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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.

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

The HD18 study for patients with newly diagnosed advanced-stage Hodgkin lymphoma (HL) used positron emission tomography (PET) after 2 cycles (PET-2) of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses (eBEACOPP) to guide further treatment. Here, we analyzed the impact of PET-2 results in the context of eBEACOPP according to the Deauville score (DS) in patients treated within the HD18 trial. Residual tissue was visually compared with reference regions according to DS. We analyzed the association between PET-2 uptake and baseline characteristics, progression-free survival (PFS), and overall survival (OS). One thousand five patients (52%) had DS1 or DS2, 471 (24%) had DS3, and 469 (24%) DS4. PET-2 uptake was associated with baseline risk factors large mediastinal mass, extranodal disease, and high International Prognostic Score (P < .0001 each). Among 722 patients receiving standard therapy with 6 cycles of eBEACOPP, 3-year PFS rates were 92.2%, 95.9%, and 87.6% with DS1-2, DS3, and DS4, respectively. Univariate hazard ratio (HR) for PFS in patients with DS4 vs DS1-3 was 2.3 (1.3-3.8; P = .002). DS4 was the only factor remaining significant for PFS in a multivariate analysis including the associated baseline risk factors. Three-year OS rates were 97.6% for DS1-2, 99.0% for DS3, and 96.8% for DS4, with a univariate HR for DS4 vs DS1-3 of 2.6 (1.0-6.6; P = .04). Residual uptake above that in the liver at PET-2 (ie, DS4) is an important risk factor regarding survival outcomes for patients treated with eBEACOPP upfront. We thus recommend DS4 as the cutoff value for PET-2 positivity. This trial was registered at www.clinicaltrials.gov as #NCT00515554.

The HD18 study for patients with newly diagnosed advanced-stage Hodgkin lymphoma (HL) used positron emission tomography (PET) after 2 cycles (PET-2) of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses (eBEACOPP) to guide further treatment. Here, we analyzed the impact of PET-2 results in the context of eBEACOPP according to the Deauville score (DS) in patients treated within the HD18 trial. Residual tissue was visually compared with reference regions according to DS. We analyzed the association between PET-2 uptake and baseline characteristics, progression-free survival (PFS), and overall survival (OS). One thousand five patients (52%) had DS1 or DS2, 471 (24%) had DS3, and 469 (24%) DS4. PET-2 uptake was associated with baseline risk factors large mediastinal mass, extranodal disease, and high International Prognostic Score (P< .0001 each). Among 722 patients receiving standard therapy with 6 cycles of eBEACOPP, 3-year PFS rates were 92.2%, 95.9%, and 87.6% with DS1-2, DS3, and DS4, respectively. Univariate hazard ratio (HR) for PFS in patients with DS4 vs DS1-3 was 2.3 (1.3-3.8; P= .002). DS4 was the only factor remaining significant for PFS in a multivariate analysis including the associated baseline risk factors. Three-year OS rates were 97.6% for DS1-2, 99.0% for DS3, and 96.8% for DS4, with a univariate HR for DS4 vs DS1-3 of 2.6 (1.0-6.6; P= .04). Residual uptake above that in the liver at PET-2 (ie, DS4) is an important risk factor regarding survival outcomes for patients treated with eBEACOPP upfront. We thus recommend DS4 as the cutoff value for PET-2 positivity. This trial was registered at www.clinicaltrials.govas #NCT00515554.

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.

Doxorubicin, bleomycin, vinblastine sulfate, and dacarbazine (ABVD) is associated with severe toxicity in older patients, particularly from bleomycin-induced lung toxicity (BLT). Therefore, using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients, especially in early-stage HL. We therefore analyzed feasibility, toxicity, and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients. We included patients ≥60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2×ABVD; n = 137) or AVD (2×AVD; n = 82), each followed by involved-field radiotherapy (IF-RT), with patients randomized to 4×ABVD+IF-RT (n = 68). Patients’ median age was 65 years (range, 60-75) with comparable patient and disease characteristics. Grade III-IV adverse event rates were similar in patients receiving 2×AVD and 2×ABVD (40% and 39%, respectively), but considerably higher in patients receiving 4×ABVD (65%). Similarly, BLT was rare in patients receiving 2×ABVD/AVD, but occurred in 7/69 (10%) of patients randomized to 4×ABVD, with 3 lethal events. In conclusion, no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy. However, we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD. These trials are registered at www.clinicaltrials.gov and www.isrctn.com as #NCT00265018 (HD10) and #ISRCTN63474366 (HD13).

Doxorubicin, bleomycin, vinblastine sulfate, and dacarbazine (ABVD) is associated with severe toxicity in older patients, particularly from bleomycin-induced lung toxicity (BLT). Therefore, using bleomycin has been questioned in older Hodgkin lymphoma (HL) patients, especially in early-stage HL. We therefore analyzed feasibility, toxicity, and efficacy of ABVD or AVD in 287 older early-stage favorable HL patients. We included patients ≥60 years of age in the German Hodgkin Study Group HD10 and HD13 trials randomized to either 2 cycles of ABVD (2×ABVD; n = 137) or AVD (2×AVD; n = 82), each followed by involved-field radiotherapy (IF-RT), with patients randomized to 4×ABVD+IF-RT (n = 68). Patients' median age was 65 years (range, 60-75) with comparable patient and disease characteristics. Grade III-IV adverse event rates were similar in patients receiving 2×AVD and 2×ABVD (40% and 39%, respectively), but considerably higher in patients receiving 4×ABVD (65%). Similarly, BLT was rare in patients receiving 2×ABVD/AVD, but occurred in 7/69 (10%) of patients randomized to 4×ABVD, with 3 lethal events. In conclusion, no effects of bleomycin on toxicity rates were detectable in older patients receiving 2 cycles of chemotherapy. However, we found a high risk of severe toxicity of bleomycin in older HL patients receiving more than 2 cycles of ABVD. These trials are registered at www.clinicaltrials.govand www.isrctn.comas #NCT00265018 (HD10) and #ISRCTN63474366 (HD13).

The role of bleomycin and dacarbazine in the ABVD regimen (ie, doxorubicin, bleomycin, vinblastine, and dacarbazine) has been questioned, especially for treatment of early-stage favourable Hodgkin's lymphoma, because of the drugs' toxicity. We aimed to investigate whether omission of either bleomycin or dacarbazine, or both, from ABVD reduced the efficacy of this regimen in treatment of Hodgkin's lymphoma.

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.Nivolumab 240mg Q2W alone or in combination with AVD for 1st-line treatment of classical Hodgkin lymphoma.

The CD30-targeting Ab-drug conjugate brentuximab vedotin (SGN-35) was recently approved for the treatment of relapsed Hodgkin lymphoma and anaplastic large-cell lymphoma by the Food and Drug Administration. In the present study, we report the experience of the German Hodgkin Study Group with brentuximab vedotin as single agent in 45 patients with refractory or relapsed CD30+ Hodgkin lymphoma who were treated either in a named patient program (n = 34) or in the context of a safety study associated with the registration program of this drug. In these very heavily pretreated patients, an objective response rate of 60%, including 22% complete remissions, could be documented. The median duration of response was 8 months. This retrospective analysis supports the previously reported excellent therapeutic efficacy of brentuximab vedotin in heavily pretreated CD30+ malignancies. This trial was registered at www.clinicaltrials.gov with identifier NCT01026233.

The CD30-targeting Ab-drug conjugate brentuximab vedotin (SGN-35) was recently approved for the treatment of relapsed Hodgkin lymphoma and anaplastic large-cell lymphoma by the Food and Drug Administration. In the present study, we report the experience of the German Hodgkin Study Group with brentuximab vedotin as single agent in 45 patients with refractory or relapsed CD30+Hodgkin lymphoma who were treated either in a named patient program (n = 34) or in the context of a safety study associated with the registration program of this drug. In these very heavily pretreated patients, an objective response rate of 60%, including 22% complete remissions, could be documented. The median duration of response was 8 months. This retrospective analysis supports the previously reported excellent therapeutic efficacy of brentuximab vedotin in heavily pretreated CD30+malignancies. This trial was registered at www.clinicaltrials.govwith identifier NCT01026233.

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.Nivolumab 240mg i.v. 2-weekly for 1st-line treatment of classical Hodgkin lymphoma.

Background

Greil: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Sandoz: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. von Tresckow:MSD: Honoraria, Other: Travel support, Research Funding; Novartis: Honoraria, Other: Travel support, Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding. Borchmann:Novartis: Consultancy, Honoraria.

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.

Background:

Background.Combined modality treatment (CMT) consisting of two cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and 20 Gy of involved-field radiotherapy (IFRT) is widely accepted standard of care for early-stage favorable Hodgkin lymphoma (HL). Recent clinical research suggests that metabolic response assessment after two cycles of chemotherapy using FDG-PET (PET-2) can predict the individual outcome and PET-2 negativity might allow reducing the overall treatment intensity.

Borchmann: Novartis Pharmaceuticals Corporation: Honoraria. Greil: Takeda: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Novartis, Celgene: Research Funding; BMS, Amgen: Honoraria. Meissner: Takeda: Other: Non-Financial Support; BMS: Other: Non-Financial Support; Celgene: Other: Non-Financial Support; Amgen: Other: Non-Financial Support. Krause: Novartis: Honoraria. Engert: Affimed: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Bristol-Meyers Squibb: Consultancy, Research Funding; Takeda Oncology: Consultancy, Research Funding.

Background:

von Tresckow: Novartis: Consultancy, Other: travel grants, Research Funding; Takeda: Consultancy, Other: travel grants; Millenium: Consultancy. Engert:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding.

Background:

Off Label Use: Ofatumumab in lymphocyte-predominant Hodgkin lymphoma. von Tresckow:Takeda: Consultancy; Celgene: Other: honoraria for preparation of scientific educational events; Novartis: Consultancy, Other: Travel and accomodation, Research Funding; Amgen: Other: honoraria for preparation of scientific educational events. Borchmann:Millennium: Research Funding. Engert:Takeda: Consultancy, Research Funding.

von Tresckow: Novartis: Consultancy, Other: Travel and accomodation, Research Funding; Amgen: Other: honoraria for preparation of scientific educational events; Celgene: Other: honoraria for preparation of scientific educational events; Takeda: Consultancy. Zijlstra:Celgene: Consultancy; Roche: Consultancy. Topp:Astra: Consultancy; Regeneron: Consultancy; Affimed: Consultancy, Research Funding; Roche: Consultancy, Other: Travel Support; Jazz: Consultancy; Pfizer: Consultancy; Amgen: Consultancy, Honoraria, Other: Travel Support. Engert:Takeda: Consultancy, Research Funding. Borchmann:Millennium: Research Funding.

Background:Primary progressive disease still remains an unmet medical need in Hodgkin Lymphoma (HL). Due to missing data on treatment effects and survival there is no established standard of care. We thus performed a retrospective analysis using the German Hodgkin Study Group (GHSG) database to improve the knowledge on the course of primary progressive HL patients.

Background:

Based on the impressive results of two pivotal phase II trials, the CD30 targeting antibody-drug conjugate brentuximab vedotin (SGN-35) was approved for the treatment of relapsed Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) by the Food and Drug Administration (FDA) in 2011. Recently, we reported the experience of the German Hodgkin Study Group (GHSG) with brentuximab vedotin as single agent in 45 patients suffering from refractory or relapsed CD30-positive HL. In this cohort with a median age of 35 years and a median number of four prior chemotherapy regimens, overall survival (OS) and progression-free survival (PFS) at 12 months were 83% (95%-CI: 72%-95%) and 43% (95%-CI: 28%-58%), respectively. Interestingly, 10 of 17 patients considered very high-risk (59%) who had primary refractory disease or early relapse and refractory disease prior to brentuximab vedotin treatment, achieved an objective response, which was comparable to the overall response rate of 60% for the whole cohort (Rothe et. al., Blood, July 2012). Since very limited data is available on relapsed or refractory HL patients who received brentuximab vedotin without prior high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT), we have expanded our analysis.Since March 2010, the GHSG and associated centres have treated patients with refractory or relapsed HL or relapsed ALCL with brentuximab vedotin. In addition to six patients included in our previous analysis, we identified 10 further patients who had not undergone prior HDCT and SCT and were treated with brentuximab vedotin. All patients had histologically confirmed CD30-positive lymphoma and were treated within a named patient program (NPP). All participants gave written informed consent in accordance with the Declaration of Helsinki. Patients received a 30-minute infusion of brentuximab vedotin dosed at 1.8mg/kg body weight every three weeks. Response was defined according to the revised response criteria for malignant lymphoma. Overall survival (OS) was defined as the time from the initiation of therapy to death from any cause. Progression-free survival (PFS) was measured from initiation of therapy to progression, relapse, or death from any cause.In total, 16 patients with HL (n=14) or ALCL (n=2) with a median age of 48.5 years and a median number of three prior chemotherapy regimens were analyzed. Reasons for ineligibility for HDCT and autologous SCT prior to treatment with brentuximab vedotin were refractory disease (n=11), comorbidity (n=4) and unknown reasons (n=1). Treatment with brentuximab vedotin resulted in an objective response in 11 patients (69%), including five complete remissions. Noteworthy, six of the 11 patients with chemotherapy refractory disease and all four patients with significant comorbidity achieved an response. Six patients received a consolidating HDCT followed by autologous (n=4) or allogeneic (n=2) SCT after brentuximab vedotin treatment. OS and PFS at 12 months were 68% (95%-CI: 40%-95%) and 22% (95%-CI: 0%-48%), respectively.This retrospective analysis supports the previously reported excellent therapeutic efficacy of brentuximab vedotin in patients with heavily pre-treated CD30-positive malignancies. Moreover, we present the first data indicating therapeutic efficacy of brentuximab vedotin as reinduction therapy in chemotherapy-refractory HL and ALCL patients before HDCT and ASCT.Engert: Millenium The Takeda Oncology Company: Honoraria.

To improve fertility advice in HL patients before treatment and counseling during survivorship, detailed information on the impact of chemotherapy is needed. Therefore, we analyzed gonadal function in survivors after treatment of early favorable, early unfavorable and advanced stage HL.Women <40 years and men <50 years at diagnosis in ongoing remission at least one year after treatment within the GHSG HD13–15 trials were included. Hormone parameters, menstrual cycle, symptoms of hypogonadism, measures to preserve fertility, pregnancies, and offspring were evaluated.A total of 1,323 (55%) of 2,412 contacted female and male survivors were evaluable for the current analysis. In women and men, mean age at fertility assessment was 32 and 38 years and mean observation time from the end of treatment was 46 and 48 months, respectively. Comparison of the participating and non-participating patients qualifying for our analysis showed no relevant differences. Hormone levels correlated significantly with therapy intensity (p<.001). After 6–8 cycles BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone), mean Anti-Muellerian hormone (AMH) levels in females were 0μg/l and 88.8% of males had Follicle-stimulating hormone (FSH) and inhibin B levels corresponding to oligospermia. Furthermore, low birth rates were observed in survivors after advanced-stage treatment within the observation time (women: 6.5%, men: 3.3%). Regular menstrual cycle was reported by >90% of early-stage HL female survivors and time to resumption of menstrual activity was mostly reached within one year. After advanced-stage treatment, menstrual activity was strongly related to age. 82% of women younger than 30 years had a regular cycle, compared to only 45% in the older age group (p<.001) and time to recovery was considerably longer than in early-stage patients. 34% of women >30 years suffered severe menopausal symptoms (3–4 fold more frequently than expected). In contrast, male survivors had mean levels of testosterone within the normal range and reported no increased symptoms of hypogonadism.The present analysis in a large group of female and male HL survivors provides well-grounded information on gonadal toxicity of the currently used treatment regimens. Accordingly, the results allow a risk adapted planning of fertility preservation before therapy and a comprehensive support during survivorship.No relevant conflicts of interest to declare.

Excellent results are seen in HL patients with stage I-IIA disease treated with CMT that includes involved field radiation therapy (IFRT), as per GHSG HD10 [Engert NEJM 2010] and HD11 [Eich JCO 2010] or with ABVD alone, as per NCIC CTG/ECOG HD.6 [Meyer NEJM 2012]. Comparing these reports is complicated by differences in eligibility, staging, endpoints and follow-up duration. Our objectives were to use individual patient data from these 3 trials to compare outcomes after standardizing patient eligibility.Potentially eligible patients were those treated with 2 cycles of ABVD/20 Gy IFRT on GHSG HD10, 4 cycles of ABVD/30 Gy IFRT on GHSG HD11 and 4–6 cycles of ABVD alone on NCIC CTG HD.6. To be included in analysis, patients were required to be eligible for GHSG HD10 or HD11 and NCIC CTG HD.6. Eligibility of HD10/11 patients for HD.6 was determined by the GHSG by applying HD.6 protocol criteria. Anonymized individual patient data of eligible patients was forwarded to NCIC CTG along with reasons for ineligibility of other patients. Eligibility of HD.6 patients for HD10/11 was determined by NCIC CTG by applying HD10/11 protocol criteria with listing of reasons for ineligibility. Eligibility questions were resolved through consensus. Patients meeting mutually inclusive eligibility criteria were stratified by a propensity score (PSc) based on age, gender, stage, ESR and number of disease sites. Outcomes were based on Revised Response Criteria for Malignant Lymphoma [Cheson JCO 2007]; no trial incorporated PET scanning. The primary outcome measure was progression-free survival (PFS), which includes disease progression and death from any cause as events. Secondary outcomes included overall survival (OS) and time to progression (TTP), which includes disease progression and death from HL as events. A priori subsets for analysis included eligibility for HD10 vs. HD11 and CR/CRu status after 2 cycles of ABVD among those eligible for both HD10 and HD.6. Cox models stratified by PSc were used to obtain hazard ratios (HR) for PFS, OS and TTP; HRs are expressed as GHSG HD10/11 relative to NCIC CTG HD.6.Of 655 patients eligible for selected arms of HD10/HD11, 406 were eligible when applying the inclusion criteria for HD.6 (HD10 = 254; HD11 = 152). Most common reasons for ineligibility were B symptoms (n=127) and large mediastinal mass (n=80). Of 196 HD.6 patients, 182 were eligible for HD10 (n=110) or HD11 (n=71; 1 patient not assignable). Median follow-up for both HD10 and HD11 was 91 months and for HD.6 was 134 months. Results that include all eligible patients are shown in table; TTP was superior in GHSG trials.In the HD10/HD.6 subset, 8-yr PFS was 87% vs 82% (HR=0.58; 95% CI=0.32–1.05) and OS was 96% vs 94% (HR=0.65; 95% CI=0.25–1.72). Among those with CR/CRu after 2 cycles of ABVD, 8-yr PFS was 87% vs 95% (HR=2.8; 95% CI=0.64–12.5) and OS was 96% vs 100%. Among those without CR/CRu after 2 cycles of ABVD, 8-yr PFS was 88% vs 74% (HR=0.35; 95% CI=0.16–0.79) and OS was 95% vs 91% (HR=0.42; 95% CI=0.12–1.44). In the HD11/HD.6 subset, 8-yr PFS was 91% vs 91% (HR=1.15; 95% CI=0.45–2.97) and OS was 95% vs 97% (HR=2.03; 95% CI=0.53–7.79). Among 406 HD10/11 patients, there have been 19 deaths; 7 were attributed to HL or immediate treatment toxicity and 12 to other causes. Among 182 HD.6 patients, there have been 10 deaths; 5 were attributed to HL or immediate treatment toxicity and 5 to other causes.In this non-randomized cohort comparison, TTP was superior and PFS trended to being superior in patients treated with CMT on HD10/11. No differences in OS are evident; longer follow-up is needed to assess trade-offs between disease control and risks of late treatment effects. The role of IFRT in attaining long-term disease control appears to be especially important in those who do not attain CR/CRu status after 2 cycles of ABVD. As outcomes of those eligible for HD10/HD.6 and treated with 4–6 cycles of ABVD alone were excellent if CR/CRu was attained after 2 cycles of ABVD, these data support more recent strategies evaluating response-adapted approaches for use of IFRT.Borchmann: Millenium The Takeda Oncology Company: Research Funding; Takeda Pharma GmbH: Travel Grants, Travel Grants Other. Horning:Genentech: Employment; Roche: Equity Ownership. Engert:Millenium The Takeda Oncology Company: Honoraria. Meyer:Lilly: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen Canada: Research Funding; Ariad Pharma: Research Funding; Astex Therapeutics: Research Funding; AstraZeneca: Research Funding; Bristol-Myers Squibb: Research Funding; GlaxoSmithKline: Research Funding; Janssen Ortho: Research Funding; Novartis: Research Funding; Oncothyreon: Research Funding; Pfizer: Research Funding; Roche: Research Funding; Sanofi-Aventis: Research Funding; Schering Canada: Research Funding.

Abstract 54

In early-stage Hodgkin Lymphoma (HL), treatment according to the early favorable or unfavorable subgroup is mostly guided by a staging system including the presence of certain risk factors. However, risk factors have grown historically, they differ between the various study groups worldwide, and some experts do not recognize the necessity for an early unfavorable group at all. To shed more light on this ongoing controversy, we analyzed the impact of risk factors used in different international staging systems on treatment outcome in early-stage HL.In 1,173 qualified early-stage patients that were treated homogenously with 4 cycles of ABVD followed by involved-field radiotherapy within the GHSG trials HD10 and HD11, the impact of three international staging systems (GHSG, EORTC, NCCN) in discriminating early favorable and unfavorable treatment groups for progression free survival (PFS) and overall survival (OS) was assessed. Risk factors from the three definitions were tested for sensitivity and specificity for HL-related failure within 2.5 years, including only patients observed for at least 2.5 years (N=1,107). Univariate analyses of the respective single risk factors and of other known candidate risk factors as well as multivariate analyses were carried out using logistic regression, in order to evaluate the relevance and interaction of single factors.Median observation time was 80 months. Overall, 8% of early-stage patients had HL-related failure within 2.5 years. All three staging systems selected an unfavorable “high risk” group out of early-stage patients of comparable size (55%, 54%, and 56% of patients with the GHSG, EORTC, and NCCN system, respectively) with significant impact on PFS and OS. For example, with the GHSG system, PFS was 95.8% and 86.4% for the early favorable and unfavorable group at five years, with a significant difference of −9.4% (Figure 1).Sensitivity for HL-related failure was high for all systems (84%, 79%, and 83%, respectively); however, there were high rates of false-positive results (1-specifity 54%, 53%, and 55%, respectively). Univariately, most analyzed factors had a relevant impact on the event rate. In multivariate analyses, the GHSG-system had 4/4, the EORTC-system 2/4, and the NCCN-system 3/5 independently significant risk factors. In general, models of high sensitivity included risk factors indicating large tumor burden and high tumor activity. Most risk factors for tumor-specific endpoints such as HL-related failure and PFS were also predictive for OS.For the first time, the relevance of selecting an unfavorable risk group out of early-stage patients was proven in a large cohort of HL patients without treatment bias, with significant impact on PFS and OS. Thus, discriminating early favorable and unfavorable patients with HL by the identified risk factors is important in the modern combined modality treatment era and strongly recommended.Engert: Millenium The Takeda Oncology Company: Honoraria. Borchmann:Millenium The Takeda Oncology Company: Research Funding; Takeda Pharma GmbH: Travel Grants, Travel Grants Other.

Abstract 2743

Abstract 548

Abstract 2636

Two cycles of BEACOPPescalated followed by two cycles of ABVD (“2+2”) improves the primary outcome in early unfavorable HL patients as shown in the GHSG HD14 trial. Compared to 4xABVD, this benefit might be compromised by more gonadal toxicity in women and men. We thus analyzed gonadal function and fertility of survivors in the HD14 trial.Women between 18–40 years and men between 18–50 years at diagnosis in ongoing remission at least one year after therapy, treated with either 4xABVD (arm A) or “2+2” (arm B), were included. In women, different hormone parameters (follicle-stimulating hormone (FSH), Anti-Muellerian-Hormone (AMH)) as well as menopausal symptoms, prophylactic measures to preserve fertility, concurrent hormonal treatment, menstrual cycle, pregnancies, and offspring were evaluated. In men, serum levels of FSH, testosterone, and inhibin B were determined as well as symptoms of hypogonadism (aging males symptom scale, AMS) and children after therapy.From a total of 579 women addressed, 331 participated in the present study (57%) and 263 per-protocol treated patients qualified for the comparison of treatment arms (A: 137, B: 126; mean time from end of therapy 42 and 43 months, respectively). The rates of regular menstrual cycle after treatment (A: 87%, B: 83%) and time to recovery (≤12 months) were not different. FSH and AMH, reflecting ovarian reserve, were significantly better in arm A and AMH levels were also low after 4xABVD in women >30 years. In contrast, pregnancies after therapy favored arm B (A: 15%, B: 26%, p=0.043) and motherhood rates were equivalent to the German normal population in both arms. A multivariate analysis revealed prophylactic use of GnRH-analogues as highly relevant and significant prognostic factor for preservation of fertility (OR=12.87, p=0.001). Severe menopausal symptoms were reported frequently in women ≥30 years (A: 21%, B: 25%). From a total of 592 men addressed, 322 participated in the present study (54%) and 235 per-protocol treated patients qualified for the comparison of treatment arms (A: 111, B: 124; mean time from end of therapy 43 and 45 months, respectively). Levels of FSH (A: 4.3 U/l, B: 7.7 U/l, p<0.001) and inhibin B (A: 140.7 ng/l, B: 46.9 ng/l, p<0.001) were significantly better in arm A and children after therapy were also more frequently reported after treatment with 4xABVD (A: 12%, B: 5%, p=0.075). However, levels of testosterone and symptoms of hypogonadism were not different between treatment arms. In addition, symptoms of hypogonadism were equivalent as compared to the reference population.With focus on hormonal markers, results of the present study demonstrate higher gonadal toxicity in women and men after the “2+2” regimen compared to 4xABVD. Accordingly, in men, more children after 4xABVD are reported. In women, fertility is not compromised within the evaluated observation time, especially when GnRH-analogues were used.No relevant conflicts of interest to declare.

Abstract 432

Combined modality treatment consisting of 4 cycles of chemotherapy (CT) followed by involved field radiotherapy (IF-RT) is the standard treatment for early unfavourable HL. In our prior trial for this group of patients (HD8), overall survival (OS) and freedom from treatment failure (FFTF) at 5 years were 91% and 83%, respectively. The HD11 trial thus addressed two major questions: (1) improving outcome by intensifying CT (4xABVD vs. 4xBEACOPPbaseline; Bbas) and (2) defining the best radiation dose (30Gy vs. 20Gy IF-RT).Between May 1998 and January 2003, 1395 eligible patients aged 16–75 years with untreated early unfavourable stage HL (CS I, IIA with at least one of the risk factors large mediastinal mass (a), extranodal disease (b), elevated ESR (c) or ≥ 3 nodal areas (d); IIB with risk factors c and/or d) were randomized into one of the following 4 treatment arms: 4xABVD + 30Gy (A), 4xABVD + 20Gy (B), 4x Bbas + 30Gy (C) or 4x Bbas + 20Gy (D). Since there are strong indications for an interaction between CT- and RT-doses, a comparison of pooled treatment arms (A+B vs. C+D for comparison of 4×ABVD vs. 4× Bbas and A+C vs. B+D for comparison of 30Gy IF-RT vs. 20Gy IF-RT) would be misleading. Therefore all treatment arms were analysed separately.Patient characteristics were well balanced between the 4 arms (median age 33 years, 49% male, 6% stage I, 29% B-symptoms). CT- and RT-related acute toxicity occurred significantly more often in the arms with the more intensive therapy (CT: 74.1% vs. 51.8%; RT: 12.3% vs. 5.5%). The complete remission rate 3 months after end of therapy was 94.1% for the whole group and did not differ significantly between the 4 arms. The 5-year estimate of FFTF (primary endpoint) is 85.0% (OS 94.5%, PFS 86.0%).Bbas is more effective than ABVD if followed by 20Gy IF-RT (5y-FFTF difference 5.7%, 95%-CI [0.1%; 11.3%]). This effect does not exist in combination with 30Gy IF-RT (5y-FFTF difference 1.6% [-3.6%; 6.9%]). Similar results are observed for the RT-question: After 4 cycles of Bbas, 20Gy is not inferior to 30Gy (5y-FFTF difference -0.1%, 95%-CI [-5.1%; 4.9%]), whereas after 4xABVD, a relevant inferiority of 20Gy cannot be excluded (-4.0% [-9.5%; 1.4%]).A reduction of RT dose from 30Gy to 20Gy IF-RT seems to be justified only in combination with Bbas, but not with a less effective chemotherapy such as 4xABVD. Patients will benefit from an intensified CT such as Bbas only in combination with 20Gy IF-RT but not with 30Gy IF-RT.No relevant conflicts of interest to declare.

Abstract 717