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CD30 is a transmembrane protein selectively overexpressed on many human lymphoma cells and therefore an interesting target for antibody-based immunotherapy. However, binding of therapeutic antibodies stimulates a juxtamembrane cleavage of CD30 leading to a loss of target antigen and an enhanced release of the soluble ectodomain of CD30 (sCD30). Here, we show that sCD30 binds to CD30 ligand (CD153)–expressing non-target cells. Because antibodies bind to sCD30, this results in unwanted antibody binding to these cells via sCD30 bridging. To overcome shedding-dependent damage of normal cells in CD30-specific immunotherapy, we analyzed the mechanism involved in the release. Shedding of CD30 can be enhanced by protein kinase C (PKC) activation, implicating the disintegrin metalloproteinase ADAM17 but not free cytoplasmic calcium. However, antibody-induced CD30 shedding is calcium dependent and PKC independent. This shedding involved the related metalloproteinase ADAM10 as shown by the use of the preferential ADAM10 inhibitor GI254023X and by an ADAM10-deficient cell line generated from embryonically lethal ADAM10−/− mouse. In coculture experiments, the antibody-induced transfer of sCD30 from the human Hodgkin's lymphoma cell line L540 to the CD30-negative but CD153-expressing human mast cell line HMC-1 was inhibited by GI254023X. These findings suggest that selective metalloproteinase inhibitors blocking antibody-induced shedding of target antigens could be of therapeutic value to increase the specificity and reduce side effects of immunotherapy with monoclonal antibodies. [Cancer Res 2007;67(1):332–8]

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

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

Cetuximab is an anti-epidermal growth factor receptor (EGFR) antibody approved for the treatment of colorectal and head and neck cancer [1]. EGFR is also expressed on multiple myeloma (MM) plasma cells and bone marrow stromal cells (BMSCs) [2,3]. Th e inhibition of EGFR has been shown to induce apoptosis in myeloma cells revealing a synergistic eff ect with dexamethasone [2]. Th us, the anti-EGFR antibody cetuximab might be of clinical benefi t in the treatment of MM, especially in combination with dexamethasone. Here, we report the fi nal results of the fi rst clinical trial with an anti-EGFR antibody in MM, the EMMA1 trial. Eligible patients were adults with recurrent or refractory Durie – Salmon stage II or III MM who were not candidates for or had already undergone high-dose chemotherapy and autologous stem cell transplant (ASCT). Review boards at participating institutions approved the study, which was conducted according to the International Conference on Harmonization and the Guidelines for Good Clinical Practice. Written informed consent was obtained from all patients in accordance with the Declaration of Helsinki 1995. EMMA1 was an open-label, non-randomized phase II study (ClinicalTrials.gov Identifi er: NCT00368121). Th e primary endpoint was overall response rate (ORR) after 16 weeks of treatment. Secondary endpoints included adverse events during treatment, freedom from treatment failure (FFTF), progression-free survival (PFS) and overall survival (OS). Clinical benefi t rate (CB, defi nition: at least stable disease [SD]) was calculated in post hoc analyses. Patients received a cetuximab loading dose of 400 mg/m 2 intravenously on day 1 followed by weekly administrations of 250 mg/m 2 intravenously. Patients achieving at least SD after 4 weeks or responding to treatment within 8 weeks received cetuximab for a total of 16 weeks. Patients not achieving stable disease after 4 weeks or a response after 8 weeks of cetuximab treatment additionally received 20 mg oral dexamethasone on days 1 – 3 of each 7-day cycle. Patients achieving a response or stable disease after 16 weeks of treatment could continue study medication for an additional 6 months (patients receiving cetuximab alone) or for an additional 3 months (patients receiving cetuximab plus dexamethasone; dexamethasone was tapered down according to local guidelines). Responding patients who relapsed during the follow-up period of 2 years were off ered a second treatment with cetuximab following initial study guidelines. Tumor response was monitored by quantitative serum

Background: In our GHSG HD18 study for patients with newly diagnosed advanced-stage Hodgkin's lymphoma (HL), we used early interim positron emission tomography after 2 cycles of eBEACOPP (PET-2) to guide further treatment. In contrast to other groups, we defined a Deauville score at interim staging (iDS) ≥ 3 as positive. The prognostic impact of PET-2 in the context of eBEACOPP was and still is unclear, however. We thus investigated its association with baseline characteristics and treatment outcome in patients treated with eBEACOPP in our international phase 3 HD18 trial (NCT00515554). Methods: We recruited 2101 patients aged 18-60 years between 05/2008 and 07/2014. All patients received 2xeBEACOPP followed by centrally assessed PET-2, determining the iDS ranging from 1 (no FDG uptake) to 4 (FDG uptake above liver). Before 06/2011, patients were randomized 1:1 between 8xeBEACOPP and experimental treatment depending on iDS. After 06/2011, patients with iDS 1-2 were randomized 1:1 between 6xeBEACOPP and 4xeBEACOPP treatment, while all patients with iDS 3-4 received 6xeBEACOPP. Radiotherapy was recommended in case of residual lesions with DS ≥ 3 (until 04/2014)/ DS 4 (after 04/2014) after chemotherapy. We explored the association of iDS with baseline characteristics, and assessed treatment outcomes according to iDS among patients treated with 6xeBEACOPP within our trial after 06/2011, considering different cutoffs for positivity. We applied means of descriptive statistics, Fisher's exact test and multivariate logistic regression, and analyzed survival outcomes according to Kaplan-Meier, using Cox regression for comparisons. Findings: Among 1945 randomized patients, 1005 (52%), 471 (24%) and 469 (24%) had iDS 1-2, 3 and 4, respectively, according to central review of PET-2. Many clinical risk factors were associated with an unfavorable iDS, including adverse performance status, high international prognostic score (IPS) and the presence of large mediastinal mass (LMM), extranodal disease, 3 or more nodal areas and elevated ESR. Since patients with clinical stage (CS) IIB were only qualified for the trial when presenting with a large mediastinal mass, they had a high iDS more often than patients with CS III or IV or without B symptoms. Accordingly, in a multivariate analysis including all factors with univariate p After 06/2011, 216 patients with iDS 1-2 and all 506 patients with iDS 3-4 were assigned to receive 6xeBEACOPP. Among those 722 patients, PET after chemotherapy due to the presence of residual lesions was done in 83 (38%), 204 (76%) and 188 (80%) of patients with iDS of 1-2, 3, and 4, respectively, and FDG uptake above the liver (DS4) was observed in 3 (1%), 19 (7%) and 73 (31%), respectively (p Conclusion: The Deauville score after 2xeBEACOPP is associated with many clinical risk factors at baseline. For patients treated with 6xeBEACOPP followed by irradiation of PET-positive residuals, iDS 3 does not indicate an increased risk of treatment failure and is associated with long-term outcomes identical to those after clearly negative PET-2 (iDS 1-2). DS 4 at PET-2 adds some prognostic information to the baseline risk factors, but 3-year outcomes do not suggest a need for treatment intensification beyond standard therapy. Based on these results, the GHSG has decided to adopt the more widely used cutoff of iDS 4 for PET positivity. Thereby, about 75% of patients could take advantage of the abbreviated treatment with only 4 cycles of eBEACOPP in a PET-2-guided approach as defined in the HD18 study. Figure 1 Figure 1. Disclosures 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.

Nodular lymphocyte–predominant Hodgkin lymphoma (NLPHL) accounts for ∼ 5% of Hodgkin lymphoma cases. The disease is characterized by a strong CD20 expression on the malignant cells and a more indolent clinical course compared with classic HL. Anti-CD20 antibody treatment has shown clinical activity in relapsed NLPHL. In this phase 2 trial, we investigated rituximab in newly diagnosed stage IA NLPHL patients. Four weekly applications at 375 mg/m2 were given. Among the 28 evaluable patients, overall response rate was 100%, 24 patients (85.7%) achieved complete remission, and 4 (14.3%) achieved partial remission. At a median follow-up of 43 months, overall survival was 100%; progression-free survival at 12, 24, and 36 months was 96.4%, 85.3%, and 81.4%, respectively. No grade 3 or 4 toxicity was observed. Although treatment results with rituximab appear inferior compared with radiotherapy and combined-modality approaches in early-stage patients, investigation of anti-CD20 antibody-based combinations in NLPHL is warranted. This study was registered at [www.clinicaltrials.gov][1] as #[NCT00346684][2]. [1]: http://www.clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00346684&atom=%2Fbloodjournal%2F118%2F16%2F4363.atom

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma entity. We performed a matched-pair analysis to evaluate the prognostic impact of several histopathological features in this distinct Hodgkin lymphoma subtype. Lymph node samples of NLPHL patients were tested for CD15, IgD, phosphorylated STAT6, ICOS and Epstein-Barr virus status of the malignant lymphocyte-predominant cells as well as epithelioid cell clusters and activated T cells in the microenvironment. None of these features was associated with a particular clinical outcome. However, patients presenting with epithelioid cell clusters showed a non-significant trend towards a lower relapse rate, justifying further evaluation of this marker.

Hodgkin lymphoma (HL) is a B cell-derived lymphoid malignancy most often affecting young adults. More than 80% of HL patients achieve long-term remission after appropriate first-line treatment consisting of multiagent chemotherapy and/or radiotherapy (RT). In addition, approximately 50% of patients with disease recurrence remain relapse-free after salvage therapy with high-dose chemotherapy followed by autologous stem cell transplantation (ASCT). However, patients with multiple relapses are mostly in a palliative situation, and novel drugs for this patient group are needed. Furthermore, novel less toxic but equally effective first-line and second-line approaches are required as therapy-related late sequelae represent a relevant cause of morbidity and mortality in HL survivors. Several antibodies and antibody-drug conjugates (ADC) targeting CD30 and CD20 have recently been evaluated in HL. Excellent response rates in heavily pretreated patients were observed with the ADC brentuximab vedotin directed against CD30. Thus, ongoing trials investigate brentuximab vedotin in different additional indications. One example is the first-line treatment of advanced HL where the drug is currently being evaluated in combination with variants of the first-line protocols ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) and escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone). Anti-CD20 antibodies given either as single agent or in combination with conventional chemotherapy have also been investigated and still undergo investigation in prospective studies including HL patients. This article reviews the available data on treatment approaches including antibodies and ADC in HL patients.

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

Multiple myeloma (MM) is a plasma cell neoplasia with a steadily increasing annual incidence of 4–6/100 000, accounting for an estimated 19 000 cases in the USA in 2008 [1]. Clinical symptoms frequ...

Purpose Progression or relapse of Hodgkin lymphoma (HL) is common among older patients. However, prognosis and effects of second-line treatment are thus far unknown. Patients and Methods We investigated second-line treatment and survival in older patients with progressive or relapsed HL. Patients treated within German Hodgkin Study Group first-line studies between 1993 and 2007 were screened for refractory disease or relapse (RR-HL). Patients with RR-HL age ≥ 60 years at first-line treatment were included in this analysis. Results We identified 105 patients (median age, 66 years); 28%, 31%, and 41% had progressive disease, early relapse, or late relapse, respectively. Second-line treatment strategies included intensified salvage regimens (22%), conventional polychemotherapy and/or salvage-radiotherapy with curative intent (42%), and palliative approaches (31%). Median overall survival (OS) for the entire cohort was 12 months; OS at 3 years was 31% (95% CI, 22% to 40%). A prognostic score with risk factors (RFs) of early relapse, clinical stage III/IV, and anemia identified patients with favorable and unfavorable prognosis (≤ one RF: 3-year OS, 59%; 95% CI, 44% to 74%; ≥ two RFs: 3-year OS, 9%; 95% CI, 1% to 18%). In low-risk patients, the impact of therapy on survival was significant in favor of the conventional polychemotherapy/salvage radiotherapy approach. In high-risk patients, OS was low overall and did not differ significantly among treatment strategies. Conclusion OS in older patients with RR-HL can be predicted using a simple prognostic score. Poor outcome in high-risk patients cannot be overcome by any of the applied treatment strategies. Our results might help to guide treatment decisions and evaluate new compounds in these patients.

Today, more than 80% of patients with Hodgkin lymphoma (HL) can be cured with first-line treatment [1–3]. For patients with HL suffering from relapse or progression after first-line therapy, high d...

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) accounts for approximately 5% of all Hodgkin lymphoma cases. The aim of this study was to evaluate the prognostic implication of histopathologic NLPHL variants. Biopsies of 423 NLPHL patients treated within 9 prospective clinical trials performed by the German Hodgkin Study Group were classified as tumor cell-rich cases (n = 10), typical NLPHL (n = 308), or histopathologic variants (n = 105). Histopathologic variants were characterized by the presence of lymphoma cells outside the B-cell nodules or B-cell depletion of the microenvironment. Compared with typical NLPHL, histopathologic variants were associated with advanced disease (29.5% vs 14.6%, P = .0012) and a higher relapse rate (18.1% vs 6.5% at 5 years, P = .0009). Variant histology represented an independent prognostic factor (odds ratio = 2.955) in a multivariate model of progression/relapse. A prognostic score, including the risk factors variant histopathologic growth pattern, low serum albumin, and male gender, was derived from this model and allowed the definition of 3 distinct risk groups. NLPHL patients presenting with histopathologic variants have a poorer outcome compared with those showing typical histology. The newly developed prognostic score combining histologic and clinical features allows allocating NLPHL patients to defined risk groups.

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][1] with identifier [NCT01026233][2]. [1]: http://www.clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01026233&atom=%2Fbloodjournal%2F120%2F7%2F1470.atom

Background In the HD14 trial, 2× BEACOPPescalated+2× ABVD (2+2) has improved the primary outcome. Compared with 4× ABVD, this benefit might be compromised by more infertility in women. Therefore, we analyzed gonadal function and fertility. Patients and methods Women ≤45 years in ongoing remission at least 1 year after therapy were included. Hormone parameters, menopausal symptoms, measures to preserve fertility, menstrual cycle, pregnancies, and offspring were evaluated. Results Three hundred and thirty one of 579 women addressed participated (57.2%) and 263 per-protocol treated patients qualified (A=ABVD: 137, B=2+2: 126, mean time after therapy 42 and 43 months, respectively). Regular menstrual cycle after treatment (A: 87%, B: 83%) and time to recovery (≤12 months) were not different. Follicle-stimulating hormone and anti-Muellerian hormone were significantly better in arm A. However, pregnancies after therapy favored arm B (A: 15%, B: 26%, P=0.043) and motherhood rates were equivalent to the German normal population. Multivariate analysis revealed prophylactic use of gonadotropin-releasing hormone (GnRH) analogues as highly significant prognostic factor for preservation of fertility (odds ratio=12.87, P=0.001). Severe menopausal symptoms were frequent in women ≥30 years (A: 21%, B: 25%). Conclusions Hormonal levels after 2+2 indicate a reduced ovarian reserve. However, 2+2 in combination with GnRH analogues does not compromise fertility within the evaluated observation time

Approximately 20% of all Hodgkin lymphoma (HL) patients are older than 60 years and have a poor prognosis, mainly because of increased treatment-related toxicity resulting in reduced overall dose intensity and more treatment-related mortality. To possibly improve the treatment of elderly HL patients, the German Hodgkin Study Group developed a new regimen, PVAG (prednisone, vinblastine, doxorubicin, and gemcitabine). In this multicenter phase 2 study, elderly HL patients in early unfavorable and advanced stages received 6 to 8 cycles of PVAG and additional radiotherapy if they were not in complete remission (CR) after chemotherapy. Endpoints included feasibility, acute toxicity, and response rate. Fifty-nine patients 60 to 75 years of age (median, 68 years) were eligible for analysis; 93% had advanced stage disease. WHO grade 3/4 toxicities were documented in 43 patients; 46 patients responded with CR/CR uncertain (78%). Within 37 months median observation time, 15 progressions or relapses and 17 deaths were observed, of which 8 were related to HL and 1 was the result of treatment-related toxicity. The 3-year estimates for overall survival and progression-free survival were 66% (95% CI, 50%-78%) and 58% (95% CI, 43%-71%), respectively. We conclude that PVAG is safe and feasible in elderly HL patients. This trial was registered at www.clinicaltrials.gov as #NCT00147875.

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

Hodgkin lymphoma (HL) patients are usually being allocated to early favorable, early unfavorable, and advanced-stage risk groups. Intensity of treatment thus depends on clinical stage and the presence of clinically defined risk factors. With current standard treatment approaches including chemo- and/or radiotherapy, cure rates range from 60 to 90%. With this excellent prognosis, many patients would be sufficiently treated with less aggressive strategies than the current standard. To avoid overtreatment in low-risk patients and maintain the appropriate treatment intensity for high-risk patients at the same time, response-adapted treatment stratification based on interim positron emission tomography (PET) is under investigation. Treatment stratification on the basis of the mutation status of specific genes or upon guidance by minimal residual disease (MRD) as currently evaluated in other malignancies would be even more desirable but is difficult in HL. The reason for this is that the malignant Hodgkin and Reed−Sternberg (H-RS) cells usually account for less than 1% of cells in the lymphoma tumor tissue at initial diagnosis. However, several signaling pathways dysregulated in H-RS cells were identified recently and an increasing number of drugs specifically targeting these pathways are becoming available. Small molecules, monoclonal antibodies, and immunotoxins are among the most promising candidates for a more selective treatment and might become part of future personalized treatment approaches in HL patients. This chapter gives an overview on current and possible future targeted approaches in HL.

For older patients with early unfavorable or advanced stage Hodgkin lymphoma (HL) the prognosis is much worse than for younger HL patients. We thus developed a new regimen, BACOPP (bleomycin, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone), to improve both tolerability and efficacy of treatment for older HL patients. Between 2004 and 2005, 65 patients with early unfavorable or advanced stage HL aged between 60 and 75 years were enrolled in this phase 2 trial. Treatment consisted of 6 to 8 cycles of BACOPP. Residual tumor masses were irradiated. Primary endpoints were feasibility as determined by adherence to protocol and overall response rate. Secondary endpoints included toxicity, freedom from treatment failure, and progression free and overall survival. For the final analysis 60 patients (92%) were eligible; 75% of treatment courses were administered according to protocol. World Health Organization grade 3/4 toxicities occurred in 52 patients. Fifty-one patients (85%) achieved complete remission, 2 (3%) partial remission, and 4 (7%) developed progressive disease. With a median observation time of 33 months, 18 patients died (30%), including 7 treatment-associated deaths. Three patients died before response assessment. Thus, the BACOPP regimen is active in older HL patients but is compromised by a high rate of toxic deaths. This trial was registered at www.clinicaltrials.gov as #NCT00284271.

Combinations with proteasome inhibitors are currently being investigated to improve the therapy of hematological malignancies. We previously found that proteasome inhibition by bortezomib failed to sensitize anti-CD30 antibody (Ab)-based lymphoma cell killing. In this study, we demonstrate in L540 Hodgkin's lymphoma cells that proteasome inhibition not only communicates apoptosis but also more rapidly causes a loss of CD30 antigen from cell membrane and a simultaneous release of soluble CD30, a targeting competitor. This shedding was catalyzed by the tumor necrosis factor (TNF)-alpha-converting enzyme (TACE, ADAM17) and blocked by the ADAM17-selective inhibitor, Ro32-7315. In parallel with CD30 shedding, bortezomib caused the generation of reactive oxygen species (ROS). As apoptosis and shedding were inhibited by the radical scavenger, N-acetyl-L-cysteine, ROS might have a pivotal function in both effects. In contrast, the pan-caspase inhibitor, zVAD-fmk, blocked bortezomib-induced apoptosis but not CD30 shedding, and Ro32-7315 blocked shedding but allowed apoptosis. This suggests independent terminal signaling pathways that are conflicting in Ab-based immunotherapy. Consequently, shedding inhibition substantially improved the synergistic antitumor efficacy of the human anti-CD30 Ab, MDX-060, and bortezomib. As proteasome inhibition also stimulated loss of TNF receptors, interleukin-6 receptor and syndecan-1 in different leukemia and lymphoma cell lines, we concluded that proteasome inhibition might impede targeted therapy against antigens susceptible to shedding.

Background: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) accounts for approximately 5% of all Hodgkin lymphoma (HL) cases. One hallmark of NLPHL is the consistent expression of CD20 on the malignant lymphocyte predominant (LP) cells. To shed more light on the role of anti-CD20 antibody treatment in relapsed NLPHL, we conducted a phase II study evaluating the fully humanized anti-CD20 antibody ofatumumab in 28 patients. Treatment consisted of 8 weekly doses (week 1: 300 mg, week 2-8: 1000 mg) of the antibody. Results: The median age of study patients was 45 years (range: 22-68) and the majority were male (64%). A median of 1 line of therapy (range: 1-5) had been applied prior to study treatment and 7/28 patients (25%) already had rituximab-containing treatment. At the final restaging 3 months after the end of treatment, response was documented in 27/28 patients (96%; 95%-CI: 84%-100%). After a median follow-up of 26 months, 1-year and 2-year progression-free survival (PFS) estimates were 93% and 80%, respectively. No patient died. Transformation into aggressive non-Hodgkin lymphoma (NHL) occurred in 2/28 patients (7.1%). No grade III/IV toxic events were observed. Conclusion: In summary, the anti-CD20 antibody ofatumumab represents a highly active and well tolerated treatment option in relapsed NLPHL. Longer follow-up is required for final conclusions. Disclosures 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.

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

Over the past decades, cure rates in Hodgkin lymphoma (HL) have steadily improved. This was most obvious in patients with advanced disease after the introduction of multi-agent chemotherapy protocols such as MOPP (mechlorethamine, vincristine, procarbazine, prednisone) and ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). 1 More recently, the more intensive BEACOPP escalated (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone) was shown to be significantly superior to previous standard approaches in advanced adult HL. In this issue of Blood , Kelly and colleagues now report that BEACOPP escalated is also feasible and highly effective in high-risk pediatric and adolescent HL patients. 2

Introduction: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma entity accounting for about 5% of all HL cases. As compared with classical HL (cHL), NLPHL is characterized by the absence of CD30 and the consistent expression of CD20 on the malignant lymphocyte predominant (LP) cells. Given a more indolent clinical course, especially early-stage NLPHL is often treated less aggressive than classical HL (cHL). In stage IA patients, radiotherapy (RT) alone is applied at most institutions. However, this clinical practice is not based on data from prospective clinical trials with sufficient follow-up. To shed more light on the optimal treatment of stage IA NLPHL, we performed an analysis including patients with long-term follow-up treated within German Hodgkin Study Group (GHSG) clinical trials. Patients: A total of 256 stage IA NLPHL patients treated within 7 prospective GHSG studies between 1988 and 2009 were included in the analysis. Treatment consisted of combined-modality treatment (CMT) (n=72), extended-field RT (EF-RT) (n=49), involved-field RT (IF-RT) (n=108) or four weekly doses of the anti-CD20 antibody rituximab (n=27). Results: The median age at NLPHL diagnosis was 38.5 years (range: 17-75); 194/256 (75.8%) patients were male and 62/256 (24.2%) patients were female. Median follow-up for the whole patient group was 91 months (98 months for CMT, 118 months for EF-RT, 87 months for IF-RT, 49 months for rituximab). All patients responded to treatment irrespective of the treatment modality applied. At 8 years, progression-free survival (PFS) and overall survival (OS) rates were 88.5% and 94.5% for CMT, 84.3% and 95.7% for EF-RT and 91.9% and 99.0% for IF-RT; 4-year PFS and OS rates for patients treated with rituximab were 81.0% and 100%. Seventeen patients developed a second malignancy in the course of follow-up (8 after CMT, 3 after EF-RT, 4 after IF-RT, 2 after rituxmab). Nine of these second malignancies were solid tumors (4 after CMT, 2 after EF-RT, 1 after IF-RT, 2 after rituximab) and 8 were hematologic malignancies (4 after CMT, 1 after EF-RT, 3 after IF-RT, none after rituximab). A total 12 deaths occurred. The most common cause of death was cardiac failure (n=3). Only one patient died from NLPHL. Conclusion: Based on this large analysis with long-term follow-up, IF-RT should be the standard of care for stage IA NLPHL. Treatment with single agent rituximab is associated with an increased event rate when compared with IF-RT and should therefore not be routinely used in stage IA NLPHL patients. However, given the shorter follow-up in comparison with CMT, EF-RT and IF-RT, final conclusions regarding rituximab especially in terms of treatment-related late sequelae cannot yet be drawn. Addition of chemotherapy does not improve the excellent outcome achieved with RT alone. Disclosures Off Label Use: Rituximab in NLPHL.

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

Introduction Bleomycin is commonly omitted from the ABVD regimen (doxorubicine, vinblastine, dacarbazine and bleomycin) in older Hodgkin Lymphoma (HL) patients due to excessive toxicity, particularly bleomycin-induced lung toxicity (BLT). Very recently, however, the GHSG HD13 trial indicated that the omission of bleomycin from the ABVD regimen has a negative impact on efficacy (Behringer et al., EHA 2014). Given the high rate of BLT in older patients, the role of bleomycin in the ABVD regimen for this particular group of patients is still unclear. We therefore analyzed feasibility, toxicity and efficacy of ABVD or AVD in 287 older early stage favorable HL patients. Methods As described in detail previously elsewhere, HD10 and HD13 were prospective, randomized international multicenter trials including early stage favorable HL patients defined as stages I and II without any of the GHSG risk factors (Engert et al. NEJM 2010). For the present study, we focused on older HL patients (≥60 years), who were randomized to receive either 2 cycles ABVD (2 x ABVD) or AVD, in both cases followed by either 20 or 30 Gy involved-field radiotherapy (IF-RT). To estimate cumulative BLT, we also analyzed older HL patients who received 4 x ABVD followed by IF-RT in the HD10 trial. Results 287 patients with a median age of 65 years (range 60-75) were included with an equal distribution of gender, IPS scores, histology and age between the treatment groups. Treatment consisted of 2 x ABVD in 137 patients (HD10 and HD13), 2 x AVD in 82 patients (HD13), and 4 x ABVD in 68 patients (HD10). Pulmonary function test (PFT) prior to therapy was available for 117 patients (HD13 only) showing impaired PF in 14 (26%) and 9 (15%) of the patients randomized to receive ABVD or AVD, respectively. Although patient numbers were too small to draw statistically sound conclusions, in our analysis, patients treated with AVD tended to receive higher relative dose intensity than patients treated with 2 x ABVD. Early termination of chemotherapy was only observed in 1 patient of each treatment arm. Overall, frequency of grade III-IV adverse events was similar for both patient groups. Respiratory adverse events were rare even in patients receiving 2 cycles of bleomycin (1 and 0 cases with 2 x ABVD and AVD, respectively). However, BLT occurred in 6 patients (9%) receiving 4 cycles ABVD and was lethal in half of the affected patients. PFTs or (chest x-ray) within two years after therapy were available for 80 HD13 patients and showed pathological results for 2 patients each out of 34 and 46 patients treated with 2 x ABVD or AVD, respectively. Regarding the efficacy, patient numbers were far too small for testing on (non-)inferiority of the AVD regimen as done in the HD13 trial. However, differences in PFS and OS were about the same magnitude as observed in the HD13 trial (Behringer et al., submitted), indicating that the effect of bleomycin on efficacy observed in this trial does also hold true for the subgroup of older patients. Conclusion In this study of 219 older early stage favorable HL patients treated with 2 cycles of either ABVD or AVD, no significant effect of bleomycin on the incidence and severity of adverse events was detectable. In contrast, the additional 67 older patients receiving 4 x ABVD had more grade III/IV toxicity and a strikingly higher rate of BLT, indicating a cumulative toxicity of bleomycin in older HL patients. Disclosures Off Label Use: Everolimus in relapsed or refractory Hodgkin Lymphoma. von Tresckow:Novartis: Honoraria, Research Funding; Takeda: Honoraria, Travel grants, Travel grants Other. Borchmann:Takeda: Honoraria, Research Funding, Travel grants Other.

Introduction: AFM13 is a bispecific, tetravalent TandAb antibody that targets CD16A and CD30. Preclinical data demonstrated that AFM13 specifically harnessed NK cells to exert potent cytotoxic effects on tumor cells expressing CD30. Furthermore, AFM13 showed a favorable toxicity profile in cynomolgus monkeys. HL is characterized by the presence of CD30+ Reed-Sternberg cells and by a high medical need in the r/r setting, especially since the response to brentuximab vedotin in this patient group is mostly short. Here, we present the final results of a phase 1 clinical study in r/r HL including a focus on the pre-treatment with brentuximab vedotin. Methods: Heavily pretreated patients (pts.) with r/r HL received stepwise escalated doses of intravenous AFM13 (0.01 to 7.0 mg/kg) weekly or 4.5 mg/kg twice weekly over 4 weeks. Primary objectives were safety and tolerability, secondary objectives included pharmacokinetics (PK), pharmacodynamics (PD), and clinical efficacy measured using Cheson criteria. Results: 28 pts. were recruited, 24 pts. received AFM13 weekly and 4 pts. received AFM13 twice weekly. AFM13 was well tolerated with mainly mild to moderate adverse events. The maximum tolerated dose was not reached. AFM13 demonstrated activity, which was consistently more pronounced for all assessed parameters at doses ≥1.5 mg/kg (n=13). 3 of 13 pts. (23%) exhibited partial responses and disease control was reached in 10 of 13 pats. (77%). Importantly, AFM13 was also active in pts. refractory to brentuximab vedotin as most recent treatment. PK data revealed an AFM13 half-life of up to 19 hours. In peripheral blood, the portion of activated NK cells (CD69+), relative to total number of NK cells, increased up to 3-fold 24 hours after infusion compared to baseline. Kinetics of NK cell activation corresponded to kinetics of AFM13 serum levels. Soluble CD30 declined to zero at the end of treatment in almost all pts. Conclusion: Phase 1 data indicate that AFM13 is active and well tolerated in heavily pretreated r/r HL pts. including brentuximab vedotin failures. To further enhance efficacy of AFM13 both, the dose regimen (based on PK/PD profile) and the duration of treatment, will be optimized in a phase 2 study. This study is currently in preparation by the German Hodgkin Study Group. Disclosures Topp: Affimed Therapeutics AG: Consultancy. von Tresckow:Takeda: Honoraria, Other; Novartis: Honoraria, Research Funding. Marschner:Affimed Therapeutics AG: Employment. Engert:Millenium Takeda: Consultancy; Affimed Therapeutics AG: Consultancy.

8559 Background: 4SC-202 is a specific inhibitor of protein deacetylases HDAC1, 2 and 3 and lysine specific demethylase LSD1 (KDM1A). Enzymatic inhibition leads to transcriptional repression of Wnt...

3025^ Background: AFM13 is a bispecific anti-CD30, anti-CD16A antibody construct which recruits NK cells for targeted lysis of CD30+ tumor cells. HL cells are characterized by CD30 positivity and r...

The BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone) regimen was originally developed to improve the first-line treatment of advanced Hodgkin lymp...

Introduction Secondary malignant neoplasms (SMN) are a major late effect of treatment for Hodgkin lymphoma (HL). Single trials have inadequate power to detect differences in SMN rates, while the many large-scale cohort-based studies of SMN after HL suffer from non-randomised, potentially biased comparisons of treatment strategies. The consequences of choice of first-line treatment for SMN risk remain unclear. We performed a Cochrane systematic review addressing this question based on our previous such review in 2000-2004. Material and methods Individual patient data (IPD) were collected from randomised controlled trials testing 5 currently relevant experimental strategies: avoidance of additional radiotherapy (RT) after chemotherapy (CT); reduction of RT field; reduction of RT dose; use of fewer CT cycles; intensification of CT regimen. All trials employed modern ABVD-like regimens and limited radiation fields, and recruited at least 50 patients per treatment group. Incidence of SMN, overall survival (OS) and progression-free survival (PFS) were analysed. Due to small numbers of events, SMN was analysed using Peto’s method. Results and Discussion Data from 16 of the 21 eligible trials were obtained, including 9498 patients. These trials recruited between 1984 and 2007 and randomised between 100 and 1351 patients each. Standard chemotherapy was predominantly ABVD, followed by COPP/ABVD and MOPP/ABV. Most frequent intensified chemotherapies were escalated BEACOPP and Stanford V. For each study question, key information and resulting odds ratios are shown in the table. Avoidance of additional RT significantly reduced the SMN risk (Peto odds ratio 0.433, 95% confidence interval (0.28; 0.82), p=0.010). Intensified chemotherapy regimens were associated with a consistent slightly higher risk but the effect was not significant. Other study questions showed no marked effects on SMN risk. Regarding solid tumors, follow-up is still too short: an update after 5 to 10 years is necessary. Disclosures: No relevant conflicts of interest to declare.

Introduction The prognostic impact of isolated infradiaphragmatic Hodgkin Lymphoma (HL) is controversial and no large risk factor analysis in patients treated with state-of-the-art therapies exists. Therefore, we performed a risk factor analysis focusing on isolated infradiaphragmatic nodal disease in patients treated within the German Hodgkin Study Group (GHSG) HD13 (2xABVD vs 2xABV, 2xAVD and 2xAV; followed by 30Gy IFRT each) and HD14 (4xABVD vs 2xBEACOPPescalated plus 2xABVD; followed by 30 Gy IFRT each) trials. Methods The characteristics and outcomes of patients with isolated infradiaphragmatic nodal disease qualified for and treated within the HD13 and HD14 trials were compared to patients with supradiaphragmatic nodal disease. Patients with extranodal disease were excluded. Progression-free survival (PFS) and overall survival (OS) were estimated according to the Kaplan-Meier method and compared between groups using the log-rank test. The Cox proportional hazards regression model was applied for multivariate analyses. To assess whether the prognostic impact of infradiaphragmatic disease depends on treatment intensity, patients were divided into groups of less intensive (HD13 arms 2xABV/2xAVD/2xAV and HD14 arm 4xABVD) and more intensive (HD13 arm 2xABVD and HD14 arm 2xBEACOPPescalated plus 2xABVD) chemotherapy, and groups were analyzed separately. All Hazard Ratios (HR) reported for these subgroup analyses were obtained from Cox proportional hazards regression models adjusted for age (HRa). Results 1500 and 1403 patients with nodal disease from the HD13 and HD14 trials, respectively, qualified for the analysis. Of those, 139 patients from HD13 (9.3%) and 84 patients from HD14 (6.0%) had isolated infradiaphragmatic disease. Compared to patients with supradiaphragmatic disease, these patients were older (median age 47 vs 35 years, p0 more frequently (22.4 vs 15.2%, p Conclusion Isolated infradiaphragmatic disease is a risk factor for PFS and OS in HL patients that can be overcome with the current GHSG standard therapies for early favorable (2xABVD followed by 20Gy IFRT) and early unfavorable (2xBEACOPPescalated plus 2xABVD followed by 30Gy IFRT) disease. Disclosures: von Tresckow: Novartis: honoraria for acting as a consultant: Consultancy; Takeda Pharma GmbH: reimbursement of congress, travel, and accommodation costs and honoraria for preparation of scientific educational events: Honoraria. Böll:Celgene: Travel Grant Other. Engert:Seattle Genetics, Inc.: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Takeda: Honoraria. Borchmann:Millenium The Takeda Oncology Company: Research Funding; Takeda Pharma GmbH: Travel Grants, Travel Grants Other.

Background AFM13 is a bispecific TandAb antibody for the treatment of Hodgkin lymphoma (HL) and other CD30+ malignancies. AFM13 specifically targets both CD30, which is the antigen identifying HL tumor cells, and CD16A, for the recruitment of NK cells. Our preclinical data demonstrate a specific and potent anti-tumor activity mediated by the engagement of NK immune effector cells. Methods AFM13 was investigated in an open-label single-arm phase I dose escalation trial in patients with relapsed/refractory HL. The objective of this study was to evaluate the safety, tolerability, pharmacokinetics, immunogenicity, anti-tumor activity, and maximum tolerated dose (MTD). Each patient received 4 weekly doses of AFM13. Seven dose levels, from 0.01 to 7.0 mg/kg, were escalated in cohorts of 3 patients. In addition, one cohort of 4 patients received AFM13 twice a week at 4.5 mg/kg for 4 weeks. Results Twenty-eight (28) HL patients were enrolled, and these heavily pre-treated patients had a median number of six (6) prior therapies. 14/28 patients were refractory to their most recent therapy. 9/28 patients had a prior therapy with brentuximab vedotin. AFM13 was safe and well-tolerated, and did not reach the MTD. One dose-limiting toxicity (DLT) was observed at 0.5 mg/kg, and this dose cohort was expanded to 6 patients. No further DLTs were observed. The most frequent adverse events were infusion-related reactions (headache, fever, fatigue and myalgia) that often occurred after the first administration. Nearly all adverse events were short-lived. According to the Cheson criteria, 2 patients achieved partial responses and 13 patients achieved stable disease. In addition, AFM13 was active in brentuximab vedotin relapsing/refractory patients, with 7 out of 9 patients achieving stable disease after AFM13 treatment. The responses of the 13 patients who received AFM13 at and above the 1.5 mg/kg dose level were further analyzed for pharmacodynamic/anti-tumor activity correlations. In this group the drug exhibited substantial anti-tumor activity, with 8 out of the 13 patients experiencing a reduction in both tumor volume (as assessed by CT scan) and tumor activity (as assessed by FDG-PET scan imaging). Furthermore, 3 out of the 13 patients (23%) exhibited a reduction in tumor volume of more than 50%. The on-mechanism activity of the drug was further substantiated by the NK cell activation and soluble CD30 clearance pharmacodynamic parameters. Statistically significant correlations between increasing anti-tumor activity parameters (i.e. tumor volume reduction and FDG-PET SUV reduction) and the pharmacodynamic biomarkers were observed as: i) a dose-dependent increase in the activation of NK cells, and ii) a dose-dependent reduction in soluble CD30 levels. Variations in SUV were correlated with the number of activated NK cells (i.e. CD69+ cells) at baseline and 24 hours after the start of therapy with AFM13. The number of activated NK cells peaked 12 hrs after dosing, and dropped after 48 hrs. A decrease in SUV was observed at the highest level of activated NK cells, and was accompanied by a concomitant reduction in soluble CD30 levels. Furthermore, AFM13 exhibited a half-life of 1 day, representing a substantial increase relative to that of the alternative bispecific tandem scFv that is currently in clinical evaluation for hematological malignancies. Conclusions AFM13 has demonstrated good safety and encouraging anti-tumor activity. Furthermore, there is a solid scientific rationale suggesting that during phase I the anti-tumor potential of AFM13 was not fully realized. A compelling hypothesis for further exploration is whether we may detect much stronger activity, in refractory/relapsing HL patients, in a phase II study employing a pK-optimized regimen with an extended duration of therapy. Disclosures: Zhukovsky: Affimed Therapeutics AG: Employment, Equity Ownership. von Tresckow:Novartis: honoraria for acting as a consultant: Consultancy; Takeda Pharma GmbH: reimbursement of congress, travel, and accommodation costs and honoraria for preparation of scientific educational events: Honoraria. Topp:Affimed Therapeutics AG: Consultancy. Ravic:Affimed Therapeutics AG: Consultancy. Hucke:Affimed Therapeutics AG: Consultancy. Engert:Affimed Therapeutics AG: Consultancy.

Introduction High dose chemotherapy with autologous stem cell transplant (ASCT) is the treatment of choice for Hodgkin Lymphoma (HL) patients suffering from relapse or progression after first line therapy. However, patients with recurrence after ASCT have a very poor prognosis. Thus, the oral deacetylase inhibitor panobinostat was evaluated as maintenance therapy for patients at risk for relapse after ASCT to prevent recurrences. Methods HL patients after ASCT with at least one of the risk factors: primary refractory disease, early relapse ( Results The study was closed to enrollment and data were unblinded with only a total of 41 patients out of the planned 367 patients enrolled; 27 patients in the panobinostat arm and 14 patients in the placebo arm. Three patients (1 from the panobinostat arm and 2 from the placebo arm) never received treatment. Data are reported for patients treated during the randomized phase and no formal statistical analyses were conducted. The median duration of treatment was longer in the placebo arm (217 days) than in the panobinostat arm (176 days, randomized phase). The majority of patients in both treatment arms had an exposure of ≥ 24 weeks (53.8% in the panobinostat arm, 75% in the placebo arm). In the panobinostat arm, the most common reasons that patients discontinued were due to withdrawal of consent (29.8%) and adverse events (22.2%), whereas in the placebo arm, patients most commonly discontinued due to disease progression (28.6%). Most adverse events (AEs) occurred more frequently in the panobinostat arm (randomized phase). The most frequently reported AEs as compared to the placebo arm included: diarrhea (88.5%/25%), nausea (57.7%/8.3%), vomiting (46.2%/25%), fatigue (34.6%/25%), neutropenia (26.9%/33.3%), thrombocytopenia (26.9%/8.3%), oropharyngeal pain (26.9%/0%), headache (23.1%/0%), nasopharyngitis (19.2%/0%), upper respiratory infection (19.2%/8.3%), decreased appetite (15.4%/16.7%), pyrexia (15.4%/8.3%), influenza like illness (15.4%/0%) and sinusitis (15.4%/8.3%). Overall, the incidence of grade 3/4 AEs was 65.4% in the panobinostat arm during the randomized phase and 41.7% in the placebo arm. In the panobinostat arm, the most frequently reported grade 3/4 AEs were neutropenia (26.9%), thrombocytopenia (15.4%), and diarrhea, vomiting and fatigue (all 11.5%). In the placebo arm, the most frequently reported grade 3/4 AEs were neutropenia (33.3%), leukopenia (16.7%) and herpes zoster (16.7%). Although efficacy could not be formally evaluated due to the small number of patients in this trial, it is interesting to note that more patients from the placebo arm discontinued from the study due to disease progression (28.6% vs. 14.8% panobinostat patients). Conclusion The safety observations from this study were consistent with the general safety profile known for panobinostat. The use of panobinostat in a maintenance setting in a QOW schedule appeared to have acceptable tolerability in a population of patients with HL who are at risk for relapse after high dose chemotherapy and ASCT. Disclosures: von Tresckow: Takeda: Honoraria, Reimbursement of congress, travel, and accommodation costs , Reimbursement of congress, travel, and accommodation costs Other; Novartis: Consultancy, Honoraria. Szer:Novartis: Membership on an entity’s Board of Directors or advisory committees. Sureda:Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Engert:Seattle Genetics, Inc.: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Takeda: Honoraria.

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

Introduction BEACOPPescalated is the standard treatment for advanced Hodgkin Lymphoma (HL) within the German Hodgkin Study Group (GHSG) and other cooperative groups. Bleomycin and vincristine cause significant acute and long-term toxicity and are frequently discontinued during the course of therapy. However, the impact of dose reduction of these drugs on outcome and tolerability of BEACOPP has not been systematically assessed. Thus, we performed a retrospective analysis of patients treated within the GHSG trials HD12 (8xBEACOPPescalated versus 4xBEACOPPescalated plus 4xBEACOPPbaseline) and HD15 (8xBEACOPPescalated versus 6xBEACOPPescalated versus 8xBEACOPP14) trials for advanced stages. Methods Based on the intention-to-treat analysis, characteristics and outcome of patients receiving the full number of cycles of HD12 and HD15 were analyzed with respect to bleomycin and/or vincristine discontinuation. Progression-free survival (PFS) and overall survival (OS) were estimated from end of chemotherapy according to the Kaplan-Meier method and compared between groups using the log-rank test. To compare differences in patient characteristics, Fisher's exact test was used for rates and Wilcoxon's rank-sum test was used for continuous parameters. Receiver operating characteristic (ROC) analyses were performed in patients who had an event or were followed for at least 2 years after therapy. Results 3309 (89.4%) of patients received the full number of planned cycles and had complete chemotherapy documentation available. Bleomycin was discontinued in 10.5% and vincristine in 21.7% of cases. All other drugs had discontinuation rates less than 1.5%. 157 (4.7%) of patients received ≤4 cycles of bleomycin and 218 (6.6%) of patients received ≤3 cycles of vincristine; these were compared to patients with >4 cycles of bleomycin (3152 patients [95.3%]) and >3 cycles of vincristine (3091 patients [93.4%]). Discontinuation of bleomycin or vincristine was more frequent in patients aged 50 or older (4.4% and 7.4% with ≤4 cycles of bleomycin in patients 4 cycles of bleomycin (6-year PFS-difference 0.3% [95%CI -5.7 to 6.2%]; 6-year OS-difference 0.4% [95%CI -3.7 to 4.5%]; Figure 1A). Similarly, there was no significant PFS or OS difference in patients with ≤3 or >3 cycles of vincristine (6-year PFS-difference -1.6% [95%CI -6.4 to 3.2%]; 6-year OS-difference 1.9% [95%CI -2.5% to 6.3%]; Figure 1B). To assess if the number of bleomycin and vincristine cycles received had an impact on 2-year PFS and OS, ROC analyses were performed. However, failure could not be predicted irrespective of the number of cycles chosen as cutpoint. Detailed analyses and comparisons of patient characteristics, dose delivery of chemotherapy and toxicity will be presented. Conclusion Bleomycin and vincristine discontinuation due to drug-specific side effects seemed to be safe in this setting. Given the limitations of this retrospective analysis, our data suggest that bleomycin and vincristine may have a limited role in the BEACOPP regimen. Disclosures: von Tresckow: Novartis: honoraria for acting as a consultant: Consultancy; Takeda Pharma GmbH: reimbursement of congress, travel, and accommodation costs and honoraria for preparation of scientific educational events: Honoraria. Böll:Celgene: Travel Grant Other. Borchmann:Millenium The Takeda Oncology Company: Research Funding; Takeda Pharma GmbH: Travel Grants, Travel Grants Other. Engert:Seattle Genetics, Inc.: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Takeda: Honoraria.

Rationale Patients above 60 years of age account for up to one third of all patients with Hodgkin Lymphoma (HL). ABVD is considered standard of care for this patient cohort; however, both outcome and feasibility are poor, since tolerability of cytotoxic drugs is often markedly decreased. A major limitation is pulmonary toxicity due to bleomycin. We thus aimed at improving the ABVD regimen by replacing bleomycin with the immunomodulatory drug lenalidomide (Revlimid®, AVD-Rev), which has shown promising activity as single agent in HL. Methods We initiated the GHSG AVD-Rev dose finding trial (NCT01569204) for patients between 60 and 76 years of age, with first diagnosis of early unfavorable- or advanced-stage HL, good performance status (ECOG/WHO ≤2), and without evidence of severe organ dysfunction. Prophylactic anticoagulation (ASA or heparin) was mandatory. Depending on stage and response at interim staging, patients received four to eight cycles of AVD-Rev (standard-dose AVD on day 1 and 15 of a 28 days cycle and lenalidomide daily from day 1 to 21) followed by radiotherapy The daily lenalidomide dose for the first patient was 5 mg, and there were 8 possible dose levels ranging from 5 mg to 40 mg. Subsequently, all incoming information on dose limiting toxicities (DLT) during the first 4 cycles of therapy was used for dose level determination for the next patient using the EWOC (Escalation with Overdose Control) method. Critical adverse events including thromboembolism ≥CTC Grade II, hematological toxicity such as severe cytopenia (ANC< 500/µl >7days with G-CSF support and thrombocytopenia below 25.000/µl ≥ 1 day), and resulting complications such as neutropenic fever and prolonged therapy delay were considered as dose limiting toxicities. Results 25 patients with a median age of 67 years (range 61-76) and with a CIRS-G comorbidity scoring of up to 7 points (n=2, range 0-7) were recruited and assigned to dose levels 5 mg (n=1), 10 mg (n=1), 15 mg (n=1), 20 mg (n=6), and 25 mg (n=16). Fifteen patients were male, 68% had advanced stage disease, and 80% had B-symptoms at diagnosis. After DLT evaluation of 20 patients, a pre-specified stopping criterion was reached and the recommended dose for a phase II trial was 25 mg. Dose delivery was high with a mean relative dose intensity of 91% (all dose levels, range: 63-104%, median: 97%), however at least one CTC Grade III-IV toxicity occurred in all 22 patients who were treated at dose levels 20 mg and 25 mg, and 16 of these patients had a CTC Grade IV toxicity. Dose limiting toxicities were observed in 2 of 6 (33%) and 8 of 16 (50%) patients at 20 mg and 25 mg, respectively, and were mainly hematologic but also included 3 thromboembolic events despite documented ASA prophylaxis. No DLT occurred in patients treated with Overall response rates were 79% for all evaluable patients (19/24) and 86% (18/21) in patients treated with at least 20 mg lenalidomide. After 12 months median observation time, 5 patients had a disease progression and 3 patients died. The one-year estimates for progression-free an overall survival are 69% [95%-CI: 50-91%] and 91% [95%-CI: 79-100%], respectively. Conclusion AVD-Rev is feasible and effective in this vulnerable population of older Hodgkin patients. We thus recommend this regimen for further evaluation in a phase II study. Disclosures: Böll: Celgene: Travel Grant Other. von Tresckow:Novartis: honoraria for acting as a consultant: Consultancy; Takeda Pharma GmbH: reimbursement of congress, travel, and accommodation costs and honoraria for preparation of scientific educational events: Honoraria. Engert:Seattle Genetics, Inc.: Honoraria, Research Funding.

AFM13 represents a new class of bispecific antibodies, based on the RECRUIT-TandAb platform, which enables the generation of therapeutics with improved efficacy, convenient administration regimens, and excellent safety profiles. AFM13 was developed for the treatment of Hodgkin Lymphoma (HL) and other CD30+ malignancies. AFM13 targets CD30 on HL tumor cells and recruits NK cells via CD16A. Preclinical data demonstrate specific and highly efficient anti-tumor activity by the selectively recruited NK cell immune response, which addresses key deficiencies of monoclonal antibodies: (i) reduced binding to the 158F allotype of CD16A and (ii) non-selective binding to immune effector cells via both activating CD16A and non-signalling CD16B receptors. In vitro assays demonstrate that AFM13 binds with high affinity to both CD30 and CD16A antigens and rapidly induces lysis of CD30+ cells at picomolar concentrations. Further, AFM13 activates CD16A only in the presence of tumor cells: there is no systemic activation of NK-cells in the absence of target cells. A robust GMP process in mammalian cells and a lyophilized formulation with excellent stability are established. Finally, no toxicity is observed in Cynomolgus monkeys. AFM13 was investigated in an open-label single-arm phase I dose escalation trial in heavily pre-treated patients with relapsed/refractory HL. Each patient received 4 weekly doses of AFM13. Seven dose levels from 0.01 to 7.0 mg/kg were escalated in cohorts of 3 patients. In addition, one cohort of 4 patients received AFM13 twice a week at 4.5 mg/kg for 4 weeks. All dose levels of AFM13 proved to be well tolerated and safe and clear signs of anti-tumor activity were demonstrated. We have performed an analysis of the activation of NK cells and clearance of soluble CD30 in humans since these are key parameters for the mode of action of AFM13. We confirmed a correlation between anti-tumor activity parameters and biomarkers based on a statistically significant dose-dependent increase in the activation of NK cells and reduction in soluble CD30 levels. Since the activation of NK cells has been reported to facilitate low-level expression of CD30 on NK cells, which we also observed in several patients in the highest AFM13 dose groups, we investigated whether this may affect NK cell cytotoxicity. Our ex vivo evaluation of samples from patients that received AFM13 and in vitro evaluation of activated NK cells demonstrated no inhibition of NK cell-mediated cytotoxic activity. Furthermore, AFM13 exhibits a remarkable half-life of 1 day which represents a substantial increase relative to that of diabody-like formats currently being evaluated in the clinic for haematological malignancies. Thus, AFM13 has demonstrated encouraging biologic activity and represents a new targeted therapy for heavily pre-treated patients with HL. Citation Format: Achim Rothe, Max S. Topp, Anas Younes, Uwe Reusch, Stefan Knackmuss, Erich Rajkovic, Dennis A. Eichenauer, Horst Hummel, Katrin S. Reiners, Markus Dietlein, Joerg Kessler, Miroslav Ravic, Christian Hucke, Eugene Zhukovsky, Elke Pogge von Strandmann, Andreas Engert. The CD30/CD16A RECRUIT TandAb AFM13 activates patient NK cells resulting in specific tumor cell killing. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4572. doi:10.1158/1538-7445.AM2013-4572

Abstract 2743 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. Methods: 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. Results: 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. Conclusion: 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. Disclosures: Engert: Millenium The Takeda Oncology Company: Honoraria.

Abstract 2633 Background: Today, most patients with Hodgkin Lymphoma (HL) can be cured at first diagnosis. For HL patients suffering from relapse or progression after first line therapy, high dose chemotherapy followed by autologous stem cell transplant (ASCT) is the treatment of choice and cures about 50% of these patients. Those who relapse or progress after ASCT have a very poor prognosis and clearly represent an area of unmet medical need. However, data on this small group of patients is rather limited and no established risk factors are available. Here, we present a recent retrospective analysis from the GHSG database to better characterize HL patients with relapse or progression after ASCT in order to define possible risk factors for the prediction of overall survival. Methods: All trials in the GHSG database were searched for HL patients who relapsed or progressed after ASCT. The information for this retrospective analysis was updated in May 2012. Overall survival after progression of HL following ASCT (OSrr) was the end point of this study. Descriptive statistics and Kaplan Meier estimates of OSrr were used and risk factors for OSrr analyzed. The significance level was set to 0.05. Results: 152 patients who relapsed or progressed with HL after ASCT were identified. 149 patients fulfilled the predefined inclusion criteria. With a median observation time of 65 months after progression, 112 patients (75%) had died. OSrr was 63% (95% confidence interval [CI]; 54% to 70%), 51% (95% CI 42% to 58%), and 20% (95% CI 13% to 28%) at 1, 2 and 5 years, respectively. From several risk factors tested, stage (p=0.044) and presence of B-symptoms (p=0.005), both at relapse before ASCT, significantly predicted OSrr. Combination of these two risk factors allowed the identification of three distinct risk categories for the 4 significantly different groups (p=0.013; Figure 1). Accordingly, patients in clinical stage I or II without B-symptoms had a somewhat better prognosis (OSrr 84% [95% CI 67% to 92%], 72% [95% CI 54% to 84%] and 33% [95% CI 18% to 49%] at 1, 2 and 5 years, respectively). Other potential risk factors such as stage at first diagnosis (p=0.80), early, late or multiple relapses before ASCT (p=0.95), and time from ASCT to further progression of HL (p=0.81) were not significant. Conclusions: Current treatment approaches for patients with relapsed or progressive HL after ASCT show disappointing results with 80% of this very high-risk group dying within 5 years. Emerging new drugs such as brentuximab vedotin might improve the outcome of these patients in the future. Disclosures: von Tresckow: Takeda Pharma GmbH: Honoraria, Travel Grants Other. Borchmann:Millenium The Takeda Oncology Company: Research Funding; Takeda Pharma GmbH: Travel Grants, Travel Grants Other. Engert:Millenium The Takeda Oncology Company: Honoraria.

Abstract 4230 Background: Hodgkin Lymphoma (HL) is one of the most common malignancies in young adults and has become curable for the majority of patients even in advanced stage. Nowadays, the main challenges are to develop strategies that decrease secondary malignancies and mortality, as well as to retain fertility after treatment. So far, there is no national or international evidence-based guideline giving recommendations for clinical practice in the treatment of HL patients. For this reason, various medical societies, clinical experts from the German Hodgkin Study Group (GHSG) and methodological experts from the Cochrane Haematological Malignancies Group (CHMG) have developed and consented a clinical practice guideline to improve and standardize diagnosis, treatment and follow-up for HL patients. This project was funded by the German Program for Guidelines in Oncology Implementation. Aims: To emphasize the clinically most relevant guideline recommendations related to diagnostics, treatment and follow-up of adult HL patients. Methods: Randomized controlled trials, systeamtic reviews, cohort studies and specific sensitive data included from systematic literature searches in CENTRAL and MEDLINE were appraised for quality and summarized in evidence tables. Based on these tables and trials, guideline authors generated high quality clinical recommendation in an intensive collaboration with the methodological experts clinical experts from different multi-interdisciplinary working-groups. During the final consensus conference, a total of 160 evidence-based recommendations were consented. Results: There is a strong consensus that all patients should be treated within a clinical trial. Chemotherapy is the mainstay of treatment for all stages of HL. The histological diagnosis should be confirmed by a reference pathologist. For early favorable stages, two cycles of ABVD followed by involved-field radiotherapy (IF-RT) at 20 Gy are strongly recommended; early unfavorable stages should be treated with 2 cycles of BEACOPP escalated followed by 2 cycles of ABVD and IF-RT of 30 Gy; for advanced stages six cycles of BEACOPP escalated followed by 30 Gy radiotherapy on PET-positive residual mass ≥ 2cm is strongly recommended. It is also recommended that patients with relapses or refractory disease, and without severe co-morbidities, receive autologous stem cell transplantation, but not myeloablative allogeneic stem cell transplantation. Additionally, treatment options of subgroups, such as nodular lymphocyte predominant HL, elderly patients or those with co-morbidities such as HIV, are specified in this guideline. The additional benefit of PET remains uncertain as of the lack of high-quality evidence, therefore different recommendations have been provided for staging, interim and follow-up evaluations. It is highly important that health care professionals discuss aspects of fertility protection with female and male patients before starting any treatment. Options for preserving fertility in women have to be adopted to treatment intensity. For male patients, it is recommended to cyropreserve sperm cells before starting the therapy, independently of treatment intensity. There is strong consensus that patients have to prevent to conceive a child during treatment. Health-care professionals should encourage patients to exercise and should discuss potential harms of complementary medicine with the patient. Due to their immunomudulating effect, it is not recommended to take mistletoes at any time. It is strongly recommended to motivate patients to give up smoking, due to the strong associated increased risk of secondary tumors, especially bronchial carcinoma. Structured follow-up care should be provided and should in particular detect relapses, long-term organ toxicities and secondary malignancies. Summary/Conclusions: The first evidence-based guideline on the treatment of patients with HL translates scientific evidence and expert knowledge into precise recommendations for these patients into clinical practice. In addition to this clinical value, the guideline will enable healthcare professionals to improve patient information and quality management. Disclosures: Engert: Takeda, Millennium: Honoraria, Research Funding. Borchmann:Millenium The Takeda Oncology Company: Research Funding, Travel Grants Other. von Tresckow:Millenium The Takeda Oncology Company: Honoraria, Travel Grants Other.

Abstract 3709 Background: AFM13 is a bispecific, tetravalent human antibody construct (TandAb®) designed for the treatment of Hodgkin Lymphoma or other CD30-expressing malignancies. AFM13 specifically targets CD30, which is homogenously expressed on Hodgkin tumor cells and recruits NK cells as immune effector cells via the targeting of CD16A. Preclinical data demonstrate a specific and efficient anti-tumor activity delivering its therapeutic payload via the engagement of NK-cells. Methods: AFM13 is currently being evaluated in a single arm phase I dose escalation trial for patients with relapsed and/or refractory Hodgkin Lymphoma. The overall objective of this study is to evaluate safety, tolerability, pharmacokinetics, immunogenicity, antitumor activity, the maximum tolerated dose and the optimal biological dose of AFM13. Each patient receives a single cycle, consisting of one dose of AFM13 given once weekly for four weeks. The doses are escalated in cohorts of three patients at the dose levels of 0.01, 0.04, 0.15, 0.5, 1.5, 4.5 and 7.0 mg/kg. In responding patients, a second course of AFM13 can be considered. The safety of the maximum tolerated dose or the optimal biological dose will be confirmed in 12 additional patients. Results: So far, 15 patients with Hodgkin Lymphoma were enrolled and treated with doses of up to 0.5 mg/kg body weight. The median age was 37 years (range 20 to 57). 14/15 patients had received prior high dose chemotherapy and autologous stem cell transplantation with a median of 6 prior therapies (range 4 to 10). 8/15 patients were refractory to their most recent therapy. The study drug was well tolerated. Adverse events were generally mild, with the most frequent drug-related event being grade 1/2 fever occurring in 5/15 patients. One patient with known metastatic liver involvement developed a possibly drug-related dose-limiting grade 4 hemolytic anemia and a fatal, not drug-related suspected Aspergillus pneumonia. Of 10 evaluable patients who completed at least one cycle of therapy, 5 patients achieved stable disease, one of which showed a clear decrease in tumor volume. Biomarker analysis results show that the expression of the early activation marker CD69 on patient NK cells is significantly increased after treatment with AFM13. Moreover, in vitro cytotoxicity assays using patient NK cells demonstrate an effective killing of Hodgkin Lymphoma cells. Conclusion: This is the first clinical data on the bispecific, NK cell recruiting antibody construct AFM13 for the treatment of Hodgkin Lymphoma. AFM13 seems to be a new feasible and effective targeted therapy for heavily pre-treated patients with Hodgkin Lymphoma. Results of the ongoing phase I study will be presented. Disclosures: Younes: Genentech: Research Funding; Novartis: Honoraria, Research Funding; SBIO: Research Funding; Seattle Genetics: Honoraria, Research Funding; Syndax: Research Funding; Sanofi-Aventis: Honoraria, Research Funding. Topp:Micromet AG: Consultancy. Ravic:Affimed Therapeutics AG: Consultancy. Engert:Affimed Therapeutics AG: Honoraria, Research Funding.

Abstract 2711 Background: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare subtype of Hodgkin lymphoma (HL) accounting for about 5% of cases. The clinical course is usually more indolent than in classical HL (cHL) resulting in an excellent long-term prognosis. This is particularly true for patients diagnosed with early-stage NLPHL representing the majority of cases. However, current standard treatment consisting of chemotherapy and/or radiotherapy (RT) is associated with an increased risk of late toxicity. Thus, there is a need for novel treatment strategies. Since CD20 is consistently expressed on the malignant lymphocyte-predominant (LP) cells, anti-CD20 antibody treatment appears to be a promising option. After impressive response rates were reported in relapsed NLPHL patients, the German Hodgkin Study Group (GHSG) initiated a trial to evaluate the anti-CD20 antibody rituximab in newly diagnosed stage IA NLPHL without clinical risk factors. Methods: Between June 2006 and October 2007, 29 patients from 23 sites were enrolled in this multicenter phase II trial. Study entry was restricted to adult patients (age 18 to 75) with biopsy-proven stage IA NLPHL without clinical risk factors. Treatment consisted of four weekly infusions of the anti-CD20 antibody rituximab at a dose of 375 mg/m2. Efficacy endpoints included remission status as assessed by computed tomography (CT) four weeks after completion of treatment, overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) at two years; feasibility endpoints were acute treatment-related toxicities, adverse events, dose reductions and therapy delays. Results: Twenty-eight patients were eligible for the final analysis of this phase II trial; 71.4% of patients were male, 72% had supradiaphragmatic disease and the median age was 40 years. Treatment was conducted in the outpatient setting in the majority of cases. Rituximab was well tolerated; no grade III/IV toxicities were observed. Transfusions of erythrocytes or platelets were not required. At final restaging four weeks after the last rituximab application, 24 patients (85.7%) were in CR/CRu and four patients (14.3%) had partial remission (PR). Thus, overall response rate (ORR) was 100%. After a median follow-up of 43 months, all patients were still alive. Progression-free survival rate estimates at two, three and four years were 85.3%, 81.4% and 77.1%, respectively. Seven patients (25%) have relapsed and two patients developed secondary solid tumors. All patients with NLPHL relapse were successfully salvaged. Conclusions: The results of the present trial confirm the previously reported excellent response of NLPHL patients to rituximab. However, with a relapse rate of 25% at a median observation time of 43 months, rituximab does not seem to be as effective as RT alone or combined-modality strategies in stage IA NLPHL patients. Nonetheless, anti-CD20 antibodies have a favorable toxicity profile and may be offered to selected patients who are at particular risk for long-term side effects such as secondary malignancies. In addition, the combination of anti-CD20 antibodies and chemotherapy may also improve efficacy and decrease toxicity of NLPHL treatment in early unfavorable, advanced or relapsed disease. Disclosures: No relevant conflicts of interest to declare.

Hodgkin lymphoma (HL) is a malignancy of the lymphatic system with an incidence of 2-3/100.000/year in developed countries. With modern multi-agent chemotherapy protocols optionally combined with radiotherapy (RT), 80% to 90% of HL patients achieve long-term remission and can be considered cured. However, current standard approaches bear a considerable risk for the development of treatment-related late effects. Thus, one major focus of current clinical research in HL is reducing the incidence of these late effects that include heart failure, infertility, chronic fatigue and secondary malignancies such as secondary myelodysplastic syndrome and acute myeloid leukemia (secondary MDS/AML). In previous analyses, secondary MDS/AML after treatment for HL was associated with a poor prognosis. Nearly all patients died rapidly after diagnosis. However, more recent analyses indicated an improved outcome among patients with secondary MDS/AML who are eligible for modern anti-leukemic treatment and allogeneic stem cell transplantation (aSCT). This article gives an overview of recent reports on the incidence and the treatment of secondary MDS/AML after HL treatment and describes the efforts currently made to reduce the risk to develop this severe late effect.