Journal articles on the topic 'Duo mei ti'

In this paper, the preparation of Ni–Ti–Nb amorphous alloy materials made by mechanical alloying method has been studied. The Ni–Ti–Nb mixed powders obtained by different mechanical alloying times have been analyzed by X-ray diffraction (XRD) and scanning electron microscopy (SEM). The results show that the Ni–Ti–Nb mixed powders can be mechanically alloyed after milling for 10 hours, and retained with ball milling. Continuously, Ni, Ti and Nb alloy powders diffuse with each other. When the diffusion rate increases to a certain extent, it is too late to form an ordered structure and form a Ni–Ti–Nb amorphous alloy. The stress and displacement curves are obtained by testing the tensile strength at room temperature. The stress changes of the restrained curves are relatively stable when the displacement is 6–18 mm, and the stress changes of the unconstrained curves show a distinct upward trend when the displacement is 6–18 mm, indicating that the strength of the specimens treated with restraint is higher than that of the specimens treated with restraint. This is due to the high internal stress of the material caused by the restraint and the decrease in the tensile strength of the alloy material.

A novel lightweight Al-Ti-Cr-Mn-V medium-entropy alloy (MEA) system was developed using a nonequiatiomic approach and alloys were produced through arc melting and drop casting. These alloys comprised a body-centered cubic (BCC) and face-centered cubic (FCC) dual phase with a density of approximately 4.5 g/cm3. However, the fraction of the BCC phase and morphology of the FCC phase can be controlled by incorporating other elements. The results of compression tests indicated that these Al-Ti-Cr-Mn-V alloys exhibited a prominent compression strength (~1940 MPa) and ductility (~30%). Moreover, homogenized samples maintained a high compression strength of 1900 MPa and similar ductility (30%). Due to the high specific compressive strength (0.433 GPa·g/cm3) and excellent combination of strength and ductility, the cast lightweight Al-Ti-Cr-Mn-V MEAs are a promising alloy system for application in transportation and energy industries.

1. Introduction Various carbon materials are currently used in PEFCs.1,2 In particular, relatively expensive porous carbon materials such as carbon fiber cloth and carbon paper with a thickness of around 0.2 mm are commonly used as the gas diffusion layers (GDLs), which ensure gas flow, electron transport, and water management in fuel cells.3,4 However, electrical conductivity of these carbon materials could be lower than that of metallic materials. Another technical issue is the reduction of GDL thickness to achieve higher power density per cell stack volume, which could however lead to a decrease in mechanical strength of GDLs.5 Here in this study, we evaluate and compare several types of metallic materials to apply as GDLs. Using such alternative metallic GDLs, current-voltage (I-V) characteristics were measured and overvoltages were separated. The purpose of this study is to examine possibilities of using metallic GDLs for PEFCs, by varying materials, thickness, porosity, and preparation conditions. 2. Experimental Ti fiber sheets and stainless steel mesh sheets were used as GDL substrates, and Sn coating was made on the sheets. Then, current-voltage characteristics of the cells using these GDLs were evaluated. Five types of porous metallic sheets were used as GDLs: (i) Ti fiber sheet with a porosity of 70% and thickness of 100 μm, (ii) Ti fiber sheet with Sn plating layer (Sn/Ti sheet), (iii) Ti fiber sheet with Pt nanoparticles and Sn plating layer (Sn/Pt/Ti sheet), (iv) SUS316 mesh with a porosity of 60% and thickness of 32 μm, and (v) SUS316 mesh with porous Sn layer. For all the evaluations, the electrocatalyst layers were prepared by dispersing Pt/C (Pt 46.5%, TEC10E50E, Tanaka Kikinzoku Kogyo Corp., Japan), 99.5% ethanol, pure water, and 5% Nafion solution using an ultrasonic homogenizer. The dispersions were printed on the electrolyte membrane (Nafion 212) using a spray printer (C-3 J, Nordson). The electrode area was 1.0 cm2 (1.0 cm × 1.0 cm), and the Pt loading on both electrodes was 0.3 mg-Pt cm-2. The metallic GDL was used for the cathode, and a carbon paper (EC-TPI-060T) was used as the standard GDL for the anode. In the electrochemical characterization of this study, electrochemical impedance spectroscopy (EIS, 1255WB, Solatron) was applied to measure the current-voltage characteristics and to separate overvoltages. 3. Results and discussion I-V characteristics of the cells with the MEAs (i) to (v) are shown in Figure 1. Decrease in cell performance was mainly caused by an increase in ohmic losses. Comparing the MEA (i) and the MEA (iv), Ti fiber sheet showed higher electrical conductivity than stainless steel mesh sheet. Comparing the MEA (i) and the MEA (ii), it was confirmed that the Sn plating on the Ti fiber contributed to a reduction of ohmic loss and concentration overvoltage. Furthermore, the current-voltage curve of the MEA (iii) indicates higher conductivity than that of the MEA (ii), suggesting that the Pt coating promoted the Sn plating or acted as catalysts on the electrocatalyst layer side during the operation of the cell. When the SUS316 mesh sheet was used for the MEA (iv), the concentration overvoltage tended to fluctuate in each measurement. For the MEA (v), a decrease in cell performance was observed. These could be caused by, e.g., degradation of stainless steel due to strong acidity, and contact resistance between the Sn porous layer and the mesh sheet. Further study is in progress to improve I-V characteristics of MEAs by optimizing materials and structure of metallic GDLs. Acknowledgement Financial support from New Energy and Industrial Technology Development Organization (NEDO) is gratefully acknowledged (Contract No. 20001214-0). References Takahashi, T. Ikeda, K. Murata, O. Hotaka, S. Hasegawa, Y. Tachikawa, M. Nishihara, J. Matsuda, T. Kitahara, S. M. Lyth, A. Hayashi, and K. Sasaki, J. Electrochem. Soc., 169, 044523 (2022). Larminie, and A. Dicks, Fuel Cell Systems Explained, John Wiley & Sons, (2006). Kitahara, T. Konomi, H. Nakajima, and J. Shiraishi, kikaib, 76(761), 101 (2010). A. Reiser, L. Bregoli, T. W. Patterson, J. S. Yi, D. Yang, M. L. Perry, and T. D. Jarvi, Electrochem. Solid-State Lett., 8, A273 (2005). N. Hussain, E. V. Steen, S. Tanaka, and P. Levecque, J. Power Sources, 337, 18 (2017).

Porous IrO2/Ti/IrO2 catalyst electrodes were obtained by coating IrO2 on both sides of three types of porous Ti powder sheets (sample 1, sample 2, and sample 3) using different surface treatment methods, and a hydrogen evolution catalyst electrode was obtained by coating Pt/C on carbon gas diffusion layers. A Nafion115 membrane was used as an electrolyte for the membrane electrode assemblies (MEA). Water electrolysis was investigated at cell temperatures up to 150 °C, and the electrical characteristics of the three types of porous IrO2/Ti/IrO2 catalyst electrodes were investigated. The sheet resistance of sample 1 was higher than those of samples 2 and 3, although during water electrolysis, a high current density was observed due to the nanostructure of the IrO2 catalyst. In addition, the structural stabilities of Nafion and Aquivion membranes up to 150 °C were investigated by using small angle X-ray scattering (SAXS). The polymer structures of Nafion and Aquivion membranes were stable up to 80 °C, whereas the crystalline domains grew significantly above 120 °C. In other words, the initial polymer structure did not recover after the sample was heated above the glass transition temperature.

A low density, medium entropy alloy (LD-MEA) Ti33Al33V34 (4.44 g/cm3) was successfully developed. The microstructure was found to be composed of a disordered body-centered-cubic (BCC) matrix and minor ordered B2 precipitates based on transmission electron microscopy characterization. Equilibrium and non-equilibrium modeling, simulated using the Calphad approach, were applied to predict the phase constituent. Creep behavior of {110} grains at elevated temperatures was investigated by nanoindentation and the results were compared with Cantor alloy and Ti-6Al-4V alloy. Dislocation creep was found to be the dominant mechanism. The decreasing trend of hardness in {110} grains of BCC TiAlV is different from that in {111} grains of face-centered-cubic (FCC) Cantor alloy due to the different temperature-dependence of Peierls stress in these two lattice structures. The activation energy value of {110} grains was lower than that of {111} grains in FCC Cantor alloy because of the denser atomic stacking in FCC alloys. Compared with conventional Ti-6Al-4V alloy, TiAlV possesses considerably higher hardness and specific strength (63% higher), 83% lower creep displacement at room temperature, and 50% lower creep strain rate over the temperature range from 500 to 600 °C under the similar 1150 MPa stress, indicating a promising substitution for Ti-6Al-4V alloy as structural materials.

The superalloy FGH98 was successfully diffusion bonded (DB) with medium-entropy alloy (MEA) Al3Ti3(CrCoNi)94 using pure Ni as the interlayer at a temperature range of 1050–1170 °C for 1 h under 5 MPa. The microstructure and mechanical properties of joints were investigated. The diffusion bonding seam was composed of an interlayer zone (IZ) and two diffusion-affected zones (DAZ). The IZ and DAZ beside the FGH98 consisted of cubic Ni3(TiAl)-type γ′ phases due to the diffusion of Ti and Al atoms. Meanwhile, the DAZ adjacent to the MEA consisted of spherical γ′ phases. Both of the γ′ phases with different morphology kept the coherent relationship with the matrix. Moreover, increase of bonding temperature led to the morphology of interlayer γ′ phase to transform from sphere to cube. Due to the strengthening effect of a mass of γ′ phase distributed evenly in IZ and the DAZ beside the FGH98, the microhardness and Young’s modulus of these two zones were higher than that of DAZ near the MEA. The maximum shear strength of DB joint, 592 MPa, was achieved in the joint bonded by 1150 °C, which was the typical ductile fracture feature confirmed by the shear dimples.

Abstract. This study reports the only recent characterization of two contrasted wet deposition events collected during the PEACETIME (ProcEss studies at the Air–sEa Interface after dust deposition in the MEditerranean Sea) cruise in the open Mediterranean Sea (Med Sea) and their impact on trace metal (TM) marine stocks. Rain samples were analysed for Al, 12 TMs (Co, Cd, Cr, Cu, Fe, Mn, Mo, Ni, Pb, Ti, V and Zn) and nutrient (N, P, dissolved organic carbon) concentrations. The first rain sample collected in the Ionian Sea (Rain ION) was a typical regional background wet deposition event, whereas the second rain sample collected in the Algerian Basin (Rain FAST) was a Saharan dust wet deposition event. Even in the remote Med Sea, all background TM inputs presented an anthropogenic signature, except for Fe, Mn and Ti. The concentrations of TMs in the two rain samples were significantly lower compared to concentrations in rains collected at coastal sites reported in the literature, due to the decrease in anthropogenic emissions during the preceding decades. The atmospheric TM inputs were mainly dissolved forms, even in dusty Rain FAST. The TM stocks in the mixed layer (ML, 0–20 m) at the FAST station before and after the event showed that the atmospheric inputs were a significant supply of particulate TMs and dissolved Fe and Co for surface seawater. Even if the wet deposition delivers TMs mainly in soluble form, the post-deposition aerosol dissolution could to be a key additional pathway in the supply of dissolved TMs. At the scale of the western and central Mediterranean, the atmospheric inputs were of the same order of magnitude as ML stocks for dissolved Fe, Co and Zn, highlighting the role of the atmosphere in their biogeochemical cycles in the stratified Med Sea. In case of intense dust-rich wet deposition events, the role of atmospheric inputs as an external source was extended to dissolved Co, Fe, Mn, Pb and Zn. Our results suggest that the wet deposition constitutes only a source of some of dissolved TMs for Med Sea surface waters. The contribution of dry deposition to the atmospheric TM inputs needs to be investigated.

Abstract Lenalidomide was approved by the US Food and Drug Administration in December of 2005 for the treatment (tx) of transfusion-dependent anemia (TDA) in patients (pts) with MDS and chromosome 5q deletions (del5q). In the trial that secured the approval, 67% of 148 pts achieved red blood cell (RBC) transfusion independence (TI) with a median time to TI of 44 weeks. 90% of pts who achieved TI did so by completion of 3 months of therapy. In a companion study (MDS-002) pts lacking del5q the frequency of TI was only 26%. We report three cases of IPSS Low risk myelodysplasia MDS with a delayed response to lenalidomide. The patient characteristics are outlined in Table 1. Following a 6 to 11 month trial of lenalidomide for TDA in IPSS Low risk MDS delayed TI can occur 1 to 4 months after discontinuation of lenalidomide. Delayed TI was not associated with a cytogenetic response. The duration of response can last from 11 months to 16 months. Lenalidomide, a thalidomide analogue, is an immunomodulatory agent with anti-angiogenic and anti-neoplastic properties. Effects of lenalidomide such as increased production of interleukin-2 and interferon-γ have been linked to the appearance of lymphoid aggregates of a mixture of B and T cells in the BM specimens of responders. TI has previously been correlated with suppression of the del5q clone. In our patients, TI was achieved after discontinuation of lenalidomide following a reasonable ineffective trial and no apparent suppression of the del5 clone. A similar phenomenon was described by Raza, et al. in a single MDS patient treated with thalidomide. Interestingly, one patient had lymphoid aggregates of B and T cells throughout treatment, raising the possibility that the immune stimulatory effects of lenalidomide may be a variable against the del5q clone. The transient response may be due to immunomodulatory effects but persistence of the del5q clone in two of our patients and and dysplasia in the other, is responsible for the relapse after the immune response has waned. Re-treatment with lenalidomide in our patient did not prolong or re-induce another response. References Giagounidis AAN, Germing U, Aul C: Biologic and prognostic significance of chromosome 5q deletions in myeloid malignancies. Clin Cancer Res 2006, 12:5–10. List A, Kurtin S, Roe DJ, et al.: Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005, 352:549–557. List A: Recent advances in the treatment of MDS. Clin Advances in Hematology. Oncology. 2007, Supp 10, Vol 5, Issue 7: 4–5 Raza A, Meyer P, Dutt D, et al. Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndromes. Blood. 2001 Aug 15, 98(4):958–65.

Abstract Background: Treatment options for RBC-TD pts with lower-risk MDS without del(5q) who are unresponsive or refractory to ESAs are very limited. In a previous phase 2 study, MDS-002 (CC-5013-MDS-002), LEN was associated with achievement of RBC-transfusion independence (TI) ≥ 56 days in 26% of pts with IPSS Low/Int-1-risk MDS without del(5q) (Raza et al. Blood 2008;111:86-93). This international phase 3 study (CC-5013-MDS-005) compared the efficacy and safety of LEN versus PBO in RBC-TD pts with IPSS Low/Int-1-risk MDS without del(5q) unresponsive or refractory to ESAs. Methods: This multicenter, randomized, double-blind, parallel-group phase 3 study included RBC-TD pts (≥ 2 units packed RBCs [pRBCs]/28 days in the 112 days immediately prior to randomization) with IPSS Low/Int-1-risk MDS without del(5q), who were unresponsive or refractory to ESAs (RBC-TD despite ESA treatment with adequate dose and duration, or serum erythropoietin [EPO] > 500 mU/mL). Pts were randomized 2:1 to oral LEN 10 mg once daily (5 mg for pts with creatinine clearance 40–60 mL/min) or PBO. Pts with RBC-TI ≥ 56 days or erythroid response by Day 168 continued double-blind treatment until erythroid relapse, disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was RBC-TI ≥ 56 days (defined as absence of any RBC transfusions during any 56 consecutive days). Secondary endpoints included time to RBC-TI, duration of RBC-TI, RBC-TI ≥ 168 days, progression to acute myeloid leukemia (AML; WHO criteria), overall survival (OS), and safety. Baseline bone marrow gene expression profiles were evaluated according to the Ebert signature (PloS Med 2008;5:e35) identified as predictive of LEN response. Clinical trial identifier: CT01029262. Results: The intent-to-treat population comprises 239 pts (LEN, n = 160; PBO, n = 79). Baseline characteristics were comparable across treatment groups; median age 71 years (range 43–87), 67.8% male, and median time from diagnosis 2.6 years (range 0.1–29.6). Pts received a median of 3.0 pRBC units/28 days (range 1.5–9.8) and 83.7% received prior therapy, including ESAs (78.7%). Significantly more LEN pts achieved RBC-TI ≥ 56 days versus PBO (26.9% vs 2.5%; P < 0.001; Table). The majority (90%) of pts with RBC-TI ≥ 56 days responded within 16 weeks of treatment. Median duration of RBC-TI ≥ 56 days was 8.2 months (range 5.2–17.8). Baseline factors significantly associated with achievement of RBC-TI ≥ 56 days with LEN were: prior ESAs (vs no ESAs; P = 0.005), serum EPO ≤ 500 mU/mL (vs > 500 mU/mL; P = 0.015), < 4 pRBC units/28 days (vs ≥ 4 pRBC units/28 days; P = 0.036), and female sex (vs male; P = 0.035). RBC-TI ≥ 168 days was achieved in 17.5% and 0% of pts in the LEN and PBO groups, respectively. The incidence of AML progression (per 100 person-years) was 1.91 (95% CI 0.80–4.59) and 2.46 (95% CI 0.79–7.64) for LEN and PBO pts, respectively, with median follow-up 1.6 and 1.3 years. Death on treatment occurred in 2.5% of pts on either LEN or PBO. The follow-up period was insufficient to permit OS comparison between the 2 groups. Myelosuppression was the main adverse event (AE); in the LEN versus PBO groups, respectively, grade 3–4 neutropenia occurred in 61.9% versus 11.4% of pts, and grade 3–4 thrombocytopenia in 35.6% versus 3.8% of pts. Discontinuations due to AEs were reported in 31.9% LEN and 11.4% PBO pts; among the 51 LEN pts who discontinued due to AEs, 14 discontinuations were due to thrombocytopenia and 8 due to neutropenia. In the subset of pts evaluated for the Ebert signature (n = 203), the predictive power of the signature was not confirmed. Conclusions: LEN therapy was associated with a significant achievement of RBC-TI ≥ 56 days in 26.9% of pts with a median duration of RBC-TI of 8.2 months; 90% of pts responded within 16 weeks of treatment. These data were consistent with response rates seen in the MDS-002 trial. The overall safety profile was consistent with the known safety profile of LEN and these data suggest LEN can be safely and effectively used in this patient population. Figure 1 Figure 1. Disclosures Santini: Celgene Corporation: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Glaxo Smith Kline: Honoraria. Off Label Use: Trial of Lenalidomide in non-del5q MDS. Almeida:Celgene Corporation: Consultancy, Speakers Bureau. Giagounidis:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Vey:Celgene: Honoraria. Mufti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Buckstein:Celgene: Research Funding. Mittelman:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Platzbecker:Celgene: Research Funding. Shpilberg:Celgene Corporation: Consultancy, Honoraria. del Canizo:Celgene Corporation: Consultancy, Research Funding. Gattermann:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Ozawa:Celgene: Consultancy, not specified Other. Zhong:Celgene: Employment, Equity Ownership. Séguy:Celgene: Employment, Equity Ownership. Hoenekopp:Celgene: Employment, Equity Ownership. Beach:Celgene: Employment, Equity Ownership. Fenaux:Novartis: Research Funding; Janssen: Research Funding; Celgene: Research Funding.

Abstract Background. Factors that determine net synthesis of hepcidin and hence iron absorption and distribution depend on a balance of competing factors which may be disease specific. Such factors include anemia, ineffective erythropoiesis (IE), transferrin saturation (Tf sat), iron overload and inflammation. Recently GDF-15, a marker of erythroid maturation and hence IE, has been linked with depression of hepcidin synthesis in vitro and showed elevated levels in beta thalassemia (Tanno et al, Nat Med, 2007). The relationship of hepcidin synthesis to iron overload in sickle cell disease (SCD) is not clear and may differ from thalassemia syndromes because IE is less marked. We wished to establish whether the dominant factors determining net hepcidin synthesis differed between patients with SCD and those with thalassemia intermedia (TI) and thalassemia major (TM). Patients and methods. Serum hepcidin was measured in hypertransfused (Hb&gt;9.5g/dl) patients with TM (n=18), untransfused or sporadically transfused patients with thalassemia intermedia TI (n=18), and multi-transfused patients with SCD (n=24), and related to markers of anemia, iron overload and erythroid expansion. A newly developed mass spectrometry assay (Bansal et al, Anal Biochem, 2008, In Press) was used to determine serum hepcidin. GDF-15 was measured by an ELISA assay. Multivariate analysis was performed using SIMCA-P software and partial least squares for discriminant analysis (PLS-DA), using samples from each of the clinical groups to investigate relationships between hepcidin, serum iron, non-transferrin bound iron (NTBI), transferrin saturation (Tf sat), serum ferritin, liver iron, transfusion history, erythropoietin, hemoglobin and GDF-15. Results. Serum hepcidin levels were higher in TM (13.9 ± 10.0 nmol/L) than SCD (8.51±8.16 nmol/L, p=0.043) whereas values in TI (3.82 ±3.56 nmol/L) were close to healthy controls (4.04 ± 2.06nmol/l). However, when SCD patients were matched for levels of anemia and iron load with TM, plasma hepcidin levels were similar or higher in SCD. GDF-15 values were highest for TI (11,444± 2177 ng/l), than TM (4117 ± 577 ng/l, P&lt;0.001), whilst SCD patients had the lowest values (1227 ± 208 ng/l, P&lt;0.001 vs TM). Univariate analysis in all patients grouped together showed positive correlations of hepcidin with serum ferritin (r=0.55, p &lt;0.0001) and level of anemia (r=0.27, p= 0.045). Disease specific relationships were identified: negative correlations of serum hepcidin with Tf sat (r=−0.43) and NTBI (r=−0.45) were found for TI and TM but not in SCD, whereas ferritin showed a positive correlation in TM and SCD (r=0.51 and r= 0.56) but not in TI. GDF-15 correlated negatively with hepcidin in TI (r=0.51) but showed no relationship in SCD or TM. Positive correlations of GDF-15 with markers of plasma iron metabolism were seen in TI such as serum iron (r= 0.56), NTBI (r=0.45) and transferrin saturation (r=0.45). These were not seen in TM and tended to be negative relationships (r= −0.45, r= 0.25, r=0.59 respectively). In multivariate analysis, the variables responsible for the separation of the 3 patient groups clustered in 3 major categories including iron handling (serum iron, transferrin saturation, NTBI), ineffective erythropoiesis (GDF-15) and iron loading (ferritin, transfusion history). Hepcidin co-clustered with the iron loading group and was inversely correlated with GDF-15. Conclusion. Competing regulatory effects on hepcidin synthesis differ between TM, TI and SCD. In TI, hepcidin synthesis is suppressed by IE as shown by a dominant effect of GDF-15. In TM, GDF-15 effects on plasma hepcidin are less marked, as IE is lower due to hypertransfusion. This difference is particularly striking in patients at UCLH due to the divergent transfusion policies between TI and TM. The dominant modulating factors in TM are positive relationships to iron load (serum ferritin) but negative relationship with NTBI, serum iron and Tf saturation. However it is not yet clear whether the relationship of NTBI to hepcidin implies direct negative regulatory effect. In multi-transfused SCD patients, GDF-15 (IE) and NTBI have insignificant relationships to plasma hepcidin, with iron load (ferritin) showing the dominant effect: other effects in SCD such as those of chronic inflammation were not examined but require further investigation.

Abstract Introduction The efficacy and safety of LEN in RBC transfusion-dependent pts with International Prognostic Scoring System (IPSS) Low- or Intermediate (Int)-1-risk MDS with del(5q) was assessed in 2 large, multicenter studies (MDS-003 [List A, et al. N Engl J Med. 2006;355:1456-65] and MDS-004 [Fenaux P, et al. Blood. 2011;118:3765-76]). RBC-TI for ≥ 8 weeks and CyR was achieved in 51–67% and 25–73% of pts treated with LEN, respectively. In a multivariate analysis, achievement of RBC-TI ≥ 26 weeks with LEN was associated with a significantly reduced risk of acute myeloid leukemia (AML) progression and death (MDS-004). To further understand the effects of LEN in lower-risk del(5q) MDS pts treated in the MDS-003 and MDS-004 studies, we analyzed the association of CyR with RBC-TI ≥ 26 weeks and AML-free survival. Methods Of the 286 pts from the MDS-003 and MDS-004 studies who received LEN from study start, 181 were evaluable for both CyR and RBC-TI ≥ 26 weeks, and included in the current analysis (88 pts from MDS-003 and 93 pts from MDS-004). Cytogenetic studies by central review were performed at baseline, and at weeks 24 and 48 (MDS-003); or at week 24 and every 24 weeks thereafter (MDS-004). CyR rates were assessed using International Working Group 2000 criteria and compared with rates of RBC-TI ≥ 26 weeks. CyR and AML-free survival (Kaplan-Meier method) were assessed by baseline cytogenetic complexity [isolated del(5q), del(5q) + 1 additional abnormality, and del(5q) + > 1 additional abnormality]. A univariate Cox proportional hazards model identified factors associated with AML-free survival. CyR and RBC-TI ≥ 26 weeks were included as time varying covariates, and IPSS-R was included as a categorical variable. A best multivariate model was chosen by fitting all possible models, including all covariates with P < 0.1 in the univariate model, and using the Akaike information criterion. Results Of the 181 pts, 130 had isolated del(5q), 32 had del(5q) + 1 additional abnormality, 14 had del(5q) + > 1 additional abnormality, and 5 pts had missing cytogenetics at baseline. Median age was 68 years (range 36–89) and 73% of pts were female. Median baseline hemoglobin level was 8.0 g/dL (range 3.6–11.0) and median RBC transfusion burden was 6 units/8 weeks (range 1.0–25.0). A total of 103 pts (56.9%) achieved a CyR (complete + partial response). The likelihood of a CyR was increased in pts who achieved RBC-TI ≥ 26 weeks compared with those who did not: 71% versus 29%, respectively (hazard ratio [HR] 2.3; 95% confidence interval 1.56–3.41). RBC-TI ≥ 26 weeks preceded CyR, with median times to RBC-TI ≥ 26 weeks and CyR of 29 days (range 2–343) and 148 days (range 56–707), respectively. However, this may have been dependent on the timing of bone marrow aspirates. CyR rates were comparable across the isolated del(5q) and del(5q) + 1 additional abnormality groups (59% vs 63%; P = 0.736), but lower in the del(5q) + > 1 additional abnormality group compared to these 2 groups combined (29% vs 60%; P = 0.023) (Table). In pts with isolated del(5q) and del(5q) + 1 additional abnormality, CyR was associated with a 41% (P = 0.019) and 58% (P = 0.056) reduction, respectively, in the risk of AML or death compared with no CyR. In all cytogenetic groups, median AML-free survival was longer in those who achieved CyR compared with non-responders, although it was not statistically significant in pts with del(5q) + > 1 additional abnormality (Table). In a multivariate Cox proportional hazard model, factors associated with AML-free survival were CyR (HR 0.58; P = 0.023), RBC-TI ≥ 26 weeks (HR 0.34; P < 0.0001), lower IPSS-R categorization (P = 0.018), female gender (HR 0.44; P = 0.0004), and younger age (HR 1.03 for each additional year; P = 0.008). Conclusion In IPSS-defined Low- or Int-1-risk MDS pts with del(5q), achievement of CyR with LEN was associated with a RBC-TI ≥ 26 weeks response and a reduced risk of AML or death in pts with isolated del(5q) and del(5q) + 1 abnormality. Due to small sample size, further studies are needed to evaluate the effect of LEN in the del(5q) + > 1 additional abnormality group. These data provide evidence for LEN as a disease-modifying agent in RBC transfusion-dependent pts with Low- or Int-1-risk MDS and del(5q). Disclosures: Sekeres: Celgene: Membership on an entity’s Board of Directors or advisory committees; Amgen: Membership on an entity’s Board of Directors or advisory committees. Swern:Celgene: Employment, Equity Ownership. Giagounidis:Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. List:Celgene: Serve on Celgene Data Safety & Monitoring Committee Other. Schlegelberger:Celgene: Consultancy. Fenaux:Celgene: Honoraria. Shiansong Li:Celgene: Employment, Equity Ownership. Sugrue:Celgene: Employment, Equity Ownership.

Hvordan håndterer vi negative emotioner, og hvordan påvirker det konflikter i nære relationer? Tilknytningsteorien er velegnet som en ramme til at beskrive og forstå, hvordan voksne håndterer emotioner og konflikter i parforholdet. Artiklen evaluerer på baggrund af en systematisk litteratursøgning den nyeste forskning, der er publiceret i perioden 2000 – 2015, og som undersøger sammenhængen mellem voksnes tilknytningsmønstre (AAI) og den måde, som voksne håndterer konflikter i parforholdsrelationen. Ti studier opfyldte inklusionskriterierne. Reviewet viste, at i ni ud af ti studier har tilknytningsmønsteret betydning for konfliktadfærden i parforholdet. Således at utrygt tilknyttede viser en mere negativ adfærd, såsom kritik og afvisninger, hvor trygt tilknyttede viser en mere positiv adfærd, såsom empati og åbenhed. Desuden vil utrygt tilknyttede vise en mindre effektiv omsorgsadfærd, da utrygt tilknyttede er mindre bevidste om partnerens følelser og intentioner, hvor trygt tilknyttede vil respondere sensitivt og nøjagtigt på partnerens behov. Med det lave antal af inkluderede studier taget i betragtning, så ses der en tendens til, at tilknytningsmønsteret hos voksne i 30’erne guider konfliktadfærden i parforholdet. Tilknytningsteorien og den empiriske forskning i konfliktadfærd giver sundhedsprofessionelle indsigt i emotionelle processer og kan være med til at svare på, hvorfor nogle par sammenlignet med andre bliver fanget i uhensigtsmæssige strategier i konflikter. Det er relevant for den videre forskning at undersøge, om tilknytningsteoriens hypoteser kan generaliseres på tværs af generationer. Emotions and conflicts in adult close relationships: A systematic review of the impact of adult attachment on conflict behavior. How do we deal with negative emotions, and how do they affect conflicts in close relationships? Attachment theory is a suitable framework to describe and understand how adults handle emotions and conflicts in their relationships. This article is based on a systematic literature search identifying recent research, i.e., published from 2000 till 2015, which examines attachment pattern with the Adult Attachment Interview (AAI), and the way couples manage conflicts in their romantic relationships. The review shows that in nine out of ten studies the attachment pattern guides the couples’ behaviour during conflicts in romantic relationships. Insecurely attached couples showed more negative behaviour, such as criticism and rejection, whereas securely attached couples showed a more positive behaviour, such as empathy and openness. Likewise, insecurely attached couples showed less effective caregiving behaviour, whereas securely attached couples responded sensitively and accurately to the needs of their partners. Bearing in mind the small number of included studies, it is seen that there is a tendency for the attachment pattern in adults in their thirties to guide their behavior during conflicts in their relationships. Attachment theory and empirical research on conflict behavior give health professionals insight into emotional processes, and can help answer why some couples become trapped in inappropriate strategies during conflicts. Though there is a noticeable trend, there is a need for further research, due to the small number of studies.

Zveza Nato zajema različno večnacionalno okolje in najrazličnejše sisteme socialne podpore, saj večina družin nima na voljo infrastrukturne podpore, ki so je vajene. Družinam ob napotitvi v Natovo bazo prilagajanje na vojaško življenje, raznovrstnost kultur in jezik države gostiteljice zato pomeni izziv. Podpora in storitve vojaške skupnosti so lahko za vojaške družine še posebno koristne, saj je med napotitvami, ločenim življenjem in selitvami potreba po taki podpori večja. Namen prispevka je pripraviti pregled literature in poudariti pomen podpore skupnosti, storitev ter državnih programov, ki spodbujajo odpornost družine med življenjem v tujini, in kako se lahko ti zaščitni ukrepi uporabljajo za vse družine oboroženih sil. Ključne besede Odpornost, dobrobit, vojaška družina, podpora skupnosti, centri za podporo družinam, podporni programi in storitve. NATO encompasses a diverse multinational environment and wide-ranging social support systems as most families do not have the normal infrastructure support they are used to. Assignment to a NATO base presents a challenge as families navigate military life, a diverse culture and language of the host nation. Military community support and services may be particularly beneficial for military families due to the increased need of such support during deployments, separations, and relocations. The goal of this article is to review the existing literature and highlight the importance of community support, services, and state programs that foster family resilience while stationed overseas; and how these protective measures may be applied to all the families of the armed forces. Key words Resilience, well-being, military family, community support, family support center, support services and programs.

Polymer electrolyte membrane (PEM) water electrolysis is one of the most promising technologies which can integrate with renewable sources to produce sustainable hydrogen energy. Thin membranes were preferred for making membrane electrode assembly (MEA) for the PEM electrolyzer to increase cell efficiency. However, these membranes suffered from significant gas permeation consequently resulting in an explosion by the combination of hydrogen and oxygen, especially in the high-pressure operation. Many publications employed platinum as a recombination catalyst for reducing hydrogen concentration in the oxygen product stream to ensure safe operation [1-4]. Beside, Pt could be coated on oxidated Ti porous transport layer (PTL) to improve contact resistance between Iridium-based electrode and PTL [5]. In this work, a thin layer of platinum was sputtered on the surface of a low-loading anode (0.5 mgIr/cm2). Three MEAs prepared from commercial hydrous IrOx catalyst with 3 different loadings (1 mgIr/cm2, 2 mgIr/cm2and 3 mgIr/cm2) were used as reference. SEM images of Pt-sputtered MEA showed that the Pt layer had a thickness of approximately 80 nm corresponding to a loading of 0.4 mgPt/cm2. The electrochemical performance of Pt-sputtered MEA was significantly higher than that of bare MEA with 1 and 2 mgIr/cm2. The better performance of MEA with the presence of Pt is due to the improvement in contact resistance between the catalyst layer and PTL, in which lower HFR can be seen. In addition, its performance was comparable to high-loading MEA, while the total amount of precious metal was much lower (0.9 and 3 mg/cm2, respectively). The sputtered MEA also exhibited a slight difference in kinetic resistance compared to pristine MEA. On the other hand, the MEA with the addition of Pt shows a lower concentration of hydrogen in the oxygen product stream compared to pristine MEA at ambient pressure. [1] C. Klose et al., "Membrane interlayer with Pt recombination particles for reduction of the anodic hydrogen content in PEM water electrolysis," Journal of The Electrochemical Society, vol. 165, no. 16, p. F1271, 2018. [2] N. Briguglio, F. Pantò, S. Siracusano, and A. Aricò, "Enhanced performance of a PtCo recombination catalyst for reducing the H2 concentration in the O2 stream of a PEM electrolysis cell in the presence of a thin membrane and a high differential pressure," Electrochimica Acta, vol. 344, p. 136153, 2020. [3] S. Garbe, E. Samulesson, T. J. Schmidt, and L. Gubler, "Comparison of Pt-Doped Membranes for Gas Crossover Suppression in Polymer Electrolyte Water Electrolysis," Journal of The Electrochemical Society, vol. 168, no. 10, p. 104502, 2021. [4] A. Stähler, M. Stähler, F. Scheepers, W. Lehnert, and M. Carmo, "Scalable Implementation of Recombination Catalyst Layers to Mitigate Gas Crossover in PEM Water Electrolyzers," Journal of The Electrochemical Society, vol. 169, no. 3, p. 034522, 2022. [5] M. Bernt et al., "Effect of the IrOx Conductivity on the Anode Electrode/Porous Transport Layer Interfacial Resistance in PEM Water Electrolyzers," Journal of The Electrochemical Society, vol. 168, no. 8, p. 084513, 2021. Figure 1

Abstract Abstract 346 Background and Aims: Ineffective erythropoiesis in thalassemias and congenital dyserythropoietic anemia has been associated with hepcidin deficiency and spontaneous iron overload, potentially mediated by an abnormally high production of GDF-15, a cytokine overexpressed by maturing erythroblasts (Tanno et al. Nat Med 2007;13:1096–101; Tamary et al., Blood 2008; 112:5241–5244). In this study, we focused on analyzing hepcidin levels in different disorders affecting red cell production. Patients and Methods: Twenty patients with transfusion independent β-thalassemia intermedia (TI) were enrolled as a model of hemoglobinopathy with ineffective erythropoiesis, and were compared to 53 patients with sickle cell anemia (SCA), in which erythropoiesis is effective. Seventeen healthy volunteers and 13 patients with other anemic states with chronic hemolysis (hereditary spherocytosis, autoimmune hemolytic anemia, pyrimidine 5'-nucleotidase deficiency) were recruited for comparison. Fourteen patients with megaloblastic anemia due to cobalamin deficiency were studied before, during and after treatment as an alternative model of ineffective erythropoiesis. We have determined hepcidin levels as previously described (Ganz et al. Blood 2008;112:4292–4297), as well as serum ferritin, transferrin saturation (TS) and GDF-15 in all groups. Levels of C reactive protein (CRP) and IL-6, an inducer of hepcidin production, were also determined in controls, SCA and TI. Results and Discussion: IL-6 levels in SCA patients were increased [mean± standard error of mean (1.69±0.22pg/ml, p=0.047)] when compared to TI (1.33±0.21pg/ml) and controls (0.77±0.18pg/ml), and although there was a positive correlation between IL-6 and hepcidin levels (rS=0.25, p=0.039) this did not correspond to an absolute increase in hepcidin in this group. Indeed, circulating hepcidin levels were lower both in TI (56.24±12.14ng/ml) and SCA patients (52.53±10.97ng/ml) than in controls and other hemolytic anemias (80.23±14.3ng/ml and 120.7±12.2ng/ml, respectively, p=0.013), and did not correlate with the elevated levels of GDF-15 found in the 3 groups of patients (p>0.05). Ferritin levels correlated with both hepcidin and GDF-15 levels (rS=0.38, p=0.0005, and rS=0.63, p<0.0001, respectively). CRP correlated only weakly with IL-6 (rS=0.26, p=0.03) and was not significantly different among the groups studied. Ferritin and TS were considerably higher in TI patients than in the remaining groups (p=0.003). Ineffective erythropoiesis in cobalamin deficiency was neither associated with spontaneous ferritin or TS elevation, nor with decreased hepcidin in spite of high GDF-15 levels. Hepcidin levels at the time of diagnosis were higher than those in SCA (p<0.01) and decreased during vitamin B12 supplementation (108.8±23.36ng/ml vs. 59.37±16.23ng/ml, p=0.045). Hepcidin/ferritin ratios were significantly lower in SCA (28.91±3.08) and TI (13.76±3.98) than in controls and cobalamin deficiency (320.1±109.2 and 279.9±60.2, respectively, p<0.0001, graph represents minimum/maximum values and quartiles), better representing relative hepcidin deficiency in hemoglobin disorders than isolated hepcidin levels. Conclusions: Although both ineffective erythropoiesis and chronic hemolysis were associated with high levels of GDF-15 and low hepcidin in hemoglobinopathies as a result of erythroid compartment expansion, a similar pattern was not confirmed in other hemolytic anemias or megaloblastic anemia. In the latter case, ineffective erythropoiesis did not suppress hepcidin, and regulation of hepcidin production during recovery seemed intact and occurred independently from hepcidin-inhibitory GDF-15 production. Despite elevated IL-6 levels in SCA, chronic inflammation appeared insufficient to overcome the influence of the erythropoietic drive to increase overall hepcidin levels in these patients, but might explain why hepcidin/ferritin ratios in SCA are higher than in TI patients, and normal hepcidin/ferritin ratios corresponded to normal iron status in cobalamin deficiency patients. Our data suggest that hepcidin/ferritin ratio may be a more accurate measurement to detect patients prone to systemic iron overload secondary to increased erythropoietic activity, and corroborate the concept that chronic inflammation may protect SCA from overt iron overload to some extent. Disclosures: Olbina: Intrinsic LifeSciences LLC: Employment, Equity Ownership; Hepcidin C-ELISA: Co-developer. Westerman:Intrinsic LifeSciences LLC: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Hepcidin C-ELISA: Patents & Royalties; Centocor-Ortho R&D, Inc.: Honoraria.

Introduction: Anemia is the predominant cytopenia observed in patients with myelodysplastic syndromes (MDS), with many patients requiring regular red blood cell (RBC) transfusions. Erythropoiesis-stimulating agents (ESAs) remain a standard of care among patients with lower-risk MDS (LR-MDS), defined by International Prognostic Scoring System-Revised (IPSS-R) as Very Low-, Low-, or Intermediate-risk MDS, and endogenous serum erythropoietin (sEPO) levels ≤ 500 U/L. Recent studies of epoetin alfa and darbepoetin alfa have demonstrated efficacy among patients with LR-MDS, but the patient population in whom a clinically significant effect is seen may be limited (Fenaux P, et al. Leukemia 2018;32:2648-2658; Platzbecker U, et al. Leukemia 2017;31:1944-1950). A novel therapeutic option that increases the frequency of response and the duration of RBC transfusion independence (TI) in patients with LR-MDS would provide an important clinical benefit in this patient population. Luspatercept is a first-in-class erythroid maturation agent with a mechanism of action distinct from ESAs (Suragani RNVS, et al. Nat Med 2014;20:408-414). It is now approved in both the US and EU for patients with LR-MDS with ring sideroblasts (RS) who require RBC transfusions and are refractory, intolerant, or ineligible to receive ESAs on the basis of results from a phase 3 study (Fenaux P, Platzbecker U, et al. N Engl J Med 2020;382:140-151). Luspatercept may also be beneficial in treating anemia in patients with ESA-naive, LR-MDS who require RBC transfusions. In a phase 2 study in anemic patients with LR-MDS, 63% of patients receiving luspatercept (0.75-1.75 mg/kg) achieved a modified hematologic improvement - erythroid (mHI-E) response (Platzbecker U, et al. Lancet Oncol 2017;18:1338-1347); when analyzed by RS status, 69% of patients with ≥ 15% RS and 43% of patients with &lt; 15% RS achieved mHI-E response. Study Design and Methods: The COMMANDS trial is a phase 3, open-label randomized study to compare the efficacy and safety of luspatercept versus epoetin alfa in anemic patients with IPSS-R defined LR-MDS, either with or without ≥ 15% RS, who are ESA naive, and who require regular RBC transfusions. Eligible patients must be aged ≥ 18 years at time of consent, have a documented diagnosis of IPSS-R defined LR-MDS with &lt; 5% blasts in the bone marrow, have sEPO levels &lt; 500 U/L, and require RBC transfusions (defined as an average transfusion requirement of 2-6 RBC units/8 weeks for ≥ 8 weeks immediately prior to randomization). Exclusion criteria include prior use of ESAs (≤ 2 doses of prior epoetin alfa permitted if ≥ 8 weeks from randomization date and sEPO confirmed as ≤ 500 U/L), granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF), unless given for the treatment of febrile neutropenia; disease-modifying agents (e.g. lenalidomide), or hypomethylating agents; and presence of del(5q) cytogenetic abnormality. A total of approximately 350 eligible patients will be randomized in a 1:1 ratio to receive either luspatercept (starting dose 1.0 mg/kg with titration up to 1.75 mg/kg) subcutaneously (SC) once every 3 weeks or epoetin alfa (starting dose 450 IU/kg with titration up to 1,050 IU/kg) SC once every week, for a minimum of 24 weeks (Figure). Best supportive care, including RBC transfusions, may be used in combination with study treatment in both arms. Randomization will be stratified by baseline RBC transfusion burden (&lt; 4 vs ≥ 4 RBC units per 8 weeks), RS status (with RS+ defined as RS ≥ 15%, or ≥ 5% [but &lt; 15%] if SF3B1 mutation is present), and baseline sEPO level (≤ 200 U/L versus &gt; 200 U/L). In addition, ≥ 40% and ≤ 60% of randomized patients will be RS+, and ≥ 25% will have sEPO &gt; 200 U/L. The primary endpoint is the proportion of patients who achieve RBC-TI for 12 weeks within the first 24 weeks on study, with a concurrent mean hemoglobin (Hb) increase of ≥ 1.5 g/dL compared with baseline. Key secondary endpoints include duration of RBC-TI, change in Hb levels, achievement of HI-E response per International Working Group (IWG) 2006 criteria, and safety. The COMMANDS trial is registered at ClinicalTrials.gov (NCT03682536) and EudraCT (number 2017-003190-34). Disclosures Platzbecker: Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Geron: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; BMS: Consultancy, Honoraria. Santini:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Acceleron: Consultancy; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Garcia-Manero:Celgene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Onconova: Research Funding; Merck: Research Funding. Komrokji:Geron: Honoraria; Novartis: Honoraria; Incyte: Honoraria; JAZZ: Honoraria, Speakers Bureau; AbbVie: Honoraria; Agios: Honoraria, Speakers Bureau; Acceleron: Honoraria; BMS: Honoraria, Speakers Bureau. Ito:BMS: Current Employment, Current equity holder in publicly-traded company. Fenaux:BMS: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding.

PT Anugerah adalah salah satu perusahaan yang bergerak dalam bidang pembiayaan yang memberikan fasilitas pinjaman kepada konsumen dengan jaminan BPKB kendaraan bermotor roda dua maupun roda empat dan sistem pembayaran dicicil setiap bulan berdasarkan tenor yang telah disepakati. Penelitian ini bertujuan untuk mengetahui sejauh mana perusahaan telah menerapkan tata kelola TI yang baik. Fokus Penelitian ini pada 3 dominan COBIT 4.1 yaitu PO, DS dan ME terdiri dari 32 detailed control objective sementara domain AI telah dinilai memenuhi standar pengelolaan teknologiinformasi yang baik yaitu pada level 3 (defined). Pengumpulan data dilakukan dengan cara menyebarkan kuisioner, wawancara dan obervasi secara langsung. Ketiga metode tersebut berpatokan pada model COBIT 4.1. Temuan kelemahan atau masalah akan dibandingkan dengan kondisi ideal yang telah di tetapkan COBIT 4.1 pada setiap levelnya, sehingga dapat diketahui rekomendasi yang cocok untuk diterapkan. Masalah utama yang ditemui adalah kurangnya kontrol internal yang dilakukan pada divisi Collection, sehingga menyebabkan kesenjangan hubungan antar kantor dan konsumen, manajemen risiko yang belum dikelola dengan baik, dan kemampuan SDM yang masih kurang. Sehingga mengakibatkan kontrol teknologi menjadi lemah, biaya teknologi informasi yang tinggi tidak disertai dengan nilai balik dalam menigkatkan efektifitas, efisiensi dan keuntungan. Kantor PT Anugerah telah menerapkan tata kelola teknologi informasi pada level Defined Process. Hasil pengolahan kuisioner mendapati nilai rata-rata untuk domain PO, DS dan ME adalah 2,75 dari rentang nilai 0 sampai 5. Artinya perusahaan telah melakukan tata kelola teknologi informasi dengan baik. Hasil penelitian menemukan kelemahan terdapat pada subdomain ME2, dimana memiliki nilai kematangan paling kecil dari domain lainnya yaitu 2.54. Kata-kata kunci: COBIT 4.1, Tata Kelola Teknologi Informasi, SDM

Abstract Introduction: Around 50% of pts with de novo MDS present with chromosomal abnormalities at diagnosis. One of the most common cytogenetic abnormalities in MDS, deletion 5q [del(5q)], occurs in ~15% of pts (Haase et al. Blood 2007;110:4385-95). The presence of cytogenetic abnormalities in addition to del(5q) may be associated with shorter overall survival (OS) and increased risk of progression to acute myeloid leukemia (AML) versus del(5q) alone (Mallo et al. Leukemia 2011;25:110-20). In 2 large multicenter studies (MDS-003 and MDS-004), lenalidomide (LEN) was evaluated in RBC transfusion-dependent pts with IPSS Low/Intermediate (Int)-1-risk MDS and del(5q) (List et al. N Engl J Med 2006;355:1456-65; Fenaux et al. Blood 2011;118:3765-76). This analysis describes the prevalence and clinical impact of the most common cytogenetic abnormalities in pts with del(5q) from MDS-003 and MDS-004. Methods: Of 353 pts enrolled in MDS-003 and MDS-004, 281 pts had available cytogenetic data with ≥ 16 metaphases evaluable, and were included in the analysis. Pts received 10 mg LEN on days 1–21 of each 28-day cycle; LEN 5 mg or 10 mg continuously; or placebo. In MDS-004, placebo pts could crossover to LEN 5 mg by Week (Wk) 16. Centrally reviewed cytogenetic studies were performed at baseline, and wks 24 and 48 (MDS-003); or baseline, Wk 24, and every 24 wks thereafter (MDS-004). RBC-transfusion independence (RBC-TI) ≥ 26 wks, cytogenetic response (CyR), AML progression, and OS were assessed by most common cytogenetic abnormalities in LEN-treated pts with del(5q) plus 1 additional abnormality. Some pts did not fulfill the IPSS lower-risk classification after central pathologic/cytogenetic evaluation. For this analysis outcomes in the del(5q) plus ≥ 2 additional abnormalities group were not evaluated. Results: Of the 281 pts, 70.8% had isolated del(5q), 19.9% del(5q) plus 1 additional abnormality, and 9.3% had del(5q) plus ≥ 2 additional abnormalities. Baseline characteristics including age, time from diagnosis, RBC transfusion burden, hemoglobin level, and platelet and absolute neutrophil counts were comparable across the cytogenetic groups. In pts with del(5q) plus 1 additional abnormality at baseline, the most common numerical abnormalities were +8 (17.9%; n = 10), +21 (14.3%; n = 8), and −7 (3.6%; n = 2); the most common balanced structural rearrangements were translocation 2;11 [t(2;11)] (5.4%; n = 3) and isochromosome 21q [i(21q)] (3.6%; n = 2); and the most common unbalanced structural rearrangements were del(11q) (7.1%; n = 4), del(20q) (5.4%; n = 3), del(9q) (3.6%; n = 2), and del(12p) (3.6%; n = 2) (Figure). In the del(5q) plus 1 additional abnormality group, baseline characteristics were comparable across pts with +8, +21, or other abnormalities (i.e. excluding those with +21 and +8), with the exception of age (P = 0.023). Rates of RBC-TI ≥ 26 wks and CyR did not significantly differ among LEN-treated pts with +8 (n = 9), +21 (n = 8), or other abnormalities (n = 37). Rates of RBC-TI ≥ 26 wks were 66.7%, 50.0%, and 54.1% (P = 0.839), respectively. In pts evaluable for CyR (n = 40), CyR rates were 42.9%, 42.9%, and 65.4% (P = 0.407), respectively. Median time to AML progression was shorter in LEN-treated pts with +21 (2.6 years [yrs]; 95% CI 1.2–4.8) versus +8 (4.8 yrs; 95% CI 1.6–not estimable) or other abnormalities (7.5 yrs; 95% CI 4.1–7.5) (P = 0.0143). The 5-year AML progression rates were 68.8% (95% CI 26.6–98.7), 85.7% (95% CI 53.5–99.3), and 36.3% (95% CI 19.2–61.3) in pts with +8, +21, or other abnormalities, respectively. Median OS was 4.1 yrs (95% CI 0.9–5.3), 3.0 yrs (95% CI 1.1–4.9), and 3.4 yrs (95% CI 2.6–6.5) (P = 0.423), respectively. Of the 2 pts with −7: 1 pt with Int-1-risk MDS had a 92% to 8% reduction of −7-positive metaphases at Day 84 on treatment, but no RBC-TI ≥ 26 wks, and died at Day 709 without AML; the other Int-2-risk pt progressed to AML on Day 147 with clearance of −7 from 8%, and development of new +8 and del(16q) abnormalities. Conclusions:In MDS pts with del(5q) plus 1 additional abnormality from MDS-003 and MDS-004, the most common cytogenetic abnormalities were +8, +21, del(11q), del(20q), and t(2;11), which accounted for 50% of the additional abnormalities at baseline. In the del(5q) plus 1 additional abnormality population, median time to AML progression was shorter in pts with +21 versus either +8 or other abnormalities. Due to small pt numbers, larger prospective analyses are needed to confirm these observations. Figure 1 Figure 1. Disclosures Giagounidis: Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. List:Celgene Corporation: Consultancy. Hellstrom-Lindberg:Celgene: Research Funding. Mufti:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schlegelberger:Celgene Corporation: Consultancy. Morrill:Celgene Corporation: Employment, Equity Ownership. Wu:Celgene Corporation: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership. Fenaux:Novartis: Research Funding; Janssen: Research Funding; Celgene Corporation: Research Funding.

A286 alloy (AISI 660) is an austenitic precipitation hardness stainless steel that is widely used in the gas turbine industry, due to its high-temperature strength and oxidation resistance [1]. A286 alloy contains higher Ni (24.23 wt.%) and lower Cr (14.5 wt.%) than AISI 316 and AISI 304. The main precipitation strengthening phase of this alloy is gamma phase γ' [Ni3(Al, Ti)], and second phase particles, which form during solution treatment and aging, include eta phase η (Ni3Ti) and metal carbides and nitrides (TiC, TiN). Unlike the relation between precipitates (γ', η) and pitting corrosion [2], the influence of TiC and TiN on the pitting corrosion is rarely studied. To investigate the influence of the various second phase particles on the corrosion behavior of A286 alloys, three samples were employed, including the hot-rolled (HR), HR + solution treatment at 980 °C for 1 h, and HR + solution treatment + aging at 720 °C for 16 h. The corrosion resistance of the various A286 alloy samples were examined by potentiodynamic tests in 3.5 wt.% NaCl solution. The microstructure was investigated via scanning electron microscopy (SEM), transmission electron microscopy (TEM), and energy dispersive spectroscopy (EDS). The second phase particles of HR A286 were mainly TiC and a few TiN, which were several micrometers in size and distributed intragranularly in the austenite matrix (Fig. 1a, 1d, and 1e). After the solution treatment, many TiC particles with sizes of a couple of micrometers precipitated along the austenite grain boundaries (Fig. 1b). Further aging resulted in the formation of γ' and η particles (Fig.1c). The potentiodynamic curves (Fig.1f) showed that the HR A286 had the lowest pitting potential (Epit) and smallest passivation range, suggesting the formation of TiC particles did not deteriorate the corrosion resistance. Meanwhile, the γ' and η particles resulted in a slight decrease in the Epit and passivation range. Reference: [1] H. De Cicco, M.I. Luppo, L.M. Gribaudo, J. Ovejero-García, Microstructural development and creep behavior in A286 superalloy, Materials Characterization 52 (2004) 85-92. [2] P. De Tiedra, O. Martín, M. San-Juan, Potentiodynamic study of the influence of gamma prime and eta phases on pitting corrosion of A286 superalloy, Journal of Alloys and Compounds 673 (2016) 231-236. Figure 1

Abstract Background: Somatic gene mutations occur in the majority of MDS pts; specific mutations and high mutation frequency have prognostic relevance (Papaemmanuil et al. Blood. 2013;122:3616-27). Evaluation of somatic mutations may support the diagnosis of MDS and guide treatment (Tx) selection. The phase 3 randomized MDS-005 study compared LEN and placebo (PBO) Tx in red blood cell transfusion-dependent (RBC-TD) non-del(5q) lower-risk MDS pts ineligible for or refractory to ESAs. Deletions in chromosome 5q are associated with a high response rate to LEN in MDS pts; however, no mutations have been definitively associated with a predictable clinical response to LEN in non-del(5q) MDS. Aim:To investigate the relationship between somatic gene mutations detected by targeted next-generation sequencing (NGS) and response and overall survival (OS) in lower-risk non-del(5q) MDS pts treated with LEN in the MDS-005 study. Methods: Eligible pts were: RBC-TD (≥ 2 units packed RBCs/28 days 112 days immediately prior to randomization) with International Prognostic Scoring System defined Low-/Intermediate-1-risk non-del(5q) MDS; ineligible for ESA Tx (serum erythropoietin > 500 mU/mL); or unresponsive or refractory to ESAs (RBC-TD despite ESA Tx with adequate dose and duration). 239 pts were randomized 2:1 to oral LEN 10 mg once daily (5 mg for pts with creatinine clearance 40-60 mL/min) or PBO. DNA was isolated from bone marrow mononuclear cells or whole blood collected at screening from a subset of pts who gave informed consent for this exploratory biomarker analysis and had adequate tissue for analysis. Targeted NGS of 56 genes was performed at Munich Leukemia Laboratory; average sequencing coverage was 2,000-5,000-foldand the variant allele frequency detection cutoff was 3%. Target regions varied by gene, including all exons to hotspots. For association tests, mutant variants (heterozygous or homozygous) were scored as 1 (mutant) or 0 (wildtype) for gene-level analyses. A Fisher exact test was used to test association of mutation status with response. Median OS was calculated by the Kaplan-Meier method. Hazard ratios and 95% confidence intervals were determined by a non-stratified Cox proportional hazards model. A log-rank test was used to test treatment effect with OS for single gene mutation status. Results: The biomarker cohort included 198 of 239 pts (83%; LEN n = 130, PBO n = 68). At least 1 mutation was detected in 30/56 (54%) genes and 173/198 (87%) pts. The most frequently mutated genes were SF3B1 (59%), TET2 (33%), ASXL1 (23%), and DNMT3A (14%); the most frequent co-mutations were SF3B1/TET2 (23%), SF3B1/DNMT3A (10%), SF3B1/ASXL1 (10%), and TET2/ASXL1 (9%) (Figure). Of 116 pts with SF3B1 mutations, 115 (99%) had ≥ 5% ring sideroblasts. The 56-day RBC transfusion-independence (RBC-TI) response rate was significantly lower in LEN-treated ASXL1 mutant pts vs wildtype pts (10% vs 32%, respectively; P = 0.031). At 168 days, the RBC-TI response rate was still lower in LEN-treated ASXL1 mutant pts vs wildtype pts (7% vs 22%); however, the difference was not significant (P = 0.101). LEN-treated DNMT3A mutant pts had a higher 56-day RBC-TI response rate vs wildtype pts (44% vs 25%); however, this difference did not reach significance (P = 0.133) due to the small sample size. RBC-TI response rate with LEN was similar regardless of total number of mutations per pt. Higher numbers of mutations were significantly associated (P = 0.0005) with worse median OS. Mutation in any of the genes associated with a negative prognosis reported by Bejar et al. (N Engl J Med. 2011;346:2496-506) was also significantly associated (P = 0.0003) with worse median OS.However, OS was not significantly different in LEN- vs PBO-treated pts based on any single gene mutation status. Conclusions: In this group of lower-risk RBC-TD non-del(5q) MDS pts, somatic mutations in genes recurrently mutated in myeloid cancers were detected in 87% of pts. SF3B1 mutations (alone or in combination) were most frequent and not associated with response to LEN. ASXL1 mutant pts had a significantly lower LEN response rate vs wildtype pts, whereas DNMT3A mutant pts had a trend for improved LEN response. Median OS was influenced by mutations, but not significantly modified by LEN. Determining predictive clinical markers for Tx response in non-del(5q) MDS pts remains challenging; nevertheless, there is a significant need to identify pt subsets who may be responsive to LEN Tx. Figure. Figure. Disclosures Santini: Novartis: Consultancy, Honoraria; Amgen: Other: advisory board; Onconova: Other: advisory board; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Astex: Other: advisory board. Fenaux:Celgene, Janssen, Novartis, Astex, Teva: Research Funding; Celgene, Novartis, Teva: Honoraria. Giagounidis:Celgene Corporation: Consultancy. Platzbecker:Janssen-Cilag: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding. Zhong:Celgene Corporation: Employment, Equity Ownership. Wu:Celgene Corporation: Employment, Equity Ownership. Mavrommatis:Discitis DX: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Employment, Equity Ownership. Beach:Celgene Corporation: Employment, Equity Ownership. Hoenekopp:Celgene Corporation: Employment, Equity Ownership. MacBeth:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties, Research Funding.

Introduction: Patients (pts) with MDS/MPN-RS-T have limited treatment options for anemia due to ineffective erythropoiesis. Luspatercept, the first-in-class erythroid maturation agent that enhances late-stage erythropoiesis, is approved by the FDA for treatment of anemia in adult pts with lower-risk (LR) MDS with ring sideroblasts (RS) or MDS/MPN-RS-T after erythroid-stimulating agent (ESA) failure. In the randomized, double-blind, phase 3 MEDALIST study, luspatercept significantly reduced transfusion burden vs placebo in pts with LR-MDS (NCT02631070; Fenaux P, et al. N Engl J Med 2020;382:140-51). Here, we assess the efficacy and safety of luspatercept in pts with MDS/MPN-RS-T enrolled in the MEDALIST study. Methods: Eligible pts were ≥ 18 years; had IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS with RS; were refractory, intolerant, or unlikely to respond to ESAs (serum erythropoietin &gt; 200 U/L); and required regular RBC transfusions. Pts were randomized 2:1 to luspatercept (1.0 mg/kg, titration to 1.75 mg/kg) or placebo administered subcutaneously every 3 wks. The primary endpoint was achievement of RBC transfusion independence (RBC-TI) ≥ 8 wks during Wks 1-24. Results: A retrospective analysis identified 23/229 (10.0%) pts enrolled in the MEDALIST trial who had MDS/MPN-RS-T, per WHO 2016 criteria (Arber DA, et al. Blood 2016;127:2391-405); 14 received luspatercept and 9 received placebo. Pts in this subgroup received a median of 4.0 RBC units/8 wks (range 2.0-11.5) during the 16 wks prior to treatment. At baseline, pts had a median hemoglobin (Hb) level of 7.7 g/dL (range 7.0-9.0), a median leukocyte count of 5.1 × 109/L, a median platelet count of 447.0 × 109/L, and 18 (78.3%) pts had serum erythropoietin levels &lt; 200 U/L (Table). In the luspatercept arm, 9/14 (64.3%) pts with MDS/MPN-RS-T achieved the primary endpoint of RBC-TI for ≥ 8 wks during Wks 1-24, compared with 2/9 pts (22.2%) receiving placebo (odds ratio 11.3; 95% confidence interval [CI] 1.19, 106.12; P = 0.028). Pts receiving luspatercept were significantly more likely to achieve clinical benefit (achieving RBC-TI ≥ 8 wks and/or modified hematologic improvement-erythroid [mHI-E] per IWG 2006 criteria [≥ 4 units/8 wks reduction in RBC transfusion in pts with ≥ 4 units/8 wks baseline RBC transfusion burden; Hb increase by ≥ 1.5 g/dL] during Wks 1-24 in pts with &lt; 4 units/8 wks baseline RBC transfusion burden), compared with pts receiving placebo (78.6% vs 33.3%; P = 0.034). Median time from the start of clinical benefit response to end of treatment was 94.6 wks (range 8.0-150.0) in the luspatercept arm and 23.9 wks (range 23.7-57.9) in the placebo arm. During Wks 1-24, mHI-E was achieved by 10 luspatercept pts (6 were high transfusion burden [HTB; defined as baseline transfusion burden ≥ 4 units/8 wks] and 4 were low transfusion burden [LTB; defined as baseline transfusion burden &lt; 4 units/8 wks]) and 1 placebo pt (1/5 HTB). RBC-TI ≥ 8 wks was achieved by 4/8 HTB pts receiving luspatercept (vs 0/5 placebo) and 5/6 LTB pts (vs 2/4 placebo). After 24 wks, pts in the luspatercept arm had a mean Hb increase of +1.7 g/dL compared with an increase of +0.9 g/dL in pts in the placebo arm (least squares [LS] mean difference +0.85 g/dL; 95% CI −1.13, +2.82). Greater reductions from baseline in mean serum ferritin levels were seen with luspatercept (−121.8 μg/L) compared with placebo (−91.9 μg/L) over Wks 9-24 (LS mean difference −90.1; 95% CI −758.4, 578.2). Pts in the luspatercept arm had median platelet counts of 467.5 × 109/L and median leukocyte counts of 6.5 × 109/L post 24 wks of treatment, compared with pts in the placebo arm with 514.0 × 109/L and 6.2 × 109/L, respectively. The incidence of specific TEAEs (occurring in ≥ 1 patient) are as follows: fatigue (1/14 [7.1%] luspatercept vs 1/9 [11.1%] placebo), dizziness (7/14 [50.0%] vs 0/9), dyspnea (3/14 [21.4%] vs 0/9), nausea (6/14 [42.9%] vs 2/9 [22.2%]), arthralgia (1/14 [7.1%] vs 0/9), diarrhea (6/14 [42.9%] vs 1/9 [11.1%]), and hypertension (3/14 [21.4%] vs 0/9). In the luspatercept arm, 1/14 (7.1%) pts experienced ≥ 1 thromboembolic event (transient ischemic attack) and 1/9 (11.1%) pts in the placebo arm progressed to AML (as of July 1, 2019). Conclusions: Luspatercept demonstrated clinical efficacy in pts with MDS/MPN-RS-T with a generally well-tolerated safety profile. These data support the clinical benefits of luspatercept in this patient population with otherwise limited treatment options. Disclosures Komrokji: Geron: Honoraria; Novartis: Honoraria; Incyte: Honoraria; JAZZ: Honoraria, Speakers Bureau; AbbVie: Honoraria; Agios: Honoraria, Speakers Bureau; Acceleron: Honoraria; BMS: Honoraria, Speakers Bureau. Platzbecker:Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Fenaux:BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Honoraria, Research Funding. Garcia-Manero:Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Amphivena Therapeutics: Research Funding; Jazz Pharmaceuticals: Consultancy; H3 Biomedicine: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Novartis: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Merck: Research Funding. Mufti:Abbvie, Novartis: Consultancy; BMS, Novartis: Research Funding. Santini:Janssen: Research Funding; BMS, J&J, Novartis: Honoraria; Acceleron, BMS, Menarini, Novartis: Consultancy; Takeda, Pfizer: Membership on an entity's Board of Directors or advisory committees. Diez-Campelo:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Finelli:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees. Jurcic:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syros Pharmaceuticals: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Arog Pharmaceuticals: Research Funding; Astellas: Research Funding; Forma Therapeutics: Research Funding; Genentech: Research Funding; Kura Oncology: Research Funding; PTC Therapeutics: Research Funding. Greenberg:BMS: Research Funding; Aprea: Research Funding; Notable Labs: Research Funding; H3 Biotech: Research Funding. Sekeres:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Zeidan:Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Trovagene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Leukemia and Lymphoma Society: Other; CCITLA: Other; Astex: Research Funding; MedImmune/Astrazeneca: Research Funding; Ionis: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Aprea: Research Funding; ADC Therapeutics: Research Funding; Taiho: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Cardiff Oncology: Consultancy, Honoraria, Other; Agios: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Acceleron: Consultancy, Honoraria; Celgene / BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. DeZern:Astex: Research Funding; Celgene: Consultancy, Honoraria; MEI: Consultancy; Abbvie: Consultancy. Savona:Incyte: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; BMS: Consultancy; AbbVie: Consultancy; Gilead: Consultancy; Karyopharm: Consultancy, Current equity holder in publicly-traded company; Ryvu: Consultancy; Boehringer Ingelheim: Patents & Royalties; Astex: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Shetty:BMS: Current Employment, Current equity holder in publicly-traded company. Ito:BMS: Current Employment, Current equity holder in publicly-traded company. Zhang:BMS: Current Employment. Ha:BMS: Current Employment. Sinsimer:BMS: Current Employment, Current equity holder in publicly-traded company. Backstrom:BMS: Current equity holder in publicly-traded company; Acceleron Pharma: Current Employment, Current equity holder in publicly-traded company. Verma:BMS: Consultancy, Research Funding; acceleron: Consultancy, Honoraria; Janssen: Research Funding; Medpacto: Research Funding; stelexis: Current equity holder in private company.

Abstract Introduction: MDS is associated with an erythroid maturation defect, characterized by ineffective erythropoiesis leading to anemia and RBC transfusion dependence. Treatment of anemia in lower-risk MDS remains an unmet medical need. Luspatercept is a first-in-class erythroid maturation agent which binds to select TGFβ superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis (Suragani RN, et al. Nat Med. 2014;20:408-14). Preliminary clinical studies have shown promising activity in MDS (Platzbecker U, et al. Lancet Oncol. 2017;10:1338-47). We report the results of a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of luspatercept in patients with anemia due to Revised International Prognostic Scoring System (IPSS-R)-defined Very low-, Low-, or Intermediate-risk MDS with RS who require RBC transfusions. ClinicalTrials.gov identifier: NCT02631070. Methods: Eligible patients were aged ≥ 18 years; had IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS with RS according to the WHO 2016 criteria; were refractory, intolerant, or ineligible to receive erythropoiesis-stimulating agents (ESAs); and required RBC transfusions. Patients were randomized 2:1 to receive either luspatercept, at a starting dose level of 1.0 mg/kg with titration up to 1.75 mg/kg, if needed, or placebo, subcutaneously every 3 weeks for ≥ 24 weeks. The primary endpoint was RBC transfusion independence (RBC-TI) for ≥ 8 weeks between week 1 and week 24. A key secondary endpoint was RBC-TI for ≥ 12 weeks between week 1 and 24. Achievement of modified hematologic improvement-erythroid (mHI-E) response using IWG 2006 criteria was also assessed. Results: † A total of 229 patients were randomized and treated. Median age was 71 years (range 26-95), median time from diagnosis was 41.8 months (range 3-421), and 62.9% were male. Overall, patient baseline characteristics were balanced between the treatment groups. Patients received a median of 5 RBC units (range 1-20) transfused over 8 weeks during the 16 weeks prior to treatment (43.2% of patients had ≥ 6 RBC units/8 weeks, 27.9% had ≥ 4 to &lt; 6 RBC units/8 weeks, and 28.8% had &lt; 4 RBC units/8 weeks). At baseline, 138 (60.3%), 58 (25.3%), and 32 (14.0%) patients had serum erythropoietin levels &lt; 200 IU/L, 200-500 IU/L, and &gt; 500 IU/L, respectively. A total of 218 (95.2%) patients had previously received ESAs. Overall, 206 (90.0%) patients had an SF3B1 mutation. Of 153 patients receiving luspatercept, 58 (37.9%) achieved the primary endpoint of RBC-TI for ≥ 8 weeks compared with 10 of 76 patients (13.2%) receiving placebo (odds ratio [OR] 5.1, P &lt; 0.0001). Of those receiving luspatercept, 43 of 153 (28.1%) achieved the key secondary endpoint of RBC-TI for ≥ 12 weeks (weeks 1-24) compared with 6 of 76 (7.9%) receiving placebo (OR 5.1, P = 0.0002). Patients receiving luspatercept were more likely to achieve an mHI-E response, defined as a reduction in transfusion of ≥ 4 RBC units/8 weeks or a mean hemoglobin increase of ≥ 1.5 g/dL/8 weeks in the absence of transfusions, compared with patients receiving placebo (52.9% vs 11.8% during weeks 1-24; P &lt; 0.0001). The safety profile of luspatercept was consistent with that reported in the phase 2 PACE-MDS study (Platzbecker U, et al. Lancet Oncol. 2017;10:1338-47). Conclusions: Treatment with luspatercept resulted in a significantly reduced transfusion burden compared with placebo in patients with anemia due to IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS with RS, who require RBC transfusions, and was generally well tolerated. P.F. and U.P. contributed equally to this abstract as lead co-authors. R.S.K. and A.F.L. contributed equally to this abstract as senior co-authors. † As of May 8, 2018, cutoff date. Disclosures Fenaux: Otsuka: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Platzbecker:Celgene: Research Funding. Mufti:Celgene: Research Funding. Buckstein:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Santini:Otsuka: Consultancy; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; Novartis: Honoraria; AbbVie: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Díez-Campelo:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Finelli:Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Research Funding, Speakers Bureau. Ilhan:Alexion: Speakers Bureau; BMS: Speakers Bureau; Roche: Speakers Bureau; Celgene: Speakers Bureau. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Falantes:Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Giai:Novartis: Consultancy; Pfizer: Consultancy. Selleslag:Kiadis Pharma: Other: Financial support for study-related issues. Jurcic:Actinium Pharmaceuticals, Inc: Research Funding; Daiichi-Sankyo: Research Funding; Astellas: Research Funding; Incyte: Consultancy; AbbVie: Consultancy, Research Funding; Kura Oncology: Research Funding; Genetech: Research Funding; Celgene: Research Funding; Forma Therapeutics: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Syros Pharmaceuticals: Research Funding. Germing:Novartis: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria, Research Funding. Götze:Takeda: Honoraria, Other: Travel aid ASH 2017; Celgene: Honoraria, Research Funding; Novartis: Honoraria; JAZZ Pharmaceuticals: Honoraria. Quesnel:Celyad: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Sunesis: Honoraria. Beyne-Rauzy:Novartis: Research Funding. Cluzeau:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Menarini: Consultancy; Pfizer: Speakers Bureau. Voso:Celgene: Research Funding, Speakers Bureau. Zeidan:Otsuka: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Honoraria, Speakers Bureau; Agios: Consultancy, Honoraria. Laadem:Celgene: Employment, Equity Ownership. Benzohra:Celgene: Employment, Equity Ownership. Zhang:Celgene: Employment, Equity Ownership. Rampersad:Celgene: Employment, Equity Ownership. Linde:AbbVie: Equity Ownership; Abbott Laboratories: Equity Ownership; Fibrogen: Equity Ownership; Acceleron Pharma: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership. Komrokji:Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding. List:Celgene: Research Funding.

Abstract Background: Ectopic thyroid tissue is a rare entity with a prevalence of 1 per 300,000 persons. Malignancy in ectopic thyroid tissue is reported in &lt;1% of these cases.[1] We report a case of aggressive papillary carcinoma in ectopic thyroid gland in a patient with Graves’ disease. Case: A 65-year old woman was incidentally found to have a 3.1 cm mass with coarse calcifications in the superior mediastinum on CT scan of chest. Ultrasound confirmed the presence of hypoechoic mass which was separate from thyroid. Additionally, a 0.5cm TI-Rad 4 left thyroid lobe nodule was found. FNA of the mediastinal mass was suspicious for follicular thyroid neoplasm. Thyramir testing was positive for BRAF V600E and TERT c-124C&gt;T mutations. Thyroid function tests showed frank hyperthyroidism and elevated thyroid stimulating immunoglobulins. Thyroid uptake and scan showed diffuse uptake of 67% at 24 hours. The patient underwent simultaneous excision of mediastinal mass and total thyroidectomy. The pathology of mediastinal mass showed papillary thyroid cancer with tall and sclerosis features with one involved lymph node. The pathology of thyroid gland did not show any malignancy. She was treated with 100 mCi I-131. Post treatment Whole Body Nuclear Scan after treatment revealed metastatic disease in left lower lung area. Discussion: Ectopic thyroid gland is usually found anywhere between forman caecum and mediastinum. It is rare to find ectopic thyroid tissue in the presence of eutopic thyroid gland which can create a diagnostic dilemma. Only a very few case reports of thyroid cancer arising from ectopic thyroid tissue have been reported. Our case is unique as the eutopic thyroid gland had Graves’ disease with no malignancy but the ectopic thyroid tissue developed aggressive papillary thyroid cancer. There are no specific guidelines for the management of carcinoma in ectopic thyroid glands, possibly due to the rarity of the condition. Our case has a clear metastasis to the lungs. However, it is important to differentiate ectopic thyroid tissue with carcinoma from thyroid cancer metastasis which can be difficult at times. Without specific guidelines for the management of cancer in ectopic thyroids, an individualised approach can be taken using the same therapeutic principals used in the management of eutopic thyroid cancer. Additionally, a finding of a normal thyroid gland or a benign condition in the thyroid gland should not exclude the diagnosis of malignancy in ectopic thyroid tissues. 1) Vázquez, Oscar R., et al. “Ectopic papillary thyroid cancer with distant metastasis.” Case reports in endocrinology 2018 (2018).

Abstract Introduction. Chronic iron overload may represent a serious complication of potentially lifesaving blood transfusions in different haematological diseases. Excess iron deposits in various tissues of the body, particularly the liver, heart, and endocrine organs (Cappellini. Thalassaemia International Federation, 2014). This process leads to tissue damage and ultimately to significant morbidity and mortality (Musallam. Haematologica 2013). Indeed, organ failure due to chronic iron overload may represent the major cause of death in patients with different haematological diseases who receive blood transfusions regularly without appropriate chelation therapy (Inati. Pediatr Blood Cancer 2011; N Engl J Med 2000; Cleve Clin J Med 2005). The main aim of this study was to look for the relationships between changes in LIC and changes in serum ferritin (SF) level, during real life experience with larger setting of patients with haematological diseases and different chelation regimens, previously described at baseline, according to the LICNET protocol (Vitrano et al., Eur J Haematol 2016). Methods. This was a cross-sectional study of patients with haematological disorders attending 9 Italian centres participating in the LICNET. The LICNET protocol was approved on December 4, 2012 by our Ethical Committee. The underlying diagnoses were regularly transfused Thalassemia Major (TM), Thalassemia Intermedia (TI), Sickle Cell Disease (SCD), Myelodysplastic Syndrome (MDS), Diamond-Blackfan Anemia (DBA). Transfused status was defined as receipt of ≥7 mL/kg/month of packed red blood cells. The inclusion criteria for the cross-sectional analysis were: 1) underlying diagnosis above described; 2) determination of two R2-MRI scans performed as part of the network, for those patients presenting between February 2013 and December 2016; 3) transfusion dependence; 4) same chelation treatment at T0 (MRI1) and T1 (MRI2) . The settled R2-MRI protocol at the Centre follows that of St Pierre et al. (St Pierre et al. Magn Reson Med 2014). Descriptive analysis was provided as means, standard deviations, medians or percentages. Three classes of risk (low, intermediate and high), on the basis of LIC values ( &lt;7mg Fe/g dry weight (dw), 7-15 mg Fe/g dw, &gt;15 mg Fe/g dw ) were considered to evaluate the control of iron body burden during the study period. LIC comparisons at MRI1 and MRI2 were made using t -test and/or Wilcoxon test. All p -values are two sided with the level of significance set at &lt;0.05. Results. A total of 130 patients were evaluated, with a median age of 35 years (range: 6-78). The median duration (range) between MRI1 and MRI2 days was 483 (184-1076). Patients' characteristics for the considered chelation regimens are summarized in Table 1. Overall patients, across all chelation regimens, showed a statistically significant difference in variation of LIC between MRI1 and MRI2 (p=0.011, Table 2). Overall variation of LIC, during a period of 483 (184-1076) days, was -0.8 (-29.0-33.0) mg Fe/g dw. Median changes in LIC (range), mg Fe/g dw for single chelation regimen are reported on Tab. 2. Changes in LIC determinations, during the period of the study, according to the baseline values, are shown on Fig. 1: Overall 7.7% of patients, across different chelation regimens and during a period of 483 (184-1076) days, moved from high risk group (LIC &gt;15 mg Fe/g dw) to intermediate risk group (LIC 7-15 mg Fe/g dw) with stabilization of iron overloading in patients in low risk group at baseline; all chelation regimens were able to move LIC from high risk group to intermediate risk group. In the other combination group, the patients moved from the intermediate risk group to the low risk group. Median changes in SF level (range), ng/ml for overall patients and for single chelation regimen are reported on Tab. 2: Overall patients, across all chelation regimens, did not show any statistically significant difference in variation of SF between MRI1 and MRI2 (p= 0.566, Table 2). Conclusions. In conclusion, SF level trends are unable to predict changes in LIC, even in well chelated patients with haematological disorders. Therefore, variations of SF level must be interpreted with caution and confirmed, when it is possible, by direct measurement of LIC for more correct management of chelation treatment. Disclosures Oliva: Celgene: Consultancy; Amgen Inc.: Consultancy; La Jolla: Consultancy; Novartis: Consultancy; Janssen: Consultancy.

Abstract Background: Moyamoya syndrome is chronic stenoocclusive disease involving the intracranial internal carotid arteries and their proximal branches along with an associated condition, such as hyperthyroidism1. The concurrence of moyamoya and Graves’ disease is rare. Ischemic stroke in moyamoya syndrome is postulated to be precipitated by thyrotoxicosis-induced hemodynamic instability. Clinical Case: A 63-year old Korean female with history of moyamoya disease with two prior ischemic strokes, hypertension and type 2 diabetes mellitus presented to the ER with 6 hours of left leg weakness and involuntary arm movements. A code stroke was activated and neurologic examination was notable for left leg paresis and left arm stereotypy. CT head showed loss of gray-white matter differentiation in the right frontal lobe concerning for acute ischemia. CT angiography of the head and neck noted diffuse stenosis of intracerebral vasculature and significant stenosis of the cavernous and supraclinoid portions of the internal carotid arteries. MRI brain later confirmed an acute infarct in the right ACA distribution. Neuroimaging incidentally showed a multinodular goiter with a 1.7 cm right thyroid nodule. Subsequently TSH was obtained and resulted as &lt;0.030 mcIU/mL (0.27-5.00 mcIU/mL) with a reflex FT4 of &gt;7.00 ng/dL (0.6-1.8 ng/dL). A review of her prior TFTs showed biochemical euthyroidism. Due to iodinated contrast administration on admission, RAIU scan was deferred. Thyroid ultrasound showed multinodular goiter with diffuse increased vascularity and multiple TI-RADS 4 and 5 nodules bilaterally. On further questioning, the patient reported tachycardia, diarrhea, weight loss and decreased appetite prior to hospitalization. A diagnosis of Graves’ disease was confirmed with TSI of 70.7 IU/L (0.00-0.55 IU/L). She was started on methimazole 20 mg twice daily and propranolol 20 mg q6h. FT4 downtrend from &gt;7.00 to 3.3 ng/dL at time of discharge. Following four weeks of methimazole 20 mg daily, FT4 normalized to 1.70 ng/dL. The patient chose to continue antithyroidal drug therapy for treatment of Graves’ disease. Conclusion: Thyroid function assessment should be considered when evaluating a patient with moyamoya and acute ischemic stroke. If moyamoya syndrome associated with Graves’ disease is identified, treatment should be aimed at maintenance of euthyroidism. Reference: 1. Scott RM, Smith ER. Moyamoya disease and moyamoya syndrome. N Engl J Med. 2009 Mar 19;360(12):1226-37. Disclaimer: The views expressed herein are those of the authors and do not reflect the official policy or position of Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, the Department of the Air Force and Department of Defense or the U.S. Government.

Abstract Background/Introduction: Lower-risk (IPSS low risk and Int-1) myelodysplastic syndromes (MDS) are typically treated supportively to address cytopenias. DNA methyltransferase inhibitors (DNMTi) such as azacitidine and decitabine (DEC) are FDA-approved for higher risk MDS patients (pts), and while the DEC USPI includes IPSS Int-1 pts, it is not widely used in this population. Approved intravenous (IV) or subcutaneous (SC) regimens require 5-7 days of treatment every month burdening older cancer pts due to daily travel and treatment time and may increase potential risk from pandemic SARS-CoV-2 infection. Because DNMTis are rapidly degraded by cytidine deaminase (CDA) in the gut and liver, oral availability has only been recently possible. A randomized study with CC-486, an oral formulation of azacitidine, in the Int-1 population showed a median overall survival (mOS) of approximately 17 months for both placebo and treated patients (Garcia-Manero, 2021). Oral DEC 35 mg/cedazuridine 100 mg (ASTX727) or DEC-C, is an oral fixed dose combination (FDC) of DEC and the CDA inhibitor cedazuridine (CED) resulting in equivalent exposure (99%; 90% CI 93% to 106%) to standard IV DEC 20 mg/m 2 for 5 days in an intra-patient randomized cross-over study (Garcia-Manero et al, ASH 2019). Here, we present data on patients with lower risk MDS from that study. Methods: We used a randomized cross over design with pts randomized 1:1 in the first 2 cycles to either Sequence A: (DEC 35 mg/ CED 100 mg in Cycle 1 and IV DEC at 20 mg/m 2 in Cycle 2), or Sequence B (IV DEC in Cycle 1 and oral DEC/CED in Cycle 2). Cycles were repeated every 28 days unless delays were needed, and all patients received oral DEC-C in Cycles 3+ until disease progression or unacceptable toxicity. We conducted an intra-patient comparison of DEC PK (DEC AUC equivalence over 5 days of dosing). Pts were eligible as per the FDA-approved label of IV DEC (MDS pts by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk pts). Clinical endpoints were best response as assessed by an independent expert panel according to IWG 2006 response criteria, transfusion independence (TI), overall survival (OS), and safety. Results: Of the 133 pts treated in ASCERTAIN, 69 had a diagnosis of lower-risk MDS (93% Int-1, 7% LR). Median age was 70.0 years (range 45-87), 65% were male, median weight was 84 kg (range 50-127), median baseline hematologic parameters were: hemoglobin 89 g/L (range 69.8-146.5), WBCs 1.50 X 10 9/L (range 0.11-7.1), platelets (plt) 86 x 10 9/L (range 5-703), bone marrow blasts 4% (range 0-18), cytogenetics: 7 (10.1%) poor-risk, 21 (30.4%) intermediate risk, 37 (53.6%) better-risk, 4 (5.7%) missing or not evaluable. 27(39%) of the pts were RBC transfusion dependent (TD) and 6 (9%) plt TD. 17 (25%) had received prior MDS treatment, 3% prior DNMTi. Pts received a median of 9 cycles of therapy (range 1-28). Treatment-emergent adverse events of CTCAE Gr 3 or higher in &gt;10% of pts, independent of relationship to ASTX727, included cytopenias (neutropenia [59%], thrombocytopenia [58%], anemia [48%], leukopenia [26%]), febrile neutropenia (32%), and pneumonia (19%). Sixteen pts (23%) achieved Complete Response (CR), 18 (26%) had marrow CR (mCR), including 9 (13%) with hematologic improvement (HI). Overall Response rate (ORR; CR + PR+ mCR + HI) was 57%. Of those RBC or plt TD at baseline, 13 (48%) became RBC TI and 4 (67%) became plt TI. With approximately 32 months of median follow up, neither median leukemia-free survival (mLFS) nor mOS had been reached (Figure 1). Twelve pts (17%) went on to allogeneic stem cell transplant. Conclusions: Oral decitabine/cedazuridine given as a FDC in MDS pts produced equivalent PK exposure to 20 mg/m 2 IV DEC; in lower risk MDS pts with treatment indicated, the agent was generally well-tolerated with prolonged treatment and could result in mLFS and mOS which exceeds 32 months. This FDC and other dosing regimens of oral DEC-C should be further studied in this patient population. References: Garcia-Manero, et al, ASH 2019 Savona, et al, Int. MDS Symp. 2021 Garcia-Manero, et al, Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients with Lower-Risk Myelodysplastic Syndromes. J.Clin.Onc. 2021 39:13, 1426-1436 Figure 1 Figure 1. Disclosures McCloskey: Pfizer: Consultancy; Jazz: Consultancy, Speakers Bureau; COTA: Other: Equity Ownership; Incyte: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Novartis: Consultancy; BMS: Honoraria, Speakers Bureau; Amgen: Speakers Bureau. Griffiths: Alexion Pharmaceuticals: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria; Taiho Oncology: Consultancy, Honoraria; Genentech: Research Funding; Novartis: Honoraria; Takeda Oncology: Consultancy, Honoraria; Astex Pharmaceuticals: Honoraria, Research Funding; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Apellis Pharmaceuticals: Research Funding; Boston Biomedical: Consultancy. Yee: Paladin: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Geron: Research Funding; Janssen: Research Funding; Jazz: Research Funding; MedImmune: Research Funding; Onconova: Research Funding; Tolero: Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forma Therapeutics: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zeidan: Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Genentech: Consultancy; Ionis: Consultancy; Astellas: Consultancy; Epizyme: Consultancy; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding; Jasper: Consultancy; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; BeyondSpring: Consultancy; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Janssen: Consultancy; Acceleron: Consultancy, Research Funding; AstraZeneca: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Gilead: Consultancy, Other: Clinical Trial Committees; Agios: Consultancy; Daiichi Sankyo: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; Geron: Other: Clinical Trial Committees; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; BioCryst: Other: Clinical Trial Committees; Pfizer: Other: Travel support, Research Funding; Aprea: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Jazz: Consultancy; Incyte: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Astex: Research Funding. Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Patel: Celgene-BMS: Membership on an entity's Board of Directors or advisory committees; PVI: Honoraria; Agios: Membership on an entity's Board of Directors or advisory committees. Sabloff: Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; ROCHE: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Jaxx: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Dao: Astex Pharmaceuticals, Inc.: Current Employment. Fazal: Taiho Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Speakers Bureau; Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Karyopharm Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Janssen Oncology: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Glaxo Smith Kline: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; AMGEN: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau. Odenike: AbbVie, Celgene, Impact Biomedicines, Novartis, Taiho Oncology, Takeda: Consultancy; Celgene, Incyte, AstraZeneca, Astex, NS Pharma, AbbVie, Gilead, Janssen, Oncotherapy, Agios, CTI/Baxalta, Aprea: Research Funding. Kantarjian: AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Ipsen Pharmaceuticals: Honoraria; Jazz: Research Funding; Astellas Health: Honoraria; Immunogen: Research Funding; Astra Zeneca: Honoraria; Aptitude Health: Honoraria; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. DeZern: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Roboz: Novartis: Consultancy; Mesoblast: Consultancy; Jasper Therapeutics: Consultancy; Jazz: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Daiichi Sankyo: Consultancy; Otsuka: Consultancy; Bristol Myers Squibb: Consultancy; Blueprint Medicines: Consultancy; Bayer: Consultancy; AstraZeneca: Consultancy; Astellas: Consultancy; Astex: Consultancy; Amgen: Consultancy; Agios: Consultancy; Actinium: Consultancy; AbbVie: Consultancy; Janssen: Research Funding; Celgene: Consultancy; Glaxo SmithKline: Consultancy; Helsinn: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Busque: Novartis: Consultancy. Leber: Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TaiHo: Honoraria, Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hao: Astex Pharmaceuticals, Inc.: Current Employment. Keer: Astex Pharmaceuticals, Inc.: Current Employment. Azab: Astex Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Savona: Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS-Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Astex: Research Funding; Incyte: Research Funding.

Abstract Background Anemia is common in patients (pts) with myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF). Furthermore, anemia is an on-target effect of therapeutic Janus kinase 2 (JAK2) inhibition, and is a frequent cause of ruxolitinib (rux) discontinuation (d/c) in clinical practice (Kuykendall, Ann Hematol 2018). Current therapies for anemia of MF (erythropoietin and analogs, danazol, IMiDs®) are unsatisfactory. Sotatercept (ACE-011) is a first-in-class, activin receptor type IIA ligand trap that may improve anemia by sequestering stromal transforming growth factor beta superfamily ligands that suppress terminal erythropoiesis (Iancu-Rubin, Exp Hematol 2013). Methods This is a phase 2, investigator-initiated, open-label, single institution study of sotatercept, administered subcutaneously every 3 weeks, in 2 cohorts of anemic pts (Hgb &lt;10 g/dl on every determination for 12 w or transfusion-dependent (TD) per IWG-MRT criteria (Tefferi, Blood 2013)) with MF: as a single agent, and in combination with a stable dose of rux. Pts on rux must have been on it for ≥6 months with a stable dose for the preceding ≥8 weeks, and receive sotatercept at a dose of 0.75 mg/kg. Monotherapy pts receive either 0.75 or 1 mg/kg of sotatercept. In both cohorts, anemia response is defined as achievement of transfusion independence (TI) in TD pts, or an increase in Hgb level from baseline of ≥1.5 g/dl sustained for ≥12 wks in non-TD pts (Gale, Leuk Res 2011). Pts must be on-study for ≥12 w (84 d) to be response-evaluable. Results A total of 56 pts have been treated; one pt received only 0.3 mg/kg of sotatercept and is not considered further. Thirty four pts received sotatercept alone and 21 in combination with rux. Baseline characteristics appear in Table 1, panel A. Seventeen TD and 17 non-TD pts received sotatercept alone for a median of 11 (3-73) cycles. Sixteen pts received 0.75 mg/kg and 18, 1 mg/kg. Eight of 27 (30%) evaluable pts responded. Of these, 5 were anemia responses; 3 TD pts achieved TI. Six responses occurred at the 0.75 mg/kg dose, and 2 at the 1 mg/kg dose. Median time to response (TTR) was 19 (1-22) days and median duration of response (DOR), 23.3 (3.9-68.4) months. Seven pts (21%) were on-study for &lt;84 d and hence not response-evaluable: 2 because of stem cell transplant (SCT), 2 due to logistical (travel) issues, and 1 each d/ced sotatercept because of hypertension (HTN), unrelated medical problems and pt decision. Two pts continue on study. Reasons for d/c include lack or loss of response (14), progressive MF (6), SCT (4), travel logistics (3), patient decision (2), hypertension (1), unrelated medical complications (1) and transformation to AML (1). The combination cohort comprised 15 non-TD pts and 6 TD pts. Median rux dose at study entry was 10 (5-25) mg bid. Median number of cycles was 25 (2-49). Six of 19 (32%) evaluable pts in the combination cohort responded, all non-TD pts. Median TTR was 14 (6-147) days and median DOR, 18.2 (3.7-56.8) months. Two pts (10%) were on-study for &lt;84 d and hence not response-evaluable, 1 due to SCT and 1 due to loss of insurance. Two pts remain on study. Reasons for d/c include lack or loss of response (8), SCT (4), progressive MF (3), travel logistics (2), loss of insurance (1) and pt decision (1). Several non-response-evaluable pts in both cohorts achieved ≥1.5 g/dl increments in Hgb from baseline that were not sustained for ≥12 w because of early d/c from the study. An additional pt in the combination cohort required a rux dose increase, leading to failure to sustain a ≥1.5 g/dl Hgb improvement for ≥12 w. Across both cohorts, several responding pts required multiple protocol-specified drug holidays because of Hgb levels ≥11.5 g/dl, with resumption of sotatercept once Hgb was &lt;11 g/dl. Sotatercept was well-tolerated (Table 1, panel B). Grade 3 adverse events possibly related to sotatercept were HTN (n=7) and limb (bone/muscle/joint) or back pain (n=2). Conclusions Sotatercept is safe and effective against anemia of MPN-associated MF, both in non-TD and TD pts, with a response rate of 30% when used alone and 32% when used in conjunction with a stable dose of rux. All responses in the rux cohort occurred in non-TD pts. The trial (NCT01712308) has been closed to new pt enrollment. Figure 1 Figure 1. Disclosures Bose: Sierra Oncology: Honoraria; NS Pharma: Research Funding; Astellas: Research Funding; Pfizer: Research Funding; Constellation Pharmaceuticals: Research Funding; Blueprint Medicines: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Novartis: Honoraria; BMS: Honoraria, Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Promedior: Research Funding. Pemmaraju: Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Cellectis S.A. ADR: Other, Research Funding; Sager Strong Foundation: Other; CareDx, Inc.: Consultancy; Plexxicon: Other, Research Funding; Aptitude Health: Consultancy; DAVA Oncology: Consultancy; Celgene Corporation: Consultancy; MustangBio: Consultancy, Other; Roche Diagnostics: Consultancy; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; LFB Biotechnologies: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Samus: Other, Research Funding; Incyte: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Springer Science + Business Media: Other; Affymetrix: Consultancy, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Daver: Trovagene: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Glycomimetics: Research Funding; Novimmune: Research Funding; FATE Therapeutics: Research Funding; Astellas: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Hanmi: Research Funding; ImmunoGen: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Genentech: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Kadia: BMS: Other: Grant/research support; Amgen: Other: Grant/research support; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support; Novartis: Consultancy; AstraZeneca: Other; Astellas: Other; Genfleet: Other; Ascentage: Other; Jazz: Consultancy; Liberum: Consultancy; Dalichi Sankyo: Consultancy; Genentech: Consultancy, Other: Grant/research support; Cure: Speakers Bureau; Pfizer: Consultancy, Other; Pulmotech: Other; Sanofi-Aventis: Consultancy; Cellonkos: Other. Andreeff: Karyopharm: Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Glycomimetics: Consultancy; Syndax: Consultancy; ONO Pharmaceuticals: Research Funding; Novartis, Cancer UK; Leukemia & Lymphoma Society (LLS), German Research Council; NCI-RDCRN (Rare Disease Clin Network), CLL Foundation; Novartis: Membership on an entity's Board of Directors or advisory committees; Medicxi: Consultancy; AstraZeneca: Research Funding; Reata, Aptose, Eutropics, SentiBio; Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company; Aptose: Consultancy; Breast Cancer Research Foundation: Research Funding; Oxford Biomedica UK: Research Funding; Amgen: Research Funding; Senti-Bio: Consultancy. Cortes: Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sun Pharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Jain: ADC Therapeutics: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; Janssen: Honoraria; Fate Therapeutics: Research Funding; Beigene: Honoraria; Cellectis: Honoraria, Research Funding; TG Therapeutics: Honoraria; AstraZeneca: Honoraria, Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Genentech: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Servier: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Borthakur: Ryvu: Research Funding; Protagonist: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; University of Texas MD Anderson Cancer Center: Current Employment; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; ArgenX: Membership on an entity's Board of Directors or advisory committees. Alvarado: MEI Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; Sun Pharma: Consultancy, Research Funding; Daiichi-Sankyo: Research Funding; FibroGen: Research Funding; BerGenBio: Research Funding; CytomX Therapeutics: Consultancy; Jazz Pharmaceuticals: Research Funding. Huynh-Lu: Incyte Corporation: Speakers Bureau. Nguyen-Cao: Incyte Corporation: Speakers Bureau. Kantarjian: AbbVie: Honoraria, Research Funding; Jazz: Research Funding; Astellas Health: Honoraria; Precision Biosciences: Honoraria; NOVA Research: Honoraria; Taiho Pharmaceutical Canada: Honoraria; Immunogen: Research Funding; Ipsen Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding; Ascentage: Research Funding; Daiichi-Sankyo: Research Funding; Aptitude Health: Honoraria; Astra Zeneca: Honoraria; Pfizer: Honoraria, Research Funding; BMS: Research Funding; KAHR Medical Ltd: Honoraria; Amgen: Honoraria, Research Funding. Verstovsek: NS Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; Promedior: Research Funding; PharmaEssentia: Research Funding; AstraZeneca: Research Funding; Blueprint Medicines Corp: Research Funding; Genentech: Research Funding; Ital Pharma: Research Funding; Gilead: Research Funding; Roche: Research Funding; Protagonist Therapeutics: Research Funding; Celgene: Consultancy, Research Funding; CTI BioPharma: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. OffLabel Disclosure: Sotatercept is an activin receptor ligand trap. This trial evaluates sotatercept for the treatment of anemia in patients with MPN-associated myelofibrosis.

Background Anemia is common in patients (pts) with myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF). Furthermore, anemia is an on-target effect of therapeutic Janus kinase 2 (JAK2) inhibition, and may be the most frequent cause of ruxolitinib (rux) discontinuation (d/c) in clinical practice (Kuykendall, Ann Hematol 2018). Current therapies for anemia of MF (erythropoietin and analogs, danazol, IMiDs®) are unsatisfactory. Sotatercept (ACE-011) is a first-in-class, activin receptor type IIA ligand trap that may improve anemia by sequestering stromal transforming growth factor beta superfamily ligands that suppress terminal erythropoiesis (Iancu-Rubin, Exp Hematol 2013). Methods This is a phase 2, investigator-initiated, open-label, single institution study of sotatercept, administered subcutaneously every 3 weeks, in 2 cohorts of anemic pts (Hgb &lt;10 g/dl on every determination for 12 weeks (wks) or transfusion-dependent (TD) per IWG-MRT criteria (Tefferi, Blood 2013)) with MF: as a single agent, and in combination with a stable dose of rux. Pts on rux must have been on rux for ≥6 months with a stable dose for ≥8 weeks, and receive sotatercept at a dose of 0.75 mg/kg. Monotherapy pts receive either 0.75 or 1 mg/kg of sotatercept. In both cohorts, anemia response is defined as achievement of transfusion independence (TI) in TD pts, and an increase in Hgb level from baseline of ≥1.5 g/dl sustained for ≥12 wks in non-TD pts (Gale, Leuk Res 2011). Pts must have received ≥5 cycles of sotatercept to be response-evaluable. Results A total of 53 pts have been treated; one pt received only 0.3 mg/kg of sotatercept and is not considered further. Thirty one pts received sotatercept alone and 21 in combination with rux. Baseline characteristics appear in Table 1, panel A. Sixteen TD and 15 non-TD pts received sotatercept alone for a median of 5 (1-67) cycles. Thirteen pts received 0.75 mg/kg and 18, 1 mg/kg. Seven of 24 (29%) evaluable pts responded. Of these, 4 were anemia responses; 3 TD pts achieved TI. Five responses occurred at the 0.75 mg/kg dose, and 2 at the 1 mg/kg dose. Median time to response (TTR) was 21 (1-22) days and median duration of response (DOR) 13 (3.9-56.4) months. Seven pts (22.6%) received &lt;5 cycles and were not response-evaluable: 2 proceeded to stem cell transplant (SCT), 2 had logistical (travel) issues, and 1 each d/ced sotatercept because of hypertension (HTN), unrelated medical problems and pt decision. Three pts continue on study. Reasons for d/c included no response (11), progressive MF (6), SCT (3), travel logistics (3), patient decision (2), hypertension (1), unrelated medical complications (1) and transformation to AML (1). The combination cohort comprised 15 non-TD pts and 6 TD pts. The median number of cycles was 8 (2-43). Five of 17 (29%) evaluable pts in the combination cohort responded, all non-TD pts. Median TTR was 14 (7-147) days and median DOR 34.6 (3.1-47.9) months. Four pts (19%) received &lt;5 cycles and were not response-evaluable, 1 each due to MF progression, loss of insurance, SCT and pt decision. Five pts remain on study. Reasons for d/c included no response (6), SCT (4), progressive MF (2), travel logistics (2), loss of insurance (1) and pt decision (1). Several non-response-evaluable pts in both cohorts achieved ≥1.5 g/dl increments in Hgb from baseline that were not sustained for ≥12 wks because of early d/c of sotatercept. An additional pt in the combination cohort required a rux dose increase, leading to failure to sustain a ≥1.5 g/dl Hgb improvement. Across both cohorts, several responding pts required multiple protocol-specified drug holidays because of Hgb levels ≥11.5 g/dl, with resumption of sotatercept once Hgb was &lt;11 g/dl. Sotatercept was well-tolerated (Table 1, panel B). Grade 3 adverse events possibly related to sotatercept were HTN (n=7), limb (bone/muscle/joint) pain (n=3) and headache (1). Conclusions Sotatercept is safe and effective against anemia of MPN-associated MF, both in non-TD and TD pts, with a response rate of 29% both when used alone and in conjunction with a stable dose of rux. A total of 60 pts are planned to be treated on this trial (NCT01712308). Disclosures Bose: Blueprint Medicines Corporation: Honoraria, Research Funding; NS Pharma: Research Funding; Constellation Pharmaceuticals: Research Funding; Astellas Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene Corporation: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Promedior, Inc.: Research Funding; Kartos Therapeutics: Honoraria, Research Funding. Pemmaraju:Samus Therapeutics: Research Funding; AbbVie: Honoraria, Research Funding; MustangBio: Honoraria; SagerStrong Foundation: Other: Grant Support; Roche Diagnostics: Honoraria; Pacylex Pharmaceuticals: Consultancy; Plexxikon: Research Funding; Daiichi Sankyo: Research Funding; Stemline Therapeutics: Honoraria, Research Funding; Celgene: Honoraria; Incyte Corporation: Honoraria; Cellectis: Research Funding; Blueprint Medicines: Honoraria; Affymetrix: Other: Grant Support, Research Funding; Novartis: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; DAVA Oncology: Honoraria. Daver:Fate Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jabbour:BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding. Kadia:Astellas: Research Funding; Pulmotec: Research Funding; Incyte: Research Funding; Ascentage: Research Funding; JAZZ: Honoraria, Research Funding; Cyclacel: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Cellenkos: Research Funding; Genentech: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria; Abbvie: Honoraria, Research Funding; Astra Zeneca: Research Funding. Andreeff:Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Amgen: Research Funding; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees. Cortes:Bristol-Myers Squibb: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sun Pharma: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Telios: Research Funding; Astellas: Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; BiolineRx: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Research Funding; Immunogen: Research Funding; Novartis: Consultancy, Research Funding. Jain:BMS: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aprea Therapeutics: Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Borthakur:Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; PTC Therapeutics: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Polaris: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Curio Science LLC: Consultancy; FTC Therapeutics: Consultancy; Argenx: Consultancy; PTC Therapeutics: Consultancy; BioLine Rx: Consultancy; BioTherix: Consultancy; Cyclacel: Research Funding; GSK: Research Funding; BioLine Rx: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding. Alvarado:Sun Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Tolero Pharmaceuticals: Research Funding; FibroGen: Research Funding; Jazz Pharmaceuticals: Research Funding; BerGenBio ASA: Research Funding. Huynh-Lu:Incyte Corporation: Speakers Bureau. Nguyen-Cao:Incyte Corporation: Speakers Bureau. Garcia-Manero:Acceleron Pharmaceuticals: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Novartis: Research Funding; Onconova: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; AbbVie: Honoraria, Research Funding; H3 Biomedicine: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amphivena Therapeutics: Research Funding. Kantarjian:Oxford Biomedical: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Delta Fly: Honoraria; Janssen: Honoraria; Ascentage: Research Funding; BioAscend: Honoraria; Amgen: Honoraria, Research Funding; Aptitute Health: Honoraria; Immunogen: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; BMS: Research Funding; Adaptive biotechnologies: Honoraria; Abbvie: Honoraria, Research Funding. Verstovsek:Sierra Oncology: Consultancy, Research Funding; Gilead: Research Funding; Celgene: Consultancy, Research Funding; CTI Biopharma Corp: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Novartis: Consultancy, Research Funding; AstraZeneca: Research Funding; ItalPharma: Research Funding; Protagonist Therapeutics: Research Funding; PharmaEssentia: Research Funding; Incyte Corporation: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; Genentech: Research Funding.

Monitoring of human motor and muscle activity is used in many areas, from prosthetics during rehabilitation to training monitoring of athletes. Sensors for these tasks are usually made of flexible polymers and require recycling after the expiration date. Nanocellulose (NC) can be used as a biodegradable base for this type of sensor. The development of low-cost disposable sensors that do not require disinfection and cleaning is relevant. NC is a composite nanoscale structure of cellulose fibers (fibrils) with a high aspect ratio. The paper aim is to develop disposable wearable biodegradable bend sensors based on nanocellulose using vacuum synthesis methods and the study of their characteristics. Nanocellulose was synthesized by the TEMPO method. The sensors were created by means of magnetron sputtering of Ti/Ni or Cr/Ni thin films at the surface of nanocellulose. Measuring stand was developed to determine the change in resistance due to the bending of the sensor. It’s mechanical part consists of an elastic deformation plate made of high-alloy steel, which can be bent using a micrometric screw. The change in resistance is linearly related to the elongation of the measured sample. A Wheatstone bridge and a 24-Bit ADC HX711 were used to measure the change in resistance. During testing of the sensor for analysis of muscle activity, the sensor element was attached to the human skin with the help of medical glue BF-6. The obtained sensors were tested for biodegradability. The samples were placed in the ground at a depth of 20-30 mm. The mass of nanocellulose samples was measured using a high-precision digital balance EDIS 50 (50/0.001 g) with a built-in level. The optimal ratio of the value of sensitivity and reversibility is observed in the range of the nominal resistance of the nickel film from 10 to 100 Ohms. This is due to an increase in the surface area of ​​the Ni film, which leads to an increase in sensitivity, but at the same time there is a decrease in the repeatability of the characteristics due to a greater influence of the heterogeneous structure of nanofibrillated cellulose. In addition, sensors with different buffer layer materials - Ti and Cr - were selected for testing. For titanium-based sensors, the maximum sensitivity coefficient is 0.312%, while the deviation of the sensor signal after one bending-unfolding cycle (reversibility) is less than 0.001%. Chromium-based sensors have significantly higher sensitivity (0.9753%), but worse reversibility (7.14%). Sensors based on the Cr buffer layer showed poorly reproducible results in the cyclic mode of operation, namely: there are significant fluctuations in the signal amplitude (up to 50-60%) already after the second bending-unfolding cycle. Therefore, despite the high sensitivity of such sensors, they are unsuitable for analyzing human motor and muscle activity/ The sensors based on the Ti buffer layer showed good response (2.5-3%) and good repeatability and resistance to cyclic bending (30 times). It can be seen that the obtained dependencies are approximated by a linear law. Some deviation from linearity is obviously related to the inhomogeneity of the Ni thin film. Also, the sensors showed a good loss of mass (40% in 9 weeks) during the biodegradability test, which confirms their ability to decompose under the influence of atmospheric phenomena. So, in this work, disposable wearable sensors on a nanocellulose substrate were synthesized for the evaluation of motor and muscle activity of a person. It was found that such sensors can be used to test of finger and biceps movement during at least 10-30 full flexion-extension cycles. For test of elbow movement, it is planned to synthesize a high-elastic composite material based on nanocellulose and bioelastic material (for example, polyvinyl alcohol). Thus, the proposed sensor manufacturing technology makes it possible to obtain cheap, light, flexible disposable wearable sensors that do not require further disposal after the end of operation.