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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. In the investigator-sponsored randomized phase II NIVAHL trial for early-stage unfavorable classical Hodgkin lymphoma (HL), two schedules of four cycles of nivolumab, doxorubicin, vinblastine, and dacarbazine followed by 30 Gy involved-site radiotherapy resulted in high complete remission rates and an unprecedented 1-year progression-free survival in 109 patients. In this article, we report the preplanned final analysis conducted three years after the registration of the last patient including long-term safety results. No survival events were observed since the primary analysis, and after a median follow-up (FU) of 41 months, the overall survival was 100% in both treatment groups. The progression-free survival was 98% and 100% in the sequential and concomitant nivolumab, doxorubicin, vinblastine, and dacarbazine treatment groups, respectively. At last FU, the mean forced expiratory pressure in one second was 95.5% (standard deviation 12.7%), the mean diffusion capacity for carbon monoxide adjusted for hemoglobin was 82.8% (standard deviation 15.4%), and the left ventricular ejection fraction was in the normal range in 95% of patients. Hypothyroidism requiring long-term medication occurred in 15% of patients, who were nearly exclusively female (87%). No second primary malignancies occurred, and no patient required corticosteroid treatment at last FU. Patient-reported normalized global quality-of-life score measured by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 improved over time. This preplanned FU analysis of the largest anti–programmed death protein 1 HL first-line trial to date confirms the outstanding efficacy and relatively favorable safety profile of this therapeutic approach.

Alzheimer’s disease (AD) is characterized by excessive formation of beta-amyloid peptides (Aβ), mitochondrial dysfunction, enhanced production of reactive oxygen species (ROS), and altered glycolysis. Since the disease is currently not curable, preventive and supportive approaches are in the focus of science. Based on studies of promising single substances, the present study used a mixture (cocktail, SC) of compounds consisting of hesperetin (HstP), magnesium-orotate (MgOr), and folic acid (Fol), as well as the combination (KCC) of caffeine (Cof), kahweol (KW) and cafestol (CF). For all compounds, we showed positive results in SH-SY5Y-APP695 cells—a model of early AD. Thus, SH-SY5Y-APP695 cells were incubated with SC and the activity of the mitochondrial respiration chain complexes were measured, as well as levels of ATP, Aβ, ROS, lactate and pyruvate. Incubation of SH-SY5Y-APP695 cells with SC significantly increased the endogenous respiration of mitochondria and ATP levels, while Aβ1–40 levels were significantly decreased. Incubation with SC showed no significant effects on oxidative stress and glycolysis. In summary, this combination of compounds with proven effects on mitochondrial parameters has the potential to improve mitochondrial dysfunction in a cellular model of AD.

Alzheimer’s disease (AD) is characterized by mitochondrial dysfunction, increased Aβ levels and altered glycolysis. So far, there is no cure for AD, therefore it is important to take preventive or supportive action against AD. The cocktail (SC) tested in this study consists of the substances hesperetin (HstP), magnesium-orotate (MgOr) and folic acid (Fol), as well as the combination (KCC) of caffeine (Cof), kahweol (KW) and cafestol (CF). All the compounds showed positive results in the above mentioned fields of AD. The question arose whether a combination of all of them would also positively affect all three fields of AD. In this regard, SH-SY5Y-APP695cells were incubated with SC and ATP levels, complex respiration, Aβ levels, ROS levels, lactate and pyruvate levels were examined. The SC increased the endogenous respiration of the cells while significantly decreasing the Aβ1-40levels. SC has no significant effects on the other parameters. In summary, the combination of all compounds did not show the desired success that we hoped for, but the cocktail has potential to be further investigated. It is possible that the results will improve by changing the combinations or by adjusting the concentrations.

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

Three reports address the protection of the vulnerable population of patients with hematologic malignancies in the face of the ongoing COVID pandemic. The reports suggest that some patients who fail to mount a B-cell response to vaccine may nevertheless have protective T cell responses. As a group, these reports suggest that patients should continue to be immunized with additional doses to attempt to improve immune response but that they need to maintain the precautions recommended for the unvaccinated.

Background: Combined-modality treatment consisting of chemotherapy and consolidation radiotherapy is standard of care for patients with early-stage unfavourable Hodgkin lymphoma. However, the use of radiotherapy can have long-term sequelae, which is of particular concern, as Hodgkin lymphoma is frequently diagnosed in young adults with a median age of approximately 30 years. In the German Hodgkin Study Group HD17 trial, we investigated whether radiotherapy can be omitted without loss of efficacy in patients who have a complete metabolic response after receiving two cycles of escalated doses of etoposide, cyclophosphamide, and doxorubicin, and regular doses of bleomycin, vincristine, procarbazine, and prednisone (eBEACOPP) plus two cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy (2 + 2). Methods: In this multicentre, open-label, randomised, phase 3 trial, patients (aged 18–60 years) with newly diagnosed early-stage unfavourable Hodgkin lymphoma (all histologies) and an Eastern Cooperative Oncology Group performance status of 2 or less were enrolled at 224 hospitals and private practices in Germany, Switzerland, Austria, and the Netherlands. Patients were randomly assigned (1:1) to receive either standard combined-modality treatment, consisting of the 2 + 2 regimen (eBEACOPP consisted of 1250 mg/m2 intravenous cyclophosphamide on day 1, 35 mg/m2 intravenous doxorubicin on day 1, 200 mg/m2 intravenous etoposide on days 1–3, 100 mg/m2 oral procarbazine on days 1–7, 40 mg/m2 oral prednisone on days 1–14, 1·4 mg/m2 intravenous vincristine on day 8 [maximum dose of 2 mg per cycle], and 10 mg/m2 intravenous bleomycin on day 8; ABVD consisted of 25 mg/m2 intravenous doxorubicin, 10 mg/m2 intravenous bleomycin, 6 mg/m2 intravenous vinblastine, and 375 mg/m2 intravenous dacarbazine, all given on days 1 and 15) followed by 30 Gy involved-field radiotherapy (standard combined-modality treatment group) or PET4-guided treatment, consisting of the 2 + 2 regimen followed by 30 Gy of involved-node radiotherapy only in patients with positive PET at the end of four cycles of chemotherapy (PET4; PET4-guided treatment group). Randomisation was done centrally and used the minimisation method and seven stratification factors (centre, age, sex, clinical symptoms, disease localisation, albumin concentration, and bulky disease), and patients and investigators were masked to treatment allocation until central review of the PET4 examination had been completed. With the final analysis presented here, the primary objective was to show non-inferiority of the PET4-guided strategy in a per-protocol analysis of the primary endpoint of progression-free survival. We defined non-inferiority as an absolute difference of 8% in the 5-year progression-free survival estimates between the two groups. Safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01356680. Findings: Between Jan 13, 2012, and March 21, 2017, we enrolled and randomly assigned 1100 patients to the standard combined-modality treatment group (n=548) or to the PET4-guided treatment group (n=552); two patients in each group were found ineligible after randomisation. At a median follow-up of 46·2 months (IQR 32·7–61·2), 5-year progression-free survival was 97·3% (95% CI 94·5–98·7) in the standard combined-modality treatment group and 95·1% (92·0–97·0) in the PET4-guided treatment group (hazard ratio 0·523 [95% CI 0·226–1·211]). The between-group difference was 2·2% (95% CI −0·9 to 5·3) and excluded the non-inferiority margin of 8%. The most common grade 3 or 4 acute haematological adverse events were leucopenia (436 [83%] of 528 patients in the standard combined-modality treatment group vs 443 [84%] of 529 patients in the PET4-guided treatment group) and thrombocytopenia (139 [26%] vs 176 [33%]), and the most frequent acute non-haematological toxic effects were infection (32 [6%] vs 40 [8%]) and nausea or vomiting (38 [7%] vs 29 [6%]). The most common acute radiotherapy-associated adverse events were dysphagia (26 [6%] in the standard combined-modality treatment group vs three [2%] in the PET4-guided treatment group) and mucositis (nine [2%] vs none). 229 serious adverse events were reported by 161 (29%) of 546 patients in the combined-modality treatment group, and 235 serious adverse events were reported by 164 (30%) of 550 patients in the PET4-guided treatment group. One suspected unexpected serious adverse reaction (infection) leading to death was reported in the PET4-guided treatment group. Interpretation: PET4-negativity after treatment with 2 + 2 chemotherapy in patients with newly diagnosed early-stage unfavourable Hodgkin lymphoma allows omission of consolidation radiotherapy without a clinically relevant loss of efficacy. PET4-guided therapy could thereby reduce the proportion of patients at risk of the late effects of radiotherapy. Funding: Deutsche Krebshilfe.

Purpose: A primary analysis of the ongoing NIVAHL trial demonstrated unexpectedly high interim complete response rates to nivolumab-based first-line treatment in early-stage unfavorable Hodgkin lymphoma. However, biomarkers such as metabolic tumor volume (MTV) or total lesion glycolysis (TLG) and their change under treatment (ΔMTV and ΔTLG), measured on PET, might provide additional relevant information for response assessment in this setting. Hence, the current analysis aimed to investigate early response to checkpoint inhibitor therapy beyond conventional criteria. Patients and Methods: NIVAHL is a prospective, randomized phase II trial that recruited between April 2017 and October 2018. Patients in arms A and B were assessed for early treatment response after two courses of doxorubicin, vinblastine, and dacarbazine with two concomitant nivolumab infusions per cycle (2 × N-AVD) and 4 × nivolumab, respectively. In the current analysis, we included all 59 individuals with PET images available to the central review panel for quantitative analysis before April 30, 2019. Results: At interim restaging, we determined a mean ΔMTV and ΔTLG of −99.8% each in arm A after 2 × N-AVD, compared with −91.4% and −91.9%, respectively, for treatment group B undergoing 4 × nivolumab. This high decrease in MTV and TLG was observed regardless of the initial lymphoma burden. Conclusions: Our study showed that nivolumab-based first-line treatment leads to rapid, near-complete reduction of tumor metabolism in early-stage unfavorable Hodgkin lymphoma. Thus, PET-derived biomarkers might allow reduction or even omission of chemotherapy and radiotherapy. Furthermore, MTV and TLG could be also used to optimize immune checkpoint-targeting treatments in other cancers.

Based on centroblast frequency, follicular lymphoma (FL) is subdivided into grades 1-2, 3A, and 3B. Grade FL3A frequently coexists with FL1-2 (FL1-2-3A). Based on clinical trials, FL1-2 is treated with rituximab (R) or obinutuzumab plus bendamustine (B) or CHOP, while FL3B is treated with R-CHOP. In contrast, there are little data guiding therapy in FL3A. We present a retrospective, multicenter analysis of 95 FL3A or FL1-2-3A and 203 FL1-2 patients treated with R-CHOP or R-B first-line. R-CHOP facilitated a higher response rate (95% versus 76%) and longer overall survival (OS) (3-year OS 89% versus 73%, P = 0.008) in FL3A or FL1-2-3A, whereas the difference in progression-free survival (PFS) did not reach statistical significance. While transformation rates into aggressive lymphoma were similar between both groups, there were more additional malignancies after R-B compared with R-CHOP (6 versus 2 cases). In FL1-2, R-B achieved a higher 3-year PFS (79% versus 47%, P

We performed a survey in Hodgkin lymphoma survivors to learn more about their perspectives on treatment risks and benefits. We sent questions to 1149 survivors from the GHSG’s HD13-15 trials with (...

Summary Background To improve the long-term tumour control in early, unfavourable Hodgkin Lymphoma, the German Hodgkin Study Group (GHSG) HD14 trial compared four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with an intensified chemotherapy regimen consisting of two cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (escalated BEACOPP) plus two cycles of ABVD. The final analysis of the trial showed a significant advantage in terms of freedom from treatment failure (difference 7·2% [95% CI 3·8–10·5] at 5 years) for patients who received two cycles of escalated BEACOPP and two cycles of ABVD. However, there was no difference in overall survival between the two groups. To evaluate long-term efficacy and toxicity of this strategy, we did a follow-up analysis. Methods Patients aged 18–60 years with performance status of 2 or less and primary diagnosis of early, unfavourable Hodgkin lymphoma (all histologies) were included in an international, randomised, open-label, phase 3 trial. Patients were randomly assigned to receive four cycles of ABVD (ABVD group) or two cycles of escalated BEACOPP and two cycles of ABVD (2 + 2 group), both groups also received 30 Gy involved field radiotherapy. The ABVD dosing regimen was doxorubicin 25 mg/m2 (days 1 and 15), bleomycin 10 mg/m2 (days 1 and 15), vinblastine 6 mg/m2 (days 1 and 15), and dacarbazine 375 mg/m2 (days 1 and 15), repeated on day 29. The escalated BEACOPP dosing regimen was cyclophosphamide 1250 mg/m2 (day 1), doxorubicin 35 mg/m2 (day 1), etoposide 200 mg/m2 (days 1–3), procarbazine 100 mg/m2 (days 1–7), prednisone 40 mg/m2 (days 1–14), vincristine 1·4 mg/m2 (day 8; maximum 2 mg), and bleomycin 10 mg/m2 (day 8), repeated on day 22. After closure of the ABVD group according to prespecified rules, patients were assigned to receive two cycles of escalated BEACOPP and two cycles of ABVD (non-randomised 2 + 2 group), which continued until the end of the predefined 5-year recruitment period. In this prespecified long-term follow-up analysis, we aimed to evaluate the secondary endpoints progression-free survival, overall survival, and long-term toxicity. To this end, we did a descriptive intention-to-treat analysis of all qualified HD14 patients and on the predefined subsets of randomised qualified HD14 patients and patients in the non-randomised 2 + 2 group. The trial was registered on the International Standard Randomised Controlled Trial database, 04761296. Findings Between Jan 28, 2003, and Dec 29, 2009, 1686 patients were randomly assigned to the ABVD group (847 [50·2%] patients) and the 2 + 2 group (839 [49·8%] patients). 370 additional patients were recruited to the non-randomised 2 + 2 group. 1550 (92%) randomly assigned patients (median observation time 112 months [IQR 80–132]) and 339 (92%) patients in the non-randomised 2 + 2 group (median observation time 74 months [58–100]) were included in the qualified analysis set. 10-year overall survival in the randomly assigned patients was 94·1% (95% CI 92·0–95·7) for the ABVD group and 94·1% (91·8–95·7) for the 2 + 2 group (HR 1·0 [95% CI 0·6–1·5]; p=0·88). 8-year overall survival in the non-randomised 2 + 2 group was 95·1% (95% CI 91·6–97·2). 10-year progression-free survival in the randomly assigned patients was 85·6% (95% CI 82·6–88·1) for the ABVD group and 91·2% (88·4–93·3) for the 2 + 2 group (HR 0·5% [95% CI 0·4–0·7]; p=0·0001), accounting for a significant difference of 5·6% (95% CI 1·9–9·2) favouring the 2 + 2 group (p=0·0001). In the non-randomised 2 + 2 group, 8-year progression-free survival was 94·5% (95% CI 91·1–96·6). Standardised incidence ratios of second primary malignancies were similar between the ABVD group (2·3 [95% CI 1·6–3·1]) and the 2 + 2 group (2·5 [1·8–3·4]; Gray's p=0·80). Standardised incidence ratio of second primary malignancies was 3·1 (95% CI 1·7–5·0) in the non-randomised 2 + 2 group. Interpretation This long-term analysis confirms superior tumour control in the 2 + 2 group compared with the ABVD group without translating into an overall survival difference. At longer follow-up, there is no difference regarding second primary malignancies between groups. In conclusion, the 2 + 2 regimen spares a significant number of patients from the burden of relapse and additional treatment without increased long-term toxicity. Funding Deutsche Krebshilfe eV and Swiss Federal Government.

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

There is a high need for novel treatment options in relapsed and refractory diffuse large B-cell lymphoma. Single agent mammalian target of rapamycin (mTOR) inhibitor treatment has shown promising efficacy in this entity. Here, we report on the results of the mTOR-inhibitor temsirolimus combined to standard rituximab-DHAP salvage regimen in a prospective, multicenter, phase II, open-label study. The STORM regimen consisted of rituximab 375 mg/m(2) (day 2) and DHAP (dexamethasone 40 mg day 3-6, cisplatinum 100 mg/m(2) day 3, cytarabine 2 × 2 g/m(2) day 4) with temsirolimus added on day 1 and 8 of a 21-day cycle, with 2 to 4 cycles planned. In part I, dose levels of 25, 50, 75, and 100 mg for temsirolimus were predefined. Based on the observed toxicity profile, a temsirolimus dose of 25 mg was defined as recommended dose for the part II extension cohort of the trial. The intention-to-treat cohort comprised 53 patients. Median age was 63 years and median number of prior regimen was 1. All but 1 patient had prior rituximab exposure. Temsirolimus dose was 50 mg on day 1 and 8 in 6 patients from the part I of the trial and 25 mg in the remaining 47 patients. In general, treatment was well tolerated with leucopenia and thrombocytopenia as most frequent severe adverse events. The overall response rate after the last cycle of temsirolimus R-DHAP was 66% with 24% complete responses. The ability to mobilize stem cells was not impaired by the treatment regimen. Twenty-eight patients received consolidation treatment with high-dose therapy (HDT) and stem cell transplantation. Median duration of response was not reached. The total 2-year progression-free survival (PFS) and overall survival (OS) were 53% and 59%. Patients who were consolidated with HDT achieved a 2-year PFS and a 2-year OS of 77.8% and 82.1%, respectively. We conclude that temsirolimus can be safely added to rituximab and DHAP with promising activity.

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

Purpose of this single-centre retrospective study was to assess the outcome of allogeneic hematopoietic cell transplantation (alloHCT) for relapsed/refractory (r/r) non-Hodgkin lymphoma (NHL) by intent-to-transplant (ITT). Included were all consecutive patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and peripheral T-cell lymphoma (PTCL) for whom a donor search was performed between 2004 and 2018. Primary endpoint was overall survival (OS) measured from search initiation. A donor search was initiated for 189 patients (DLBCL 61, FL 32, MCL 43, and PTCL 53), with 76% of the patients having active disease. OS at 5 years after search initiation for DLBCL, FL, MCL, and PTCL was 26%, 44%, 52%, and 50%, respectively. AlloHCT was performed in 137 patients (72%; DLBCL 64%). Main reason for not undergoing alloHCT was disease progression, whereas donor unavailability accounted for only 4% of pretransplantation failures. These results suggest that survival of patients with r/r NHL entering the alloHCT route may be overestimated by a factor of 1.2-1.4 if based on actually transplanted patients only. This effect should be taken into account when using alloHCT as benchmark for new therapeutic approaches for the treatment of poor-risk NHL.

Das Gesamtuberleben von Patienten mit fortgeschrittenem Hodgkin-Lymphom (HL), die mit dem aktuellen Standard der Deutschen Hodgkin Studiengruppe (DHSG), bestehend aus der Interim-Positronen-Emissionstomographie(PET)-gesteuerten Gabe von 4 bis 6 Zyklen BEACOPPeskaliert (Bleomycin, Etoposid, Doxorubicin, Cyclophosphamid, Vincristin, Procarbazin und Prednison in eskalierter Dosierung) plus Bestrahlung Positronen-Emissionstomographie-positiver Reste, behandelt werden, liegt bei mehr als 95 %. Es ist dennoch notig, die Toxizitat der Therapie weiter zu minimieren, ohne dabei Einbusen in der Effektivitat zu erleiden. Langfristiges Ziel ist also die Reduktion von Nebenwirkungen bei gleichbleibend gutem Therapieerfolg. Ziel des vorliegenden Artikels ist es, eine Zusammenfassung uber die gegenwartigen Standardtherapien sowie neue Entwicklungen in der Behandlung des fortgeschrittenen HL zu geben. Mittels systematischer und manueller Literaturrecherche wurden relevante Publikationen sowie im Rahmen derzeit laufender Studien getestete neue Therapieansatze zusammengefasst. Vergleiche von BEACOPPeskaliert und ABVD (Doxorubicin, Bleomycin, Vinblastin, Dacarbazin) zeigen einen signifikanten und klinisch bedeutenden Uberlebensvorteil fur BEACOPPeskaliert sowohl im Sinne des progressionsfreien Uberlebens (PFS) als auch des Gesamtuberlebens (OS). Die Interim-PET-gesteuerte Gabe von 4−6 Zyklen BEACOPPeskaliert ist sicher und hoch effektiv. Dennoch ist eine weitere Optimierung der Therapie, z. B. durch die Implementierung zielgerichteter Substanzen wie Brentuximab Vedotin, moglich. Daher wird derzeit eine BEACOPP-Variante namens BrECADD (Brentuximab Vedotin, Etoposid, Cyclophosphamid, Doxorubicin, Dacarbazin, Dexamethason) im Rahmen der HD21-Studie randomisiert mit herkommlichem BEACOPPeskaliert verglichen. Zuvor wurde im Rahmen einer Phase-II-Studie gezeigt, dass BrECADD bei Patienten mit fortgeschrittenem HL sicher angewendet werden kann. Langfristiges Ziel in der Behandlung des HL ist die Reduktion der Toxizitat der Therapie ohne Verschlechterung der Tumorkontrolle und des lymphomspezifischen Outcomes. Dies kann moglicherweise durch die Implementierung zielgerichteter Substanzen in die Erstlinientherapie erreicht werden. Daher wird momentan die Brentuximab Vedotin enthaltende BEACOPP-Variante BrECADD im Rahmen der HD21-Studie randomisiert gegen konventionelles BEACOPPeskaliert getestet.

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

Whilst autologous stem cell transplantation (auto-SCT) is considered standard of care for relapsed/refractory classical Hodgkin lymphoma, the role of auto-SCT in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is not well defined due to limited data. We report the first study on auto-SCT for NLPHL with a larger cohort. Eligible for this retrospective registry study were patients reported to the EBMT between 2003 and 2013, aged 18 or older with relapsed/refractory NLPHL who underwent first auto-SCT with disease chemosensitive to salvage therapy. NLPHL transformed to diffuse large B cell lymphoma were excluded. Sixty patients (83% male; median age 40 years) met the eligibility criteria. The median time between diagnosis and transplant was 21 months (IQR 13-58), and the median number of prior treatment lines was 2 (range 1-5), including rituximab in 63% of the patients. At auto-SCT, 62% of the patients were in complete remission (CR) and 38% in partial remission. Seventy-two percent of the patients received BEAM as high-dose therapy. With a median follow-up of 56 months (range 3-105), 5-year progression-free and overall survival (OS) were 66% and 87%, respectively. Univariate comparisons considering age, time from diagnosis to transplant, prior chemotherapy lines, and prior rituximab use failed to identify significant predictors for any survival endpoint except for being in CR at the time of auto-SCT (vs PR, P = .049) for OS. Auto-SCT in patients with relapsed/refractory NLPHL who are sensitive to salvage therapy gives excellent disease control and long-term survival independent of the time interval between diagnosis and transplant.

Background The primary analysis of the investigator-sponsored randomized multicenter phase II GHSG NIVAHL trial showed feasibility and excellent short-term efficacy of anti-PD1 based 1st-line treatment of early-stage unfavorable classical Hodgkin lymphoma (cHL). Achieving long-term disease control without excessive treatment-related morbidity is of utmost importance when developing innovative 1st-line cHL therapies. Duration of response and development of persisting immune-related toxicities are of concern in the setting of 1st-line anti-PD1 treatment. Methods NIVAHL enrolled treatment naïve early-stage unfavorable cHL patients at 28 German centers and individuals were randomized to either receive fully concomitant 4x Nivo-AVD (group A) or sequential 4xnivolumab, followed by 2x Nivo-AVD and 2x AVD (group B). Both groups received consolidative 30Gy IS-RT and the primary endpoint was complete response (CR) rate at end of study treatment. Detailed methods, patient characteristics and the primary endpoint analysis of NIVAHL have been recently published (Bröckelmann PJ et al. JAMA Oncol 2020). Herein we present extended follow-up of the NIVAHL trial to assess efficacy in terms of 2-year progression-free (PFS) and overall survival (OS) as well as safety with regards to long-term toxicities or organ impairment documented during the first year of follow-up after treatment. Results A total of 109 patients with cHL confirmed by central pathology review were enrolled between 04/2017 - 10/2018 and followed for a median of 20 and 21 months in groups A (n=55) and B (n=54), respectively, for the present analysis. All of the 7 patients deemed in partial remission (PR) at end of study treatment (EOT) converted into an ongoing CR after end of study without additional treatment during follow-up. With no relapse and no death observed since the primary analysis, the 2-year PFS estimates are 100% and 98% (95%CI 88-100%) in groups A and B, respectively, and the 2-year OS is 100% in both groups. With a median observation time for late-toxicities of 14 months after EOT (range 6-26 months) among 103 patients, any potentially treatment-related AE during follow-up was reported in 65% of patients (A: 74%, B: 56%). The highest documented CTCAE grade of late AEs was °I in 33%, °II in 25% and °III in 7% of patients with no °IV-V AEs observed. A total of 54% had at least one late event related to AVD, 47% to nivolumab and 32% to RT, with multiple relations attributable per event. Mean FEV1 and DLCOc did not decrease from baseline (91.1% -> 96.4% and 86.2% -> 83.3%, respectively). Decreased LVEF after EOT was reported in 2/56 patients with available data (4%). After EOT, 18% of patients required medication for adverse events. Corticosteroid ≥ and < 10mg prednisolone equivalent was required in 3% and 2% of patients, respectively, for a toxicity at any time during follow-up. No patient required corticosteroid treatment at last available follow-up. Most frequent toxicities reported after EOT included fatigue (21%), hypothyroidism (17%), respiratory tract disorders (16%), leukopenia (14%) and nervous system disorders (14%). Hypothyroidism was the event most frequently solely attributed to nivolumab during follow-up. The median time to onset after EOT was 5 months and affected patients nearly exclusively female (15/16 [94%]). After median follow-up of 10 months (range 0-21), hypothyroidism remained unchanged in 10 of 16 affected patients and resolved in 3 patients. Conclusion The excellent disease control of concomitant and sequential nivolumab and AVD in early-stage unfavorable cHL is confirmed with the currently available follow-up. Treatment-related toxicities ongoing or emerging during follow-up are predominantly associated with chemo- and/or RT. The most frequent nivolumab-associated late toxicity is hypothyroidism. No patient currently requires chronic corticosteroid treatment. Disclosures Bröckelmann: Bristol Myers Squibb: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; MSD Sharp & Dohme: Research Funding. Keller:Bristol Myers Squibb: Honoraria, Other: Travel support, Speakers Bureau. Meissner:Celgene: Other: Travel support; Bristol Myers Squibb: Other: Travel support; Takeda: Other: Travel support; Merck Sharp & Dohme: Other: Travel support; Hexal: Other: Travel support. Trautmann:Bristol Myers Squibb: Honoraria. Kerkhoff:BMS: Honoraria. Hüttmann:Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Lead Discovery Center GmbH: Consultancy; Seattle Genetics: Research Funding; Gilead: Honoraria; University Hospital Essen, University of Duisburg-Essen, Essen, Germany: Current Employment; Roche: Other: Travel expenses; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Zimmermann:Takeda: Consultancy, Honoraria, Other: Travel Expenses; Bristol-Myers Squibb: Other: Travel Expenses; MSD: Other: Travel Expenses; Novartis: Other: Travel Expenses. Fuchs:Bristol Myers Squibb: Honoraria, Research Funding; Affimed: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria. von Tresckow:Takeda: Honoraria, Other: Travel support, Research Funding; Novartis: Other: Travel support, Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding; MSD Sharp & Dohme: Honoraria, Research Funding; Roche: Honoraria; Kite/Gilead: Honoraria; Pfizer: Honoraria; Amgen: Honoraria. Borchmann:Takeda: Research Funding; Bristol Myers Squibb: Research Funding. Engert:Bristol Myers Squibb: Honoraria, Research Funding; Affimed Therapeutics: Research Funding; Takeda: Honoraria, Research Funding; MSD Sharp & Dohme: Honoraria; AstraZeneca: Honoraria; Sandoz: Honoraria. OffLabel Disclosure: Nivolumab 240mg Q2W alone or in combination with AVD for 1st-line treatment of classical Hodgkin lymphoma.

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

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 KEYNOTE-087, pembrolizumab had a 69% overall response rate and acceptable safety in patients with relapsed/refractory classical Hodgkin lymphoma (rrHL). We assessed health-related quality of life (HRQoL) in KEYNOTE-087. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30) and the EuroQoL Five Dimensions Questionnaire 3-level version (EQ-5D) were administered to 206 patients across three cohorts defined by lymphoma progression after: (1) autologous stem cell transplantation (ASCT) and subsequent brentuximab vedotin (BV) (n = 69); (2) salvage chemotherapy and BV (n = 79); and (3) ASCT without post-transplantation BV (n = 58). Compliance/completion rates were ≥90% at week 12 and ≥70% at week 24. QLQ-C30 global health status/QoL and EQ-5D visual analog scale scores showed mean increases from baseline in overall health at all assessed timepoints. With few exceptions, mean improvements from baseline to weeks 12 and 24 in QLQ-C30 functional and symptom scores occurred in all cohorts.Clinicaltrials.gov identifier: NCT02453594.

PURPOSE Combined-modality treatment (CMT) with 2× ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and small-field radiotherapy is standard of care for patients with early-stage favorable Hodgkin lymphoma (HL). However, the role of radiotherapy has been challenged. Positron emission tomography (PET) after 2× ABVD (PET-2) might help to predict individual outcomes and guide treatment. METHODS Between November 2009 and December 2015, we recruited patients age 18 to 75 years with newly diagnosed, early-stage favorable HL for this international randomized phase III trial. Patients were assigned to standard CMT of 2× ABVD and 20-Gy involved-field radiotherapy or PET-guided treatment, omitting involved-field radiotherapy after negative PET-2 (Deauville score < 3). Primary objectives were to exclude inferiority of 10% or more in 5-year progression-free survival (PFS) of ABVD alone compared with CMT in a per-protocol analysis among PET-2–negative patients (noninferiority margin for hazard ratio, 3.01) and to confirm PET-2 positivity (Deauville score ≥ 3) as a risk factor for PFS among CMT-treated patients. RESULTS We enrolled 1,150 patients. Median follow-up was 45 months. Among 628 PET-2–negative, per-protocol–treated patients, 5-year PFS was 93.4% (95% CI, 90.4% to 96.5%) with CMT and 86.1% (95% CI, 81.4% to 90.9%) with ABVD (difference 7.3% [95% CI, 1.6% to 13.0%]; hazard ratio, 1.78 [95% CI, 1.02 to 3.12]). Five-year overall survival was 98.1% (95% CI, 96.5% to 99.8%) with CMT and 98.4% (95% CI, 96.5% to 100.0%) with ABVD. Among 693 patients who were assigned to CMT, 5-year PFS was 93.2% (95% CI, 90.2% to 96.2%) among PET-2–negative patients and 88.4% (95% CI, 84.2% to 92.6%) in PET-2–positive patients ( P = .047). When using the more common liver cutoff (Deauville score, 4) for PET-2 positivity, the difference was more pronounced (5-year PFS, 93.1% [95% CI, 90.7% to 95.5%] v 80.9% [95% CI, 72.2% to 89.7%]; P = .0011). CONCLUSION In early-stage favorable HL, a positive PET after two cycles ABVD indicates a high risk for treatment failure, particularly when a Deauville score of 4 is used as a cutoff for positivity. In PET-2–negative patients, radiotherapy cannot be omitted from CMT without clinically relevant loss of tumor control.

Background: About 20% of patients diagnosed with classical Hodgkin lymphoma (cHL) are 60 years or older. They have a comparatively poor prognosis, particularly when presenting in advanced stages. In previous trials, older patients did not benefit from intensified regimens in terms of overall survival due to a high toxicity-related death rate. In order to improve tolerability, we developed the B-CAP regimen (brentuximab vedotin, cyclophosphamide, doxorubicin and predniso(lo)ne), incorporating the antibody-drug conjugate brentuximab vedotin into a CHOP-based chemotherapy backbone. We report the first results of our multicenter phase II study evaluating B-CAP in older cHL patients. Methods: We recruited patients with newly diagnosed advanced-stage cHL aged 60 years or older and eligible for polychemotherapy (Cumulative Illness Rating Scale for Geriatrics ≤6 in total and ≤3 per organ system) in five European countries. Treatment consisted of six cycles B-CAP; radiotherapy to Positron Emission Tomography (PET) positive residuals was applied. The primary endpoint was the CT-based objective response rate (ORR; complete [CR] or partial remission (PR]) after six cycles of B-CAP, aiming at excluding an ORR of 60% or less via a one-sided 95% confidence interval. All patients completing interim staging after two cycles were considered eligible. Results: Between November 2015 and September 2017, 50 patients were recruited, of whom one withdrew consent before start of treatment. Of the remaining 49, 26 patients (53%) were male, 47 (96%) had stage III-IV disease, and the median age was 66 years (range 60-84). One patient died from infection before interim staging, and 48 patients were eligible for the primary endpoint. There were no further treatment-related deaths. The CT-based ORR was 98% (one-sided 95% CI 90.5%-100%) with 21 patients having CR, 26 patients having PR, and one patient having progressive disease in the restaging after completion of B-CAP therapy. All patients with CT-based CR and 10/26 patients with PR had a negative PET (Deauville < 4), resulting in a complete metabolic response rate of 65%. Dose delivery was high with only two patients stopping treatment after four and five cycles, respectively, due to toxicity. Progression-free and overall survival as well as safety data will be presented. Conclusion: B-CAP is feasible and effective in patients older than 60 years with advanced-stage cHL and should be subject of further research. Disclosures Boell: honoraria and research funding from Celgene, MSD, Mundipharma, Johnson & Johnson and Takeda: Consultancy, Honoraria, Research Funding. Fosså:Janssen Pharmaceuticals, Inc.: Honoraria. Leppa:Roche: Consultancy, Honoraria, Research Funding; Celgene: Consultancy; Bayer: Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Molin:Bristol-Myers Squibb: Honoraria; Roche Holding AG: Honoraria; Merck & Co., Inc: Honoraria; Takeda Pharmaceuticals: Research Funding. Borchmann:Novartis: Consultancy, Honoraria.

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

Background: In early unfavorable Hodgkin Lymphoma (HL), long-term tumor control with 4xABVD and 30Gy involved field radiotherapy (IFRT) is approximately 80%. To improve these results, the GHSG HD14 trial compared an intensified chemotherapy regimen consisting of 2xBEACOPPescalated plus 2xABVD (2+2) to 4xABVD. All patients received 30Gy IFRT. Due to a progression-free survival (PFS) difference of 6.2% at five years in favor of the intensified treatment, 2+2 plus 30Gy RT is the current GHSG standard and is a treatment option in the NCCN guidelines for early unfavorable HL. However, there was no overall survival (OS) difference between 2+2 and 4xABVD at the final analysis of HD14 and the potential long-term toxicity of 2+2 is debated. We therefore performed a long-term follow up analysis of HD14. Patients and Methods: Between January 2003 and July 2008, 1,550 patients with early unfavorable HL ≤60 years were randomized and treated with 4xABVD or 2+2, followed by 30Gy IFRT in all patients. Randomization was discontinued after the third planned interim analysis showed a significant advantage of 2+2 in terms of the primary endpoint freedom from treatment failure (FFTF, difference 7.2% at 5 years). Accrual to the 2+2 arm continued from July 2008 to December 2009 and 339 additional qualified patients were treated with 2+2 plus 30Gy IFRT. These patients were not reported in the initial report and are added to all analyses of this long-term follow-up. Time-to-event end points were compared between groups using the Kaplan-Meier method as well as univariate and multivariate Cox regression models. Results: After a median observation time of 97 months, 10.2% (79 of 777) and 3.4% (38 of 1112) of patients treated with 4xABVD and 2+2, respectively, had progression or relapse. The 10-year PFS was 85.6% for 4xABVD (95%-CI 82.9% to 88.4%) and 91.2% for 2+2 (95%-CI 89.0% to 93.4%) accounting for a significant PFS difference of 5.6% (95%-CI 2.1% to 9.1%) in favor of 2+2 (Figure 1). Two or more relapses were experienced by 21 of 777 (2.7%) and 10 of 1112 (0.9%) patients who had received 4xABVD or 2+2 as first-line treatment, respectively. However, there was still no OS difference between the two groups (OS 94.1% [95%-CI 92.3% to 96%] and 94% [95%-CI 92.3% to 95.8%] for 4xABVD and 2+2, respectively; difference at 10 years -0.1% [95%-CI -2.6% to 2.4%], median observation time for OS 104 months). In a multivariate regression analysis adjusting for age, B-symptoms, infra-diaphragmatic disease, and the 4 GHSG risk factors (elevated ESR, involvement of ≥3 lymph node areas, extranodal disease, and large mediastinal tumor) as predictive factors for PFS, age ≥50 (HR 2.260, 95%-CI 1.543 to 3.309), presence of infra-diaphragmatic disease (HR 1.766, 95%-CI 1.055 to 2.955), or of a large mediastinal tumor (HR 1.811, 95%-CI 1.226 to 2.675) and treatment with 4xABVD (HR 1.929, 95%-CI 1.423 to 2.614) were significant predictors of PFS. Slightly more patients in the 4xABVD group died from toxicity of salvage therapy as compared to 2+2 patients (1% [8 of 777] versus 0.6% [7 of 1112]) whereas there were relatively more deaths due to study therapy in the 2+2 group as compared to 4xABVD patients (0.6% [7 of 1112] versus 0.1% [1 of 777]), leading to a similar OS in both groups. There were no apparent differences in other causes of death including HL (5 of 777 [0.6%] versus 9 of 1112 [0.8%]) and second neoplasms (12 of 777 [1.5%] versus 16 of 1112 [1.4%]) between 4xABVD and 2+2, respectively. A total of 95 second malignancies corresponding to 10-year cumulative second malignancy incidences of 4.7% and 6.4% were reported for 4xABVD and 2+2, respectively, without a difference between the two groups (p=0.86). Standardized incidence ratios (SIR) showed elevation compared to the general German population and no significant difference between 4xABVD (2.3 [95%-CI 1.6 to 3.2]) and 2+2 (2.6 [95%-CI 2.0 to 3.4]). Conclusions: This long-term analysis confirms the superior tumor control of 2+2 as compared to 4xABVD in patients ≤60 with early unfavorable HL. However, this does not translate into an OS difference. At longer follow-up, there is no difference regarding second primary malignancies between the groups. In comparison to 4xABVD, the 2+2 regimen spares a significant number of patients from the burden of cancer recurrence and additional treatment without increased long-term toxicity. Therefore, 2+2 remains the GHSG standard for patients with early unfavorable HL ≤60. Disclosures Greil: Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; GSK: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Ratiopharm: Research Funding; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Eisai: Honoraria; Boehringer Ingelheim: Honoraria; Pfizer: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Sandoz: Honoraria; Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Sanofi Aventis: Honoraria; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Merck: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding. Topp:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Zijlstra:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria. Borchmann:Novartis: Honoraria, Research Funding. von Tresckow:Takeda: Consultancy, Honoraria, Other: Travel and congress funding, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel and congress funding, Research Funding; Pfizer: Honoraria; Amgen: Honoraria; Roche: Honoraria; MSD: Consultancy, Honoraria, Other: Travel and congress funding, Research Funding.

Background The anti-PD1 antibody nivolumab is approved for relapsed or refractory classical Hodgkin lymphoma (cHL) showing high overall response rates (ORR) and a favorable safety profile. However, complete response (CR) is rare in this setting, and most patients develop progressive disease. To evaluate the efficacy of combined nivolumab and doxorubicin, vinblastine and dacarbazine (AVD) as 1st-line treatment for early-stage unfavorable cHL, we conducted the GHSG NIVAHL trial. Methods NIVAHL is a prospective, randomized, investigator-sponsored single-stage phase II trial that enrolled treatment-naïve early-stage unfavorable cHL patients between 18 and 60 years at 35 German centers (NCT03004833). In arm A, patients received 240mg nivolumab and AVD at standard doses on day 1 and 15 of each 28-day cycle for a total of four cycles (4xNivoAVD). In arm B, the same treatment was administered sequentially, starting with 4x nivolumab in 2-weekly intervals, followed by 2xNivoAVD and 2xAVD. Both groups received 30Gy involved-site radiotherapy (IS-RT). Primary endpoint is the centrally reviewed PET/CT-based CR rate after completion of protocol therapy including IS-RT. 55 patients per group were enrolled in order to exclude a CR rate ≤80% with a power of 90% on a one-sided alpha level of 2.5% each. Secondary endpoints will be analyzed descriptively and include treatment-related morbidity (TRMorbidity), progression-free (PFS), overall survival (OS), response at interim and final restaging as well as patient-reported outcomes. Sequential biopsies, blood and microbiome samples were collected for correlative studies. Results Between 04/2017 and 10/2018, a total of 110 patients were enrolled with one patient disqualified due to alteration of HL diagnosis by central pathology review (N=109, group A n=55, group B n=54). The median age of the predominantly female patients (60%) was 27 years. Stage II was present in 95% of cases with ≥3 involved areas as most common risk factor (69%), followed by elevated ESR (48%), large mediastinal mass (20%) and extranodal disease (13%). Mean duration of chemoimmunotherapy was 15 (standard deviation (SD) 3) weeks and 22 (SD 6) weeks with a mean relative dose intensity of 87.4 (SD 15.9)% and 85.8 (SD 24.2)% in groups A and B, respectively. Severe protocol deviations occurred in 4 patients in group A and 5 in group B. Reasons were toxicity (n=5), patient's wish (n=2), incorrect allocation to early-stage unfavorable risk group (n=1) and progressive disease (n=1). Another 2 patients refused to receive IS-RT. Any adverse events (AEs) were reported for 98% of patients. AEs ≥°3 were observed in 73% and 78%, respectively, and serious AEs occurred in 38% and 28% of patients in groups A and B, respectively. TRMorbidity defined as organ toxicity ≥°3 or anemia, thrombocytopenia or infection °4 was documented in 16% and 22% of patients; all of these were organ toxicities predominantly of liver and gastrointestinal tract, with 19/21 events occurring during the first 2 treatment cycles. Data on ongoing or late toxicities is limited by short follow-up. Until 07/2019, 4 cases of persistent hypothyroidism have been reported. At the 1st interim restaging after 2xNivoAVD and 4x nivolumab, the ORR was 100% (54/54) and 96% (49/51), with a CR rate of 85% and 53% in groups A and B, respectively. Interim remission status was not assessed in 1 and 3 patients, respectively, due to treatment discontinuation after incorrect allocation to early-stage unfavorable risk group (n=1) or toxicity (n=3). After completion of systemic therapy, ORR was 100% (54/54) and 98% (50/51) with a CR rate of 81% and 86%, respectively. One patient in group B developed histologically proven primary progressive HL during nivolumab monotherapy while no other case of progressive or relapsed disease or death has been documented so far. The centrally reviewed CR rate at the end of treatment will be reported at the meeting. Additionally, initial data from currently ongoing histopathologic and immunologic studies will also be presented. Conclusion Concomitant and sequential therapy with nivolumab and AVD is feasible with acceptable toxicity. In early-stage unfavorable cHL, concomitant Nivo-AVD induces a high early CR rate. The interim CR rate observed with 4x nivolumab monotherapy is higher than previously reported in relapsed or advanced-stage disease. The primary endpoint and initial PFS data will be reported at the meeting. Disclosures Bröckelmann: Bristol-Myers Squibb: Honoraria, Other: Travel Support, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel Support, Research Funding; MSD Sharpe & Dohme: Research Funding. Kerkhoff:EUSA: Honoraria; Hexal: Honoraria; Celgene: Honoraria, Other: Travel Support; Roche: Honoraria; Novartis: Honoraria. Hüttmann:University Hospital Essen: Employment; Takeda: Honoraria; Gilead: Honoraria. Zimmermann:Takeda: Honoraria, Other: Travel Expenses; Novartis: Other: Travel Expenses; MSD: Other: Travel Expenses; BMS: Other: Travel Expenses. von Tresckow:MSD Sharpe & Dohme: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Roche: Honoraria; Amgen: Honoraria. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding. Borchmann:Novartis: Honoraria, Research Funding. OffLabel Disclosure: Nivolumab 240mg i.v. 2-weekly for 1st-line treatment of classical Hodgkin lymphoma.

Background The anti-PD1 antibodies nivolumab and pembrolizumab are approved for relapsed or refractory classical Hodgkin lymphoma (r/r cHL) due to high overall response rates (ORR) with a favorable safety profile. However, complete responses (CR) are rare, and patients eventually develop progressive disease. Treatment options in this situation are very limited and usually regarded palliative. Innovative therapies for patients with progressive r/r cHL or insufficient response to anti-PD1 antibodies are hence an unmet clinical need. Radiotherapy (RT) is highly effective and potentially curative in cHL. Local RT results in immunogeneic cell-death at times leading to immune-mediated systemic effects termed abscopal response (AR). Case reports in different cancers including cHL highlight this effect of local therapies potentially enhanced by systemic immunotherapies. Combining the approved systemic anti-PD1 treatment with local RT to a single cHL lesion might hence work synergistically and result in improved tumor control with limited additional toxicity. It thereby would constitute a viable therapeutic option for patients with r/r cHL and could in the future also be incorporated in earlier lines of therapy. However, prospective data regarding this treatment strategy is lacking and will be generated with the recently activated herein presented GHSG AERN trial. Study Design & Methods AERN is an investigator-sponsored, prospective, international, multicenter, single-arm, two-stage phase II trial (NCT03480334) conducted at 10 European trial sites in Austria, Germany, United Kingdom, Netherlands and Norway. Patients with r/r cHL on active anti-PD1 therapy >18 years of age without serious concomitant diseases or organ dysfunction are eligible for enrollment. Patients either have to present with progressive disease (PD) or stable disease (SD) >6 months as best response to the ongoing anti-PD1 antibody. After registration for the screening phase, eligibility will be verified by a centralized GHSG review facility who will also define a single target lesion for RT to ensure at least one cHL lesion outside the 10% RT isodose for evaluation of the primary endpoint (abscopal response rate after 6x nivolumab, ARR-6). All patients will receive 240mg nivolumab at 2-weekly intervals and 20 Gy RT to the target lesion at 2 Gy fractions on ten consecutive working days starting day 6 of nivolumab treatment. Nivolumab will be discontinued in case of inacceptable toxicity or further disease progression and continued for a maximum of 18 months within the AERN trial. During the first stage of the trial, 9 qualified patients will be treated and their response to treatment will be centrally evaluated after the first 6 nivolumab doses. If no AR is observed in stage I, the trial will be terminated for futility. Otherwise 20 additional patients will be enrolled into the second stage for a total trial population of 29 r/r cHL patients. The null hypothesis H0: ARR-6 < 5% will be tested against a one-sided alternative at a confidence level of α = 5%, and at least 4 AR need to be observed for the rejection of H0. Secondary endpoints include e.g. ORR, overall ARR, CR rate, PFS and OS but also feasibility aspects, (S)AEs and quality of life (QoL) measures. To understand the underlying mechanisms of efficacy but also resistance or toxicity a comprehensive set of correlative studies will be conducted. Baseline and sequential blood samples as well as tumor biopsies and rectal swabs for microbiome analyses will be taken during AERN in patients with separate informed consent. This allows detailed evaluation of serological, cellular, functional, histological and genetic parameters to elucidate synergies between anti-PD1 and RT. Ultimately the correlative studies should help to further refine anti-PD1 based combination therapies, ideally beyond the setting of r/r cHL. In summary AERN, to our knowledge, is the first prospective trial formally evaluating the postulated abscopal effect in r/r cHL. The trial addresses an unmet clinical need in r/r cHL patients with insufficient or lost response to anti-PD1 antibodies. AERN additionally will provide proof-of-concept for a synergy of local RT with checkpoint inhibition substantiated by comprehensive correlative studies in blood, tumor tissue and microbiome. Recruitment has started but preliminary data regarding safety or efficacy are not yet available. Figure Disclosures Bröckelmann: MSD Sharpe & Dohme: Research Funding; Takeda: Consultancy, Honoraria, Other: Travel Support, Research Funding; Bristol-Myers Squibb: Honoraria, Other: Travel Support, Research Funding. Greil:Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Eisai: Honoraria; Mundipharma: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Ratiopharm: Research Funding; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Janssen-Cilag: Honoraria; Sanofi Aventis: Honoraria; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Sandoz: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Genentech: Honoraria, Research Funding; GSK: Research Funding; Daiichi Sankyo: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Boehringer Ingelheim: Honoraria. Zijlstra:Janssen: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Illidge:Div of Cancer Sciences, Faculty of Biology, Medicine and Health, Univ of Manchester, National Institutes of Health and Research Biomedical Research Center, Manchester Academic Health Sciences, Christie Hospital National Health Service Foundation Trust: Employment; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics, Inc.: Research Funding. Zimmermann:Takeda: Honoraria, Other: Travel Expenses; Novartis: Other: Travel Expenses; MSD: Other: Travel Expenses; BMS: Other: Travel Expenses.

Although alloHCT is an accepted salvage treatment in defined settings of poor-risk NHL, its potential benefit in these indications remains controversial because virtually all published studies are uncontrolled and restricted to patients who were actually able to undergo transplantation. Here, we aimed at assessing the impact of alloHCT by measuring its outcome from the time of donor search indication rather than from the time of transplant, thereby taking into account those patients who fail to proceed to allografting for any reason. Study design and patients : In a single centre retrospective analysis, course and outcome of all patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) mantle cell lymphoma (MCL) and peripheral T-cell lymphoma (PTCL) who were considered as having an alloHCT indication according to accepted guidelines between 2004 and 2018 were recorded. Primary endpoint was overall survival (OS) from start of donor search. A key secondary endpoint was comparison of OS from the 3-month landmark by donor availability. Accepted donors were matched related donors (MRD), 10/10 matched unrelated donors (MUD), 9/10 compatible unrelated donors (MMUD), and mismatched related donors (MMRD), with haplo donors being used at our institution only since 2014. Results : Altogether a donor search was initiated in 187 patients (DLBCL 32%, FL 17%, MCL 23%, PTCL 28%). Median age was 54 (19-69) years with 74% being male. Within a median time from diagnosis to search initiation of 1.1 (0.1-19) years, a median of 4 (1-9) treatment lines had been administered, including an autoHCT in 50%. 69% of the patients had active disease at the time of search initiation. Only 2 patients underwent donor search in 1st remission (for Richter transformation and hepatosplenic T cell lymphoma, respectively). With a median follow-up of 6.2 (0.6-15.9) years, OS at 5 years after search initiation for DLBCL, FL, MCL, and PTCL was 25%, 44%, 52%, and 50%, respectively (Fig 1). 171 patients (91%) were alive at the 3-month landmark. For these, an MRD (20%), MUD (44%), MMUD (25%), or MMRD (7%) could be identified in 96% of the cases. AlloHCT was performed in 72% of all 187 patients, and in 79% of the patients alive at the 3-month landmark, with a significantly lower rate in DLBCL (69%) compared to the other entities. In patients who were actually transplanted, 5-year OS from landmark for DLBCL, FL, MCL and PTCL was 32%, 63%, 62%, and 62%, respectively, whereas only 5 of the 36 patients (14%) alive at the 3-month landmark not undergoing alloHCT for any reason survived long term. Due to the low rate of unsuccessful searches, donor vs no-donor landmark survival analyses were not possible. Conclusions: Despite donor search now being successful in virtually all cases, 20-30% of those patients intended for alloHCT for NHL will never proceed to transplant. However, long-term OS by ITT does not seem substantially worse than alloHCT outcome observed in registry studies restricted to patients actually transplanted, with DLBCL appearing inferior to the other 3 entities. Patients surviving the 3-month landmark but not undergoing alloHCT for any reason have a poor outlook. These results may serve as benchmark for novel therapeutic options entering the NHL treatment landscape. Disclosures Luft: Neovii: Research Funding; JAZZ: Research Funding. Schmitt:MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; Therakos Mallinckrodt: Other: Financial Support. Dreger:Neovii, Riemser: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy.

Aim The aim of this official guideline published by the German Society of Gynecology and Obstetrics (DGGG) and coordinated with the German Society of Urology (DGU) and the German Society of Reproductive Medicine (DGRM) is to provide consensus-based recommendations, obtained by evaluating the relevant literature, on counseling and fertility preservation for prepubertal girls and boys as well as patients of reproductive age. Statements and recommendations for girls and women are presented below. Statements or recommendations for boys and men are not the focus of this guideline. Methods This S2k guideline was developed at the suggestion of the guideline commission of the DGGG, DGU and DGRM and represents the structured consensus of representative members from various professional associations (n = 40). Recommendations The guideline provides recommendations on counseling and fertility preservation for women and girls which take account of the patient's personal circumstances, the planned oncologic therapy and the individual risk profile as well as the preferred approach for selected tumor entities. Ziel Das Ziel dieser offiziellen Leitlinie, die von der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe (DGGG) publiziert und zusammen mit der Deutschen Gesellschaft für Urologie (DGU) sowie Deutschen Gesellschaft für Reproduktionsmedizin (DGRM) koordiniert wurde, ist es, durch die Evaluation der relevanten Literatur konsensbasierte Handlungsempfehlungen für die Beratung und den Einsatz von fertilitätserhaltenden Maßnahmen bei präpubertären Mädchen und Jungen sowie für Patienten/-innen im reproduktiven Alter zu geben. Im Folgendem werden die Statements und Empfehlungen für Mädchen und Frauen dargestellt. Die Statements und Empfehlungen für Jungen und Männer sind nicht Inhalt dieser Publikation. Methoden Diese S2k-Leitlinie wurde durch einen strukturierten Konsens von repräsentativen Mitgliedern verschiedener Fachgesellschaften (n = 40) im Auftrag der Leitlinienkommission der DGGG, DGU und DGRM entwickelt. Empfehlungen Es werden Empfehlungen zur Beratung und dem Einsatz von fertilitätserhaltenden Maßnahmen bei Patientinnen unter Berücksichtigung der Lebensumstände, der geplanten onkologischen Therapie und des individuellen Risikoprofils dargestellt sowie über das Vorgehen bei ausgewählten Tumorentitäten.

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

Background The intensive polychemotherapy regimen eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) is very active in patients with advanced-stage Hodgkin's lymphoma, albeit at the expense of severe toxicities. Individual patients might be cured with less burdensome therapy. We investigated whether metabolic response determined by PET after two cycles of standard regimen eBEACOPP (PET-2) would allow adaption of treatment intensity, increasing it for PET-2-positive patients and reducing it for PET-2-negative patients. Methods In this open-label, randomised, parallel-group phase 3 trial, we recruited patients aged 18–60 years with newly diagnosed, advanced-stage Hodgkin's lymphoma in 301 hospitals and private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. After central review of PET-2, patients were assigned (1:1) to one of two parallel treatment groups on the basis of their PET-2 result. Patients with positive PET-2 were randomised to receive six additional cycles of either standard eBEACOPP (8 × eBEACOPP in total) or eBEACOPP with rituximab (8 × R-eBEACOPP). Those with negative PET-2 were randomised between standard treatment with six additional cycles of eBEACOPP (8 × eBEACOPP) or experimental treatment with two additional cycles (4 × eBEACOPP). A protocol amendment in June, 2011, introduced a reduction of standard therapy to 6 × eBEACOPP; after this point, patients with positive PET-2 were no longer randomised and were all assigned to receive 6 × eBEACOPP and patients with negative PET-2 were randomly assigned to 6 × eBEACOPP (standard) or 4 × eBEACOPP (experimental). Randomisation was done centrally using the minimisation method including a random component, stratified according to centre, age (2 (maximum total dose 700 mg). The primary objectives were to show superiority of the experimental treatment in the PET-2-positive cohort, and to show non-inferiority of the experimental treatment in the PET-2-negative cohort in terms of the primary endpoint, progression-free survival. We defined non-inferiority as an absolute difference of 6% in the 5-year progression-free survival estimates. Primary analyses in the PET-2-negative cohort were per protocol; all other analyses were by intention to treat. This trial was registered with ClinicalTrials.gov, number NCT00515554. Findings Between May 14, 2008, and July 18, 2014, we recruited 2101 patients, of whom 137 were found ineligible before randomisation and a further 19 were found ineligible after randomisation. Among 434 randomised patients (217 per arm) with positive PET-2, 5-year progression-free survival was 89·7% (95% CI 85·4–94·0) with eBEACOPP and 88·1% (83·5–92·7) with R-eBEACOPP (log-rank p=0·46). Patients with negative PET-2 randomly assigned to either 8 × eBEACOPP or 6 × eBEACOPP (n=504) or 4 × eBEACOPP (n=501) had 5-year progression-free survival of 90·8% (95% CI 87·9–93·7) and 92·2% (89·4–95·0), respectively (difference 1·4%, 95% CI −2·7 to 5·4). 4 × eBEACOPP was associated with fewer severe infections (40 [8%] of 498 vs 75 [15%] of 502) and organ toxicities (38 [8%] of 498 vs 91 [18%] of 502) than were 8 × eBEACOPP or 6 × eBEACOPP in PET-2-negative patients. Ten treatment-related deaths occurred: four in the PET-2-positive cohort (one [

In the multicentre prospective randomized HD2002 trial, rituximab maintenance therapy (375 mg/m(2) every 3 months for 2 years) versus observation was evaluated for CD20(+) B-cell lymphoma. Out of 321 patients [161 randomized to the treatment group (TG), 160 to the observation group (OG)], 295 data sets were evaluable for statistical analysis. Estimated 5-year relapse-free survival (RFS) was 81% in the TG and 70% in the OG (logrank test, P = 0·047). In the diffuse large B-cell lymphoma (DLBCL) subgroup (n = 152), 5-year RFS was excellent, at 87% in the TG and 84% in the OG (logrank test, P = 0·35). Of note, only in male patients of the DLBCL subgroup was RFS significantly superior in the TG in comparison to the OG (5-year RFS: 88% vs. 74%; logrank test, P = 0·05). Cox regression analysis showed a significant interaction between treatment and gender regarding overall survival (OS) (P = 0·006) and RFS (P = 0·02), with a lower hazard in females than males in the OG [OS: hazard ratio (HR) (female:male) = 0·11; 95% confidence interval (CI) = 0·00-1·03; RFS: HR (female:male) = 0·27; 95% CI = 0·05-0·97], and no significant differences between males and females in the TG. We conclude that Rituximab maintenance therapy improves survival in male patients with DLBCL.

Aims To examine the diagnostic accuracy of sensitive cardiac troponin (cTn) assays in elderly patients, since elevated levels with sensitive cTn assays were reported in 20% of elderly patients without acute myocardial infarction (AMI). Methods and results In this multi-centre study, we included 1098 consecutive patients presenting with symptoms suggestive of AMI, 406 (37%) were >70 years old. Measurement of three investigational sensitive cTn assays [Roche high-sensitive cTnT (hs-cTnT), Siemens cTnI-Ultra, and Abbott-Architect cTnI) and the standard assay (Roche cTnT) was performed in a blinded fashion. The final diagnosis was adjudicated by two independent cardiologists. Acute myocardial infarction was the adjudicated final diagnosis in 24% of elderly patients. Among elderly patients without AMI, baseline cTn levels were elevated above the 99th percentile in 51% with Roche hs-cTnT, in 17% with Siemens TnI-Ultra, and 13% with Abbott-Architect cTnI. The diagnostic accuracy as quantified by the area under the receiver operating characteristic (ROC) curve (AUC) was significantly greater for the sensitive cTn assays compared with the standard assay (AUC for Roche hs-cTnT, 0.94; Siemens cTnI-Ultra, 0.95; and Abbott-Architect cTnI, 0.95 vs. AUC for the standard assay, 0.90; P < 0.05 for comparisons). The best cut-offs for the sensitive cTn-assays determined by the ROC-curve in elderly patients differed clearly from those in younger patients. Furthermore, the prognostic value regarding 90-day mortality varied among the sensitive cTn assays. Conclusion Sensitive cTn assays have high diagnostic accuracy also in the elderly. Mild elevations are common in elderly non-AMI patients, therefore the optimal cut-off levels are substantially higher in elderly as compared with younger patients. Furthermore, sensitive cTn assays yielded different prognostic value (ClinicalTrials.gov number, [NCT00470587][1]). [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00470587&atom=%2Fehj%2Fearly%2F2011%2F02%2F28%2Feurheartj.ehr033.atom

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.

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

Autologous hematopoietic stem cell transplantation for intravascular large B-cell lymphoma: the European Society for Blood and Marrow Transplantation experience

Background In a single-center retrospective donor versus no-donor comparison, we investigated if allogeneic stem cell transplantation (alloSCT) can improve the dismal course of poor-risk chronic lymphocytic leukemia (CLL). Patients and methods All patients with CLL who were referred for evaluation of alloSCT within a 7-year time frame and had a donor search indication according to the EBMT criteria or because of Richter's transformation were included. Patients for whom a matched donor could be found within 3 months (matches) were compared with patients without such a donor (controls). Primary end point was overall survival measured from the 3-month landmark after search initiation. Results Of 105 patients with donor search, 97 (matches 83; controls 14) were assessable at the 3-month landmark. Matches and controls were comparable for age, gender, time from diagnosis, number of previous regimens, and remission status. Disregarding if alloSCT was actually carried out or not, survival from the 3-month landmark was significantly better in matches versus controls [hazard ratio 0.38, 95% confidence interval (CI) 0.17–0.85; P = 0.014]. The survival benefit of matches remained significant on multivariate analysis. Conclusion This study provides first comparative evidence that alloSCT may have the potential to improve the natural course of poor-risk CLL as defined by the EBMT criteria.

Purpose Cancer-related fatigue occurs frequently in patients with Hodgkin lymphoma (HL) and has a major impact on their quality of life. We hypothesized that severe fatigue (sFA) might have an impact on patients’ treatment outcome and social reintegration. Methods Of 5,306 patients enrolled in the German Hodgkin Study Group’s fifth generation of clinical trials in HL (HD13, HD14, and HD15; nonqualified and older [> 60 years] patients excluded), 4,529 provided data on health-related quality of life. We describe sFA (defined as a score ≥ 50 on the 0 to 100 scale from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30) before and up to 9 years after therapy and analyze its impact on treatment outcome and social reintegration. Results The proportion of patients reporting sFA was 37% at baseline and ranged from 20% to 24% during follow-up. Baseline sFA was associated with significantly impaired progression-free survival and a trend to impaired overall survival, which can be overcome in patients receiving highly effective HL therapies as applied in our fifth-generation trials. Our analysis revealed a significant negative association of sFA and employment in survivors: 5 years after therapy, 51% and 63% of female and male survivors, respectively, with sFA were working or in professional education, compared with 78% and 90% without sFA, respectively ( P < .001 adjusted for age, sex, stage, baseline employment status, and treatment outcome). sFA was also associated with financial problems and the number of visits to a general practitioner and medical specialists. Conclusion sFA is an important factor preventing survivors from social reintegration during follow-up. This observation underscores the need to address fatigue as a significant diagnosis when treating patients with and survivors of cancer.

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

Background: A substantial proportion of patients fail first line treatment of diffuse large B-cell lymphoma. Currently available salvage therapies are often ineffective and cannot be tolerated, especially for elderly patients. Thus, probably less than 25% of patients achieve a long lasting remission. Regimens like gemcitabine/oxaliplatin, or bendamustin, both in combination with rituximab are available for elderly or after failure of HDT, however induce only short lived responses. Obinutuzumab (GA101) is a type II anti-CD20 antibody, with preclinical evidence of superiority over rituximab in xenograft models of MCL and DLBCL. Recently a large phase III trial failed to show a benefit in patients with untreated DLBCL, although a subset analysis showed a potential benefit in a subset GCB DLBCL of patients, its value in relapsed disease is not yet finally determined. Although desirable, cumulative dose-related, progressive cardiotoxicity eliminates anthracyclines from relapse treatments. With pixantrone, a drug related to anthracyclines, a re-exposition against this drug class has been shown to be feasible, a best EOT-ORR of 37% (20% CR/CRu) was observed in a phase III trial. We thus initiated a trial combining both agents for the first time. The trial has opened in Q3/2015 and recruitment of 70 patients is completed as of 7/2018. Primary endpoint is the ORR, secondary endpoints being safety, PFS and OS. We report about available data after enrollment of the last patient. Methods: this is a multicenter, national, prospective trial. Main inclusion criteria: histologically proven DLBCL, FL grade IIIb or transformed iNHL (20% Quorum), no curative option available, relapsed and measurable disease, ECOG < 3, sufficient BM reserve, no severe concomitant diseases and given informed consent. There was no upper limit of prior treatment lines. Treatment consisted of up to 6 cycles of pixantrone 50mg/m² day 1, 8 and 15 of each cycle, obinutuzumab 1000 mg flat dose day 1, 8 and 15 of cycle one and day 1 of each subsequent cycle. Interim staging was scheduled after 3 cycles. Results: Basic data are available of 67 patients, all were caucasian, 37 were female the other 30 male and median age was 75 years. Most of the patients suffered from DLBCL (49 pts, 68%), 68% had advanced stage at diagnosis and the median secondary IPI was 3. Data collection is ongoing, until now data of 32 patients are fully available and updated results will be presented. Median number of prior therapies was 2 (1 to 6). Treatment seemed to be well tolerated, median number of cycles applied was 3, pre-mature stop of treatment was primarily based on progression. Response evaluation: at this time 13/32 (40.6%) evaluable patients responded with 5 patients achieving CR/CRu (15.6%) and 8 a PR. One year after initiation of treatment 54% of patients remained alive. Median follow up is 8.2 months. Median PFS and OS is 82 day and not reached, 1 year PFS and OS are 37% and 54%, respectively, no patient experienced relapse if the patient remained free from relapse at one year. Observed toxicity was predominantly hematologic. The following hematologic grade 3/4 adverse events were observed: leukopenia (9.4%) neutropenia (75%), thrombocytopenia (12.5%). The febrile neutropenia rate was 6.3%. Non-hematologic grade 3/4 adverse events were very rare, no single side effect was observed with a frequency of 5% or more. Summary: the combination of Obinutuzumab and Pixantrone is feasible and safe. Early response rates are interesting. Importantly, although some patients experience progress early, a promising proportion shows long lasting remissions. Molecular analyses are ongoing, as well as a detailed analysis on the impact of factors such as of number of prior treatments, status at inclusion. Figure. Figure. Disclosures Hess: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Other: travel expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hüttmann:Celgene: Other: Travel expenses; Roche: Other: Travel expenses. Marks:BMS: Honoraria; Merck: Honoraria; Servier: Honoraria. Dreyling:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Acerta: Consultancy; Sandoz: Consultancy. Keller:Takeda: Consultancy, Research Funding; MSD: Consultancy; Janssen-Cilag: Consultancy, Equity Ownership; Roche: Consultancy; BMS: Consultancy; Celgene: Research Funding. Ernst:Novartis: Research Funding. Viardot:Roche: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy; Gilead Kite: Consultancy, Honoraria. Lenz:Novartis: Research Funding; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Celgene Corp.: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria.