did not identify anti-erythropoietin antibodies in hemodialysis patient’s hyporesponsive to epoetin and does not support presumptive antibody screening as a routine work-up in these patients.

For decreasing the risk of coronary heart disease (CHD) it has been proposed to enrich food such as margarine with plant sterol esters which have been shown to reduce total and LDL cholesterol concentrations, two of the major risk factors. A Markov model was developed to assess the costs and benefits of consuming a low-fat plant sterol containing margarine (PS margarine). A health insurer's perspective was taken with a time frame of 10 years. Transition probabilities for CHD and CHD-related death were calculated on the basis of the Framingham risk equations. These were applied to a representative sample of the German population. The alteration in cholesterol levels after intake of PS margarine was estimated based on a meta-analysis of ten randomized controlled trials with parallel or crossover design that found a reduction of 5.7% in total cholesterol. Average annual costs of CHD were assumed to be at 3,000 euro. Costs for "no CHD" and "CHD-related death" were set to 0 euro since the intervention would solely be paid by the consumers. Sensitivity analyses were performed with regard to annual costs, risk estimation, PS margarine reduction in total cholesterol, discount factor, and risk of CHD-related death. The 10-year CHD risks are 6.1% (PS margarine) vs. 6.5% (control). Thus expected 10-year CHD costs are 696 euro (PS margarine) vs. 748 euro (control). The cost savings of 52 euro varied between 32 euro and 74 euro in the sensitivity analysis. A projection at the level of the population for which evidence (randomized controlled trials) exists that plant sterols lower cholesterol (25.35 million) leads to a reduction of 117,000 CHD cases over 10 years and a cost reduction of 1.3 billion euro for this time period (sensitivity analysis 0.8-1.9 billion euro).

Purpose Several scores have described sex as a prognostic factor in patients with Hodgkin's lymphoma (HL). However, little is known how sex-specific factors influence treatment outcome. We systematically investigated sex differences with regard to pretreatment characteristics and therapy-related variables, and examined their influence on the outcome of HL patients. Patients and Methods This analysis comprises 4,626 HL patients of all prognostic risk groups who were enrolled onto the multicenter studies HD4 to HD9 of the German Hodgkin Study Group. At 5.5 years, 2,050 female and 2,576 male patients were analyzed. Results Male and female patients had similar prognostic factors. There was more acute chemotherapy-related hematotoxicity in women, especially more severe leucopenia (WHO grade 3/4, 69.9% female and 55.2% male; P < .0001). Importantly, this did not translate into more infections. Female patients had similar response rates but fewer relapses and deaths, leading to a significantly better freedom from treatment failure (FFTF; at 66 months, 81% female [95% CI, 79% to 82%] and 74% male [95% CI, 72% to 76%]). Severe leucopenia during chemotherapy was strongly associated with better FFTF, both for males and females. In addition, when only those patients who developed severe leucopenia within the first two cycles of chemotherapy were included, the factor maintained its protective role. Conclusion The protective role of severe leucopenia suggests the testing of a more individualized therapy. In future trials, this therapy may be tailored in a response-adapted manner depending on the individual toxicity profile within the first cycles.

In contrast to younger patients, the prognosis of elderly patients with advanced Hodgkin's disease (HD) has not improved substantially over the last 20 years. We thus carried out a prospectively randomized study (HD9(elderly)) to compare the BEACOPP regimen in this setting against standard COPP-ABVD. Between February 1993 and 1998, 75 patients aged 66-75 years with newly diagnosed HD in advanced stages were recruited into the HD9 trial as a separate stratum (HD9(elderly)). Patients were assigned to eight alternating cycles of COPP and ABVD or eight cycles of BEACOPP in baseline doses. Radiotherapy was given to initial bulky or residual disease. In total, 68 of 75 registered patients were assessable: 26 were treated with COPP-ABVD and 42 with BEACOPP baseline. There were no significant differences between COPP-ABVD and BEACOPP in terms of complete remission (76%), overall survival (50%) and freedom from treatment failure (FFTF) (46%) at 5 years. At a median follow-up of 80 months, a total of 37 patients died: 14/26 patients (54%) treated with COPP-ABVD and 23/42 patients (55%) with BEACOPP. Two patients (8%) treated with COPP-ABVD and nine patients (21%) treated with BEACOPP died of acute toxicity. Hodgkin-specific FFTF at 5 years was 55% after COPP-ABVD and 74% after BEACOPP (P=0.13). Thus, there are no differences in survival between these regimens in elderly patients.

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

Purpose Positron emission tomography (PET) after chemotherapy can guide consolidating radiotherapy in advanced-stage Hodgkin lymphoma (HL). This analysis aims to improve outcome prediction by integrating additional criteria derived by computed tomography (CT). Patients and Methods The analysis set consisted of 739 patients with residues ≥ 2.5 cm after chemotherapy from a total of 2,126 patients treated in the HD15 trial (HD15 for advanced stage Hodgkin's disease: Quality assurance protocol for reduction of toxicity and the prognostic relevance of fluorodeoxyglucose-positron-emission tomography [FDG-PET] in the first-line treatment of advanced-stage Hodgkin's disease) performed by the German Hodgkin Study Group. A central panel performed image analysis and interpretation of CT scans before and after chemotherapy as well as PET scans after chemotherapy. Prognosis was evaluated by using progression-free survival (PFS); groups were compared with the log-rank test. Potential prognostic factors were investigated by using receiver operating characteristic analysis and logistic regression. Results In all, 548 (74%) of 739 patients had PET-negative residues after chemotherapy; these patients did not receive additional radiotherapy and showed a 4-year PFS of 91.5%. The 191 PET-positive patients (26%) receiving additional radiotherapy had a 4-year PFS of 86.1% (P = .022). CT alone did not allow further separation of patients in partial remission by risk of recurrence (P = .9). In the subgroup of the 54 PET-positive patients with a relative reduction of less than 40%, the risk of progression or relapse within the first year was 23.1% compared with 5.3% for patients with a larger reduction (difference, 17.9%; 95% CI, 5.8% to 30%). Conclusion Patients with HL who have PET-positive residual disease after chemotherapy and poor tumor shrinkage are at high risk of progression or relapse.

Summary Background Several treatment strategies are available for adults with advanced-stage Hodgkin's lymphoma, but studies assessing two alternative standards of care—increased dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP escalated ), and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD)—were not powered to test differences in overall survival. To guide treatment decisions in this population of patients, we did a systematic review and network meta-analysis to identify the best initial treatment strategy. Methods We searched the Cochrane Library, Medline, and conference proceedings for randomised controlled trials published between January, 1980, and June, 2013, that assessed overall survival in patients with advanced-stage Hodgkin's lymphoma given BEACOPP baseline , BEACOPP escalated , BEACOPP variants, ABVD, cyclophosphamide (mechlorethamine), vincristine, procarbazine, and prednisone (C[M]OPP), hybrid or alternating chemotherapy regimens with ABVD as the backbone (eg, COPP/ABVD, MOPP/ABVD), or doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone combined with radiation therapy (the Stanford V regimen). We assessed studies for eligibility, extracted data, and assessed their quality. We then pooled the data and used a Bayesian random-effects model to combine direct comparisons with indirect evidence. We also reconstructed individual patient survival data from published Kaplan-Meier curves and did standard random-effects Poisson regression. Results are reported relative to ABVD. The primary outcome was overall survival. Findings We screened 2055 records and identified 75 papers covering 14 eligible trials that assessed 11 different regimens in 9993 patients, providing 59 651 patient-years of follow-up. 1189 patients died, and the median follow-up was 5·9 years (IQR 4·9–6·7). Included studies were of high methodological quality, and between-trial heterogeneity was negligible (τ 2 =0·01). Overall survival was highest in patients who received six cycles of BEACOPP escalated (HR 0·38, 95% credibility interval [CrI] 0·20–0·75). Compared with a 5 year survival of 88% for ABVD, the survival benefit for six cycles of BEACOPP escalated is 7% (95% CrI 3–10)—ie, a 5 year survival of 95%. Reconstructed individual survival data showed that, at 5 years, BEACOPP escalated has a 10% (95% CI 3–15) advantage over ABVD in overall survival. Interpretation Six cycles of BEACOPP escalated significantly improves overall survival compared with ABVD and other regimens, and thus we recommend this treatment strategy as standard of care for patients with access to the appropriate supportive care. Funding None.

Thrombotic events are regularly observed in patients receiving treatment for Hodgkin Lymphoma (HL). However, sound data on incidence and risk factors are not known. The aim of the present study was thus to provide a comprehensive analysis of thrombotic events after multimodality treatment for HL. A total of 5,773 patients ≤ 60 years treated within the German Hodgkin Study Group (GHSG) trials HD13-15 between January 2003 and December 2009 were included in this analysis. All reported venous and arterial thrombotic events occurring within 1 year after trial enrollment were evaluated and detailed information on patient characteristics, localizations, time of occurrence and risk factors were collected. We excluded thromboses of superficial veins and thrombophlebitis. Descriptive statistics and logistic regression were used for statistical analysis. A total of 193 thrombotic events occurred for an incidence of 3.3%; there were 11 events in early-favorable, 27 in early-unfavorable and 155 in advanced stage HL, resulting in incidence rates of 0.7%, 1.3% and 7.3%, respectively. The incidence in advanced stage HL was significantly higher than in early stage HL (p We found that 2.6% (n=5), 77.2% (n=149) and 20.2% (n=39) of cases occurred before, during and after chemotherapy respectively. In advanced HL patients treated with 8 x BEACOPPesc, 6 x BEACOPPesc or 8 x BEACOPP-14 , the incidence rates were 6.2% (n=44), 5.5% (n=39) and 10.1% (n=72) respectively. The incidence in patients treated with BEACOPP-14 was significantly higher than in patients treated with the other two regimens (p We then analyzed potential risk factors in advanced stage patients using logistic regression analysis, adjusting for treatment in order to identify a high-risk group for developing a thrombotic event. The well-established Khorana score was not associated with a higher risk of thrombosis (odds ratio (OR) per unit [95% confidence interval]: 0.91 [0.76-1.1], p=0.33). Additionally, we screened 21 potential risk factors, including the thrombocyte-to-lymphocyte ratio. Only age (OR per year: 1.02 [1.01-1.03], p=0.01) and smoking (OR: 1.61 [1.07-2.43], p=0.02) emerged as significant risk factors. None of the other following potential risk factors was prognostic: thrombocyte-to-lymphocyte ratio, thrombocytes, leukocytes, lymphocytes, hemoglobin, albumin, WHO activity index, erythropoietin treatment, sex, body mass index, B-symptoms, erythrocyte sedimentation rate, extranodal disease, large mediastinal mass, more than 2 affected areas or Ann Arbor stage (all p≥0.10). Yet, when only including venous events, which are potentially preventable by prophylactic anticoagulation, neither age nor smoking were significant risk factors anymore (p≥0.10). This study is the largest and most comprehensive analysis of thrombotic events in HL patients to date. Compared to both, early-favorable and early-unfavorable HL, advanced stage patients are at higher risk for thrombotic events. The most widely used Khorana score estimating thrombosis risk in cancer outpatients was not prognostic in the HL population investigated here. This is unsurprising considering the young age of the patient population investigated. Other risk factors were also not prognostic. This data does not imply a need for prophylactic anti-coagulation in outpatients treated for early-stage HL. In advanced-stage HL patients, routine prophylactic anticoagulation is not warranted. However, individual patients with additional risk factors that could not be evaluated such as history of thrombosis or reduced mobility might still benefit from prophylactic treatment. Disclosures Engert: Takeda, BMS: Consultancy, Honoraria, Research Funding.

Background: The HD9 trial established 8 cycles of BEACOPPescalated followed by radiotherapy (RT) of initial bulk or residual tumors as German Hodgkin Study Group (GHSG) standard of care for advanced stage Hodgkin Lymphoma (HL) at that time. The succeeding HD12 trial aimed at reducing treatment intensity while maintaining efficacy. It compared 8 cycles of BEACOPPescalated with 4 cycles of BEACOPPescalated followed by 4 cycles of BEACOPPbaseline ("4+4" regimen) as well as RT with no RT of initial bulk or residual disease. Although tumor control is outstanding, long-term safety of BEACOPPescalated still is a matter of concern, and the need of consolidating RT in advanced stage HL is discussed controversially. We therefore performed a long-term follow up of the HD9 and HD12 trials in order to address these open questions. Patients and Methods: Between February 1993 and March 1998, 1,282 patients in the HD9 trial were treated with either 8 cycles of COPP/ABVD, 8 cycles of BEACOPPbaseline, or 8 cycles of BEACOPPescalated. Between January 1999 and January 2003, 1,670 HD12 patients were randomized for two questions in a factorial design: first, for 8 cycles of BEACOPPescalated or "4+4", and second for consolidation RT or no RT to regions of initial bulk or residual disease. Patients with inadequate response or skeletal involvement were irradiated irrespective of randomized RT group based on the recommendation of a central diagnostic panel blinded to treatment groups. Results: In HD9-patients treated with COPP/ABVD, BEACOPPbaseline, and BEACOPPescalated, the 15-year progression-free survival (PFS) was 57%, 66.8%, and 74% with overall survival (OS) rates of 72.3%, 74.5%, and 80.9%, respectively. BEACOPPescalated remains significantly better than COPP/ABVD in terms of PFS (difference 17.0%; 95%-CI 8.3% to 25.6%) and OS (difference 8.6%; 95%-CI 1.4% to 15.7%) with consistent effects in subgroups by gender, IPS and ages up to 60 years. A total of 123 second malignancies corresponding to 15-year cumulative secondary malignancy incidences of 7.2%, 13%, and 11.4% were reported for COPP/ABVD, BEACOPPbaseline, and BEACOPPescalated, respectively, without a difference between COPP/ABVD and BEACOPPescalated (p=0.5). Standardized incidence ratios (SIR) with 95%-CI showed elevation compared to the general German population in all groups: 2.0 [1.2 to 3.2], 2.6 [1.9 to 3.4] and 2.6 [1.9 to 3.4]. Regarding HD12, the 10-year PFS and OS rates in the two chemotherapy groups were not significantly different with 82.6% and 87.3% in the BEACOPPescalated group and 80.6% and 86.8% in the 4+4 group, respectively. After chemotherapy, 153 of 1,481 (10.3%) patients with complete information had an RT recommendation irrespective of group and 378 (25.5%) had neither bulk nor residual disease. Amongst the remaining 950 patients (64.1%) with bulk or residual disease, patients randomized to no RT showed a significantly inferior 10-year PFS of 83.5% compared to patients in the RT group (88.6%, difference -5.1%; 95%-CI,-9.9% to -0.4%, hazard ratio [HR] 1.47) and a trend towards inferior OS in no RT patients (RT 93%; no RT 90.2%; difference -2.7%; 95%-CI,-6.5% to 1%). Patients with residual lesions without RT had both an inferior PFS and OS as compared to patients with RT (as treated comparison: 10-year PFS RT 89.7%; no RT 83.4%; difference -6.3%; 95%-CI,-12.8% to -0.1%; 10-year OS RT 94.4%; no RT 88.4%; difference -6%; 95%-CI,-11.4% to -0.5%). 10-year cumulative incidence of second malignancies ranged between 6.4% (4+4) and 9.7% (BEACOPPescalated+RT) without a significant difference between pooled chemo- or radiotherapy groups. Conclusions: These long-term follow-up observations indicate an ongoing benefit of an intensive first-line therapy strategy for the PFS and OS of patients with newly diagnosed advanced stage HL. The observed OS benefit suggests an important role of consolidating RT for patients with newly diagnosed advanced stage HL. The OS benefit does not seem to be relevantly compromised by the incidence of second malignancies. Disclosures von Tresckow: Novartis: Consultancy, Other: travel grants, Research Funding; Takeda: Consultancy, Other: travel grants; Millenium: Consultancy. Engert:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding.

Purpose 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). Patients and Methods 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. Results 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). Conclusion 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.

Rationale: The intensified BEACOPPescalated (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) regimen has substantially improved the survival of advanced stage Hodgkin Lymphoma (HL) patients. However, the efficacy of this regimen comes along with severe acute toxicities. Brentuximab vedotin (BV) is an anti-CD30 directed antibody-drug conjugate that has shown very promising single-agent activity and good tolerability in relapsed/refractory HL. We introduced BV into the BEACOPP regimen in order to improve its toxicity profile while maintaining its efficacy. Methods: Two modified BEACOPP regimens were developed. In a more conservative variant (BrECAPP: BV, etoposide, cyclophosphamide, doxorubicin, procarbazine, prednisone), vincristine was replaced by BV and bleomycin omitted. A more experimental variant (BrECADD: BV, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) was designed to reduce procarbazine induced gonadal toxicity. Both regimens are administered q21d for 6 cycles. This is a randomized phase II study with the combined primary endpoint being the PET-based complete response rate (CRR) after chemotherapy and the complete remission rate (CR/CRu rate) at final restaging including early follow-up for each of the regimens. Safety and feasibility are secondary trial objectives. Results: From October 2012 to May 2014, 104 patients have been enrolled and are evaluable for this analysis (52 patients in each treatment arm). Median age is 29 years (range 18-60 years), 61% are male, and 83% have Ann-Arbor stage III or IV disease. Overall, risk factors were well balanced between the treatment arms and in line with the previous GHSG studies besides a higher number of patients presenting with large mediastinal mass (40% in each treatment arm). 102 patients qualify for the safety analysis (BrECADD n=52, BrECAPP n=50) with two patients not having commenced treatment in the latter group. All 52 patients with BrECADD received the planned number of cycles, 2/50 terminated BrECAPP after 2 and 3 cycles due to toxicity and revision of initial staging by expert panel, respectively. 70% and 60% with complete cycles of BrECADD and BrECAPP received the last treatment cycle at full dose level. The majority of patients did not have treatment delays. 101 patients qualify for the efficacy analysis (BrECADD n=52, BrECAPP n=49). CRR is 88% (95%-CI: 77% - 96%) for the BrECADD regimen and 86% (95%-CI: 73% - 94%) for BrECAPP with both groups achieving the required number of 42 patients with CRR demanded by the protocol. Regarding the co-primary endpoint CR/CRu, the corresponding rates were 88% for BrECADD (95%-CI: 77% - 96%), and 94% (95%-CI: 83% to 99%) for BrECAPP. Survival analyses for the BrECADD regimen revealed a progression free survival (PFS) of 94% (95%-CI: 87% - 100%) at 12 months, and 89% (95%-CI: 77% - 100%) at 18 months. Corresponding numbers for BrECAPP were 98% (95%-CI: 94% - 100%), and 93% (95%-CI: 83% - 100%). Overall survival (OS) after a median follow-up time of 18 months for BrECADD was 100%. In the BrECAPP group the median follow-up was 16 months and one patient died. This patient had never received the study treatment. However, this event led to a 1-year OS of 98% (95%-CI: 94% - 100%) in the BrECAPP group. Hematological toxicity grade 3 or 4 occurred in 42/52 (88%) of BrECADD treated patients, and in 47/50 (96%) with BrECAPP. Main hematotoxicity was leukopenia resulting in 15% (BrECADD) and 8% (BrECAPP) grade 3 or 4 infections. Organ toxicity grade 3 or 4 occurred in 4% of BrECADD treated patients (all events grade 3), and in 17% in the BrECAPP group (5% grade 4). Severe neurotoxicity (i.e. grade 3 or 4) was not observed in the BrECADD group and in one patient (2%) in the BrECAPP group (grade 3 sensory neuropathy). Grade 1 or 2 sensory neuropathy occurred in 35% and 30%, respectively. Conclusion: This is the largest study of BV in combination with chemotherapy in the first line treatment of HL reported so far. Both targeted BEACOPP variants are active and well feasible. Based on its superior organ toxicity profile, we have chosen the BrECADD regimen to challenge the GHSG standard of care escalated BEACOPP for advanced stage HL patients in an international, randomized phase III study. Disclosures Borchmann: Millennium: Research Funding. Engert:Milennium: Research Funding.

The prevalence of anti-erythropoietin antibodies in renal patients without clinical evidence of pure red cell aplasia (PRCA) who respond poorly to epoetin is unknown. This study tested for anti-erythropoietin antibodies in hemodialysis patients who were either hypo- or normoresponsive to epoetin treatment.Epoetin hyporesponsiveness (hemoglobinor =10.5 g/dl and epoetinor =9,000 IU/week) and normoresponsiveness (hemoglobin10.5 g/dl and epoetin7,000 IU/week) were arbitrarily defined. Prevalence of anti-erythropoietin antibodies in hemodialysis patients without symptoms of PRCA was determined by screening sera of 536 patients from 35 German KfH dialysis units, using enzyme-linked immunosorbent assay (ELISA). Positive results were verified by radioimmunoprecipitation assay (RIP) and neutralizing activity was determined by bioassay.Anti-erythropoietin antibodies were detected in 3 hyporesponsive and 3 normoresponsive patients using ELISA. One patient per group was verified as borderline by RIP testing; the other 4 were negative. The bioassay was negative for 1 patient; the other died unrelated to PRCA before testing. Follow-up with RIP testing after 15 months under continuous epoetin treatment was negative (4 patients, 2 deceased).This survey did not identify anti-erythropoietin antibodies in hemodialysis patient's hyporesponsive to epoetin and does not support presumptive antibody screening as a routine work-up in these patients.

Purpose To investigate the clinical characteristics and treatment outcome of patients with lymphocyte-rich classical Hodgkin's lymphoma (LRCHL) compared with other histologic subtypes of Hodgkin's lymphoma (HL). Patients and Methods From a total of 2,715 patients with biopsy-proven HL treated within the trials HD7 to HD12 of the German Hodgkin's Study Group, 100 patients (4%) with LRCHL, 145 patients (5%) with lymphocyte-predominant HL (LPHL), 1,688 patients (62%) with nodular sclerosis, 731 patients (27%) with mixed cellularity, and 23 patients (1%) with lymphocyte depletion were identified. Patients with LRCHL had a median age of 38 years (range, 16 to 74 years). Results Compared with other histologic subtypes, patients with LRCHL are, on average, older and usually present with early stages of disease (stage I, 34%; stage II, 46%). The median time of follow-up was 32.2 months (95% CI, 28.2 to 37.0 months). Complete and partial remission was achieved in 96 patients (96%) and four patients (4%), respectively, with LRCHL. The event-free and overall survival rates were 97% (95% CI, 96.7% to 96.9%) and 97% (95% CI, 96.8% to 97.0%), respectively, at 30 months. Only three patients died; all of the deaths were caused by treatment-related toxicities. Conclusion LRCHL is a distinct subtype of CHL, with features of CHL and LPHL, and is a rare entity accounting for only 4% of HLs. LRCHL has a different pattern of clinical presentation and age and sex distribution than other CHLs. It is associated with an excellent prognosis if treated with current treatment regimens. When treating patients with LRCHL, great attention should be paid to avoid acute toxicities.

The CC thymus and activation-related chemokine (TARC) is a protein, which is highly expressed by Reed-Sternberg cells in Hodgkin's disease and is found in the majority of Hodgkin's disease patients. Within several trials conducted by the German Hodgkin study group, 62 Hodgkin's disease patients were elected based on availability of serum samples post and prior therapy to assess TARC levels by ELISA. TARC levels from 33 patients with continuous complete response (CCR), 20 patients with relapse, and nine patients with progressive disease (PD) were correlated with freedom from treatment failure and survival. As defined in healthy donors (mean value ± 2× SD), a TARC level of >500 pg/mL was considered as elevated. The median TARC levels of all patients at baseline and after completed primary treatment were 5,803 pg/mL (range, 116-73,074 pg/mL) and 663 pg/mL (50-24,709 pg/mL), respectively. TARC levels of patients with PD were higher than those of patients with CCR at baseline and after therapy. Baseline TARC correlated significantly with stage (P = 0.019), erythrocyte sedimentation rate (P = 0.004), leukocyte count (P < 0.001), and lymphocyte count (P = 0.026). A TARC level of >2,000 pg/mL after completed treatment was a significant risk factor for poorer survival (P = 0.02) but not for relapse. In conclusion, monitoring serum TARC levels in Hodgkin's disease patients may add valuable information about therapy success in Hodgkin's disease patients, especially those with PD and should therefore be prospectively evaluated in future trials.

Purpose With improved prognosis for patients with Hodgkin's lymphoma (HL), interest increasingly focuses on high-risk groups such as elderly patients. We thus performed a retrospective analysis using the German Hodgkin's Study Group (GHSG) database to determine clinical risk factors, course of treatment, and outcome in elderly HL patients in comparison with younger adults. Patients and Methods A total of 4,251 patients included in the GHSG studies HD5 to HD9 were analyzed, of whom 372 (8.8%) were 60 years or older and 3,879 (91.2%) were younger than 60 years. Patient characteristics, treatment results, toxicity, freedom from treatment failure (FFTF), and overall survival (OS) were compared. Results Elderly patients more often had mixed cellularity subtype, “B” symptoms, elevated erythrocyte sedimentation rate, and poorer performance status. Less frequently observed were nodular sclerosis subtype, large mediastinal mass, and bulky disease. Acute toxicity during chemotherapy was generally higher in elderly patients. This was most obvious for severe infections (grade 3 or 4; 15% v 6%) correlating with more severe leukopenia in elderly patients (grade 4; 38% v 23%). As a result, significantly fewer elderly patients received the intended full chemotherapy dose (75% v 91%). The survival analysis showed a significantly poorer treatment outcome for elderly patients in terms of 5-year OS (65% v 90%), FFTF (60% v 80%), and HL-specific FFTF (73% v 82%). Conclusion Elderly patients have a poorer risk profile compared with younger HL patients and experience more severe treatment-associated toxicity. Higher mortality during treatment as well as lower dose-intensity are the major factors explaining the poorer overall outcome of elderly HL patients.

Introduction: The standard treatment for patients with relapsed or refractory (r/r) classical Hodgkin Lymphoma (cHL) is salvage chemotherapy followed by autologous stem cell transplantation (ASCT). The best outcome from the transplant is expected in patients who achieve complete remission (CR) after the salvage chemotherapy. Everolimus is a mammalian target of rapamycin (mTOR) inhibitor that has shown activity and an acceptable toxicity profile in patients with r/r cHL (Johnston PB et al. Am J Hematol 2010; Johnston PB et al. ISHL-9 2013). We therefore aim to improve the CR rate after salvage by an enforced salvage regimen consisting of everolimus plus time-intensified standard DHAP (Dexamethasone, High-Dose AraC [Cytarabine], Cisplatinum). Methods: We conducted a phase I trial of everolimus plus DHAP (ever-DHAP) for patients with r/r cHL eligible for ASCT to assess the recommended phase II dose (RPTD) of oral everolimus in this combination. Everolimus was administered for 14 days in each DHAP cycle starting from one day before DHAP. The second cycle of ever-DHAP was scheduled to start at day 14 of cycle one. Patients received two cycles of ever-DHAP. Everolimus dose levels of 2.5mg, 5mg, 7.5mg and 10mg were assessed in a modified 3+3 design. Generally, dose-limiting toxicity (DLT) was defined as CTCAE grade III/IV toxicity or unsuccessful stem cell mobilization. However, grade III/IV non-hematological toxicities known from DHAP were only counted as DLT from second occurrence in any patient onwards. Grade III/IV hematological toxicities were only counted as DLTs in case of prolonged time to recovery. Restaging by (PET)-CT was performed at day 21 of the second cycle given that the patient had recovered; PET was mandatory for all patients not achieving a CR in the CT scan. The rate of patients experiencing DLTs during 2 cycles of the combination therapy was the primary endpoint of the study. Secondary endpoints included adverse events, tumor related results of therapy or death, treatment administration, time to recovery after end of treatment and stem cell mobilization. Results: 14 patients were recruited between August 2012 and January 2014, all patients received at least one dose of everolimus. The median age was 33.5 years; six were female and eight were male. Eleven patients presented with stage III/IV disease. Overall, treatment was well tolerated. Two patients (both at the 7.5mg level) had a premature treatment termination and did not receive the 2nd cycle, one patient due to ototoxicity of grade I at investigator’s discretion and one patient due to neurotoxicity of grade III/IV. One additional patient (7.5mg cohort) suffered from ototoxicity of grade III/IV between end of treatment and restaging. Both grade III/IV toxicities were pre-defined as known from DHAP, thus they were not considered dose limiting at this first occurrence. No further non-hematological grade III/IV adverse events were reported. All patients but one experienced grade III/IV thrombocytopenia and leukopenia. No DLTs occurred and therefore 10mg of everolimus/day was chosen as RPTD. Duration of induction therapy including restaging after two cycles was 35-54 days. All patients who completed the 1st treatment cycle (n=13) had adequate stem cell mobilization (CD34+ cell count 2.9 - 31.1 x 106/kg; median 10 x 106/kg). So far one death occurred in a patient with pneumococcal sepsis one year after restaging. Responses according to CT scan in 12 patients who received two cycles of ever-DHAP were CR in 3 patients, CR unconfirmed (CRu) in 3 patients, partial remission (PR) in 5 patients and stable disease (SD) in 1 patient. This accounts for a CR/CRu rate of 50% (6/12) and an overall response rate of 92% (11/12). A PET scan was performed in 4 of 6 patients with CR/CRu; all had a negative PET (Deauville 1). In the 6 patients not achieving a CR/CRu 5 patients had a PET scan; 4 were PET positive (2 patients with Deauville 4 and 5 each) and 1 was PET negative (Deauville 1). Conclusions: Ever-DHAP with 10mg everolimus/day is safe and feasible in patients with r/r cHL. Based on the results of this phase I trial a randomized, placebo-controlled trial of ever-DHAP has been initiated and is currently recruiting. Disclosures von Tresckow: Takeda: Honoraria, Travel grants, Travel grants Other; Novartis: Honoraria, Research Funding. Off Label Use: Everolimus in relapsed or refractory Hodgkin Lymphoma. Topp:Affimed: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria. Engert:Millennium: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Affimed: Consultancy. Borchmann:Takeda: Honoraria, Research Funding, Travel grants Other.

Introduction: Positron emission tomography (PET) assessment early during treatment of advanced stage Hodgkin lymphoma (HL) patients might be suited to determine the individual risk for treatment failure. In the HD18 study, PET was performed after induction therapy with two courses of BEACOPPescalated (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and procarbazine). Depending on this PET-2 result, patients were either classified as high-risk or low-risk patients and escalation or de-escalation treatment strategies were tested, respectively. To improve the presumably poor progression free survival (PFS) of PET-2 positive patients, we introduced the anti-CD20 antibody rituximab into the BEACOPPescalated regimen (R- BEACOPPescalated). Here, we report the results of the second planned interim analysis for the PET-2 positive patient cohort. Methods: HD18 is an open-label, multicenter, prospective, randomized, phase III study (ClinicalTrials.gov ID: NCT00515554) for patients with newly diagnosed advanced stage HL aged 18–60 years. Patients with PET positive disease (standard uptake value above mediastinal background) after two courses of BEACOPPescalated were randomly assigned to receive additional six courses of BEACOPPescalated (BEACOPP group), or rituximab in conjunction with six cycles of BEACOPPescalated (R-BEACOPP group). We centrally performed a 1:1 randomization by stratified minimization. Primary endpoint was progression free survival (PFS) using an adaptive study design with three interim analyses. Sample size was determined to ensure that an improvement by at least 15 percentage points could be detected by the addition of rituximab to BEACOPPescalated assuming a 5-year PFS rate of 68% for PET-2 positive patients with BEACOPPescalated. Results: Between May 2008 and May 2011, 1,100 patients were enrolled into the HD18 trial, of whom 440 were PET-2 positive and randomized (BEACOPP n=220; R-BEACOPP n=220), corresponding to 43% of all randomized patients. One patient in the BEACOPPescalated group was excluded from intention-to-treat analysis because HL was not confirmed by reference histology. Median age was 30 years (range 18-60), 177 were female (40%). One patient had stage IIA disease, 103 patients (23%) had Ann Arbor stage IIB disease with the risk factors large mediastinal mass or extranodal involvement, the remaining patients had stage III/IV disease. IPS risk groups were distributed as follows: 120 patients 0-1 (28%), 241 2-3 (55%), and 75 4-6 (17%). Overall, grade 4 toxicity occurred in 197/218 (90.4%) and 206/220 (93.6%) of the documented patients in the BEACOPP and R-BEACOPP group, respectively. Grade 4 leukopenia was documented in 193 (88.5%) and 201 (91.4%) patients, grade 4 thrombocytopenia in 112 (51.4%) and 123 (55.9%) patients, anemia in 27 (12.4%) and 31 (14.1%) patients, and grade 4 infections in 9 (4.1%) and 13 (5.9%) patients. Other grade 4 toxicities had a frequency of less than 2%. Treatment related mortality occurred in 1 (0.5%) and 3 patients (1.4%), respectively. Overall, 16 patients died, 6 in the BEACOPPescalated group and 10 in the R-BEACOPPescalated group. With a median follow-up of 35 months, Kaplan-Meier PFS estimates were largely overlapping (log rank p=0.99) with an estimated 3 year PFS of 91.4% for BEACOPP (95% CI: 87.0% – 95.7%) and 93% for R-BEACOPP (95% CI: 89.4% – 96.6%). Accordingly, overall survival was not different (96.5% versus 94.4% at 3 years for BEACOPP versus R-BEACOPP, p=0.31). The data monitoring committee (DMC) recommended publication of this second interim analysis, since a futility analysis indicated a low likelihood of the trial to become successful. Conclusion: Importantly, the definition of PET positivity used in the HD18 study failed to determine a high-risk patient group. PFS in PET-2 positive patients receiving standard treatment with BEACOPPescalated was much better than expected. Accordingly, the chance to improve the overall excellent PFS of these patients with rituximab was low. In fact, we did not observe any benefit. Future analyses of the PET-2 negative patient cohort will show if PET guided risk group allocation allows treatment reduction in advanced stage HL patients. Disclosures Off Label Use: Rituximab for Hodgkin Lymphoma.

Rationale BEACOPPescalated (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) has substantially improved the outcome for patients with advanced stage Hodgkin Lymphoma (HL) achieving an overall survival of 95% at five years. Although this certainly is the most important endpoint for these mainly young patients, there still is concern about the toxicities of this intensified chemotherapy regimen. Brentuximab vedotin (BV) is an anti-CD30 directed antibody-drug conjugate that has shown very promising single-agent activity and good tolerability in HL. We aimed at improving the toxicity profile of BEACOPPescalated while maintaining its efficacy by introducing BV (targeted BEACOPP). Methods Two modified BEACOPP regimens were developed. In a more conservative variant (BrECAPP: BV, etoposide, cyclophosphamide, doxorubicin, procarbazine, prednisone), we replaced vincristine by BV and omitted bleomycin. In the more experimental variant (BrECADD: BV, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) we additionally replaced procarbazine by dacarbazine to reduce gonadal toxicity, reduced the dose of etoposide to decrease risk of second acute myeloid leukemia while slightly increasing the dose of doxorubicin to maintain efficacy, and introduced dexamethasone (day 1-4) substituting for prednisone (day 1-14) to avoid immunosuppressive steroid treatment during neutropenia (please see table 1). Both regimens are administered q21d for 6 cycles. This is an ongoing randomized phase II study with the combined primary endpoint being the PET-based complete response rate after chemotherapy and the complete remission rate at final restaging including early follow-up. Here we report on the first 48 patients (planned n=100). Results The study started in October 2012. 48 patients have been enrolled by June 2013 and are included in this analysis. Median age is 29 years (range 19-60 years), 60% are male, and 83% have Ann-Arbor stage III or IV disease. 14 patients have been staged after 6 cycles of chemotherapy, 6 in the BrECAPP and 8 in the BrECADD arm. Four of these patients have not reached a complete response. The 95% confidence interval for the number of treatment successes is 42% to 92% and contains both the margin for failure (65%) as well as the margin for success (85%). Regarding feasibility, 6 of 15 patients (60%) with 6 cycles of chemotherapy required no dose reductions of etoposide, cyclophosphamide or doxorubicin during the entire treatment period (corresponding number for 6 cycles of BEACOPPescalated in the HD15 study: 50%). Hematological toxicity grade 3 or 4 of the targeted BEACOPP variants was documented in 26 of 32 patients (81%) with at least 1 cycle of chemotherapy documented (corresponding number for 4-6 cycles of BEACOPPescalated in the GHSG HD15 study: 91.7%), and grade 3 or 4 organ toxicity in 1 patient (3%, GHSG HD15 study: 14.1%). Four patients reported symptoms of peripheral sensory neuropathy so far (grade 1 n=2; grade 2 n=2). BV was not given in the 6th cycle in two of these patients. Conclusion These ongoing phase II trial results indicate that anti-CD30 targeted BEACOPP variants may be well feasible without compromising the efficacy associated with BEACOPPescalated. Enrollment is ongoing and updated results will be presented. Disclosures: Borchmann: Takeda: Honoraria, Research Funding. Off Label Use: Brentuximab vedotin first line Treatment of Hodgkin´s Lymphoma. Diehl:Takeda: Membership on an entity’s Board of Directors or advisory committees. Engert:Takeda: Consultancy.

Introduction BEACOPPescalated 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. Methods Based 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. Results 3309 (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 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. Conclusion Bleomycin 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.

Thirteen healthy subjects were asked to maintain a constant index finger position in Experiment 1 or a constant eye position in Experiment 2 using visual feedback. The finger or eye position along with a stationary baseline target was displayed on an oscilloscope placed in front of the subject. Experiments 1 and 2 were carried out under sixteen combinations of delay and amplification of displacement on the screen (i.e., gain). In Experiment 1, increasing the gain in the visual feedback decreased the Root Mean Square (RMS) errors while increasing the delay increased these errors. An interaction between gains and delays was also observed in Experiment 1. In Experiment 2, the RMS errors were systematically higher than those recorded in Experiment 1 for the finger. No systematic pattern was recognized across all conditions of gains and delays for eye movements in Experiment 2. This study clearly illustrates differences in dynamics of motor control systems regulating eye and finger positions, respectively.

Abstract 3684 Purpose: Positron emission tomography (PET) is being established as a valuable marker to guide the use of additional radiotherapy (RT) after effective chemotherapy in patients with advanced stage Hodgkin Lymphoma (HL). The present analysis compares the prognostic impact of PET with conventional imaging methods (CIM). Methods: A prospective cohort of 739 patients with advanced stage HL treated within the GHSG HD15 trial who achieved at least partial remission and presented with persistent mass ≥2.5 cm after 6–8 cycles of BEACOPP chemotherapy underwent PET scanning at one of 37 participating GHSG PET centers. A central multidisciplinary panel consisting of experts from medical oncology, radiology, radiation oncology, and nuclear medicine reviewed PET and CT scans as well as available conventional X-rays. This panel decided on the need of additional radiotherapy (30Gy to residual masses) if PET was positive according to standard criteria, or no further treatment if PET was negative. Prognosis was evaluated using progression free survival (PFS) measured from the panel decision; groups were compared using the log rank test. Potential prognostic factors were investigated using ROC analysis and logistic regression. The latter analysis included 710 patients with progression, relapse or at least one year of follow-up after PET review without tumor recurrence. Findings: The 548 PET negative of 739 patients (74%) had a 4-year PFS of 91.5%. In contrast, the 191 PET positive patients (26%) had a 4-year PFS of 86.1% (p=0.022). Compared to PET, CIM would have resulted in a different treatment recommendation for 28% of patients. CIM was unable to separate patients by risk of recurrence, both, for all patients and in PET negative or PET positive subgroups. Concordance between local and central review was observed in 90% of cases with only 3 recurrences so far in the 10% (n=71) discordant patients. Half of the discordant patients (n=36) were judged PET positive by central review and accordingly had additional radiotherapy. When investigating other potential indicators of response, ROC analysis showed that only the relative reduction of residual tumors was significantly associated with outcome (AUC 0.65, 95% CI 0.57 to 0.73), while other factors such as the largest diameter of the residual tumor at initial staging or restaging as well as IPS were not. When the 54 PET positive patients who had a tumor reduction of less than or equal to 40% were compared to those 135 PET positive patients having a tumor reduction of more than 40%, the OR for recurrence within a year was 5.6 (95% CI 2.1 to 15.2). However, even in this high-risk group, most of the patients did not relapse: the 4-year PFS was 72.8% and most events occurred in the first year after PET review. The low risk group had a 4-year PFS comparable to the rate of PET negative patients (92%). However, 94% of these patients were irradiated, while more than 98% of PET negative patients were not. Both PET negative groups had favorable 4-year rates of 89.4 (≤ 40% reduction) and 92.4% (more than 40% reduction). Conclusion: The rate of concordance between local and central PET review in the present analysis was 90%. While morphological imaging alone did not sufficiently predict PFS, the magnitude of tumor shrinkage may help to identify those PET positive patients at higher risk for progression or relapse despite additional radiotherapy. Since the risk for relapse is highest in the first year after treatment, maintenance treatment should be discussed for this rather small group of patients. Disclosures: Engert: Takeda, Millennium: Honoraria, Research Funding. Borchmann:Millenium The Takeda Oncology Company: Research Funding; Takeda Pharma GmbH: Travel Grants, Travel Grants Other.

Abstract 551 Background: The best treatment strategy for advanced stage Hodgkin lymphoma (HL) is still a matter of debate. The German Hodgkin Study Group (GHSG) advocates aggressive treatment with BEACOPPescalated (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) to cure as many patients as possible with first-line therapy. However, BEACOPPescalated may expose patients to excessive toxicity. Treatment with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) is supposed to be better tolerable. Proponents of primary ABVD therapy acknowledge a lower progression-free survival (PFS) compared to BEACOPPescalated. However, they argue that relapsing patients can subsequently be cured by high-dose chemotherapy resulting in comparable overall survival (OS). All trials evaluating these two strategies directly were either very small or included patient subgroups only. Although they congruently showed a significant PFS advantage for BEACOPPescalated, they were not powered to detect differences in OS, which obviously is the most important endpoint. Purpose: To assess the benefits and risks of different initial treatment strategies for adult patients with advanced stage HL and to provide patients and physicians with a high-level evidence for treatment decisions. Methods: Data Sources: We developed sensitive search strategies for CENTRAL, MEDLINE, and conference proceedings (searched from 01/1980 to 03/2012). Missing data was obtained from investigators. Study selection: Randomized trials that compared at least two out of twelve pre-defined chemotherapy regimens in adults with advanced stage HL. Two authors independently assessed studies for eligibility. Data extraction: We extracted data and assessed quality of trials in duplicate. The primary outcome was OS. Secondary outcomes included freedom-from-treatment failure (FFTF) and secondary malignancies. Data relates to four or five years of follow-up depending on the status of the trial. Data synthesis: We pooled data using network meta-analysis. Direct comparisons within trials were combined with indirect evidence from other trials by using a Bayesian random-effects model. Results are reported relative to ABVD with a hazard ratio (HR) >1 indicating superiority of ABVD. Results: 1,984 references were identified, of which 77 publications, reporting 14 trials, evaluating 11 different regimens were included. A total of 10,011 patients with 59,000 patient-years of follow-up were evaluable for the analyses of survival outcomes. Six cycles of BEACOPPescalated and 8 cycles of BEACOPP-14 were associated with the lowest risk for death of any cause (HR 0.38, 95%-CrI 0.20 to 0.75 and HR 0.43, 95%-CrI 0.22 to 0.86, respectively). Assuming a five-year survival rate of 89% for ABVD this would result in a 5-year survival benefit of 7% and 6% for 6 cycles of BEACOPPescalated and 8 cycles of BEACOPP-14, respectively (95%-CrI 3% to 9% and 2% to 9%, respectively). Eight cycles of BEACOPPescalated were also statistically significantly better as compared to ABVD but the effect was less pronounced. All other treatment strategies showed no statistically significant difference to ABVD. Similar results were obtained for FFTF. Between-trial heterogeneity was negligible in both analyses (tau-square 0.01 and 0.05, respectively). Overall, 327 secondary malignancy and 109 leukemia events accumulated over 57,529 patient-years of follow-up. Given the low number of events we were not able to accurately quantify the risk associated with each regimen; however, Stanford V might be associated with the lowest risk and C(M)OPP/EBV/CAD with the highest risk for secondary leukemias. Limitations: Some of the regimens were only evaluated in one trial. The number of secondary malignancies, especially leukemias, was low. Conclusions: The comparison of different first-line treatment strategies for advanced stage HL in this network meta-analysis shows a significant and relevant OS benefit for both, 6 cycles of BEACOPPescalated and 8 cycles of BEACOPP-14 over standard ABVD treatment. This analysis provides the currently best available evidence on OS of different initial treatment strategies for advanced stage HL patients and therefore adds valid and important information for both, patients and physicians. Disclosures: No relevant conflicts of interest to declare.