ALBERT

Description: Abstract 2060 Poster Board II-37 Introduction: The Flt3-internal tandem duplication can be found in up to 30% of all acute myeloid leukemia (AML) patients and confers a poor risk status characterized by an increased relapse rate and poor overall survival. Moreover, Flt3-ITD-positive AML patients relapsing after allogenic stem cell transplantation (SCT) have very limited therapeutic options. Sorafenib is a multikinase inhibitor that is approved for the treatment of metastatic renal cell and hepatocellular carcinoma. Besides targeting Raf, the platelet derived growth factor receptor (PDGFR) and the vascular endothelial growth factor receptor (VEGFR) it has also significant inhibitory activity against the Flt3 receptor tyrosine kinase, and, specifically the mutated variant of Flt3, Flt3-ITD. It has previously been shown that sorafenib monotherapy may have considerable activity in relapsed Flt3-ITD positive AML. Nevertheless, clinical experience is still limited. Here we report compassionate use experience on 18 relapsed or refractory Flt3-ITD positive AML patients treated with sorafenib monotherapy. Methods: A questionnaire was developed and sent to 28 centers in Germany in order to obtain more insight into the clinical efficacy and tolerablilty of sorafenib monotherapy in Flt3-ITD positive AML. Forms were returned from 13 centers, reporting 26 patients. Among them, eight had to be excluded from further analysis. Five of them were Flt3-ITD mutation negative and three received contemporary chemotherapy. Available patient information included age, FAB-classification, karyotype, type and response to prior therapy, sorafenib dosing, tolerability, treatment duration, and response. Results: Of the 18 patients (12 male, 6 female), five were primary refractory to induction chemotherapy and 13 received sorafenib in first (n=11) or second (n=2) relapse. Eight of 18 patients relapsed after SCT and were treated with sorafenib. One patient was treated for steadily increasing Flt3-ITD copy numbers, that is, in molecular relapse after SCT. Patients received between 200mg and 800mg sorafenib p.o. daily. The median treatment duration was 98 days (range, 16-425 days). All patients achieved a hematological response (HR) characterized by complete (n=17) or near complete peripheral blast clearance (n=2). Of the 18 patients the documented best response to sorafenib were: HR in 9 cases, bone marrow response (HR and blast reduction in marrow) in 4 cases, complete remission (normalization of peripheral blood counts and bone marrow blasts 〈 5%) in one case and complete molecular remission (molecular negativity for Flt3-ITD) in 4 patients. After a median treatment duration of 180 days (range, 82-270 days) 7 of the 18 (39%) patients developed clinical sorafenib resistance: two of eight (25%) of the SCT-group and 5 of 10 (50%) of the non-SCT group. Sorafenib was generally well tolerated. Pancytopenia or thrombocytopenia grade III and IV were the most significant side effects, observed in 13 patients. Other reported side effects such as diarrhea, exanthema were documented from the centers as being minor. Conclusion: Sorafenib monotherapy has significant clinical activity in Flt3-ITD positive relapsed and refractory AML and may be particularly effective in the context of allo-immunotherapy where 3 CMR could be seen. Disclosures: Enghofer: Bayer Schering Pharma: Employment. Off Label Use: sorafenib, used to treat Flt3-ITD positive AML patients.

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

Description: The Gimballed Limb Observer for Radiance Imaging of the Atmosphere (GLORIA) was operated on board the German High Altitude and Long Range Research Aircraft (HALO) during the PGS (POLSTRACC/GW-LCYCLE/SALSA) aircraft campaigns in the Arctic winter 2015/2016. Research flights were conducted from 17 December 2015 until 18 March 2016 within 25–87∘ N, 80∘ W–30∘ E. From the GLORIA infrared limb-emission measurements, two-dimensional cross sections of temperature, HNO3, O3, ClONO2, H2O and CFC-12 are retrieved. During 15 scientific flights of the PGS campaigns the GLORIA instrument measured more than 15 000 atmospheric profiles at high spectral resolution. Dependent on flight altitude and tropospheric cloud cover, the profiles retrieved from the measurements typically range between 5 and 14 km, and vertical resolutions between 400 and 1000 m are achieved. The estimated total (random and systematic) 1σ errors are in the range of 1 to 2 K for temperature and 10 % to 20 % relative error for the discussed trace gases. Comparisons to in situ instruments deployed on board HALO have been performed. Over all flights of this campaign the median differences and median absolute deviations between in situ and GLORIA observations are -0.75K±0.88 K for temperature, -0.03ppbv±0.85 ppbv for HNO3, -3.5ppbv±116.8 ppbv for O3, -15.4pptv±102.8 pptv for ClONO2, -0.13ppmv±0.63 ppmv for H2O and -19.8pptv±46.9 pptv for CFC-12. Seventy-three percent of these differences are within twice the combined estimated errors of the cross-compared instruments. Events with larger deviations are explained by atmospheric variability and different sampling characteristics of the instruments. Additionally, comparisons of GLORIA HNO3 and O3 with measurements of the Aura Microwave Limb Sounder (MLS) instrument show highly consistent structures in trace gas distributions and illustrate the potential of the high-spectral-resolution limb-imaging GLORIA observations for resolving narrow mesoscale structures in the upper troposphere and lower stratosphere (UTLS).

Description: The HD(CP)2 Observational Prototype Experiment (HOPE) was performed as a major 2-month field experiment in Jülich, Germany, in April and May 2013, followed by a smaller campaign in Melpitz, Germany, in September 2013. HOPE has been designed to provide an observational dataset for a critical evaluation of the new German community atmospheric icosahedral non-hydrostatic (ICON) model at the scale of the model simulations and further to provide information on land-surface–atmospheric boundary layer exchange, cloud and precipitation processes, as well as sub-grid variability and microphysical properties that are subject to parameterizations. HOPE focuses on the onset of clouds and precipitation in the convective atmospheric boundary layer. This paper summarizes the instrument set-ups, the intensive observation periods, and example results from both campaigns. HOPE-Jülich instrumentation included a radio sounding station, 4 Doppler lidars, 4 Raman lidars (3 of them provide temperature, 3 of them water vapour, and all of them particle backscatter data), 1 water vapour differential absorption lidar, 3 cloud radars, 5 microwave radiometers, 3 rain radars, 6 sky imagers, 99 pyranometers, and 5 sun photometers operated at different sites, some of them in synergy. The HOPE-Melpitz campaign combined ground-based remote sensing of aerosols and clouds with helicopter- and balloon-based in situ observations in the atmospheric column and at the surface. HOPE provided an unprecedented collection of atmospheric dynamical, thermodynamical, and micro- and macrophysical properties of aerosols, clouds, and precipitation with high spatial and temporal resolution within a cube of approximately 10  ×  10  ×  10 km3. HOPE data will significantly contribute to our understanding of boundary layer dynamics and the formation of clouds and precipitation. The datasets have been made available through a dedicated data portal. First applications of HOPE data for model evaluation have shown a general agreement between observed and modelled boundary layer height, turbulence characteristics, and cloud coverage, but they also point to significant differences that deserve further investigations from both the observational and the modelling perspective.

Description: The Gimballed Limb Observer for Radiance Imaging of the Atmosphere (GLORIA) was operated on board the German High Altitude and LOng range (HALO) research aircraft during the PGS (POLSTRACC/GW-LCYCLE/SALSA) aircraft campaigns in the Arctic winter 2015/2016. Research flights were conducted from 17 December 2015 until 18 March 2016 between 80°W–30°E longitude and 25°N–87°N latitude. From the GLORIA infrared limb emission measurements, two dimensional cross sections of temperature, HNO3, O3, ClONO2, H2O and CFC-12 are retrieved. During 15 scientific flights of the PGS campaigns the GLORIA instrument measured more than 15000 atmospheric profiles at high spectral resolution. Dependent on flight altitude and tropospheric cloud cover, the profiles retrieved from the measurements typically range between 5 and 14km, and vertical resolutions between 400m and 1000m are achieved. The estimated total (random and systematic) 1σ errors are in the range of 1 to 2K for temperature and 10% to 20% relative error for the discussed trace gases. Comparisons to in-situ instruments deployed on board HALO have been performed. Over all flights of this campaign the median differences and median absolute deviations between in-situ and GLORIA observations are −0.75K±0.88K for temperature, −0.03ppbv±0.85ppbv for HNO3, −3.5ppbv±116.8ppbv for O3, −15.4pptv±102.8pptv for ClONO2, −0.13ppmv±0.63ppmv for H2O and −19.8pptv±46.9pptv for CFC-12. These differences are mainly within the expected performances of the cross-compared instruments. Events with stronger deviations are explained by atmospheric variability and different sampling characteristics of the instruments. Additionally comparisons of GLORIA HNO3 and O3 with measurements of the Aura Microwave Limb Sounder (MLS) instrument show highly consistent structures in trace gas distributions and illustrate the potential of the high spectral resolution limb-imaging GLORIA observations for resolving narrow mesoscale structures in the UTLS.

Description: The "HD(CP)2 Observational Prototype Experiment" (HOPE) was executed as a major 2-month field experiment in Jülich, Germany, performed in April and May 2013, followed by a smaller campaign in Melpitz, Germany in September 2013. HOPE has been designed to provide a critical evaluation of the new German community atmospheric Icosahedral non-hydrostatic (ICON) model at the scale of the model simulations and further to provide information on land-surface-atmospheric boundary layer exchange, cloud and precipitation processes as well as on sub-grid variability and microphysical properties that are subject to parameterizations. HOPE focuses on the onset of clouds and precipitation in the convective atmospheric boundary layer. The paper summarizes the instrument set-ups, the intensive observation periods as well as example results from both campaigns. HOPE-Jülich instrumentation included a radio sounding station, 4 Doppler lidars, 4 Raman lidars (3, 3, and 4 of these provide temperature, water vapor, and particle backscatter data, respectively), 1 water vapour differential absorption lidar, 3 cloud radars, 5 microwave radiometers, 3 rain radars, 6 sky imagers, 99 pyranometers, and 5 Sun photometers operated in synergy at different supersites. The HOPE-Melpitz campaign combined ground-based remote sensing of aerosols and clouds with helicopter- and balloon-based in-situ observations in the atmospheric column and at the surface. HOPE provided an unprecedented collection of atmospheric dynamical, thermodynamical, and micro- and macrophysical properties of aerosols, clouds and precipitation with high spatial and temporal resolution within a cube of approximately 10 × 10 × 10 km3. HOPE data will significantly contribute to our understanding of boundary layer dynamics and the formation of clouds and precipitation. The datasets are made available through a dedicated data portal.

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

Description: Background: The addition of sorafenib to standard induction and consolidation therapy in newly diagnosed patients (pts) ≤60 years (yrs) with acute myeloid leukemia (AML) led to significant prolongation of event-free survival (EFS) and relapse-free survival (RFS) in the randomized placebo-controlled SORAML trial (NCT00893373). After a median follow-up of 3 yrs, a benefit for sorafenib treated pts was observed also in overall survival (OS), but this difference was not significant. Here, we present updated survival data and information on relapse treatment and outcome. Methods: In the SORAML trial, 267 newly diagnosed untreated fit AML pts up to 60 yrs of age and irrespective of FLT3 mutation status received two cycles of induction chemotherapy with DA (daunorubicin 60 mg/m2 days 3-5 plus cytarabine 100 mg/m2 cont. inf. days 1-7), followed by three cycles of high-dose cytarabine consolidation (3 g/m2 b.i.d. days 1, 3, 5). Allogeneic stem cell transplantation (SCT) was scheduled for all intermediate-risk pts in first complete remission (CR) with a sibling donor and for all high-risk pts with a matched related or unrelated donor. At study inclusion, pts were randomized to receive either sorafenib (2x400 mg/day) or placebo as add-on to standard treatment in a double blinded fashion. Study medication was given on days 10-19 of DA I+II, from day 8 of each consolidation until 3 days before the start of the next consolidation and as maintenance for 12 months (mos) after the end of consolidation. The primary endpoint of the trial was EFS. The results after follow-up of 3 yrs were presented at ASH 2014 (Röllig et al., Blood 2014; 124: 6) and fully published (Röllig et al., Lancet Oncol 2015; 16: 1691-9). Here, we present the results after prolonged follow-up. For this analysis, information on remission and survival status, mode and outcome of relapse treatment including SCT were collected for all randomized pts and analyzed by standard statistical methods. Results: Of 267 treated pts, 134 were randomized in the sorafenib arm and 133 in the placebo arm with a resulting CR rate of 60% and 59%, respectively. After a median observation time of 78 mos, the primary study endpoint EFS in the placebo vs sorafenib arm was 9 mos vs 26 mos (HR 0.68, p=0.01) in univariate Kaplan Meier analysis. The beneficial effect of sorafenib on EFS was confirmed in multivariate Cox regression analysis with a HR of 0.61 (p=0.005). Median RFS in the placebo vs sorafenib arms was 22 vs 63 mos, corresponding to a HR of 0.64 (p=0.033). Exploratory analyses were performed in the 70 relapsing pts (40 after placebo vs 30 after sorafenib treatment). Among relapsing pts, 82% vs 73% achieved a second CR. In these two groups, 88% and 87% of pts received a SCT as part of salvage treatment. A lower proportion of pts in the placebo arm received a second SCT as salvage treatment (5% vs 13%). In the context of salvage SCT, the proportion of haploident donors in the placebo and sorafenib group was 3% vs 15% and the incidence of Grade 3/4 GVDH was 17% vs 0%. SCT-related non-relapse mortality (NRM) was similar in both groups, but the cumulative incidence of second relapse (CIR) was higher in the sorafenib group (35% vs 54% after 48 mos). Therefore, median OS from relapse in the placebo vs sorafenib groups were 27 mos vs 10 mos, corresponding to a HR of 1.68 (p=0.098). The projected median OS from randomization is 83 mos in the placebo arm and was not reached for the sorafenib arm, corresponding to a 5-year OS of 52% vs 61% (HR 0.81, p=0.263). Conclusion: Mature follow-up data confirms the antileukemic efficacy of sorafenib in younger AML pts with and without FLT3 mutation. The addition of sorafenib to standard chemotherapy resulted in a significantly longer EFS and clinically relevant 36% risk reduction for relapse or death. Five pts need to be treated (NNT) to prevent one relapse or death at 3 years and six pts at 5 yrs. Exploratory analyses in relapsing pts show that survival after relapse is shorter after sorafenib which might be due to i) a higher rate of second SCTs and a higher incidence of haploidentical SCT despite the lower frequency of severe GVHD, most likely by chance and not explainable by systematic reasons and ii) a lower response to salvage treatment after sorafenib therapy. Despite these observations, primary sorafenib treatment led to an OS benefit with a 19% risk reduction for death which was not statistically significant since this phase II trial was not adequately powered to detect OS differences. Figure Figure. Disclosures Rollig: Bayer: Research Funding; Janssen: Research Funding. Hüttmann: Gilead, Amgen: Other: Travel cost; Bristol-Myers Squibb, Takeda, Celgene, Roche: Honoraria. Giagounidis: Acceleron: Consultancy; Celgene: Consultancy. Mackensen: AMGEN: Research Funding. Hänel: Roche: Honoraria; Novartis: Honoraria. Thiede: Roche: Consultancy; Novartis: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Agendix: Employment. Schetelig: Sanofi Aventis: Consultancy, Research Funding; Roche: Honoraria; Abbvie: Honoraria; Janssen: Consultancy, Honoraria.

Description: The science guiding the EUREC4A campaign and its measurements is presented. EUREC4A comprised roughly 5 weeks of measurements in the downstream winter trades of the North Atlantic – eastward and southeastward of Barbados. Through its ability to characterize processes operating across a wide range of scales, EUREC4A marked a turning point in our ability to observationally study factors influencing clouds in the trades, how they will respond to warming, and their link to other components of the earth system, such as upper-ocean processes or the life cycle of particulate matter. This characterization was made possible by thousands (2500) of sondes distributed to measure circulations on meso- (200 km) and larger (500 km) scales, roughly 400 h of flight time by four heavily instrumented research aircraft; four global-class research vessels; an advanced ground-based cloud observatory; scores of autonomous observing platforms operating in the upper ocean (nearly 10 000 profiles), lower atmosphere (continuous profiling), and along the air–sea interface; a network of water stable isotopologue measurements; targeted tasking of satellite remote sensing; and modeling with a new generation of weather and climate models. In addition to providing an outline of the novel measurements and their composition into a unified and coordinated campaign, the six distinct scientific facets that EUREC4A explored – from North Brazil Current rings to turbulence-induced clustering of cloud droplets and its influence on warm-rain formation – are presented along with an overview of EUREC4A's outreach activities, environmental impact, and guidelines for scientific practice. Track data for all platforms are standardized and accessible at https://doi.org/10.25326/165 (Stevens, 2021), and a film documenting the campaign is provided as a video supplement.

Description: Cell adhesion in the multiple myeloma (MM) microenvironment is a mechanism by which MM plasma cells escape the effects of therapy and survive. To improve clinical strategies and overcome drug resistance, approaches directed to both MMPCs and bone marrow microenvironment are under investigation. Here, we examined the cell membrane protein Junctional adhesion molecule-A (JAM-A) as a clinical biomarker and novel therapeutic target for MM. We evaluated JAM-A expression by real time PCR (RT-PCR), flow cytometry and immunofluorescence microscopy in 132 MM patients at different stages and various MM cell lines. Next, we measured the concentrations of soluble JAM-A from MM and healthy subjects sera by enzyme linked immune assay (ELISA). We investigated JAM-A functionally in vitro and in vivo by transient gene silencing (siRNA) and with blocking antibodies. Patient-derived plasma cells (MMPCs) expressed increased JAM-A expression levels when compared to control PC from healthy individuals. Elevated JAM-A expression correlated with poor prognosis (Figure 1A,B). Furthermore, soluble JAM-A was significantly increased in MM patient sera when compared to healthy subjects. Additionally, MM cell lines showed high expression of both membrane and cytoplasmic JAM-A. Consequently, inhibition of JAM-A using specific siRNA treatment resulted in diminished tumorigenic potential, including decreased colony formation, chemotaxis and migration. Importantly, treatment of luciferase+RPMI-8226 MM bearing NSG with a JAM-A blocking monoclonal antibody reduced significantly MM progression and dissemination in vivo when compared to MM bearing mice that received an non-specific isotype control antibody (Figure 1C). Conclusively, our data suggest that JAM-A can serve as a biomarker of malignancy in MM patients. Soluble plasma JAM-A could contribute to serum-based clinical stratification. Furthermore, therapeutic targeting of JAM-A appears attractive for clinical translation. Figure 1 Figure 1. Disclosures Einsele: Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria.