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

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

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

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

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

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

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

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.

Purpose. To evaluate the safety, tolerability and efficacy of the combination of the mTOR inhibitor Temsirolimus and a standard salvage regimen (R-DHAP) in patients with relapsed or refractory diffuse large cell B-Cell lymphoma (DLBCL). Methods. This is a prospective, multicenter, phase II, open-label study. Patients with relapsed or refractory DLBCL with a maximum of two prior treatment lines were eligible. The STORM regimen consisted of Rituximab 375 mg/m² (day 2) and DHAP (Dexamethasone 40mg day 3-6, Cisplatine 100 mg/m² day 3, Cytarabine 2x2 g/m² day 4) with Temsirolimus added on day 1 and 8 of a 21 d cycle, with 2-4 cycles planned. In part I, dose levels of 25, 50, 75 and 100 mg for Temsirolimus were predefined. Based on the observed toxicity profile, the independent data safety committee recommended a Temsirolimus dose of 25 mg given on day 1 and 8 for the part II extension cohort of the trial. Results. We here report on 46 patients (pts), 15 from part I and 31 from part II. Seven pts were not evaluable for response. Of the evaluable 39 patients, median age was 63 and median number of prior regimen was 1. Temsirolimus dose was 50 mg on day 1 and 8 in 7 pts from the part I of the trial and 25 mg in the remaining 39 pts. The overall response rate was 82% (32/39pts) with 22 partial and 10 complete responses. After a median follow up of 10 months for the total study population, median PFS and OS have not been reached (Figure 1A and 1B). Early safety analysis includes preliminary data of 22 pts. The most frequent non-hematologic side effects were nausea (14 pts, 64%), epistaxis (11 pts, 50%), fatigue (12 pts, 55%), fever (11 pts, 50%) and diarrhea (11 pts, 50%). Frequent grade 3/4 events (n>2) included leukopenia (21 pts, 95%), thrombocytopenia (20 pts, 91%), lymphopenia (11pts, 50%), anemia (8 pts, 36%), neutropenia (10 pts, 45%), renal failure (3 pts, 20%) and infections (7 pts, 32%, bladder infection, esophagus infection, central venous access infection, soft tissue infection, mucositis). Two therapy-related deaths occurred (one patient died from sepsis during neutropenia, another from cerebral bleeding, both events occurring after cycle 3). Conclusion. Temsirolimus can be safely added to DHAP and Rituximab with promising activity. Figure 1 Progression free survival Figure 1. Progression free survival Figure 2 Overall survival Figure 2. Overall survival Disclosures Witzens-Harig: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Viardot:Pfizer: Honoraria; Takeda: Other: travel support; Roche: Honoraria; BMS: Consultancy; Janssen: Consultancy; Amgen: Consultancy. Keller:Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Spectrum Pharmaceutical: Consultancy, Membership on an entity's Board of Directors or advisory committees. Buske:Celltrion, Inc.: Consultancy, Honoraria. Meissner:Amgen: Other: Travel Support; Takeda: Other: Travel Support; Teva: Other: Travel Support; Celgene: Other: Travel Support. LaRosee:Pfizer: Honoraria. Marks:Pfizer: Honoraria. Hess:Celgene: Honoraria; Roche, CTI, Pfizer, Celgene: Research Funding; Janssen: Honoraria; Roche: Honoraria; Pfizer: Honoraria; Novartis: Honoraria.

Background: NLPHL is a relatively uncommon subtype of Hodgkin lymphoma (HL) accounting for about 5-6% of all HL cases. It has unique clinico-pathological, morphologic and immunohistochemical features with CD20-positive "lymphocyte predominant cells". Although long-term survival is better than in classical HL, frequent relapses are common and progression/transformation to aggressive non-Hodgkin lymphoma (NHL) may occur. Whilst HDC auto-SCT is considered as standard of care for relapsed/refractory classical HL, data on HDC auto-SCT in relapsed/refractory NLPHL is sparse. Here, we report a registry study of HDC auto-SCT for NLPHL using the EBMT database, representing the largest sample analyzed to date. Design: Eligible were patients with NLPHL18 years or older who underwent a first auto-SCT between 2003 and 2013, and were registered with the EBMT. Patients with NLPHL transformed to DLBCL were not eligible. The primary objective was 5-year progression-free survival (PFS). Baseline patient, disease and transplant data were collected from EBMT MED-A standard forms. Centers with potentially eligible patients were contacted to provide additional treatment and follow-up details with a copy of written diagnostic report for central review. Statistical analysis was descriptive and employed log rank comparisons for univariate assessment of the impact of baseline characteristics on survival endpoints. Results: We identified 92 patients who met the inclusion criteria with full data including a written diagnostic pathology report available. Of these, 36 patients were excluded after histopathology report review (17 classical HL, 2 NHL, 17 no sufficient information). The final sample comprised 56 patients. There was a predominance of male patients with a male:female ratio of 88%:12%. Median age was 36 (interquartile range (IQR) 29-50) years. Most patients (65%) had advanced stage (III-IV) at diagnosis and one third had B-symptoms. Prior to HDC auto-SCT, 71% patients had 2, 20% had 3, and the remainder had more than 3 lines of treatment (median: 2 lines). Rituximab was used in 62% of patients. The median time from diagnosis to HDC auto-SCT was 21 (IQR 14-51) months. Disease status prior to HDC auto-SCT was complete remission (CR) in 54% and partial remission (PR) in 43%. Most commonly used HDC was BEAM (84% patients), with additional rituximab in 13%. With a median follow-up of survivors of 5 (IQR 3.6-6.6) years, 5-year PFS and overall survival were 67% (95%CI 55-82) and 86% (95%CI 77%-96%), respectively. The 5-year incidence of relapse was 32% (95%CI 20-46). There were no transplant-related deaths. Univariate comparisons considering age, time from diagnosis to transplant, number of pre-treatment lines and rituximab use during induction, salvage and/or HDT failed to identify significant predictors of PFS or OS endpoints. Conclusions: This study, the largest reported thus far on HDC auto-SCT in NLPHL, shows that two thirds of patients remain free of disease 5 years after HDC auto-SCT. In contrast with the usual characteristics of patients with NLPHL, those included in this series had high-risk disease with B-symptoms and advanced stage at diagnosis, and half the patients had HDC auto-SCT less than 2 years after diagnosis. This study demonstrates that patients with NLPHL and adverse features can benefit from HDC auto SCT at relapse. Figure. Figure. Disclosures Montoto: Roche: Honoraria; Gilead: Research Funding. Masszi:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Moraleda:Pfizer: Research Funding. Bloor:Janssen: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Speakers Bureau; Gilead: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees. Meissner:Amgen: Other: Travel Support; Takeda: Other: Travel Support; Celgene: Other: Travel Support; Teva: Other: Travel Support. Dreger:Novartis: Speakers Bureau; Gilead: Consultancy; Gilead: Speakers Bureau; Novartis: Consultancy; Janssen: Consultancy; Roche: Consultancy.

Purpose. To evaluate the safety, tolerability and efficacy of the combination of the mTOR inhibitor Temsirolimus and a standard salvage regimen (R-DHAP) in patients with relapsed or refractory diffuse large cell B-Cell lymphoma (DLBCL). Patients and Methods. This is a prospective, multicenter, phase II, open-label study. Patients with relapsed or refractory DLBCL with a maximum of two prior treatment lines were eligible. The STORM regimen consisted of Rituximab 375 mg/m² (day 2) and DHAP (Dexamethasone 40mg day 3-6, Cisplatine 100 mg/m² day 3, Cytarabine 2x2 g/m² day 4) with Temsirolimus added on day 1 and 8 of a 21 d cycle, with 2-4 cycles planned. In part I, dose levels for the mTOR inhibitor Temsirolimus from 25, 50, 75 and 100 mg were predefined. Results. Here we report on the preliminary results of part I of this clinical trial. 15 patients were included - 8 patients in the 25 mg cohort and 7 patients in the 50 mg cohort. Median age was 70 (range 49-76) years and median number of prior regimen was 1. Two DLTs (one venous thrombosis in the 25 mg cohort, one esophagus infection in the 50 mg cohort) were observed. The most frequent non-hematologic side effects were nausea (9 pts, 60%), epistaxis (7 pts, 47%), fatigue (6 pts, 40%), increased ALT (6 pts, 40%) and increased creatinine (6 pts, 40%). Frequent grade 3/4 events (n>2) in both cohorts (25mg|50mg) included leukopenia (11 pts, 73% - with a mean duration of 4.4 days | 6.7 days ), thrombocytopenia (11 pts, 73% - with a mean duration of 4.6 days | 11.9 days), lymphopenia (6pts, 40%), anemia (5 pts, 33%), neutropenia (3 pts, 20%), renal failure (3 pts, 20%) and infections (4 pts, 27%, bladder infection, esophagus infection, central venous access infection, soft tissue infection, mucositis). Based on the observed toxicity profile, the independent data safety committee recommended a Temsirolimus dose of 25 mg given on day 1 and 8 for the part II extension cohort of the trial. All but one evaluable patient responded (10/11 pts, 91%), with two CRs and one CRu (27%). Four patients could not be evaluated for response at the time of this report. After a median follow up of 12 (range 5-22) months, no relapse has been documented so far (1 pt lost to follow up). Conclusion. Temsirolimus can be safely added to DHAP and Rituximab with promising activity. Recruitment into part II is ongoing and updated results will be presented. Disclosures Witzens-Harig: Pfizer: Honoraria, Research Funding; Roche: Honoraria. Keller:Roche: Consultancy, Honoraria; Pfizer: Consultancy. Viardot:Roche: Honoraria; CTI: Consultancy; Pfizer: Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy. Buske:Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria. Ho:Sanofi: Research Funding. Hess:Janssen, Roche, Celgene, Novartis: Consultancy; Pfizer, Janssen, Roche, Mundipharma: Honoraria, Research Funding.

Background: Primary progressive disease still remains an unmet medical need in Hodgkin Lymphoma (HL). Due to missing data on treatment effects and survival there is no established standard of care. We thus performed a retrospective analysis using the German Hodgkin Study Group (GHSG) database to improve the knowledge on the course of primary progressive HL patients. Methods: Patients aged between 18 and 60 years treated within the GHSG first-line trials HD13-HD15 were screened for primary progressive HL. Primary progression was defined as progressive disease during ongoing therapy, within 3 months after the end of treatment, or up to 6 months after the end of treatment in patients with partial response or stable disease in the final restaging. We investigated types and outcome of second-line treatment approaches and overall survival, which was calculated from first diagnosis of HL (OS) and from diagnosis of first progression or relapse (OSp). Results: We analyzed 5,126 patients, of whom 112 (2.2%) were identified with primary progressive disease. Of those, 62 (55%) patients had initially been treated for advanced-stage HL with BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) variants, 30 (27%) for early-stage unfavorable HL with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine)- or BEACOPP-like regimens (24 and 6 patients, respectively) and 20 (18%) for early-stage favorable HL with ABVD variants. The median age at the time of progression was 33 years. 3 patients (3%) died before a salvage therapy was started. Second-line treatment strategies included reinduction with intensified salvage regimens (77%), conventional chemotherapy (14%), and radiotherapy (8%). Autologous stem cell transplantation (ASCT) was performed in 76% of the patients who had received intensified reinduction chemotherapy, and allogeneic stem cell transplantation in ten (9%) patients. After the first salvage therapy, 42% of all patients achieved a complete remission (CR) and did not require further treatment. In total, 66% of the patient cohort achieved a CR after one or more second-line approaches. Median duration of the first CR was 61 months. After a median observation time of 7 years, 55 of the patients with primary progressive disease (49%) had died, mostly from progressive or relapsed HL (n=36) or toxicity of salvage treatment (n=10). The majority of the 57 survivors was in CR at the time of analysis; 2 were under treatment for HL and there was no information available for one patient. Median OSp for the entire cohort was 83 months, 5-year OSp was 55.4% (95%-CI, 46% to 65%). Since OSp differed among patients of different initial stages and types of pre-treatment (early-stage favorable and unfavorable patients treated with ABVD variants, OSp 74.2% [61%-87%] vs. higher-stage patients treated with BEACOPP variants, OSp 42.9% [31% - 55%]), treatment groups were analyzed for survival separately. In both groups, patients responding to the first salvage therapy had a significantly better OSp compared to those not responding (each p Conclusion: Overall, the 5-year OSp in this unselected patient cohort of primary progressive HL patients is encouraging and supports the use of aggressive salvage regimens and consolidating high-dose chemotherapy in general. However, this approach is known to induce severe long-term toxicities and has limited efficacy in patients failing first-line treatment for advanced stage disease. We conclude that there is a need to develop different treatment approaches in primary progressive HL patients. Disclosures von Tresckow: Novartis: Consultancy, Other: Travel and accomodation, Research Funding; Amgen: Other: honoraria for preparation of scientific educational events; Celgene: Other: honoraria for preparation of scientific educational events; Takeda: Consultancy. Zijlstra:Celgene: Consultancy; Roche: Consultancy. Topp:Astra: Consultancy; Regeneron: Consultancy; Affimed: Consultancy, Research Funding; Roche: Consultancy, Other: Travel Support; Jazz: Consultancy; Pfizer: Consultancy; Amgen: Consultancy, Honoraria, Other: Travel Support. Engert:Takeda: Consultancy, Research Funding. Borchmann:Millennium: Research Funding.

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

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

Background It was recently shown that rituximab maintenance therapy prolongs progression free (PFS) and overall survival (OS) in patients with mantle cell lymphoma (MCL) after conventional chemotherapy treatment. However, it is not clear if rituximab maintenance can further improve outcome of MCL patients after autologous stem cell transplantation (autoSCT). Methods All patients with MCL who underwent an autoSCT at the University Hospital of Heidelberg from 2000 onwards were selected for this analysis. MCL patients who have received rituximab maintenance therapy after autoSCT in a prospective phase-2 trial were compared with regard to PFS and OS with MCL patients who were transplanted during the same time period but did not receive rituximab maintenance therapy by multivariate cox regression analysis correcting for known confounders. For the comparison of rituximab maintenance therapy with the control group, rituximab maintenance therapy was considered as a time dependent event in order to avoid that early progression before start of rituximab maintenance therapy may compromise results. Results A total of 72 patients met the inclusion criteria. Twenty-two patients participated in a phase-2 trial and received rituximab maintenance therapy for two years. Median age was 60 years (30-74). Prior to autoSCT all patients received rituximab and 45 patients were treated with high dose cytarabine (HD-ARA-C). AutoSCT was performed after first line treatment in 51 patients. A complete response (CR) before autoSCT was achieved by 27 patients. Patients with and without rituximab maintenance therapy did not significantly differ with regard to age, upfront autoSCT, CR rates and HD-ARA-C treatment prior to autoSCT. However, there was a trend that patients who received rituximab maintenance therapy were transplanted more recently (p=0.06). Median observation time after autoSCT was 56 months. Two-year PFS and OS of the control group were 65% and 80%, respectively, as compared to 90% and 88%, respectively, of the rituximab maintenance group. By univariate analysis rituximab maintenance therapy was associated with significantly better PFS (HR 0.21, p=0.014; Figure 1A) but so far not OS (Figure 1B). Multivariate adjustment for age (HR per year 0.98; p=0.79), year of transplant (HR per calendar year 1.0; p=0.96), achievement of CR prior autoSCT (HR 1.59; p=0.26), upfront autoSCT (HR 0.81; p=0.80) and high dose ARA-C treatment (HR 0.69; p=0.63) confirmed the beneficial impact of rituximab maintenance therapy (p=0.02 HR 0.23). Summary Rituximab may prolong PFS in MCL patients who have undergone autoSCT. Prospective studies are highly warranted to confirm our preliminary finding. Disclosures: Ho: Sanofi-Genzyme: Research Funding, travel grant Other.

Abstract 3649 Background: A growing number of patients with aggressive lymphoma experience long term survival after front-line treatment and survivorship issues have been increasingly addressed in recent years. Within treatment-induced sequelae, gonadal failure represents a major late-effect of chemotherapy. With respect to hematologic malignancies the majority of data on fertility effects pertains to Hodgkin Lymphoma treatment regimens whereas information on gonadal toxicity of non-Hodgkin Lymphoma treatments is limited. While CHOP as the standard treatment for aggressive lymphoma is supposed to be associated with only temporary side-effects on fertility in both sexes, nothing is known about the fertility effect of a moderate intensification of CHOP by adding etoposide in frequently used regimens such as CHOEP or dose-adjusted EPOCH. Methods: Our study assessed fertility aspects in young patients with aggressive lymphoma who enjoy ongoing first remission after treatment in the Mabthera International Trial or the German DSHNHL NHLB1 study between 1995 and 2003. Long term survivors of both prospective studies were contacted and invited to answer a questionnaire. Patients who received radiotherapy to the gonadal area as part of their primary treatment as well as those who received chemotherapy for secondary neoplasia were excluded from the analysis. Data on parenthood obtained in the subgroup of patients who received 6 complete cycles (R)-CHOEP (total cyclophosphamide and etoposide dose 4,500 mg/m2 and 1,800 mg/m2, respectively) is reported here. Results: Altogether 66 (31 female, 35 male) patients agreed to participate in the survey. Median age at treatment was 32.5 years (range: 18 – 40) and at time of data collection 44 years (range: 28 – 55), respectively, with a median follow-up after treatment completion of 11 years (range: 7 – 17). While 31 (46.9%) patients already had children before treatment (18 female – 58.1%, 13 male – 37.1%), 35 (53.0%) expressed a clear desire for children after treatment (14 female – 45.2%, 21 male – 60.0%). Ten of these 35 patients did not try to achieve pregnancy, with lack of partner being the main reason. Of the remaining 25 patients (12 female, 13 male) who tried to achieve pregnancy, 18 (9 female – 75%, 9 male – 69%) were finally successful. Apart from 2 deliberate abortions all pregnancies were uncomplicated and resulted in 25 live births. No major health problems were reported in the children. The interval between completion of treatment and birth of first child after treatment ranged from 21 to 146 months (median 58 months) in female patients and from 25 months to 106 months (median 60.5 months) in male patients. Patients not achieving pregnancy tended to be older then patients who successfully achieved pregnancy (median age 30 versus 25 in female patients and 34.5 versus 28 years in male patients). Not achieving parenthood after treatment was associated with emotional stress in 3 of 3 female patients but only in 1 of 4 male patients. Fourteen patients chose cryopreservation of sperm before treatment but none of them utilized preserved sperm for reproductive purposes. Cryopreservation techniques were not used in female patients. Only one female patient received a GnRH analogue in parallel to chemotherapy and gave birth to two children after treatment. Comparison of the presented patient data with the German general population (The German Socio-Economic Panel, 2011) revealed only non-significant differences in the overall percentage of childless women (16.1% in the study population versus 26.0% in the general population, p=0.15) and men (45.7% versus 33.8%, p=0.07). Total fertility rate in female study patients (1.45) paralleled that in the general population (around 1.4 between 1980 and 2010). Conclusions: Parenthood after treatment with CHOP plus etoposide seems not to be significantly impaired in comparison to the general population. Most patients who had attempted post-treatment parenthood were successful. The small percentage of patients not achieving pregnancy despite a clear desire for parenthood after treatment is in line with previous reports on the fertility effects of CHOP. However, all patients of reproductive age should be offered counselling with regard to the impact of planned therapy on their fertility. Disclosures: No relevant conflicts of interest to declare.

Abstract 4600 Targeted intervention against driver mutations is beginning to transform cancer treatment. A particular activating mutation of the BRAF serine/threonine protein kinase, BRAF V600E, is found in virtually all cases of hairy-cell leukemia (HCL), suggesting disease-specific oncogene dependence. Here, we present the extended follow up of a patient with chemotherapy refractory HCL who was treated with a short course of vemurafenib, a specific BRAF inhibitor. Before vemurafenib treatment, the patient had an almost complete bone marrow (BM) infiltration by hairy cells and massive splenomegaly (24.8×8.3 cm) leading to severe cytopenias (leukocytes, 680/μl; hemoglobin, 10 g/dl; platelets, 36,000/μl). No objective response could be achieved by three lines of purine analogue based treatment regimens (Cladribine, Pentostatin and R-Cladribine). We demonstrated the presence of the BRAFV600E mutation with a mutation specific antibody and 454 sequencing. In order to investigate if recurrent mutations may have contributed to refractoriness to purine analogues, a panel of genes commonly mutated across lymphoid malignancies were analysed (EZH2, KRAS, MYD88, NOTCH1, NRAS, PIK3CA, SF3B1, or TP53). No mutations were demonstrated Because of limited treatment options and recent success with vemurafenib in BRAF mutated melanoma we decided to use experimental treatment with vemurafenib after intensive counseling and started treatment with 240 mg twice daily after a single loading dose of 960 mg. The dose was slowly escalated to 1,920 mg/d which is the standard dose used in melanoma. After 6 and 16 days of 240mg bid the spleen size had shrunk to 18.8 × 5.8 and 14×5 cm, respectively. Blood counts rapidly recovered and sCD25 which is considered a reliable marker of HCL cell load dropped quickly to normal levels already at the lowest dose of 240 mg vemurafenib bid (Figure 1). There was no evidence of tumor lysis. Response was further evaluated by repeated trephine biopsies on days -1, 6, 17 and 36. After only 6 days of vemurafenib treatment p-ERK signaling was almost completely abolished in HCL cells in vivo, followed by apoptosis of HCL cells as shown by Tunnel staining and finally complete clearance of hairy cells on day 36. CR criteria were achieved on day 43. Because of the excellent disease control and the risk of short-latency non-melanoma skin cancers during therapy with vemurafenib, we discontinued vemurafenib after 56 days. CR continues to persist in the absence of drug exposure for more than 6 months at the time of abstract preparation (Figure 1). Massively parallel DNA sequencing was used to detect remaining mutant BRAF alleles in peripheral blood leukocytes on day 36. Among over 105 sequencing reads, the BRAF V600E mutation was not detectable above background ( Our observations show that targeting of a single mutated oncogene can provide durable disease control in this leukemia. Trials exploring chemotherapy-free treatment approaches with BRAF inhibitors in HCL are highly warranted. Disclosures: No relevant conflicts of interest to declare.

Abstract 2495 Poster Board II-472 Introduction: High-dose chemotherapy (HDCT) followed by peripheral blood stem cell transplantation (PBSCT) is frequently applied in eligible patients with relapsed or refractory Hodgkin's disease. The toxicity of HDCT, however, might manifest itself in the respective patients' reduced quality of life (QoL). In this study we investigated the QoL of long term survivors after HDCT in comparison with patients after conventional chemotherapy and the healthy German population. Patients and Methods: QoL was evaluated with two standardized questionnaires: EORTC QLQ-C30 and EQ-5D. The cancer-specific EORTC-QLQ-C30 consists of thirty questions concerning three main categories: global health state, functional and symptomatic state. The single questions belonging to functional and symptomatic state can furthermore be grouped into different subcategories. The EQ-5D visualizes five dimensions of health: mobility, self-care, daily activities, pain, and anxiety. In addition to that, the visual analogue scale (VAS) is included to outline the patients' overall health state. A total of 98 patients were included in the study. 37 patients (13 female, 24 male) with a median age of 46 (range 23-72) received HDCT with PBSCT between 1986 and 2007. This group was compared with 61 patients (36 female, 25 male; median age 41, range 21-72) treated with conventional chemotherapy and supplementary radiation in our institution. In the conventional chemotherapy group BEACOPP was used in most cases (n=31), followed by ABVD (n=20), a combination of both (n=8) and ABV (n=2). All patients were in continuous clinical remission. Median follow-up for the HDCT group is 11 and for the conventional chemotherapy group 3.5 years. In addition, Qol of the patients was compared to QoL of healthy people on the basis of two studies about the general health status of the German population (R. Schwarz and A. Hinz: “Reference data for the quality of life questionnaire EORTC QLQ-C30 in the general German population,” European Journal of Cancer 37 [2001]: 1345-1351; H. H. König et al.: “Health Status of the German Population: Results of a Representative Survey Using the EuroQoL Questionnaire,” Gesundheitswesen 67 [2005]: 173-182). Results: In the HDCT group, the results of the questionnaires show a reduced QoL compared to the healthy population. Regarding the three main categories of the EORTC QLQ-C30, the mean sum score for global health state (ghs) is 68.69, for functional state (fs) 72.49 and for symptomatic state (ss) 21.55 (the ideal score being 100.00 for the first two items and 0.00 for the latter). The mean value for EQ-5D is 0.880 (ideal value: 1.000) and that for VAS is 71.60 (ideal value: 100.00). The one sample t-test evaluation shows that the decrease in QoL is significant with p Conclusions: In this long term follow up study, QoL is reduced in patients after HDCT as well as in patients after conventional treatment compared to the healthy population. There was a trend that QoL might be worse in the HDCT group compared to the conventional therapy group; however this effect was not statistically significant. We conclude that the negative impact of both HDCT and conventional therapy on the QoL of long term survivors with Hodgkin's lymphoma should not be underestimated and should lead to the development of less toxic therapy strategies. Disclosures: No relevant conflicts of interest to declare.

Most patients with Hodgkin disease achieve durable remission with radiation therapy, combination chemotherapy, or both. However, patients who relapse after attaining complete remission with chemotherapy and those who have primary refractory disease have a poor outcome with conventional dose salvage chemoradiotherapy regimens. In the past 20 years, several clinical trials using high-dose chemotherapy (HDCT) or chemoradiotherapy with autologous stem cell transplantation have been reported, but only few of them focused on long term outcome, late toxicity and different treatment options after relapse. From March 1986 to August 2007, 107 patients with relapsed or refractory Hodgkin’s disease underwent HDCT with peripheral blood stem cell transplantation in our center. There were 64 males and 43 females with a median age of 31 years (range 17 – 63 years). For HDCT, 82 patients were treated with CBV (cyclophosphamide, etoposide, carmustine), while 20 patients received BEAM (carmustine, etoposide, cytarabine, melphalan) or other regimens (n=5). For the entire group, the probabilities of freedom from progression (FFP), overall survival (OS) and event-free survival (EFS) after HDCT were 65%, 61%, and 53% at 10 years, respectively, after a median follow-up of 12.4 years (range, 0.15 – 20.3 years). Notably, no relapse occurred later than 48 months post transplant. Cox analyses identified duration of remission (≤12 versus >12 months) as well as disease status prior to transplantation (complete remission versus partial remission versus stable / refractory disease) as significant prognostic factors for FFP, EFS, and OS. Early mortality rate (≤100 days) declined from 17.1% to 8.3% after 1992 subsequent to introduction of hematopoietic growth factors for stem cell mobilization. Late mortality rate (>100 days) was 30.8% (n=33), causes of death were Hodgkin’s disease (n=21), secondary malignancies (n=6), fibrosis of the lung (n=3), myocardial fibrosis (n=1), perforated sigmoid diverticulitis (n=1) and septicemia (n=1). The probability of secondary malignancies was 6.4% and 12.1% after 5 and 10 years, respectively. For the patients relapsing after HDCT (n=33), the median OS was 17.3% at 5 years. We found that patients with a remission time of >6 months after transplantation had a prolonged 5-year OS of 50.3% versus 0% (p=0.03) in patients with remission times of ≤6 months. To date, three of 33 patients live disease-free more than 5 years after relapse. These patients were treated with allogeneic transplantation (n=1), secondary HDCT (n=1) or conventional chemotherapy (n=1), suggesting that different treatment approaches have the potential to rescue individual patients although the overall outcome after HDCT failure is poor. In conclusion, HDCT can provide long-term disease control in patients who have failed primary therapy for Hodgkin’s disease. Although the results as a whole are encouraging for chemosensitive patients and have improved over time, new therapeutic strategies are needed to reduce toxicity of HDCT and improve the clinical outcome of those patients who relapse after HDCT.