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Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with respect to outcome. Features of the tumor microenvironment (TME) are associated with prognosis when assessed by gene expression profiling. However, it is uncertain whether assessment of the microenvironment can add prognostic information to the most relevant and clinically well-established molecular subgroups when analyzed by immunohistochemistry (IHC).We carried out a histopathologic analysis of biomarkers related to TME in a very large cohort (n = 455) of DLBCL treated in prospective trials and correlated with clinicopathologic and molecular data, including chromosomal rearrangements and gene expression profiles for cell-of-origin and TME.The content of PD1+, FoxP3+ and CD8+, as well as vessel density, was not associated with outcome. However, we found a low content of CD68+ macrophages to be associated with inferior progression-free survival (PFS) and overall survival (OS; P = 0.023 and 0.040, respectively) at both univariable and multivariable analyses, adjusted for the factors of the International Prognostic Index (IPI), MYC break and BCL2/MYC and BCL6/MYC double-hit status. The subgroup of PDL1+ macrophages was not associated with survival. Instead, secreted protein acidic and cysteine rich (SPARC)-positive macrophages were identified as the subtype of macrophages most associated with survival. SPARC-positive macrophages and stromal cells directly correlated with favorable PFS and OS (both, P[log rank]0.001, P[trend]0.001). The association of SPARC with prognosis was independent of the factors of the IPI, MYC double-/triple-hit status, Bcl2/c-myc double expression, cell-of-origin subtype and a recently published gene expression signature [lymphoma-associated macrophage interaction signature (LAMIS)].SPARC expression in the TME detected by a single IHC staining with fair-to-good interobserver reproducibility is a powerful prognostic parameter. Thus SPARC expression is a strong candidate for risk assessment in DLBCL in daily practice.

The majority of patients with diffuse large B-cell lymphoma (DLBCL) can be cured with immunochemotherapy comprising rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Patients suffering progression or relapse in the central nervous system (CNS) face dismal outcomes. The impact of more aggressive regimens used in front-line therapy has not systematically been investigated in this context. To this end, we analyzed a large cohort of 2203 younger DLBCL patients treated on ten German and French prospective phase II and III trials following first-line therapy with R-CHOP, R-CHOEP (R-CHOP + etoposide), dose-escalated R-CHOEP followed by repetitive stem cell transplantation (R-MegaCHOEP), or rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycine, prednisone (R-ACVBP) followed by consolidation including multiple drugs crossing the blood-brain-barrier (BBB). DLBCL patients with age-adjusted International Prognostic Index (aaIPI) of 0–1 showed very low cumulative incidence (CI) rates of CNS relapse regardless of first-line therapy and CNS prophylaxis (3-year CI 0% − 1%). Younger high-risk patients with aaIPI of 2–3 had 3-year CI rates of 1.6% and 4% after R-ACVBP plus consolidation or R-(Mega)CHO(E)P, respectively (Hazard Ratio 2.4 (95% confidence interval: 0.8–7.4), p = 0.118). Thus, for younger high-risk patients, front-line regimens incorporating multiple agents crossing the BBB may reduce often fatal CNS relapse.

Summary Background R-MegaCHOEP was the first phase 3 study comparing high-dose chemotherapy plus rituximab followed by autologous haematopoietic stem-cell transplantation (HSCT) with conventional chemotherapy plus rituximab in first-line therapy for patients aged 60 years or younger with high-risk aggressive B-cell lymphoma. Little is known about the long-term outcomes of these patients. We aimed to evaluate the long-term efficacy and safety of conventional chemotherapy versus high-dose chemotherapy after 10 years of follow-up in the R-MegaCHOEP trial. Methods In this open-label, randomised, phase 3 trial done across 61 centres in Germany, patients aged 18–60 years with newly diagnosed, high-risk (age-adjusted International Prognostic Index [IPI] 2 or 3) aggressive B-cell lymphoma were randomly assigned (1:1, using Pocock minimisation) to eight cycles of conventional chemotherapy (cyclosphosphamide, doxorubicin, vincristine, etoposide, and prednisolone) plus rituximab (R-CHOEP-14) or four cycles of high-dose chemotherapy plus rituximab followed by autologous HSCT (R-MegaCHOEP). The trial was unmasked. Patients were stratified by age-adjusted IPI factors, presence of bulky disease (tumour mass ≥7·5 cm diameter), and treatment centre. The primary endpoint was event-free survival, analysed here 10 years after randomisation. 10-year overall survival, progression-free survival, conditional survival, relapse patterns, secondary malignancies, and molecular characteristics were also analysed. All analyses were done on the intention-to-treat population. This trial is registered with ClinicalTrials.gov , NCT00129090 . Findings Between March 3, 2003, and April 7, 2009, 275 patients were randomly assigned to R-CHOEP-14 (n=136) or R-MegaCHOEP (n=139). 130 patients in the R-CHOEP-14 group and 132 patients in the R-MegaCHOEP group were included in the intention-to-treat population. After a median follow-up of 9·3 years (IQR 5·1–11·1), 10-year event-free survival was 51% (95% CI 42–61) in the R-MegaCHOEP group and 57% (47–67) in the R-CHOEP-14 group (adjusted hazard ratio [HR] 1·3 [95% CI 0·9–1·8], p=0·23). 10-year progression-free survival was 59% (50–68) in the R-MegaCHOEP group and 60% (51–70) in the R-CHOEP-14 group (adjusted HR 1·1 [0·7–1·7], p=0·64). 10-year overall survival was 66% (57–76) in the R-MegaCHOEP group and 72% (63–81) in the R-CHOEP-14 group (adjusted HR 1·3 [0·8–2·1], p=0·26). Relapse occurred in 30 (16% [95% CI 11–22]) of 190 patients who had complete remission or unconfirmed complete remission; 17 (17%) of 100 patients in the R-CHOEP-14 group and 13 (14%) of 90 patients in the R-MegaCHOEP group. Seven (23%) of 30 patients had low-grade histology at relapse and had better outcomes compared with patients who relapsed with aggressive histologies. Lymphoma affected the CNS in 18 (28%) of 64 patients with treatment failure. 22 secondary malignancies were reported in the intention-to-treat population; in 12 (9%) of 127 patients in the R-CHOEP-14 group and ten (8%) of 126 patients in the R-MegaCHOEP group. Interpretation Event-free survival and overall survival were similar between groups after 10 years of follow-up; outcomes were not improved in the R-MegaCHOEP group by high-dose chemotherapy and autologous HSCT. Patients who relapsed with aggressive histology showed a high incidence of CNS involvement and poor prognosis. For these patients, novel therapies are greatly warranted. Funding Deutsche Krebshilfe (German Cancer Aid).

In elderly patients (pts) with aggressive B cell lymphoma (aNHL), curative treatment often cannot be administered because of comorbidities and tolerability. We analyzed the influence of age in pts > 60 years receiving the R-CHOP-14 regimen within different prospective DSHNHL trials. Of the RICOVER-60 trial and CHOP-R-ESC trials, 1171 aNHL pts were included in this retrospective analysis of age-dependent event-free survival (EFS), progression-free survival (PFS), and overall survival (OS). All patients received prophylactic G-CSF, and anti-infective prophylaxis with amphotericin B mouth wash and oral fluorchinolone was optional. In the CHOP-R-ESC trials, prophylaxis was augmented to include mandatory continuous orally administered aciclovir and a pneumocystis prophylaxis with cotrimoxazole as well as oral fluorchinolones during neutropenia. The patient population was separated into 4 age groups (61–65 years, 66–70 years, 71–75 years, and 76–80 years). The results from the RICOVER-60 trial were subsequently confirmed in the following CHOP-R-ESC trials by a multivariate analysis adjusted for IPI factors and gender. Significant differences (p < 0.001) in EFS, PFS, and OS were seen between age groups (RICOVER-60). Hematotoxicity, infections, and TRM increased with age. TRM was significantly elevated in the age group 76–80 years. Therefore, this analysis shows that an age above 75 years defines an especially vulnerable patient population when being treated with chemoimmunotherapy for aNHL. Prophylactic anti-infective drugs are essential and clinically effective in reducing morbidity when treating elderly aNHL pts. Supplementary Information The online version contains supplementary material available at 10.1007/s00277-020-04345-3.

The addition of rituximab to chemotherapy has substantially improved outcomes for patients with B-cell malignancies. The mechanisms of action of rituximab include activation of natural killer cells. Killer-cell immunoglobulin-like receptors (KIRs) mediate natural killer cell function through interaction with HLA. We evaluated the clinical impact of KIR-HLA genotypes on rituximab-containing therapy.For this post-hoc analysis, we used data from the RICOVER-60 trial (NCT00052936) as the discovery cohort and the CLL8 trial (NCT00281918) as the validation cohort. RICOVER-60 included patients aged 61-80 years with aggressive B-cell lymphoma treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with or without rituximab. CLL8 included patients aged 30-81 years with chronic lymphocytic leukaemia treated with chemotherapy (fludarabine and cyclophosphamide; FC) with or without rituximab. We evaluated the KIR and HLA-C status of 519 patients with available blood samples in the RICOVER-60 trial and the KIR2DS1 and HLA-C status of 549 patients with available blood samples in the CLL8 trial, and evaluated their associations with event-free survival (RICOVER-60), progression-free survival, and overall survival (RICOVER-60 and CLL8).In the RICOVER-60 trial, 201 (39%) patients were positive for KIR2DS1, 79 (15%) were homozygous for HLA-C2, and 36 (7%) were positive for KIR2DS1 and homozygous for HLA-C2. In the CLL8 trial, 206 (38%) patients were positive for KIR2DS1, 75 (14%) were homozygous for HLA-C2, and 26 (5%) were positive for KIR2DS1 and homozygous for HLA-C2. In the RICOVER-60 trial, both KIR2DS1 and HLA-C status were identified as independent risk factors for survival. KIR2DS1 positivity, homozygosity for HLA-C2, and subsequent KIR2DS1-HLA-C status were associated with adverse clinical outcome in patients receiving rituximab-containing therapy (event-free survival for patients with KIR2DS1-HLA-C2/C2 vs all other patients, HR 2·6 [95% CI 1·4-4·7], p=0·0015; progression-free survival, 2·7 [1·5-5·1], p=0·0013; overall survival, 2·8 [1·5-5·4], p=0·0016) but not in patients receiving CHOP chemotherapy only (event-free survival, 0·9 [0·5-1·7], p=0·85; progression-free survival, 1·1 [0·6-2·0], p=0·81; overall survival, 1·2 [0·6-2·4], p=0·53). A significant interaction between KIR2DS1-HLA-C status and rituximab was observed (p=0·018 for event-free survival and p=0·034 for progression-free survival). In contrast to all other patients, those positive for KIR2DS1 and homozygous for HLA-C2 did not benefit from adding rituximab to CHOP chemotherapy (event-free survival, 1·9 [0·8-4·6], p=0·16; progression-free survival, 1·4 [0·6-3·4], p=0·48; overall survival, 1·6 [0·6-4·3], p=0·33). In the CLL8 trial, KIR2DS1-HLA-C status was confirmed as a predictive marker for benefit from rituximab therapy (p=0·024 for the interaction of KIR2DS1-HLA-C status and rituximab regarding progression-free survival). In contrast to all other patients, those positive for KIR2DS1 and homozygous for HLA-C2 did not benefit from adding rituximab to FC chemotherapy (progression-free survival, 2·1 [0·9-4·9], p=0·094; overall survival, 2·6 [0·5-12·7], p=0·21).Assessment of KIR2DS1 and HLA-C genotype might identify patients who would not benefit from rituximab, thereby allowing alternative therapies to be given. Further validation of these findings in prospective clinical trials is needed.F Hoffman La Roche.

Standard first-line therapy for younger patients with peripheral T-cell lymphoma consists of six courses of CHOP or CHOEP consolidated by high-dose therapy and autologous stem cell transplantation (AutoSCT). We hypothesized that consolidative allogeneic transplantation (AlloSCT) could improve outcome. 104 patients with nodal peripheral T-cell lymphoma except ALK+ ALCL, 18 to 60 years of age, all stages and IPI scores except stage 1 and aaIPI 0, were randomized to receive 4 x CHOEP and 1 x DHAP followed by high-dose therapy and AutoSCT or myeloablative conditioning and AlloSCT. The primary endpoint was event-free survival (EFS) at three years. After a median follow-up of 42 months, 3-year EFS of patients undergoing AlloSCT was 43% (95% confidence interval [CI]: 29%; 57%) as compared to 38% (95% CI: 25%; 52%) after AutoSCT. Overall survival at 3 years was 57% (95% CI: 43%; 71%) versus 70% (95% CI: 57%; 82%) after AlloSCT or AutoSCT, without significant differences between treatment arms. None of 21 responding patients proceeding to AlloSCT as opposed to 13 of 36 patients (36%) proceeding to AutoSCT relapsed. Eight of 26 patients (31%) and none of 41 patients died due to transplant-related toxicity after allogeneic and autologous transplantation, respectively. In younger patients with T-cell lymphoma standard chemotherapy consolidated by autologous or allogeneic transplantation results in comparable survival. The strong graft-versus-lymphoma effect after AlloSCT was counterbalanced by transplant-related mortality. CHO(E)P followed by AutoSCT remains the preferred treatment option for transplant-eligible patients. AlloSCT is the treatment of choice for relapsing patients also after AutoSCT.

An image derotator is a device that can compensate the image blur caused by the rotation of an object. However, a key problem when using a derotator is to ensure the coincident alignment between the rotation axes of the derotator and measured object. An approach of machine-vision-guided rotation axis alignment is proposed in this paper. Circular markers and a laser dot are deployed to indicate the rotation axes of the derotator and object, respectively. A binocular stereo sensor is established to estimate the poses of both axes. With the misalignment information between the two axes updated in real-time, axis alignment can be achieved through manual adjustment. The validity and precision of the proposed approach are demonstrated through experiments.

Purpose Fluorine-18 fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG PET/CT) is the standard for staging aggressive non-Hodgkin lymphoma (NHL). Limited data from prospective studies is available to determine whether initial staging by FDG PET/CT provides treatment-relevant information of bone marrow (BM) involvement (BMI) and thus could spare BM biopsy (BMB). Methods Patients from PETAL (NCT00554164) and OPTIMAL>60 (NCT01478542) with aggressive B-cell NHL initially staged by FDG PET/CT and BMB were included in this pooled analysis. The reference standard to confirm BMI included a positive BMB and/or FDG PET/CT confirmed by targeted biopsy, complementary imaging (CT or magnetic resonance imaging), or concurrent disappearance of focal FDG-avid BM lesions with other lymphoma manifestations during immunochemotherapy. Results Among 930 patients, BMI was detected by BMB in 85 (prevalence 9%) and by FDG PET/CT in 185 (20%) cases, for a total of 221 cases (24%). All 185 PET-positive cases were true positive, and 709 of 745 PET-negative cases were true negative. For BMB and FDG PET/CT, sensitivity was 38% (95% confidence interval [CI]: 32–45%) and 84% (CI: 78–88%), specificity 100% (CI: 99–100%) and 100% (CI: 99–100%), positive predictive value 100% (CI: 96–100%) and 100% (CI: 98–100%), and negative predictive value 84% (CI: 81–86%) and 95% (CI: 93–97%), respectively. In all of the 36 PET-negative cases with confirmed BMI patients had other adverse factors according to IPI that precluded a change of standard treatment. Thus, the BMB would not have influenced the patient management. Conclusion In patients with aggressive B-cell NHL, routine BMB provides no critical staging information compared to FDG PET/CT and could therefore be omitted. Trial registration NCT00554164 and NCT01478542

Due to their high availability and versatility, rolling bearings are a standard solution for mounting and support of rotating components. The service life of an entire rotating machine is often limited by the service life of rolling bearings. This can be shorter than expected if the rolling bearing is operated in harmful operating conditions, e.g. in the presence of slip. Slip means that there is a deviation between the theoretical angular velocity of the rolling element set and the actual angular velocity. In this context, slip is harmful if it leads to increased friction and thus heating of the bearing. The occurrence and properties of slip are not completely understood yet. Therefore, it is of interest to investigate a relationship between slip and heating of the rolling bearing in order to better understand damages of the rolling bearing. In this work, a method is presented in which, in addition to slip measurements with a high-speed camera, a thermal imaging camera is used to investigate the heating of the bearing during operation. Since the rotational movement and exposure time of the camera would cause motion blur, the thermal imaging camera is operated together with a derotator to optically eliminate the rotational movement. The investigations of the rolling bearing are carried out under different operating conditions (different loads and rotational speeds), which have an influence on the slip behavior of the bearing. Thus, the potential of this investigation method for deepening the understanding of heating and friction in rolling bearings is demonstrated.

An optomechanical derotator is an optical system that can be used to extend various measurement methods so they can be applied to rotating measurement objects. The function principle is to manipulate the image of the rotating measurement object by means of rotating reflective components inside the derotator. Thus it appears stationary in the measurement data. For this it is inevitably that the angular position and velocity of the derotator are controlled in such way that they always amount to half that of the measurement object. It is therefore necessary to adjust the derotator with the help of an implemented controller. Since we want to acquire the reference input of the control with a high-speed camera and image processing algorithms the sampling time of the control must be adapted to the rather long computation time of the image processing. As a result, the use of analog control techniques is prohibited so that a digital controller has to be implemented. This paper proposes an approach where an image-based discrete-time linear-quadratic regulator is used to satisfy the requirements concerning the angular position and velocity of the derotator. To improve its performance, it is supplemented by integral action and a model-based feedforward control. Furthermore, the image processing algorithms by which the reference input of the control is determined are described. Finally, it is demonstrated that this controller concept produces the desired result by generating a standing image of a rotating object with a camera and the derotator.

To study if obesity is a risk factor in elderly patients (>60 years) with aggressive B-cell lymphoma, the outcomes of 576 elderly patients treated with rituximab in the RICOVER-60 trial were analysed in a retrospective study with regard to body mass index (BMI) and gender. Of the 576 patients, 1% had low body weight (BMI

Introduction:Considering the increasing numbers of lymphoma patients (pts) surviving long-term, late effects of current treatment strategies such as secondary (sec) malignancies gain increasing importance. Many treatment regimens used in pts with lymphoma (R-CHOEP, DA-EPOCH-R, BEACOPP) include etoposide, a cytotoxic agent reported to increase sec leukemias. In order to further investigate the role of etoposide in inducing sec malignancies in pts with aggressive lymphoma we analyzed the R-MegaCHOEP trial (Schmitz et al., Lancet Oncology 2012) where young, high-risk pts with aggressive B-cell lymphomas had received R-CHOEP or R-MegaCHOEP, a regimen containing very high doses of etoposide (4g/m2). We compared rates of secondary tumors to incidences found in young patients treated with R-CHOP only. Methods:We analyzed 1536 pts aged 18-60 years with aggressive B-cell lymphoma treated in the prospective phase 3 trials FLYER (NCT00278421; n=588, median observation time (OT)=66 months), UNFOLDER (NCT00278408; n=695, median OT=72 months) and MegaCHOEP (NCT00129090; n=253, median OT=112 months) to compare the cumulative incidences of sec neoplasms. We performed a competing risk analysis for time from randomization to occurrence of sec malignancy (myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) or other) according to first-line therapy with R-CHOP (n=1283) vs. R-CHOEP (n=127) vs. R-MegaCHOEP (n=126). We used a cause-specific hazard model adjusted for gender, age (>50 vs. Results:Adjusting for competing events, we found sec MDS/AML in 0.3% of pts treated with R-CHOP, in 1% of pts treated with R-CHOEP and in 2% of pts following treatment with R-MegaCHOEP. Cause-specific hazard ratios showed a trend for increased risk for sec AML following R-MegaCHOEP in comparison to R-CHOP (HR 5.2, 95%CI (1.0; 27.5), p=0.052) while R-CHOEP did not significantly increase the incidence of sec AML (HR 1.4, 95%CI (0.1; 14.0), p=0.777). Male gender and age >50 years showed a trend for increasing sec AML. We found very similar incidences of sec solid tumors (not MDS/AML) affecting 4% of pts treated with R-CHOP or R-MegaCHOEP and 6% of pts following R-CHOEP regimen. The only factor significantly increasing the risk of sec solid tumors was age >50 years (HR 2.6, 95%CI (1.5; 4.3), p Conclusions:This analysis shows that sec malignancies represent rare events in younger patients with aggressive B-cell lymphoma, even after extreme dose-escalation of etoposide. Compared to standard R-CHOP, 8 cycles of R-CHOEP were not associated with increased risk of sec AML or solid tumors thus remaining an attractive first-line treatment for young high-risk pts with DLBCL. Disclosures Haenel: Amgen, Novartis, Roche, Celgene, Takeda, Bayer:Honoraria.Truemper:Janssen:Consultancy;Mundipharma:Research Funding;Nordic Nanovector:Consultancy;Roche:Research Funding;Seattle Genetics:Research Funding;Takeda Europe:Consultancy, Research Funding.Held:MSD:Consultancy;Acrotech, Spectrum:Research Funding;Amgen:Research Funding;BMS:Consultancy, Other: Travel Grants, Research Funding;Roche:Consultancy, Other: travel grants, Research Funding.Borchmann:Bristol Myers Squibb:Research Funding;Takeda:Research Funding.Dreyling:Celgene:Consultancy, Research Funding, Speakers Bureau;Roche:Consultancy, Research Funding, Speakers Bureau;Beigene:Consultancy;Janssen:Consultancy, Research Funding, Speakers Bureau;Novartis:Consultancy;Abbvie:Research Funding;Astra Zeneca:Consultancy;Bayer:Consultancy, Speakers Bureau;Gilead:Consultancy, Research Funding, Speakers Bureau.Viardot:Roche:Honoraria, Other: advisory board;Kite/Gilead:Honoraria, Other: advisory board;Novartis:Honoraria, Other: advisory board;Amgen:Honoraria, Other: advisory board.Kroschinsky:Riemsser:Research Funding;Roche:Consultancy, Honoraria, Other: Support of parent study and funding of editorial support;Gilead:Consultancy;BMS/Celgene:Consultancy, Honoraria;Sandoz:Research Funding.Ott:NIH:Consultancy, Other: Co-inventor on a patent related to the MCL35 assay filed at the National Institutes of Health, United States of America..Lenz:Bayer:Consultancy, Honoraria, Research Funding, Speakers Bureau;Janssen:Consultancy, Honoraria, Research Funding, Speakers Bureau;Novartis:Consultancy;Gilead:Consultancy, Honoraria, Research Funding, Speakers Bureau;AQUINOX:Research Funding;AstraZeneca:Consultancy, Honoraria, Research Funding;Celgene:Consultancy, Honoraria, Speakers Bureau;Verastem:Research Funding;Morphosys:Consultancy, Honoraria, Research Funding;Roche:Consultancy, Honoraria, Research Funding, Speakers Bureau;Agios:Research Funding;BMS:Consultancy.Schmitz:Riemser:Honoraria;Takeda:Honoraria;Janssen:Research Funding;Bristol-Myers Squibb:Current equity holder in publicly-traded company.

Introduction Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of aggressive lymphomas, which usually carry a poor prognosis. Malignant T-cells may overexpress programmed death ligand 1 (PD-L1), which signals via programmed death-1 (PD-1) receptor, and provides an inhibitory signal on normal T-cells further suppressing antitumor immunity. They can also express PD1 which may act as a tumor suppressor on malignant T-cells (Wartewig et al, Nature 2017). Thus, blocking the PD1/PDL1 synapse in PTCL may lead to tumor regression or progression. The NIVEAU trial is an ongoing international, multicenter, randomized, open label, phase 3 study testing Nivolumab (Nivo) in combination with (Rituximab), Gemcitabine, Oxaliplatin ((R-)GemOx) for patients with aggressive (B and T-cell) Non-Hodgkin Lymphoma in first relapse or progression not eligible for High-Dose Chemotherapy (NCT03366272). Here, we performed a preliminary analysis of the experimental arm (Nivo-GemOx) of the PTCL cohort to assess the safety and efficacy of this regimen in this population. Methods Key eligibility criteria include: first relapse or progression of peripheral T-cell lymphoma (PTCL), ineligibility for high dose therapy (defined as >65 years of age or older than 18 years if HCT-CI score > 2), only one prior chemotherapy regimen including an anthracycline. Pts were planned to receive 8 cycles Nivolumab (3mg/kg) plus Gemcitabine and Oxaliplatin in 2-wk intervals followed by additional 18 Nivolumab (3mg/kg) biweekly as consolidation or until progression. Response was evaluated after 4 and 8 cycles of GemOx. Each progression/relapse of PTCL had to be reported as a SAE. Results The analysis (data cut-off 13-July-2020) included 12 PTCL pts enrolled in the experimental arm (Table 1): 4 (33%) PTCL NOS, 3 (25%) AITL, 1 (8%) PTCL TFH-type, 2 (17%) ALCL ALK-, 1 (8%) EATL, and 1 (8%) MEITL. Median age was 69.5 years (range, 53-80), 7 (58%) patients were male, 2 (17%) had received a prior autologous stem cell transplantation, and 5 (42%) were refractory to first line therapy. At enrollment, performance status was 0-1 in 9 (75%) pts and 2 in 3 (25%) pts, 11 (92%) had Ann Arbor stage III-IV, 2 (17%) had B-symptoms, 7 (58%) had more than one extra-nodal site and 4 (33%) had elevated LDH. PD1 and PD-L1 were expressed by the tumor cells in 6/10 (60%) and 2/11 (18%) patients, respectively (Table 1). Pts have received a median of 6 (1-8) cycles of GemOx and 7 (1-26) infusions of nivolumab. Treatment was prematurely discontinued in 9 pts (7 during induction and 2 during consolidation), due to lymphoma progression (n=6), toxicity (n=2) and an intercurrent disease (n=1). There were 26 SAE in 10 patients, including 8 progressive diseases. Nine (75%) patients achieved an objective response (4 CR and 5 PR). Two patients (pt 9: MEITL PD1-negative; and pt 12: PTCL-NOS strongly PD1-positive) experienced primary progression upon Nivo-GemOx (Table 1). Median PFS2 (time from randomisation to 2nd rel/prog/death) was 6.9 months (95% CI: 1.9-11.9) vs 7.7 months (95% CI: 7.2-8.2) for PFS1 (time from diagnosis to 1st rel/prog). PFS2 was superior to PFS1 in 2 out of 8 patients (25%), and not informative in 4 pts: 3 who are still on therapy (ongoing PFS) and 1 who died prematurely due to infection (pt 8) (Figure 1). Median OS was 24.8 months (95% CI: 0-49.8). After a median follow-up of 22.8 months, 7 patients have died (5 from lymphoma and 2 from infection (1 COVID-19 infection and 1 yeast septicemia)), and 5 remain alive. Conclusions Nivolumab in combination with GemOx was well tolerated in PTCL. The response rate and PFS2 (compared to PFS1) are encouraging. Marked differences in PFS2 might reflect heterogeneity of biology and susceptibility to PD-1 blockade in combination with GemOx chemotherapy. Furthermore, the translational research program of the study might help to identify markers which are predictive for efficacy of PD-1 blockade in PTCL. This phase 3 trial is actively enrolling patients and an update of these results will be presented at the meeting. Disclosure: ISR financially supported by Bristol Myers Squibb. Disclosures Houot: Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Kite: Honoraria; Gilead: Honoraria; MSD: Honoraria; Bristol-Myers Squibb: Honoraria. Poeschel:Roche: Other: Travel, Accommodations, Expenses; Amgen: Other: Travel, Accommodations, Expenses; Abbvie: Other: Travel, Accommodations, Expenses. André:Abbvie: Consultancy; Celgene: Other, Research Funding; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Takeda: Consultancy; Bristol-Myers-Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Karyopharm: Consultancy; CHU UCL Namur, site Godinne, Yvoir, Belgium: Current Employment; Seattle Genetics: Consultancy; Gilead: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Johnson & Johnson: Research Funding; Novartis: Consultancy, Research Funding; Amgen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Dreyling:Beigene: Consultancy; Bayer: Consultancy, Speakers Bureau; Astra Zeneca: Consultancy; Abbvie: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau. Tilly:BMS: Honoraria. Casasnovas:Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses, Research Funding; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Amgen: Consultancy, Honoraria; MSD: Consultancy, Honoraria. Le Gouill:Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier: Honoraria; Loxo Oncology at Lilly: Consultancy. Cartron:Celgene: Consultancy, Honoraria; Gilead: Honoraria; Abbvie: Honoraria; Jansen: Honoraria; Sanofi: Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria. Kerkhoff:BMS: Honoraria. De Leval:Lausanne University Hospital & Lausanne University Institute of Pathology: Current Employment; Lunaphore Technologies SA: Consultancy, Honoraria; Abbvie: Honoraria; Roche Diagnostics: Honoraria. Gaulard:takeda: Honoraria, Research Funding; innate pharma: Research Funding. Held:Roche: Consultancy, Other: travel grants, Research Funding; MSD: Consultancy; Acrotech, Spectrum: Research Funding; Amgen: Research Funding; BMS: Consultancy, Other: Travel Grants, Research Funding. OffLabel Disclosure: Nivolumab in peripheral T-cell lymphoma

7543 Background: Central nervous system (CNS) relapse occurs in 2-6% of DLBCL patients (pts) increasing to 10% or more in high-risk groups. Intrathecal (IT) or intravenous high-dose methotrexate (HD MTX) have limited if any prophylactic impact on CNS relapse. To address the role of systemic first-line therapy in pts tolerating intensified strategies (R-ACVBP, R-(Mega)CHOEP, R-CHO(E)P), we compared CNS relapses occurring in a large cohort of pts ≤60 years. Methods: We conducted a retrospective analysis including previously untreated pts with DLBCL by central review, age 18-60 years, from multicenter clinical trials conducted by LYSA and GLA/DSHNHL (Table). We assessed the risk of CNS relapse in matched cohorts based on the aaIPI. Results: A total of 2203 pts were included. Median age was 47 years (18-60). 455 pts were treated with R-ACVBP, 444 with R-(Mega)CHOEP, 1304 with R-CHOP. Distribution of CNS IPI was not significantly different comparing R-ACVBP to R-CHO(E)P groups within aaIPI categories (Table). PFS and OS were comparable according to treatment within aaIPI groups, also adjusted for prognostic factors. No CNS events occured during observation time of 3 years in pts with aaIPI 0. In pts with aaIPI 1, no CNS event occured in the R-ACVPB arm, the 3y-cumulative incidence of CNS relapse for pts treated with R-CHO(E)P group was 1.0% (95%CI 0.3-1.7). In pts with aaIPI 2,3 and intermediate/high CNS IPI, four (1.6%) treated with R-ACVBP experienced relapse in the CNS compared to 15 (3.9%) pts treated with R-(Mega)CHO(E)P (3y-cumulative incidence 1.6% (95%CI 0-3.2) vs. 4.0% (95%CI 2.0-6.0). Conclusions: CNS relapse was extremely rare in younger DLBCL pts with aaIPI 0 or 1; prophylactic measures are not warranted. In pts with aaIPI 2,3 (and intermediate/high CNS-IPI), only 4 (1.6%) CNS relapses were seen with the R-ACVBP while 15 (3.9%) relapses did occur after R-(Mega)CHO(E)P. This analysis underlines the important role of the systemic therapy in controling CNS relapse.[Table: see text]

When monitoring the condition of technical components, it is of particular interest to obtain information of the current condition of the component during operation. The main objectives are safety and machine efficiency. A special extension in this area is the derotator, since the derotator can be used to extend measuring methods designed for static components to rotating systems. In this paper, we present a new, to the best of our knowledge, approach to align a derotator using a laser Doppler vibrometer (LDV). When aligning the derotator, the optical axis must be coaxial with the rotating object to be measured. Current conventional approaches only ensure that the optical axis and the rotational axis intersect at the center of the measuring object. In our approach, a LDV is used to determine the angular deviation between the two axes, which cannot be determined by common methods. Our approach is easy to implement because the LDV is often already used in combination with the derotator as a measuring device. Experiments are carried out to show that this approach is feasible. In addition, several investigations are being performed to analyze how different parameters affect the result, creating reproducible conditions and deriving an alignment approach. By combining the approach developed in this work for determining a rotational deviation with common image-based approaches for determining a translational deviation of the axes, the derotator can be calibrated entirely. In this way, the quality of the measurement with the derotator can be further increased, as calibration errors can be reduced.

Background: Six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) or R-CHOP-like chemotherapy are the standard treatment for aggressive B-cell non-Hodgkin's lymphoma. We hypothesized that four cycles of CHOP plus six applications of rituximab (4x R-CHOP+2xR) are non-inferior to six cycles of R-CHOP in a population with favorable prognosis. Methods: We randomized patients 18 to 60 years of age, stage I-II disease, normal serum lactate dehydrogenase concentration, good ECOG performance status 0-1, without bulky disease (maximal tumor diameter

BACKGROUND: According to the Lugano classification (Cheson et al., JCO 2014, 32: 3059-3067) fludeoxyglucose positron emission tomography combined with computed tomography (FDG PET/CT) is the standard for evaluation and staging of aggressive non-Hodgkin Lymphoma (NHL). It is a matter of debate whether FDG PET/CT is sufficient to determine bone marrow (BM) involvement. We performed a pooled analysis of data from the PETAL (EudraCT 2006-001641-33) and OPTIMAL>60 trials (EudraCT 2010-019587-36) as prospective, open-label, randomized, multicenter Phase-III trials to determine whether initial staging with FDG PET/CT would allow non-invasive diagnosis of BM involvement and thus could avoid established but potentially painful and unpleasant BM biopsy (BMB). PATIENTS AND METHODS: Patients treated within the trials were included if both FDG PET/CT and BMB were performed during initial staging. Only patients with a biopsy-proven, centrally confirmed diagnosis of diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma or follicular lymphoma grade 3b were included. FDG PET/CT images and BM findings were blinded for central review by board certified PET/CT readers. Discordant findings were documented and resolved after unblinding by interdisciplinary discussion using findings of complementary imaging and/or subsequent PET examinations. Based on literature (Berthet et al., J Nucl Med 2013), a newly defined gold standard was used to confirm BM involvement. It includes a positive BMB or a positive FDG PET confirmed by targeted biopsy, complementary CT imaging or targeted MRI, or concurrent disappearance of focal FDG-avid BM lesions with other lymphoma manifestations during immunochemotherapy. RESULTS: Out of 1,976 patients a total of 930 patients met the inclusion criteria. BMB confirmed BM involvement in 85 of 930 patients (9%). According to FDG PET/CT, BM was involved in 185 out of 930 patients (20%) with 36 discordances (4%) between negative initial FDG PET/CT and positive BMB ("false negatives" with respect to previous reference standard, PRS). Discordances between positive initial FDG PET/CT and negative BMB ("false positives" by PRS) occurred in 136 patients (15%). If only BMB is used as in the PRS, the negative predictive value (NPV) of FDG PET/CT was 709/745=95% (95% confidence interval [95%CI]: 93%-97%) with a sensitivity (Sens) of 58% (95%CI: 46%-68%) and a specificity (Spec) of 84% (95%CI: 81%-86%). After discussion of these cases, 185 out of 221 cases with BM involvement were identified as true positive, resulting in a Sens of 84% for FDG PET/CT (95%CI: 78%-88%). By means of FDG PET/CT 745 cases were negative of which 709 were confirmed as true negatives, resulting in an NPV of 95% (95%CI: 93%-97%). All 185 cases with positive FDG PET/CT were evaluated as true positive for BM involvement in the unblinded synopsis of all findings, resulting in a positive predictive value (PPV) of 100% (95%CI: 98%-100%). All 709 negative FDG PET/CT findings were finally confirmed as such, so Spec was 100% (95%CI: 99%-100%). Thus, the prevalence in our total cohort analyzed was 24%, since 221 out of 930 cases had confirmed BM involvement. Diagnostic performance parameters for BMB as compared to the newly defined gold standard were Sens 85/221=38% (95%CI: 32%-45%), Spec 709/709=100% (95%CI: 99%-100%), PPV 85/85=100% (95%CI: 96%-100%) and NPV 709/845=84% (95%CI: 81%-86%), respectively. Differences between the PRS in the diagnosis of BM involvement by only BMB and the newly defined gold standard result mainly from false negative BMB due to sampling errors, which are detected by FDG PET/CT. DISCUSSION: In the majority of patients with aggressive B-cell lymphoma, routine BMB does not give any additional relevant diagnostic or prognostic information over FDG PET/CT alone and could therefore be omitted. BMB should only be performed if results would have direct therapeutic impact e.g. in patients with limited stage disease and lack of further risk factors according to the international prognostic index (IPI). Disclosures Held: MSD: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Roche: Consultancy, Other: Travel support, Research Funding; Amgen: Research Funding; Acrotech: Research Funding. Stilgenbauer:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Hoffmann La-Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Duehrsen:Amgen: Consultancy; University Hospital Essen, Germany: Employment; Takeda: Consultancy; Novartis: Consultancy; Gilead: Honoraria; Janssen: Honoraria; Gilead: Consultancy; AbbVie: Consultancy; Celgene: Research Funding; CPT: Consultancy; Takeda: Honoraria; Novartis: Honoraria; Amgen: Research Funding; Roche: Research Funding; AbbVie: Honoraria; Amgen: Honoraria; CPT: Honoraria. Hüttmann:University Hospital Essen: Employment; Takeda: Honoraria; Gilead: Honoraria. Poeschel:Amgen: Other: Travel, accommodations, expenses; Abbvie: Other: Travel, accomodations, expenses; Roche: Other: Travel, accomodations, expenses; Hexal: Speakers Bureau.

A key problem when using the derotator is to ensure the coaxial alignment between the optical axis of the derotator and the rotation axis of the measured object. Moreover, accurate measurement of the rotation axis is the prerequisite of achieving the coaxial alignment. In this paper, we propose a strategy for estimation of the rotation axis with the assistant of an auxiliary laser and a binocular stereo vision sensor. When a laser source is temporarily attached to the measured object or the rotor shaft, the rotation of the laser will generate a ruled surface. The binocular sensor can accurately measure the coordinates of laser dots in three-dimensional (3D) space. The pose vector of the laser in each certain rotation angle can be estimated with measured 3D coordinates of the laser dots. Finally, the rotation axis of the object can be estimated with multiple pose vectors considering the constraint of the fixed axis rotation. The validity and precision of this proposed strategy are demonstrated by means of experiments.

Background: Anti-PD1 antibodies have the potential to increase rituximab-mediated effector mechanisms, to target the microenvironment and PD-1 in aggressive Non-Hodgkin Lymphoma (NHL). Addition of Nivolumab (Nivo) might increase efficacy of chemotherapy. The NIVEAU trial is an ongoing international, multicenter, randomized, open label, phase 3 study testing Nivo in combination with Rituximab, Gemcitabine, Oxaliplatin ((R-)GemOx) (NCT03366272). We performed a pre-planned safety analysis comparing the experimental arm (including safety run-in phase) and standard arm. Methods: Key eligibility criteria include: first relapse or progression of an aggressive lymphoma (B-cell and peripheral T-cell lymphoma (PTCL)), ineligibility for HDT (defined as >65 years of age or older than 18 years if HCT-CI score >2), only 1 prior chemotherapy including an anthracycline and R in case of B-NHL. Patients (Pts) were planned to receive 8 bi-weekly cycles of GemOx (Gem 1000 mg/m2, Ox 100 mg/m2) and R 375 mg/m2 for B-NHL at d1 of each cycle. Pts randomized into the experimental arm additionally received Nivo 3 mg/kg every two weeks for a total of 26 applications or until progression. Safety analysis was performed after 30 pts had been included into the experimental arm. Results: The analysis (data cut-off 29-August-2019) included 59 pts (44 with B-NHL, 15 with PTCL). 22 pts with B-NHL were randomized in the standard arm, 22 in the experimental arm. 7 pts with PTCL were randomized in the standard arm, 8 in the experimental arm. Median age was 78 years (range: 59; 87) for B-NHL and 70 years (range: 53; 80) for PTCL. 18 (41%) pts with B-NHL and 7 (47%) with PTCL were male. Twenty-five (57%) pts with B-NHL and 11 (73%) with PTCL had duration of first response ≤ 12 months. Due to the non-randomized safety run-in phase where all pts were treated in the experimental arm, the cumulative observation time of the experimental arm was longer. The most common adverse events (AE) (≥5%) during (immuno-)chemotherapy for pts treated with (R-)GemOx (grade ≥3) per documented cycles were thrombocytopenia 9/64 (14%), infection 7/64 (11%), leukocytopenia 5/64 (8%), peripheral sensory neuropathy 4/64 (6%) and anemia 4/63 (6%). Other frequent AEs gr. 3 (n>1) and/or life-threatening AEs (grade ≥4) were 2 gastrointestinal hemorrhages (1x gr. 4, 1x gr. 3), 1 gastric perforation gr. 4 and 2 tumor lysis syndromes gr. 3. In pts treated with (R-)GemOx 1 therapy-related death occurred after 2 cycles of (immuno-)chemotherapy. One pt with gastric involvement of lymphoma terminated treatment early due to sepsis after surgical intervention after gastrointestinal bleeding. The most common AEs (≥5%) during immunochemotherapy for pts treated with (R-)GemOx+Nivo (grade ≥3) per documented cycles were thrombocytopenia 37/140 (26%), anemia 22/140 (16%), increased lipase 13/129 (10%), leukocytopenia 11/140 (8%) and infection 7/141 (5%). Other frequent AEs gr. 3 (n>1) and/or life-threatening AEs (grade ≥4) were 2 gastrointestinal hemorrhages (1x gr. 5, 1x gr. 3), 1 renal failure gr. 5, 1 CNS vasculitis (gr. 4), 9 neutropenia (1x gr. 4, 8x gr. 3), 5 lymphopenias (2x gr. 4, 3x gr. 3), 19 increased yGT (each gr. 3), 2 hypertension (2x gr. 3), 2 syncopes (2x gr. 3) and 2 infusion related reactions (2x gr. 3). During consolidation with Nivo until 100 days after end of therapy most common AEs (≥5%, grade ≥3) were: lymphopenia 15/114 (13%), neutropenia 9/114 (8%) and leukocytopenia 8/114 (7%). Other frequent AEs gr. 3 (n>1) and/or life-threatening AEs (grade ≥4) were 6x increased yGT (each gr. 3) and 3 back pains (gr. 3). In pts treated with (R-)GemOx+Nivo 2 pts terminated treatment early, 1 due to elevated liver enzymes and 1 due to CNS vasculitis. Conclusion: So far, a moderately higher toxicity of the experimental arm, the combination of (R)-GemOx with Nivo, was observed. However, this does not influence the overall risk profile of the trial. No increased rate of progressions in pts with PTCL treated with Nivo was observed. The randomized phase 3 study continues as planned with continuous evaluation of toxicity. Supported by BMS Disclosures Thurner: EUSA-Pharm: Other: travel grants; Takeda: Consultancy; Astra-Zeneca: Consultancy; Merck: Consultancy; Janssen: Other: travel grants. Poeschel:Amgen: Other: travel grants; Abbvie: Other: travel grants; Roche: Other: travel grants. Tilly:BMS: Honoraria. Andre:Takeda: Consultancy; BMS: Consultancy, Other: travel grants; Karyopharm: Consultancy; Gilead: Consultancy, Other: travel grants; Novartis: Consultancy, Research Funding; Seattle Genetics: Consultancy; Abbvie: Consultancy; Roche: Other: travel grants; Amgen: Other: travel grants; Johnson & Johnson: Research Funding; Celgene: Other, Research Funding. Dreyling:Roche: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy; Bayer: Consultancy, Speakers Bureau; Astra Zeneca: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; Abbvie: Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau; Beigene: Consultancy. Kerkhoff:BMS: Honoraria. Le Gouill:Loxo Oncology at Lilly: Consultancy; Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier: Honoraria. Stilgenbauer:Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; Genzyme: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Other, Research Funding; Novartis: Consultancy, Honoraria, Other, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Other: travel support, Research Funding; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; Genentech: Consultancy, Honoraria, Other: travel support, Research Funding. Houot:Bristol-Myers Squibb: Honoraria; MSD: Honoraria; Gilead: Honoraria; Kite: Honoraria; Roche: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Haioun:Novartis: Honoraria; Takeda: Honoraria; Gilead: Honoraria; Roche: Honoraria; Servier: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Miltenyi: Honoraria. Held:BMS: Consultancy, Other: Travel Grants, Research Funding; Roche: Consultancy, Other: travel grants, Research Funding; MSD: Consultancy; Acrotech, Spectrum: Research Funding; Amgen: Research Funding. OffLabel Disclosure: The IMP is Nivolumab. The Trial is for patients with Aggressive Non-Hodgkin Lymphoma (B -and T- cell lymphoma) in First Relapse or Progression Not Eligible for High-Dose Chemotherapy (HDT), Testing Nivolumab in Combination with Gemcitabine, Oxaliplatin (GemOx) Plus Rituximab (R) in Case of B-Cell Lymphoma

Vitamin D deficient patients suffering from diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP have lower overall survival. This especially applies for patients with vitamin D levels ≤8 ng/ml (Bittenbring et al. J Clin Oncol. 2014; 32:3242-8). Vitamin D up to 65 ng/ml may be necessary for optimal efficacy of R-CHOP (Neumann et al. Cancer Immunol Immunother. 2018; 67:1709-18). To study the clinical benefit of vitamin D substitution, we established a fast-track schedule to appropriately substitute patients to these vitamin D levels. The pre-treatment baseline vitamin D level was determined in 99 patients included in the ongoing, randomized, multicenter, phase-III, open-label OPTIMAL>60 trial (NCT01478542) from November 2014 to July 2015. It was intended that patients reach a vitamin D level of 65 ng/ml. We calculated the dose needed using patient weight and baseline vitamin D: IU = 100 x ΔVitD3 x kg body weight (Van Groningen et al. Eur J Endocrinol. 2010; 162:805-11) and substitution started before treatment. Patients received 20.000 IU capsules of vitamin D, split over several days, with a daily maximum of 200.000 IU. Vitamin D level was checked again after substitution and at all restagings. Patients, who did not reach the intended vitamin D level of 65 ng/ml, received a second or third cycle of substitution. Baseline vitamin D level was 17.8±12.7 ng/ml. 14.3% of the patients reached the target value of up to 65 ng/ml after one substitution cycle with a mean dose of 386.000±137.000 IU. The average increase was 27.8 ng/ml, to a mean of 45.6±18.7 ng/ml. After the second substitution cycle with a median dose of 188.000±102.000 IU patients had vitamin D serum levels of 52.6±13.8 ng/ml. After a third substitution with 91.000±56.000 IU mean level of vitamin D was 56.0±9.6 ng/ml. By administering vitamin D in a dosage calculated by the van Groningen formula, we were able to increase the vitamin D level of our patients reliably after 2-3 cycles of substitution. After second and third substitution, a saturation effect was seen. The clinical effect of vitamin D substitution is the subject of the current study and the results are presently pending. The OPTIMAL>60 trial is supported by Amgen, Roche, Acrotech. Disclosures Poeschel: Roche:Other: Travel, Accommodations, Expenses;Amgen:Other: Travel, Accommodations, Expenses;Abbvie:Other: Travel, Accommodations, Expenses.Habersang:Rheinlandklinikum Neuss:Current Employment.Mahlberg:Janssen:Other: Travel, Accommodations, Expenses;Mutterhaus der Borromaeerinnen, Trier:Current Employment;Novartis:Honoraria, Other: Travel, Accommodations, Expenses;Labor Synlab:Ended employment in the past 24 months;Abbvie:Other: Travel, Accommodations, Expenses;Roche:Honoraria;Amgen:Honoraria, Other: Travel, Accommodations, Expenses;Merck:Honoraria, Other: Travel, Accommodations, Expenses.Keller:Janssen-Cilag:Consultancy, Other: Travel, Accommodations, Expenses;Takeda:Consultancy, Other: Travel, Accommodations, Expenses;Celgene:Consultancy, Other: Travel, Accommodations, Expenses;BMS:Consultancy, Other: Travel, Accommodations, Expenses;Roche:Consultancy, Other: Travel, Accommodations, Expenses;Hexal:Consultancy;Novartis:Consultancy;MSD:Consultancy;Pfizer:Consultancy;Astra-Zeneca:Consultancy;Pentixapharm:Consultancy.Viardot:Kite/Gilead:Honoraria, Other: advisory board;Roche:Honoraria, Other: advisory board;Amgen:Honoraria, Other: advisory board;Novartis:Honoraria, Other: advisory board.Stilgenbauer:Novartis:Consultancy, Honoraria, Other, Research Funding;Pharmacyclics:Consultancy, Honoraria, Other, Research Funding;GlaxoSmithKline:Consultancy, Honoraria, Other: travel support, Research Funding;Janssen-Cilag:Consultancy, Honoraria, Other: travel support, Research Funding;Mundipharma:Consultancy, Honoraria, Other, Research Funding;Genzyme:Consultancy, Honoraria, Other: travel support, Research Funding;Genentech:Consultancy, Honoraria, Other: travel support, Research Funding;F. Hoffmann-LaRoche:Consultancy, Honoraria, Other: travel support, Research Funding;Celgene:Consultancy, Honoraria, Other: travel support, Research Funding;Gilead:Consultancy, Honoraria, Other: travel support, Research Funding;AbbVie:Consultancy, Honoraria, Other: travel support, Research Funding;Boehringer-Ingelheim:Consultancy, Honoraria, Other: travel support, Research Funding;Amgen:Consultancy, Honoraria, Other: travel support, Research Funding.Held:Roche:Consultancy, Other: Travel, Accommodations, Expenses, Research Funding;BMS:Consultancy, Other: Travel, Accommodations, Expenses, Research Funding;MSD:Consultancy;Acrotech:Research Funding;Spectrum:Research Funding;Amgen:Research Funding.Bittenbring:Gilead:Honoraria, Other: Travel, Accommodations, Expenses;Bluebird Bio:Honoraria, Other: Travel, Accommodations, Expenses;Roche:Honoraria, Other: Travel, Accommodations, Expenses, Advisory board;Celgene:Honoraria, Other: Travel, Accommodations, Expenses, Advisory Board;Pfizer:Honoraria, Other: Travel, Accommodations, Expenses.

Introduction For patients (pts) with aggressive B-cell lymphoma immunochemotherapy with R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone) represents the standard of care with curative intention. For elderly pts a dose-reduced R-mini-CHOP protocol is feasible. No standard of care exists for frail or very old (>80 yrs) pts not eligible for CHOP-like treatment. Here we present the final results of the prospective DSHNHL-phase-2 trial for old or frail pts receiving Rituximab/Bendamustine (RB) for 1st-line treatment of aggressive B-cell lymphoma. Our goal was to determine feasibility, toxicity of the BR regimen in this pt cohort, and to determine which pts groups might potentially benefit from this reduced-intensity approach. Methods The open-label, multicenter, prospective, non-randomized phase-II trial "Subcutaneous Rituximab and Intravenous Bendamustine in very Elderly Patients or Elderly Medically Non Fit Patients ("Slow Go") with Aggressive CD20-positive B-cell Lymphoma" (B-R-ENDA, DSHNHL 2010-1, EudraCT 2010-024004-98) included all pts aged ≥81 yrs or 61-80 yrs and elevated CIRS >6, not qualifying for R- CHOP, with histologically confirmed CD20+aggressive lymphoma of any Ann Arbor-stage and IPI score, and ECOG 80 yr cohort), and treatment-associated deaths, frequency of grade 3/4 adverse events and SAEs, adherence to the protocol, complete and partial remission rate, rate of primary progression and relapse, and quality of life assessed by geriatric assessment and EORTC-QLQ-C30 for feasibility. Results: From 2012 to 2016, 68 pts (22 male, 46 female) were recruited in 24 centers into the trial and included into this intent-to-treat analysis (ITT). The median age was 81 yrs with 21% of pts older than 85 yrs. The median CIRS score was 8 and 72% had a CIRS >6. The IPI was >2 in 59% of pts. The patient population was per protocol divided into two subgroups: pts 61 to 80 yrs old and medically non-fit (29 pts) and pts older than 80 yrs (39 pts). For the 61 to 80 yrs old medically non-fit patients median age was 77 yrs (64-80), median CIRS score was 10 (2-22), IPI was > 2 in 76% of pts, 66% of pts had stage 3 or 4 disease, and ECOG was >1 in 52% of pts. For the subgroup of pts > 80 yrs, median age was 84 yrs (81-95), median CIRS score was 7 (1-17), IPI was > 2 in 46% of pts, 51% of pts had stage 3 or 4 disease, and ECOG was >1 in 23% of pts. 49% of pts received the complete treatment as planned (61-80 yrs: 38%; >80 yrs: 56%). Reasons for early termination of treatment were PD in 15% (17%; 13%) and toxicity in 24% (24%; 23%) of pts. 29% 95% Confidence interval 19-42% of pts (38%; 23%) had grade 3-5 infections. Treatment related mortality was 15% (17%; 13%). Overall response rate (ORR) was 41% (28%; 51%) with 31% CR (10%; 46%). Median observation time was 29 months for EFS, PFS and OS. 2-yrs EFS was 23% (10%; 37%), PFS was 40% (32%; 45%), OS was 42% (37%; 46%). In a multivariate analysis adjusted for IPI factors elevated LDH and ECOG >1 constituted the most significant risk factors for poor outcome. Conclusions: We describe a frail patient cohort with a median CIRS score of 8, with 72% pts with a CIRS >6, considerable comorbidities and a high percentage of high-risk IPI. The primary efficacy endpoint (2 yr PFS > 80 yrs 45%) was met; for R-mini-CHOP, this was reported at 47% (Peyrade et al., Lancet Haemat, 2011). The IPI predicts outcome in the >80 yrs cohort reliably. The RB regimen is active even in very elderly and frail pts up to 90 yrs of age. Therefore, in pts not eligible for full- or reduced dose R-CHOP treatment, it represents a tolerable and efficient alternative, albeit with a limited curative potential preferably in IPI low/intermediate-risk pts. Biomarker, comorbidity and QoL data will be analysed subsequently. Disclosures Zettl: Roche: Other: travel grants, Research Funding; Mundipharma: Research Funding. Viardot:Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Korfel:Mundipharma: Consultancy, Research Funding. Dreyling:Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Novartis: Other: scientific advisory board; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Sandoz: Other: scientific advisory board; Acerta: Other: scientific advisory board; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau. Illmer:Roche: Other: travel support. Schmitz:Novartis: Honoraria; Gilead: Honoraria; Celgene: Equity Ownership; Riemser: Consultancy, Honoraria. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding. Poeschel:Hexal: Speakers Bureau; Roche: Other: Travel support; Amgen: Other: Travel support; Abbvie: Other: Travel support; Astra Zeneca: Other: Travel support. Truemper:Takeda: Consultancy, Research Funding; Roche: Research Funding; Seattle Genetics, Inc.: Research Funding; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Nordic Nanovector: Consultancy.

Background: Nivolumab, a human anti-PD1 antibody has the potential to increase rituximab-mediated effector mechanism, to target the microenviroment and PD-1 in aggressive Non-Hodgkin lymphoma. Addition of nivolumab might increase efficacy conventional chemotherapy, which is always combined with rituximab in case of B-cell lymphoma. Therefore, a safety run-in was conducted to determine the tolerability of the combination prior to proceeding with a larger randomized phase 3 study aimed to compare of (R)-GemOx vs. Nivolumab plus (R)-GemOx. Methods: This is an ongoing international, multicenter, randomized, open label study. Key eligibility criteria include: first relapse or progression of an aggressive lymphoma (B-cell as well as peripheral T-cell lymphoma (PTCL)), ineligibility for HDT (defined as >65 years of age or older than 18 years if HCT-CI score > 2), only one prior chemotherapy regimen including an anthracycline and rituximab (R) in case of B-cell lymphoma. A non-randomized safety run-in phase was performed in 16 pts to assess potential toxicities of Nivolumab in combination with (R)-GemOx. Pts were planned to receive 8 bi-weekly cycles of Gemcitabine 1000 mg/m2, Oxaliplatin 100 mg/m2, R 375 mg/m2 all given on day 1. Nivolumab 3 mg/kg was given every two weeks for a total of 26 applications or until progression. Importantly, first application of Nivolumab was prior to first application of R. Response was evaluated after 4 and 8 cycles of (R)-Gemox. Safety analysis was performed after the last patient had gone through interim restaging after 4 cycles of (R)-GemOx. Progression/relapse of PTCL was scored as severe adverse event (SAE). Results: Sixteen pts were enrolled in the safety run-in, 10 pts with B cell lymphoma, all DLBCLs and 6 with PTCL. Recruitment was from 12-Jan-2018 until 17-May-2018, snapshot of database on 09-Aug-2018. Median age was 76 years, 9 (56%) pts were male, 8 (50%) had time-to-treatment failure Because inhibition of PD-1 might conversely induce progression of PTCL, efficacy is part of the safety analysis. So far 3/6 PTCL pts are in ongoing CR for 17, 16 and 14 months, respectively (an update will be presented at the meeting). Conclusion: The overall safety profile of nivolumab in combination with (R)-GemOx was consistent with those previously reported for (R)-GemOx and nivolumab. The combination does not to result in an increased frequency of immune-related AEs. However, the occurrence of very rare events needs assessment of longer follow-up and recruitment of more pts. Duration of response in PTCL is promising, without evidence for hyperprogression. The trial proceeded to the randomized phase 3 study and is actively recruiting. An additional safety analysis will be performed after 30 pts have been randomized to the experimental arm. Disclosures Held: Acrotech: Research Funding; Amgen: Research Funding; Roche: Consultancy, Other: Travel support, Research Funding; MSD: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding. Haioun:novartis: Honoraria; celgene: Honoraria; roche: Consultancy; celgene: Consultancy; gilead: Consultancy; takeda: Consultancy; janssen cilag: Consultancy; amgen: Honoraria; servier: Honoraria. Houot:Bristol Myers Squibb: Honoraria; Merck Sharp Dohme: Honoraria. Molina:merck: Consultancy; novartis: Consultancy; celgene: Consultancy. Rosenwald:MorphoSys: Consultancy. André:Celgene: Other: Travel grants, Research Funding; Chugai: Research Funding; Takeda Millenium: Research Funding; Johnson & Johnson: Research Funding; Amgen: Other: Travel grants, Research Funding; Roche: Other: Travel grants, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Dreyling:Acerta: Other: Scientific advisory board; Bayer: Other: Scientific advisory board, Speakers Bureau; Celgene: Other: Scientific advisory board, Research Funding, Speakers Bureau; Gilead: Other: Scientific advisory board, Speakers Bureau; Janssen: Other: Scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Other: Scientific advisory board, Research Funding; Novartis: Other: Scientific advisory board; Roche: Other: Scientific advisory board, Research Funding, Speakers Bureau; Sandoz: Other: Scientific advisory board. Tilly:roche: Membership on an entity's Board of Directors or advisory committees; servier: Honoraria; merck: Honoraria; Gilead: Honoraria; Janssen: Honoraria; BMS: Honoraria; Karyopharm: Consultancy; Roche: Consultancy; Celgene: Consultancy, Research Funding; Astra-Zeneca: Consultancy. La Rosée:Novartis: Research Funding; Bristol-Myers-Squibb: Consultancy, Other: Travel support, Speakers Bureau. Poeschel:Astra Zeneca: Other: Travel support; Hexal: Speakers Bureau; Roche: Other: Travel support; Amgen: Other: Travel support; Abbvie: Other: Travel support. OffLabel Disclosure: nivolumab, aggressive Non-Hodgkin Lymphoma

Introduction: The R-MegaCHOEP trial showed that dose-escalation of conventional chemotherapy necessitating autologous stem cell transplantation (ASCT) does not confer a survival benefit for younger patients (pts) with high-risk aggressive B-cell lymphoma in the Rituximab era (Schmitz et al., Lancet Oncology 2012; 13, 1250-1259). To describe efficacy and toxicity over time and document the long-term risks of relapse and secondary malignancy we present the 10-year follow-up of this study. Methods: In the randomized, prospective phase 3 trial R-MegaCHOEP younger pts aged 18-60 years with newly diagnosed, high-risk (aaIPI 2-3) aggressive B-cell lymphoma were assigned to 8 cycles of CHOEP (cyclophosphamide, doxorubcine, vincristine, etoposide, prednisone) or 4 cycles of dose-escalated high-dose therapy (HDT) necessitating repetitive ASCT both combined with Rituximab. Both arms were stratified according to aaIPI, bulky disease, and center. Primary endpoint was event-free survival (EFS). All analyses were calculated for the intention-to-treat population. This follow-up report includes molecular data based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) for MYC (IHC: 31/92 positive [40-100%], FISH: 14/103 positive), BCL2 (IHC: 65/89 positive [50-100%], FISH: 23/111 positive) and BCL6 (IHC: 52/86 positive [30-100%], FISH: 34/110 positive) and data on cell of origin (COO) classification according to the Lymph2CX assay (GCB: 53/88; ABC: 24/88; unclassified: 11/88). Results: 130 pts had been assigned to R-CHOEP and 132 to R-MegaCHOEP. DLBCL was the most common lymphoma subtype (~80%). 73% of pts scored an aaIPI of 2 and 27% an aaIPI of 3. 60% of pts had an initial lymphoma bulk and in 40% more than 1 extranodal site was involved. After a median observation time of 111 months, EFS at 10 years was 57% (95% CI 47-67%) in the R-CHOEP vs. 51% in the R-MegaCHOEP arm (42-61%) (hazard ratio 1.3, 95% CI 0.9-1.8, p=0.228), overall survival (OS) after 10 years was 72% (63-81%) vs. 66% (57-76%) respectively (p=0.249). With regard to molecular characterization, we were unable to detect a significant benefit for HDT/ASCT in any subgroup analyzed. In total, 16% of pts (30 pts) relapsed after having achieved a complete remission (CR). 23% of all relapses (7 pts) showed an indolent histology (follicular lymphoma grade 1-3a) and 6 of these pts survived long-term. In contrast, of 23 pts (77%) relapsing with aggressive DLBCL or unknown histology 18 pts died due to lymphoma or related therapy. The majority of relapses occurred during the first 3 years after randomization (median time: 22 months) while after 5 years we detected relapses only in 5 pts (3% of all 190 pts prior CR). 11% of pts were initially progressive (28 pts) among whom 71% (20 pts) died rapidly due to lymphoma. Interestingly, the remaining 29% (8 pts) showed a long-term survival after salvage therapy (+/- ASCT); only 1 pt received allogeneic transplantation. The frequency of secondary malignancies was very similar in both treatment arms (9% vs. 8%) despite the very high dose of etoposide (total 4g/m2)in the R-MegaCHOEP arm. We observed 2 cases of AML and 1 case of MDS per arm. In total 70 pts (28%) have died: 30 pts due to lymphoma (12%), 22 pts therapy-related (11 pts due to salvage therapy) (9%), 8 pts of secondary neoplasia (3%), 5 pts due to concomitant disease (2%) and 5 pts for unknown reasons. Conclusions: This 10-year long-term follow-up of the R-MegaCHOEP trial confirms the very encouraging outcome of young high-risk pts following conventional chemotherapy with R-CHOEP. High-dose therapy did not improve outcome in any subgroup analysis including molecular high-risk groups. Relapse rate was generally low. Pts with aggressive relapse showed a very poor long-term outcome while pts with indolent histology at relapse survived long-term. Secondary malignancies occurred; however, they were rare with no excess leukemias/MDS following treatment with very high doses of etoposide and other cytotoxic agents. Supported by Deutsche Krebshilfe. Figure Disclosures Nickelsen: Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees. Hänel:Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board; Roche: Honoraria. Truemper:Nordic Nanovector: Consultancy; Roche: Research Funding; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding. Held:Roche: Consultancy, Other: Travel support, Research Funding; Amgen: Research Funding; Acrotech: Research Funding; MSD: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board. Viardot:Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosenwald:MorphoSys: Consultancy. Lenz:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Employment, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy. Schmitz:Novartis: Honoraria; Gilead: Honoraria; Celgene: Equity Ownership; Riemser: Consultancy, Honoraria.

To further improve outcome in young high-risk patients with diffuse large B-cell lymphoma (DLBCL) the number of rituximab (R) infusions was doubled in combination with standard CHOEP (cyclophosphamide, doxorubicin, etoposide, vincristine, prednisone) chemotherapy. Seventy-seven patients (aged 18-60 years) with an age-adjusted International Prognostic Index of 2-3 received 12 × R (375 mg/m2 ) on days 0, 1, 4, 8, 15, 22, 29, 43, 57, 71, 85 and 99 together with eight cycles of CHOEP-14. Results were retrospectively compared to those of patients receiving 6 × R and 8 × CHOEP-14 in the standard arm of the randomized R-MegaCHOEP trial. Two-year overall survival (OS) was 82% [95% confidence interval (CI) 73%-92%]; 2-year event-free (EFS) and progression-free survival (PFS) was 69% (95% CI 59-80%) and 76% (95% CI 66%--6%), respectively. Comparing 12 to six doses of R revealed no differences (univariate/multivariate) in EFS (at 2 years: 69% vs. 71%), PFS (76% vs. 75%) and OS (82% vs. 85%), with P = 0·766, P = 0·871 and P = 0·843, respectively. Doubling the number of R infusions concomitant to CHOEP did not improve treatment outcomes. Nonetheless, OS and PFS of young high-risk patients who received only six infusions of R combined with CHOEP remain excellent and were confirmed in an independent cohort of patients.

Biosecurity is defined as the implementation of measures that reduce the risk of disease agents being introduced and/or spread. For pig production, several of these measures are routinely implemented (e.g. cleaning, disinfection, segregation). However, air as a potential vector of pathogens has long been disregarded. Filters for incoming and recirculating air were installed into an already existing ventilation plant at a fattening piggery (3,840 pigs at maximum) in Saxony, Germany. Over a period of three consecutive fattening periods, we evaluated various parameters including air quality indices, environmental and operating parameters, and pig performance. Animal data regarding respiratory diseases, presence of antibodies against influenza A viruses, PRRSV, and Actinobacillus pleuropneumoniae and lung health score at slaughter were recorded, additionally. There were no significant differences (p = 0.824) in total bacterial counts between barns with and without air filtration. Recirculating air filtration resulted in the lowest total dust concentration (0.12 mg/m3) and lung health was best in animals from the barn equipped with recirculating air filtration modules. However, there was no difference in animal performance. Antibodies against all above mentioned pathogens were detected but mostly animals were already antibody-positive at re-stocking. We demonstrated that supply air filtration as well as recirculating air filtration technique can easily be implemented in an already existing ventilation system and that recirculating air filtration resulted in enhanced lung health compared to supply air-filtered and non-filtered barns. A more prominent effect might have been obtained in a breeding facility because of the longer life span of sows and a higher biosecurity level with air filtration as an add-on measure.

7503 Background: In patients (pts) with peripheral T-cell lymphoma (PTCL) results of first-line therapy remain poor; guidelines recommend consolidation with autologous transplantation (autoSCT) in transplant-eligible pts. AATT (Autologous or Allogeneic Transplantation in T-cell lymphoma) sought to improve first-line therapy and compared alloSCT with autoSCT. Methods: This was a prospective randomized trial comparing autoSCT with alloSCT in younger pts (18-60 yrs) with newly diagnosed PTCL who had achieved CR, PR, or SD after 4 courses of CHOEP and 1 course of DHAP. Pts were to receive BEAM followed by autoSCT or myeloablative conditioning (fludarabine, busulfan, cyclophosphamide) followed by alloSCT from a matched related or unrelated donor. Primary endpoint was 3-year event-free survival (EFS). The study was stopped prematurely after a pre-planned interim analysis (JCO 33, 2015, suppl 8507a). Results: 103 pts randomized upfront to autoSCT (n=54) or alloSCT (n=49) formed the full analysis set. Median age was 50 years, 63% were male. 36 pts (35%) could not proceed to transplantation mostly due to early progression. Median observation time for EFS was 42 months. 3-year EFS and overall survival (OS) did not significantly differ between alloSCT and autoSCT (EFS: 43% (95% CI29-57%) vs. 38% (25-52%), p=0.58, OS: 57% (43-71%) vs. 70% (57-82%) (p=0.41). Comparing pts who actually received autoSCT (n=41) or alloSCT (n=26) EFS, PFS, and OS also showed no significant difference. No patient relapsed but eight pts (31%) died of treatment-related mortality (TRM) after alloSCT compared to 13 relapses (36%) but no TRM observed after autoSCT. Comparison of pts with aaIPI 2/3 vs. 0/1 showed significant differences for all endpoints. Conclusions: AlloSCT or autoSCT given to consolidate response in pts with PTCL showed no significant survival differences. While exerting a strong GvL-effect alloSCT resulted in substantial TRM. For younger pts with PTCL autoSCT remains the preferred consolidation, in particular, because pts. relapsing after autoSCT can be successfully salvaged with alloSCT. Clinical trial information: 2007-001052-39.

[§ share last authorship] Background: In 2000-2010, the first large prospective trials in peripheral T-cell lymphoma (PTCL) showed outcomes burdened by high failure rates during induction. Concurrently, trials with the anti-CD52 monoclonal antibody alemtuzumab (ALZ) yielded promising responses in PTCL while demonstrating the feasibility of combining ALZ with CHOP. Hence, the Nordic Lymphoma Group initiated the randomized ACT-1 trial to test, in younger patients (pts) (18-65yrs), the addition of ALZ to CHOP + autologous stem cell transplant (ASCT). Primary endpoint was the 3 years event-free survival (EFS). Here, we present the final analysis of the ACT-1 trial (ClinicalTrials.gov: NCT00646854). Patients and Methods: Overall, 136 pts were randomized (43% of planned sample size due to slow accrual), five did not receive study treatment, and 131 were analyzed (ALZ-CHOP: 65; CHOP: 66). Due to lack of tumoral CD52 expression, anaplastic large cell lymphomas (ALCL) were not included in the ACT-1 trial. An amendment tapering ALZ dose from 360 mg (30 mg on days 1+2 of each CHOP course) to 120 mg (30 mg on day 1 of CHOP courses 1-4) was introduced early on due to systemic fungal infections in 2 pts. Of the 65 pts treated with ALZ-CHOP, 4 received the pre- and 61 (94%) the post-amendment dose. Monitoring for CMV- and EBV-DNA and antimicrobial prophylaxis were mandatory. Results: The median observation time for the Full Analysis Set was 66 months and the median age 51 yrs. The ALZ-CHOP and CHOP cohorts were well balanced with regard to classical prognostic factors and histological subtypes (PTCL-NOS 58% vs 54%, AILT 21% vs 25%, other 21% vs 21%). Feasibility: Neither CHOP nor ALZ-CHOP pts experienced substantial treatment delay. ALZ exposure did not affect stem cell harvest nor hematopoietic recovery. Grade 4 leucopenia was more frequent in ALZ-CHOP pts (73% vs 35%; p=0.001), whereas the occurrence of grade 3-4 anemia and thrombocytopenia did not differ significantly. After ALZ dose amendment, the frequency of bacterial and fungal infections of grade ≥3 was similar in both treatment arms. ALZ treated pts had more viral events (22/57=42% vs 4/23=17%), mainly due to asymptomatic CMV reactivations. The ratio of serious adverse events per ALZ-CHOP treated patient dropped markedly (from 3.25 to 0.86, comparable with 0.46 for CHOP) after dose amendment. Additional toxicity was mild and similar in both arms. Treatment related mortality was 4% (5% vs 3%). Efficacy: Complete remission (CR) was 52% in ALZ-CHOP vs 42% in CHOP. Primary refractory disease occurred for ALZ-CHOP and CHOP in 23% and 38% of pts, respectively. Overall, females had a significantly better outcome than males (p=0.004), also after adjustment for classical prognostic factors. Analyzing time-related endpoints without knowledge of CD52 expression, 3-years EFS, progression-free, and overall survival (PFS, OS) did not differ significantly between ALZ-CHOP and CHOP (EFS 35% vs 26%, PFS 37% vs 26%, OS 52% vs 50%). Fig.1A shows EFS by treatment arm, by gender, and by gender and treatment arm. Although not significantly different, EFS, PFS and OS values of ALZ-CHOP treated females in the ACT-1 trial were consistently higher than those of non-ALZ treated females or of males regardless of treatment group. RNA sequencing from evaluable pre-therapeutic tumor biopsies defined a signature of differentially expressed genes to be predictive of clinical outcome in ALZ-CHOP but not CHOP treated pts (n=33). Tumor microenvironment genes were prominent in determining response to ALZ. Tumors rich in B-cell milieu showed good responses, while the opposite was observed in tumors with signatures enriched with high endothelial cell genes (p Disclosures Leppä: Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Bayer: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy. Silva:Gilead Sciences: Research Funding; Abbvie, Gilead Sciences, Janssen, BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche, Janssen, Celgene: Other: Travel Support; Roche, Janssen: Other: Institution's payment for consultancy. Hagberg:Roche: Honoraria. Lugtenburg:takeda: Consultancy, Research Funding; servier: Consultancy, Research Funding; roche: Consultancy; BMS: Consultancy; Celgene: Consultancy; Sandoz: Consultancy; GenMab: Research Funding. Walewski:Roche, GSK/Novartis, Takeda, and Janssen-Cilag: Research Funding; Roche, Celgene, Takeda, Janssen-Cilag, and Servier: Honoraria; Roche, Celegene, Takeda, Janssen-Cilag, and Servier: Membership on an entity's Board of Directors or advisory committees. Hopfinger:Janssen: Honoraria; Gilead: Honoraria, Research Funding; GlaxoSmithKline: Honoraria; Celgene: Honoraria; Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Jantunen:Amgen: Honoraria; Genzyme/Sanofi: Honoraria; Takeda: Honoraria. Steidl:Seattle Genetics: Consultancy; Juno Therapeutics: Consultancy; Tioma: Research Funding; Bristol-Myers Squibb: Research Funding; Nanostring: Patents & Royalties: patent holding; Roche: Consultancy. Gascoyne:NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies. Scott:Celgene: Consultancy, Honoraria; Janssen: Research Funding; Roche: Research Funding; NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding.

Background: Standard treatment in PTCL pts is unsatisfactory due to a high rate of early progression. Alemtuzumab (A), a monoclonal anti CD52 antibody, has demonstrated efficacy in relapsed PTCL pts. The results of the final analyses of the ACT-1 phase III and the ACT-2 phase III trial, comparing standard CHOP to A-CHOP showed higher response rates, but did not yield significant differences in EFS, PFS and OS in both previously untreated young and elderly patients, but the planned sample sizes could not be reached due to low recruitment. We undertook a planned pooled analysis of both ACT trials comparing CHOP with A-CHOP to increase statistical power. Patients and Methods: Between 2007 and 2013, 252 pts from Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Norway, Poland, Portugal, Sweden and The Netherlands were randomized to receive either 6 cycles CHOP or A-CHOP at 14 day intervals. The planned pooled analysis was performed to compare patient outcome adding A to CHOP with patients treated with CHOP alone. Primary endpoint within ACT-1 and ACT-2 trial was the 3 years event free survival (EFS), secondary endpoints were progression free survival (PFS) and overall survival (OS). EFS is defined as the time from randomization to disease progression, start of salvage treatment, additional (unplanned) treatments, relapse, or death of any cause. Results: 252 pts were randomized (ACT-1: 136; ACT-2: 116). Five patients received no study treatment; therefore, 247 pts were analyzed (CHOP: 124; A-CHOP: 123). Median age was 61 years. 62% were male. Histologies were 33% AITL, 34% PTCL NOS, 33% other subtypes. In the pooled data set, the two treatment groups were comparable. Infections grade ≥3 occurred more often in patients treated with Alemtuzumab (A-CHOP: 55% [95% CI: 45% - 64%] vs. CHOP 23% [16% - 32%]; p 1 (HR 2.1) and bulky disease (HR 2.1) were the most prominent unfavorable risk factors for EFS. With the sample size of 247 pts the power for detecting the planned EFS difference of 15% was 74%. Conclusion: Adding Alemtuzumab to CHOP increased the rate of CR in PTCL patients, albeit at the costs of higher treatment related toxicity. Addition of Alemtuzumab did not improve EFS, PFS, or OS. Female gender is associated with a significantly better prognosis. This is the largest prospective dataset collected for PTCL. Supported by Federal Ministry of Research BMBF FKZ 01KG0705 and unrestricted research grants by Genzyme-Sanofi and AMGEN Disclosures No relevant conflicts of interest to declare.

Background: 6 cycles CHOP-like chemotherapy plus rituximab (6x R-CHOP) are the standard treatment for young patients with DLBCL. The MInT trial established a subgroup with favourable prognosis as defined as aaIPI=0 and no bulky disease [Pfreundschuh et al., Lancet Oncol 2006; 7: 379-391] with a 3-year EFS of 89%, PFS of 95% and OS of 98%. We hypothesized that 4 cycles of CHOP plus 6 applications of rituximab are non-inferior to the standard treatment of 6x R-CHOP in this population. Patients and Methods: 18 to 60 year-old patients, aaIPI =0 without bulky (≥7.5 cm) disease were randomized to receive 6x R-CHOP or 4x R-CHOP+2xR at 21-day cycles. Radiotherapy was not planned to be given except for prophylactic radiotherapy of the contralateral testis in patients with testicular lymphoma. The primary endpoint was progression free survival (PFS) with events defined as progressive disease, relapse or death. Assuming a 93% 3-years PFS for the 6x R-CHOP arm, it was planned to tolerate an impairment of 5.5% by reducing the number of courses to 4x R-CHOP+2xR to prove non-inferiority with a power of 80% and an alpha-error of 5% (one-sided). Results: Between 12/2005 and 10/2016, 592 patients were randomized in the international multi-center FLYER trial and 588 patients were evaluable for this final analysis. 295 patients were assigned to receive 6x R-CHOP and 293 were assigned to receive 4x R-CHOP+2xR. There were no relevant differences in demographics (median age: 48 years, 99% aaIPI=0, 1% aaIPI=1, 0.3% bulky disease), protocol adherence and toxicity between the two arms. PFS, EFS and OS after 4x R-CHOP+2xR were as good as after 6x R-CHOP. After 66 months median observation, the 3-year PFS rate of the patients receiving 4x R-CHOP+2xR was 96% vs. 94% of patients receiving 6x R-CHOP (p=0.760). The lower limit of the 95% CI of the difference between treatment arms was 0% and excludes -5.5% demonstrating the non-inferiority. The 3-year EFS was identical (89%) in both treatment arms. The 3-years OS was 99% in patients receiving 4x R-CHOP+2xR and 98% in patients receiving 6x R-CHOP. In a multivariable analysis adjusting for strata (stage and E-involvement), the hazard ratio of 4x R-CHOP+2xR compared to 6x R-CHOP was 1.0 (95% CI: 0.7-1.6; p=0.896) for EFS, 0.9 (95% CI: 0.5-1.6; p=0.797) for PFS, and 0.8 (95% CI: 0.4-1.9; p=0.671) for OS. With respect to relapse rate there was also no significant difference between the two treatment arms. 4% (95% CI 2-7%) of the patients in the 4x R-CHOP+2xR arm relapsed vs. 5% (95% CI 3-8%) of the patients in the 6x R-CHOP arm. 33% of relapses occurred in the first two years after study inclusion but continue to be seen with longer follow-up in both arms. Conclusion: In young patients with favourable prognosis DLBCL outcome after 4x R-CHOP+ 2xR is non-inferior compared to the previous standard 6x R-CHOP. Thus, chemotherapy can be spared without compromising prognosis in this population. Supported by Deutsche Krebshilfe Figure. Figure. Disclosures Poeschel: Roche: Other: Travel grants; Amgen: Other: Travel grants. Held:BMS: Consultancy, Other: Travel grants, Research Funding; Amgen: Research Funding; Roche: Consultancy, Other: Travel grants, Research Funding; MSD: Consultancy; Spectrum: Research Funding. Holte:Roche, Norway: Research Funding; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Viardot:Roche: Consultancy, Honoraria; Amgen: Consultancy; Gilead Kite: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Borchmann:Novartis: Consultancy, Honoraria. Keller:Celgene: Research Funding; BMS: Consultancy; Takeda: Consultancy, Research Funding; Janssen-Cilag: Consultancy, Equity Ownership; Roche: Consultancy; MSD: Consultancy. Schmidt:Gilead: Honoraria, Other: Travel Grants; Celgene: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants. Marks:Merck: Honoraria; BMS: Honoraria; Servier: Honoraria. Stilgenbauer:Boehringer-Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmcyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffmann La-Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schmitz:Riemser: Honoraria, Other: Travel grants; Kite/Gilead: Honoraria, Other: Travel grants; Novartis: Honoraria, Other: Travel grants; Celgene: Other: Travel grants; Roche: Honoraria. Murawski:Takeda: Consultancy; Janssen: Other: Travel grants.

The mitotic spindle assembly checkpoint (SAC) maintains genome stability and marks an important target for antineoplastic therapies. However, it has remained unclear how cells execute cell fate decisions under conditions of SAC-induced mitotic arrest. Here, we identify USP9X as the mitotic deubiquitinase of the X-linked inhibitor of apoptosis protein (XIAP) and demonstrate that deubiquitylation and stabilization of XIAP by USP9X lead to increased resistance toward mitotic spindle poisons. We find that primary human aggressive B-cell lymphoma samples exhibit high USP9X expression that correlate with XIAP overexpression. We show that high USP9X/XIAP expression is associated with shorter event-free survival in patients treated with spindle poison-containing chemotherapy. Accordingly, aggressive B-cell lymphoma lines with USP9X and associated XIAP overexpression exhibit increased chemoresistance, reversed by specific inhibition of either USP9X or XIAP. Moreover, knockdown of USP9X or XIAP significantly delays lymphoma development and increases sensitivity to spindle poisons in a murine El-Myc lymphoma model. Together, we specify the USP9X–XIAP axis as a regulator of the mitotic cell fate decision and propose that USP9X and XIAP are potential prognostic biomarkers and therapeutic targets in aggressive B-cell lymphoma. peerReviewed

7574Background: The role of RT to B and E for young patients with good-prognosis DLBCL is ill-defined. Methods: 18-60 year-old patients (aaIPI = 0 with B [≥7.5 cm], aaIPI 1) qualifying for radiothe...

7506 Background: RT to bulky sites improves outcome of elderly DLBCL patients [Lancet Oncol 2008; 9: 105-116; J Clin Oncol 2014; 32:112-1118]. Whether RT can be spared in PET-negative pts. after R-CHOP was prospectively addressed in OPTIMAL >60. Methods: 61 to 80 y-old pts. were randomized in a 2x2 factorial design to 6xCHOP-14 or 6xCHLIP-14 (liposomal instead of conventional vincristine) plus 8 x rituximab 375 mg/m2(R) q 2 wks. or 12xR (days -4,-1,1,4,14,28,42,56,91,126,175, 238). Pts. with bulk (>=7.5 cm) PET-positive after 6 cycles chemotherapy were assigned to RT (39.6 Gy), while PET-negative bulks were observed. Results: 187/505 (37%) had bulky disease and were compared to 117/306 (38%) RICOVER-60 pts. (38%) who had received 6xCHOP-14+8R. OPTIMAL>60 pts. were older (70 vs. 68 years) and had more IPI=3 (33% vs. 29%) and IPI=4,5 (34% vs. 23%) compared to RICOVER-60. PET was performed in 166/187 OPTIMAL>60 bulk pts. (reasons for no PET: early death: 5; excessive toxicity: 3; protocol violation: 1, non-compliance: 4, change of diagnosis: 6, others: 2). 80/166 (48%) bulks remained PET-positive after 6 cycles of chemotherapy and 62/80 (78%) were irradiated (reasons for no RT: progression: 8; medical reasons: 9; negative biopsy: 1), reducing RT from 67/117 (57%) in RICOVER-60 by 42% to 62/187 (33%) in OPTIMAL>60. Despite the unfavorable demographics, outcome of the 187 bulk pts. in OPTIMAL>60 was non-inferior to RICOVER-60, not even in the least intensive of the 4 OPTIMAL>60 treatment arms consisting of 47 pts. who received 6xCHOP-14+8R as in RICOVER-60. 2-year PFS and OS in OPTIMAL>60 was 79% and 88%, respectively, compared to 75% and 78% of the 117 RICOVER-60 pts. In a multivariable analysis adjusting for the IPI risk factors, the hazard ratio of the OPTIMAL>60 compared to the RICOVER-60 bulk pts. was 0.7 (95% CI: 03.; 1.5; p=0.345) for PFS and 0.5 (95% CI: 02.; 1.3; p=0.154) for OS. Conclusions: RT can be spared in bulky disease PET-negative after chemotherapy. This strategy results in a 42% reduction of RT without compromising the outcome of these patients. Supported by Amgen, Roche, Spectrum. Clinical trial information: NCT01478542.